Podcast appearances and mentions of mei pharma

Dr. Neeraj Agarwal and Dr. Jeanny Aragon-Ching discuss important advances in the treatment of prostate, bladder, and kidney cancers that were presented at the 2025 ASCO Annual Meeting. TRANSCRIPT Dr. Neeraj Agarwal: Hello, and welcome to the ASCO Daily News Podcast. I am Dr. Neeraj Agarwal, your guest host of the ASCO Daily News Podcast today. I am the director of the Genitourinary Oncology Program and a professor of medicine at the University of Utah Huntsman Cancer Institute and editor-in-chief of the ASCO Daily News.  I am delighted to be joined by Dr. Jeanny Aragon-Ching, a GU medical oncologist and the clinical program director of the GU Center at the Inova Schar Cancer Institute in Virginia. Today, we will be discussing some key abstracts in GU oncology that were presented at the 2025 ASCO Annual Meeting.  Our full disclosures are available in the transcript of this episode.  Jeanny, it is great to have you on the podcast. Dr. Jeanny Aragon-Ching: Oh, thank you so much, Neeraj. Dr. Neeraj Agarwal: Jeanny, let's begin with some prostate cancer abstracts. Let's begin with Abstract 5017 titled, “Phase 1 study results of JNJ-78278343 (pasritamig) in metastatic castration-resistant prostate cancer.” Can you walk us through the design and the key findings of this first-in-human trial? Dr. Jeanny Aragon-Ching: Yeah, absolutely, Neeraj. So this study, presented by Dr. Capucine Baldini, introduces pasritamig, a first-in-class T-cell redirecting bispecific antibody that simultaneously binds KLK2 on prostate cancer cells and CD3 receptor complexes on T cells. KLK2 is also known as human kallikrein 2, which is selectively expressed in prostate tissue. And for reference, KLK3 is what we now know as the PSA, prostate-specific antigen, therefore making it an attractive and specific target for therapeutic engagement. Now, while this was an early, first-in-human, phase 1 study, it enrolled 174 heavily pretreated metastatic CRPC patients. So many were previously treated with ARPIs, taxanes, and radioligand therapy. So given the phase 1 nature of this study, the primary objective was to determine the safety and the RP2D, which is the recommended phase 2 dose. Secondary objectives included preliminary assessment of antitumor activity. So, pasritamig was generally well tolerated. There were no treatment-related deaths. Serious adverse events were rare. And in the RP2D safety cohort, where patients received the step-up dosing up to 300 mg of IV every 6 weeks, the most common treatment-related adverse events were low-grade infusion reactions. There was fatigue and grade 1 cytokine release syndrome, what we call CRS. And no cases of neurotoxicity, or what we call ICANS, the immune effector cell-associated neurotoxicity syndrome, reported. Importantly, the CRS occurred in just about 8.9% of patients. All were grade 1. No patients required tocilizumab or discontinued treatment due to adverse events. So, this suggests a favorable safety profile, allowing hopefully for outpatient administration without hospitalization, which will be very important when we're thinking about bispecifics moving forward. In terms of efficacy, pasritamig showed promising activity. About 42.4% of evaluable patients achieved a PSA50 response. Radiographic PFS was about 6.8 months. And among patients with measurable disease, the objective response rate was about 16.1% in those with lymph node or bone metastases, and about 3.7% in those with visceral disease, with a median duration of response of about 11.3 months. So, altogether, this data suggests that pasritamig may offer a well-tolerated and active new potential option for patients with metastatic CRPC.   Again, as a reminder, with the caveat that this is still an early phase 1 study. Dr. Neeraj Agarwal: Thank you, Jeanny. These are promising results for a bispecific T-cell engager, pasritamig, in prostate cancer. I agree, the safety and durability observed here stand out, and this opens the door for further development, possibly even in earlier disease settings.  So, shifting now from immunotherapy to the evolving role of genomics in prostate cancer. So let's discuss Abstract 5094, a real-world, retrospective analysis exploring the prognostic impact of homologous recombination repair gene mutations, especially BRCA1 and BRCA2 mutations, in metastatic hormone-sensitive prostate cancer. Can you tell us more about this abstract, Jeanny? Dr. Jeanny Aragon-Ching: Sure, Neeraj. So this study was presented by Dr. David Olmos, represents one of the largest real-world analyses we have evaluating the impact of homologous recombination repair, or what we would call HRR, alterations in metastatic hormone-sensitive prostate cancer. So, this cohort included 556 men who underwent paired germline and somatic testing. Now, about 30% of patients had HRR alterations, with about 12% harboring BRCA1 or BRCA2 mutations and 16% having alterations in other HRR genes. Importantly, patients were stratified via CHAARTED disease volume, and outcomes were examined across treatment approaches, including ADT alone, doublet therapy, and triplet therapy. The prevalence of BRCA and HRR alterations were about similar between the metastatic hormone-sensitive prostate cancer and the metastatic castrate-resistant prostate cancer, with no differences observed, actually, between the patients with high volume versus low volume disease.  So, the key finding was that BRCA and HRR alterations were associated with poor clinical outcomes in metastatic hormone-sensitive prostate cancer. And notably, the impact of these alterations may actually be even greater in metastatic hormone-sensitive prostate cancer than previously reported in metastatic CRPC. So, the data showed that when BRCA mutations are present, the impact of the volume of disease is actually limited. So, poor outcomes were observed across the board for both high-volume and low-volume groups. So, the analysis showed that patients with HRR alterations had significantly worse outcomes compared to patients without HRR alterations. Median radiographic progression-free survival was about 20.5 months for the HRR-altered patients versus 30.6 months for the non-HRR patients, with a hazard ratio of 1.6. Median overall survival was 39 months for HRR-altered patients compared to 55.7 months for the non-HRR patients, with a hazard ratio of 1.5. Similar significant differences were observed when BRCA-mutant patients were compared with patients harboring non-BRCA HRR mutations. Overall, poor outcomes were independent of treatment of ARPI or taxanes. Dr. Neeraj Agarwal: Thank you, Jeanny. So, these data reinforce homologous recombination repair mutations as both a predictive and prognostic biomarker, not only in the mCRPC, but also in the metastatic hormone-sensitive setting as well. It also makes a strong case for incorporating genomic testing early in the disease course and not waiting until our patients have castration-resistant disease. Dr. Jeanny Aragon-Ching: Absolutely, Neeraj. And I think this really brings home the point and the lead up to the AMPLITUDE trial, which is LBA5006, a phase 3 trial that builds on this very concept of testing with a PARP inhibitor, niraparib, in the hormone-sensitive space. Can you tell us a little bit more about this abstract, Neeraj? Dr. Neeraj Agarwal: Sure. So, the AMPLITUDE trial, a phase 3 trial presented by Dr. Gerhardt Attard, enrolled 696 patients with metastatic hormone-sensitive prostate cancer and HRR gene alterations. 56% of these patients had BRCA1 and BRCA2 mutations. Patients were randomized to receive abiraterone with or without niraparib, a PARP inhibitor. The majority of patients, 78% of these patients, had high-volume metastatic hormone-sensitive prostate cancer, and 87% of these patients had de novo metastatic HSPC. And 16% of these patients received prior docetaxel, which was allowed in the clinical trial. So, with a median follow-up of nearly 31 months, radiographic progression-free survival was significantly prolonged with the niraparib plus abiraterone combination, and median was not reached in this arm, compared to abiraterone alone, which was 29.5 months, with a hazard ratio of 0.63, translating to a 37% reduction in risk of progression or death. This benefit was even more pronounced in the BRCA1 and BRCA2 subgroup, with a 48% reduction in risk of progression, with a hazard ratio of 0.52. Time to symptomatic progression also improved significantly across all patients, including patients with BRCA1, BRCA2, and HRR mutations. Although overall survival data remain immature, early trends favored the niraparib plus abiraterone combination. The safety profile was consistent with prior PARP inhibitor studies, with grade 3 or higher anemia and hypertension were more common but manageable. Treatment discontinuation due to adverse events remained low at 11%, suggesting that timely dose modifications when our patients experience grade 3 side effects may allow our patients to continue treatment without discontinuation. These findings support niraparib plus abiraterone as a potential new standard of care in our patients with metastatic hormone-sensitive prostate cancer with HRR alterations, and especially in those who had BRCA1 and BRCA2 mutations. Dr. Jeanny Aragon-Ching: Thank you, Neeraj. This trial is especially exciting because it brings PARP inhibitors earlier into the treatment paradigm. Dr. Neeraj Agarwal: Exactly. And it is exciting to see the effect of PARP inhibitors in the earlier setting.  So Jeanny, now let's switch gears a bit to bladder cancer, which also saw several impactful studies. Could you tell us about Abstract 4502, an exploratory analysis from the EV-302 trial, which led to approval of enfortumab vedotin plus pembrolizumab for our patients with newly diagnosed metastatic bladder cancer? So here, the authors looked at the outcomes in patients who achieved a confirmed complete response with EV plus pembrolizumab. Dr. Jeanny Aragon-Ching: Sure, Neeraj. So, EV-302 demonstrated significant improvements in progression-free and overall survival for patients previously treated locally advanced or metastatic urothelial cancer, I'll just call it metastatic UC, as a frontline strategy, establishing EV, which is enfortumab vedotin, plus pembro, with pembrolizumab as standard of care in this setting.  So, this year at ASCO, Dr Shilpa Gupta presented this exploratory responder analysis from the phase 3 EV-302 trial. Among 886 randomized patients, about 30.4% of patients, this is about 133, in the EV+P arm, and 14.5% of the patients in the chemotherapy arm, achieved a confirmed complete response. They call it the CCR rates. So for patients who achieved this, median PFS was not reached with EV+P compared to 26.9 months with chemotherapy, with a hazard ratio of 0.36, translating to a 64% reduction in the risk of progression. Overall survival was also improved. So the median OS was not reached in either arm, but the hazard ratio favored the EV+P at 0.37, translating to a 63% reduction in the risk of death. The median duration of complete response was not reached with EV+P compared to 15.2 months with chemotherapy. And among those patients who had confirmed CRs at 24 months, 78% of patients with the EV+P arm remained progression-free, and around 95% of the patients were alive, compared to 54% of patients who were progression-free and 86% alive of the patients in the chemotherapy arm. Safety among responders were also consistent with prior reports. Grade 3 or higher treatment-related adverse events occurred in 62% of EV+P responders and 72% of chemotherapy responders. Most adverse events were managed with dose modifications, and importantly, no treatment-related deaths were reported among those who were able to achieve complete response.  So these findings further reinforce EV and pembro as the preferred first-line therapy for metastatic urothelial carcinoma, offering a higher likelihood of deep, durable responses with a fairly manageable safety profile. Dr. Neeraj Agarwal: Thank you for the great summary, Jeanny. These findings underscore the depth and durability of responses achievable with this combination and also suggest that achieving a response may be a surrogate for long-term benefit in patients with metastatic urothelial carcinoma.  So now, let's move to Abstract 4503, an exploratory ctDNA analysis from the NIAGARA trial, which evaluated perioperative durvalumab, an immune checkpoint inhibitor, in muscle-invasive bladder cancer. So what can you tell us about this abstract? Dr. Jeanny Aragon-Ching: Absolutely, Neeraj. So, in NIAGARA, presented by Dr. Tom Powles, the addition of perioperative durvalumab to neoadjuvant chemotherapy, gem/cis, significantly improved event-free survival, overall survival, and pathologic complete response in patients with cisplatin-eligible muscle-invasive bladder cancer. Recall that this led to the U.S. FDA approval of this treatment regimen on March 28, 2025.  So, a planned exploratory analysis evaluated the ctDNA dynamics and their association with clinical outcomes, which was the one presented recently at ASCO. So, the study found that the incidence of finding ctDNA positivity in these patients was about 57%. Following neoadjuvant treatment, this dropped to about 22%, with ctDNA clearance being more common in the durvalumab arm, about 41%, compared to the chemotherapy control arm of 31%. Notably, 97% of patients who remained ctDNA positive prior to surgery failed to achieve a pathologic CR. So, this indicates a strong association between ctDNA persistence and lack of tumor eradication. So, postoperatively, only about 9% of patients were ctDNA positive. So, importantly, durvalumab conferred an event-free survival benefit regardless of ctDNA status at both baseline and post-surgery. Among patients who were ctDNA positive at baseline, durvalumab led to a hazard ratio of 0.73 for EFS. So, this translates to a 27% reduction in the risk of disease recurrence, progression, or death compared to the control arm. In the post-surgical ctDNA-positive group, the disease-free survival was also improved with a hazard ratio of 0.49, translating to a 51% reduction in the risk of recurrence.  So, these findings underscore the prognostic value of ctDNA and suggest that durvalumab provides clinical benefit irrespective of molecular residual disease status. So, the data also supports that ctDNA is a promising biomarker for future personalized strategies in the perioperative treatment of muscle-invasive bladder cancer. Dr. Neeraj Agarwal: Thank you, Jeanny. It is great to see that durvalumab is improving outcomes in these patients regardless of ctDNA status. However, based on these data, presence of ctDNA in our patients warrants a closer follow-up with imaging studies, because these patients with positive ctDNA seem to have a higher risk of recurrence. Dr. Jeanny Aragon-Ching: I agree, Neeraj.  Let's round out the bladder cancer discussion with Abstract 4518, which reported the interim results of SURE-02, which is a phase 2 study evaluating neoadjuvant sacituzumab govitecan plus pembrolizumab in cisplatin-ineligible muscle-invasive bladder cancer. Can you tell us more about this abstract, Neeraj? Dr. Neeraj Agarwal: Sure, Jeanny. So, Dr Andrea Necchi presented interim results from the SURE-02 trial. This is a phase 2 study evaluating neoadjuvant sacituzumab govitecan plus pembrolizumab, followed by a response-adapted bladder-sparing treatment and adjuvant pembrolizumab in patients with muscle-invasive bladder cancer.  So, in this interim analysis, 40 patients were treated and 31 patients were evaluable for efficacy. So, the clinical complete response rate was 38.7%. All patients achieving clinical complete response underwent bladder-sparing approach with a repeat TURBT instead of radical cystectomy. Additionally, 51.6% of patients achieved excellent pathologic response with a T stage of 1 or less after neoadjuvant therapy. The treatment was well tolerated, with only 12.9% of patients experiencing grade 3 or higher adverse events without needing dose reduction of sacituzumab. Molecular profiling, interestingly, showed that clinical complete response correlated with luminal and genomically unstable subtypes, while high stromal gene expression was associated with lack of response.  These results suggest that sacituzumab plus pembrolizumab combination has promising activity in this setting, and tolerability, and along with other factors may potentially allow a bladder preservation approach in a substantial number of patients down the line. Dr. Jeanny Aragon-Ching: Yeah, agree with you, Neeraj. And the findings are very provocative and support completing the full trial enrollment and further exploration of this strategy in muscle-invasive bladder cancer in order to improve and provide further bladder-sparing strategies. Dr. Neeraj Agarwal: Agree. So, let's now turn to the kidney cancer, starting with Abstract 4505, the final overall analysis from CheckMate-214 trial, which evaluated nivolumab plus ipilimumab, so dual checkpoint inhibition strategy, versus sunitinib in our patients with metastatic clear cell renal cell carcinoma. Dr. Jeanny Aragon-Ching: Yeah, absolutely, Neeraj. So, the final 9-year analysis of the phase 3 CheckMate-214 trial confirms the long-term superiority of nivolumab and ipilimumab over sunitinib for first-line treatment of advanced metastatic renal cell carcinoma. So, this has a median follow-up of 9 years. Overall survival remains significantly improved with the combination. So, in the ITT patient population, the intention-to-treat, the hazard ratio for overall survival was 0.71. So, this translates to a 29% reduction in the risk of death. 31% of patients were alive at this 108-month follow-up compared to 20% only in those who got sunitinib. So, similar benefits were observed in the intermediate- and poor-risk groups with a hazard ratio of 0.69, and 30% versus 19% survival at 108 months.  Importantly, a delayed benefit was also seen in those favorable-risk patients. So, the hazard ratio for overall survival improved from 1.45 in the initial report and now at 0.8 at 9 years follow-up, with 35% of patients alive at 108 months compared to 22% in those who got sunitinib. Progression-free survival also favored the nivo-ipi arm across all risk groups. At 96 months, the probability of remaining progression-free was about 23% compared to 9% in the sunitinib arm in the ITT patient population, 25% versus 9% in the intermediate- and poor-risk patients, and 13% compared to 11% in the favorable-risk patients. Importantly, at 96 months, 48% of patients in the nivo-ipi responders remained in response compared to just 19% in those who got sunitinib. And in the favorable-risk group, 36% of patients who responded remained in response, although data were not available for sunitinib in this subgroup.  So, this data reinforces the use of nivolumab and ipilimumab as a durable and effective first-line effective strategy for standard of care across all risk groups for advanced renal cell carcinoma. Dr. Neeraj Agarwal: Thank you, Jeanny. And of course, since ipi-nivo data were presented, several other novel ICI-TKI combinations have emerged. And I'm really hoping to see very similar data with TKI-ICI combinations down the line. It is really important to note that we are not seeing any new safety signals with the ICI combinations or ICI-based therapies, which is very reassuring given the extended exposure. Dr. Jeanny Aragon-Ching: Absolutely agree with you there, Neeraj.  Now, going on and moving on to Abstract 4514, which is the KEYNOTE-564 trial, and they reported on the 5-year outcomes of adjuvant pembrolizumab in clear cell RCC in patients who are at high risk for recurrence. Can you tell us a little bit more about this abstract, Neeraj? Dr. Neeraj Agarwal: Sure. So, the KEYNOTE-564 trial established pembrolizumab monotherapy as the first adjuvant regimen to significantly improve both disease-free survival and overall survival compared to placebo after surgery for patients with clear cell renal cell carcinoma. So, Dr Naomi Haas presented the 5-year update from this landmark trial.  A total of 994 patients were randomized to receive either pembrolizumab or placebo. The median follow-up at the time of this analysis was approximately 70 months. Disease-free survival remained significantly improved with pembrolizumab. The median DFS was not reached with pembrolizumab compared to 68.3 months with placebo, with a hazard ratio of 0.71, translating to a 29% reduction in risk of recurrence. At 5 years, 60.9% of patients receiving pembrolizumab remained disease-free compared to 52.2% with placebo. Overall survival also favored pembrolizumab. The hazard ratio for OS was 0.66, translating to a 34% reduction in risk of death, with an estimated 5-year overall survival rate of 87.7% with pembrolizumab compared to 82.3% for placebo. Importantly, these benefits were consistent across all key subgroups, including patients with sarcomatoid features. In addition, no new serious treatment-related adverse events have been reported in the 3 years since treatment completion.  So, these long-term data confirm pembrolizumab as a durable and effective standard adjuvant therapy for patients with resected, high-risk clear cell renal cell carcinoma. Dr. Jeanny Aragon-Ching: Thank you for that wonderful summary, Neeraj. Dr. Neeraj Agarwal: That wraps up our kidney cancer highlights. Any closing thoughts, Jeanny, before we conclude? Dr. Jeanny Aragon-Ching: It's been so wonderful reviewing these abstracts with you, Neeraj. So, the 2025 ASCO Annual Meeting showcased a lot of transformative data across GU cancers, from first-in-class bispecifics to long-term survival in RCC. And these findings are already shaping our clinical practices. Dr. Neeraj Agarwal: I agree. And we have covered a broad spectrum of innovations in GU cancers with strong clinical relevance.  So, thank you, Jeanny, for joining me today and sharing your insights.  And thank you to our listeners for joining us. You will find links to the abstracts discussed today in the transcript of this episode. If you find these conversations valuable, please take a moment to rate, review, and subscribe to the ASCO Daily News Podcast wherever you listen. Thank you so much. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Find out more about today's speakers:    Dr. Neeraj Agarwal     @neerajaiims     Dr. Jeanny Aragon-Ching   Follow ASCO on social media:       @ASCO on Twitter       ASCO on Bluesky   ASCO on Facebook       ASCO on LinkedIn       Disclosures:   Dr. Neeraj Agarwal:   Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, AstraZeneca, Pfizer, Merck, Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences  Research Funding (Institution): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, Crispr Therapeutics, Arvinas  Dr. Jeanny Aragon-Ching:   Honoraria: Bristol-Myers Squibb, EMD Serono, Astellas Scientific and Medical Affairs Inc., Pfizer/EMD Serono   Consulting or Advisory Role: Algeta/Bayer, Dendreon, AstraZeneca, Janssen Biotech, Sanofi, EMD Serono, MedImmune, Bayer, Merck, Seattle Genetics, Pfizer, Immunomedics, Amgen, AVEO, Pfizer/Myovant, Exelixis,    Speakers' Bureau: Astellas Pharma, Janssen-Ortho, Bristol-Myers Squibb, Astellas/Seattle Genetics

Dr. Neeraj Agarwal and Dr. Peter Hoskin discuss key abstracts in GU cancers from the 2025 ASCO Genitourinary Cancers Symposium, including novel therapies in prostate, bladder, and kidney cancer and the impact of combination therapies on patient outcomes. TRANSCSRIPT Dr. Neeraj Agarwal: Hello, and welcome to the ASCO Daily News Podcast. I'm Dr. Neeraj Agarwal, the director of the Genitourinary Oncology Program and professor of medicine at the Huntsman Cancer Institute at the University of Utah, and editor-in-chief of ASCO Daily News. Today, we'll be discussing practice-informing abstracts and other key advances in GU oncology featured at the 2025 ASCO Genitourinary Cancers Symposium. Joining me for this discussion is Dr. Peter Hoskin, the chair of this year's ASCO GU Symposium. Dr. Hoskin is a professor in clinical oncology in the University of Manchester and honorary consultant in clinical oncology at the Christie Hospital, Manchester, and University College Hospital London, in the United Kingdom. Our full disclosures are available in the transcript of this episode. Peter, thank you for joining us today. Dr. Peter Hoskin: Thank you so much, Neeraj. I am very pleased to be here. Dr. Neeraj Agarwal: The GU meeting highlighted remarkable advancements across the spectrum of GU malignancies. What stood out to you as the most exciting developments at the ASCO GU Symposium?  Dr. Peter Hoskin: The theme of this year's meeting was "Driving Innovation, Improving Patient Care," and this reflected ASCO GU's incredible milestone in GU cancer research over the years. We were thrilled to welcome almost 6,000 attendees on this occasion from over 70 countries, and most of them were attending in person and not online, although this was a hybrid meeting. Furthermore, we had more than 1,000 abstract submissions. You can imagine then that it fostered fantastic networking opportunities and facilitated valuable knowledge and idea exchanges among experts, trainees, and mentees. So, to start I'd like to come back to you for a second because the first day started with a focus on prostate cancer and some of the key clinical trials. And congratulations to you, Neeraj, on sharing the data from the TALAPRO-2 trial, which we were eagerly awaiting. I'd love to get your thoughts on the data that you presented. Could you tell us more about that trial, Abstract LBA18?  Dr. Neeraj Agarwal: Yes, Peter, I agree with you. It was such an exciting conference overall and thank you for your leadership of this conference. So, let's talk about the TALAPRO-2 trial. First of all, I would like to remind our audience that the combination of talazoparib plus enzalutamide was approved by the U.S. FDA in June 2023 in patients with metastatic castration-resistant prostate cancer harboring HRR gene alterations, after this combination improved the primary endpoint of radiographic progression-free survival compared to enzalutamide alone in the randomized, double-blind, placebo-controlled, multi-cohort phase 3 TALAPRO-2 trial. In the abstract I presented at ASCO GU 2025, we reported the final overall survival data, which was a key alpha-protected secondary endpoint in cohort 1, which enrolled an all-comer population of patients with mCRPC. So, at a median follow-up of around 53 months, in the intention-to-treat population, the combination of talazoparib plus enzalutamide significantly reduced the risk of death by 20% compared to enzalutamide alone, with a median OS of 45.8 months in the experimental arm versus 37 months in the control arm, which was an active control arm of enzalutamide. This improvement was consistent in patients with HRR alterations with a hazard ratio of 0.54 and in those with non-deficient or unknown HRR status, with a hazard ratio of 0.87. In a post hoc analysis, the hazard ratio for OS was 0.78 favoring the combination in those patients who did not have any HRR gene alteration in their tumors by both tissue and ctDNA testing. Consistent with the primary analysis, the updated rPFS data also favored the experimental arm with a median rPFS of 33.1 compared to 19.5 months in the control arm, and a hazard ratio of 0.667. No new safety signals were identified with extended follow-up. Thus, TALAPRO-2 is the first PARP inhibitor plus ARPI study to show a statistically significant and a clinically meaningful improvement in OS compared to standard-of-care enzalutamide as first-line treatment in patients with mCRPC unselected for HRR gene alterations. Dr. Peter Hoskin: Thank you, Neeraj. That's a great summary of the data presented and very important data indeed. There was another abstract also featured in the same session, Abstract 20, titled “Which patients with metastatic hormone-sensitive prostate cancer benefit more from androgen receptor pathway inhibitors? STOPCAP meta-analyses of individual participant data.” Neeraj, could you tell us more about this abstract? Dr. Neeraj Agarwal: Absolutely, I would be delighted to. So, in this meta-analysis, Dr. David Fischer and colleagues pooled individual participant data from different randomized phase 3 trials in the mHSPC setting to assess the potential ARPI effect modifiers and determine who benefits more from an ARPI plus ADT doublet. The primary outcome was OS for main effects and PFS for subgroup analyses. Prostate cancer specific survival was a sensitivity outcome. The investigators pooled data from 11 ARPI trials and more than 11,000 patients. Overall, there was a clear benefit of adding an ARPI on both OS and PFS, with hazard ratios of 0.66 and 0.51, respectively, representing a 13% and 21% absolute improvement at 5 years, respectively, with no clear difference by the class of agent. When stratifying the patients by age group, the effects of adding an ARPI on OS and PFS were slightly smaller in patients older than 75, than in those younger than 65, or aged between 65 and 75 years. Notably, in the trials assessing the use of abiraterone, we saw very little OS effects in the group of patients older than 75, however there was some benefit maintained in prostate-cancer specific survival, suggesting that other causes of death may be having an impact. The effects of the other ARPIs, or ‘lutamides' as I would call them, were similar across all three age subgroups on both OS and PFS. Therefore, the majority of patients with mHSPC benefit from the addition of ARPIs, and the benefits/risks of abiraterone and other ‘amides' must be considered in older patients.  Dr. Peter Hoskin: Thanks, Neeraj. Another great summary relevant to our day-to-day practice. Of course, there's ongoing collection of individual patient data from other key trials, which will allow robust comparison of ARPI doublet with triplet therapy (including docetaxel), guiding more personalized treatment.   Dr. Neeraj Agarwal: I agree with you, Peter, we need more data to help guide personalized treatment for patients with mHSPC and potentially guide de-escalation versus escalation strategies. Now, moving on to a different setting in prostate cancer, would you like to mention Abstract 17 titled, “Overall survival and quality of life with Lu-PSMA-617 plus enzalutamide versus enzalutamide alone in poor-risk, metastatic, castration-resistant prostate cancer in ENZA-p (ANZUP 1901),” presented by Dr. Louise Emmett? Dr. Peter Hoskin: Of course I will. So, ENZA-p was a multicenter, open-label, randomized, phase 2 trial conducted in Australia. It randomized 163 patients into adaptive doses (2 or 4 cycles) of Lu-PSMA-617 plus enzalutamide versus enzalutamide alone as first-line treatment in PSMA-PET-CT-positive, poor-risk, mCRPC. The interim analysis of ENZA-p with median follow-up 20 months showed improved PSA-progression-free survival with the addition of Lu-PSMA-617 to enzalutamide. Here, the investigators reported the secondary outcomes, overall survival, and health-related quality of life (HRQOL). After a median follow up of 34 months, overall survival was longer in the combination arm compared to the enzalutamide arm, with a median OS of 34 months compared to 26 months; with an HR of 0.55. Moreover, the combination improved both deterioration-free survival and health-related quality of life indicators for pain, fatigue, physical function, and overall health and quality of life compared to the control arm. Consistent with the primary analysis, the rPFS also favored the experimental arm with a median rPFS of 17 months compared to 14 months with a HR of 0.61. So, the addition of LuPSMA improved overall survival, and HRQOL in patients with high-risk mCRPC. Dr. Neeraj Agarwal: Thank you, Peter. Great summary, and promising results with Lu-177 and ARPI combination in first line treatment for mCRPC among patients who had two or more high risk features associated with early enzalutamide failure. Before we move on to bladder cancer, would you like to tell us about Abstract 15 titled, “World-wide oligometastatic prostate cancer (omPC) meta-analysis leveraging individual patient data (IPD) from randomized trials (WOLVERINE): An analysis from the X-MET collaboration,” presented by Dr. Chad Tang?  Dr. Peter Hoskin: Sure. So, with metastatic-directed therapy (MDT), we have a number of phase 2 studies making up the database, and the X-MET collaboration aimed to consolidate all randomized data on oligometastatic solid tumors. This abstract presented pooled individual patient data from all the published trials involving patients with oligometastatic prostate cancer who received MDT alongside standard of care (SOC) against SOC alone. The analysis included data from five trials, encompassing 472 patients with oligometastatic prostate cancer, and followed for a median of 41 months. Patients were randomly assigned in a 1:1 ratio to receive either MDT plus SOC or SOC alone. The addition of MDT significantly improved PFS. The median PFS was 32 months with MDT compared to 14.9 months with SOC alone, with an HR of 0.45. Subgroup analyses further confirmed the consistent benefits of MDT across different patient groups. Regardless of factors like castration status, receipt of prior primary treatment, stage, or number of metastases, MDT consistently improved PFS. In patients with mHSPC, MDT significantly delayed the time to castration resistance by nine months, extending it to a median of 72 months compared to 63 months in the SOC group with an HR of 0.58. In terms of OS, the addition of MDT improved the 48-month survival rate by 12%, with OS rates of 87% in the MDT+SOC group compared to 75% in the SOC alone group. Dr. Neeraj Agarwal: Thank you, Peter. These data demonstrate that adding MDT to systemic therapy significantly improves PFS, rPFS, and castration resistance-free survival, reinforcing its potential role in the treatment of oligometastatic prostate cancer. So, let's switch gears to bladder cancer and start with Abstract 658 reporting the OS analysis of the CheckMate-274 trial. Would you like to tell us about this abstract?  Dr. Peter Hoskin: Yes, sure, Neeraj. This was presented by Dr. Matt Milowsky, and it was additional efficacy outcomes, including overall survival, from the CheckMate-274 trial which evaluated adjuvant nivolumab versus placebo in patients with high-risk muscle-invasive bladder cancer after radical surgery. The phase 3 trial previously demonstrated a significant improvement in disease-free survival with nivolumab. With a median follow-up of 36.1 months, disease-free survival was longer with nivolumab compared to placebo across all patients with muscle-invasive bladder cancer, reducing the risk of disease recurrence or death by 37%. Among patients who had received prior neoadjuvant cisplatin-based chemotherapy, nivolumab reduced this risk by 42%, whilst in those who had not received chemotherapy, the risk was reduced by 31%. Overall survival also favored nivolumab over placebo, reducing the risk of death by 30% in all patients with muscle-invasive bladder cancer and by 52% in those with tumors expressing PD-L1 at 1% or higher. Among patients who had received prior neoadjuvant chemotherapy, nivolumab reduced the risk of death by 26%, whilst in those who had not received chemotherapy, the risk was reduced by 33%. Alongside this, the safety profile remained consistent with previous findings. Dr. Neeraj Agarwal: Thank you, Peter, for such a nice overview of this abstract. These results reinforce adjuvant nivolumab as a standard of care for high-risk muscle-invasive bladder cancer, offering the potential for a curative outcome for our patients. Dr. Peter Hoskin: I agree with you Neeraj. Perhaps you would like to mention Abstract 659 titled, “Additional efficacy and safety outcomes and an exploratory analysis of the impact of pathological complete response (pCR) on long-term outcomes from NIAGARA.” Dr. Neeraj Agarwal: Of course. Dr. Galsky presented additional outcomes from the phase 3 NIAGARA study, which evaluated perioperative durvalumab combined with neoadjuvant chemotherapy in patients with muscle-invasive bladder cancer. The study previously demonstrated a significant improvement in event-free survival and overall survival with durvalumab compared to chemotherapy alone, with a manageable safety profile and no negative impact on the ability to undergo radical cystectomy. Among the 1,063 randomized patients, those who received durvalumab had a 33% reduction in the risk of developing distant metastases or death and a 31% reduction in the risk of dying from bladder cancer compared to those who received chemotherapy alone. More patients who received durvalumab achieved a pathological complete response at the time of surgery with 37% compared to 28% in the chemotherapy-alone group. Patients who achieved a pathological complete response had better event-free survival and overall survival compared to those who did not. In both groups, durvalumab provided additional survival benefits, reducing the risk of disease progression or death by 42% and the risk of death by 28% in patients with a pathological complete response, while in those patients without a pathological complete response, the risk of disease progression or death was reduced by 23% and the risk of death by 16% when durvalumab was added to the chemotherapy. Immune-mediated adverse events occurred in 21% of patients in the durvalumab group compared to 3% in the chemotherapy-alone group, with grade 3 or higher events occurring in 3% compared to 0.2%. The most common immune-related adverse events included hypothyroidism in 10% of patients treated with durvalumab compared to 1% in the chemotherapy-alone group, and hyperthyroidism in 3% versus 0.8%. At the time of the data cutoff, these adverse events had resolved in 41% of affected patients in the durvalumab group and 44% in the chemotherapy-alone group. Dr. Peter Hoskin: Thank you, Neeraj, for the great summary. These findings further support the role of perioperative durvalumab as a potential standard of care for patients with muscle-invasive bladder cancer. Dr. Neeraj Agarwal: I concur with your thoughts, Peter. Before wrapping up the bladder cancer section, would you like to mention Abstract 664 reporting updated results from the EV-302 trial, which evaluated enfortumab vedotin in combination with pembrolizumab compared to chemotherapy as first-line treatment for patients with previously untreated locally advanced or metastatic urothelial carcinoma? Dr. Peter Hoskin: Yes, of course. Dr. Tom Powles presented updated findings from the EV-302 study, and in this abstract presented 12 months of additional follow-up for EV-302 (>2 y of median follow-up) and an exploratory analysis of patients with confirmed complete response (cCR). The study had a median follow-up of 29.1 months and previously demonstrated significant improvements in progression-free survival and overall survival with enfortumab vedotin and pembrolizumab. This is now the standard of care in global treatment guidelines. Among the 886 randomized patients, enfortumab vedotin and pembrolizumab reduced the risk of disease progression or death by 52% and the risk of death by 49% compared to chemotherapy. The survival benefit was consistent regardless of cisplatin eligibility or the presence of liver metastases. The confirmed objective response rate was higher with enfortumab vedotin and pembrolizumab at 67.5% compared to 44.2% with chemotherapy. The median duration of response was 23.3 months with enfortumab vedotin and pembrolizumab compared to 7.0 months with chemotherapy. A complete response was achieved in 30.4% of patients in the enfortumab vedotin and pembrolizumab group compared to 14.5% in the chemotherapy group, with the median duration of complete response not yet reached in the enfortumab vedotin and pembrolizumab group compared to 15.2 months in the chemotherapy group. Severe treatment-related adverse events occurred in 57.3% of patients treated with enfortumab vedotin and pembrolizumab compared to 69.5% in the chemotherapy group, while in patients who achieved a complete response, severe adverse events occurred in 61.7% of those treated with enfortumab vedotin and pembrolizumab compared to 71.9% with chemotherapy. Treatment-related deaths were reported in 1.1% of patients treated with enfortumab vedotin and pembrolizumab compared to 0.9% with chemotherapy, with no treatment-related deaths occurring in those who achieved a complete response. These findings clearly confirm the durable efficacy of enfortumab vedotin and pembrolizumab, reinforcing its role as the standard of care for the first-line treatment of patients with locally advanced or metastatic urothelial carcinoma, and no new safety concerns have been identified. Dr. Neeraj Agarwal: Thank you for this great summary. Moving on to kidney cancer, let's talk about Abstract 439 titled, “Nivolumab plus cabozantinib (N+C) vs sunitinib (S) for previously untreated advanced renal cell carcinoma (aRCC): Final follow-up results from the CheckMate-9ER trial.” Dr. Peter Hoskin: Sure. Dr. Motzer presented the final results from the phase 3 CheckMate-9ER trial, which compared the combination of cabozantinib and nivolumab against sunitinib in previously untreated advanced renal cell carcinoma. The data after more than five years follow-up show that the combination therapy provided sustained superior efficacy compared to sunitinib. In terms of overall survival, we see an 11-month improvement in median OS, 46.5 months for the cabo-nivo versus 35.5 months for sunitinib and a 42% reduction in the risk of disease progression or death, with median progression-free survival nearly doubling – that's 16.4 months in the combination group and 8.3 months with sunitinib. Importantly, the safety profile was consistent with the known safety profiles of the individual medicines, with no new safety concerns identified. Dr. Neeraj Agarwal: Great summary, Peter. These data further support the efficacy of cabo-nivo combination therapy in advanced renal cell carcinoma, which is showing a 11-month difference in overall survival. Dr. Peter Hoskin: Neeraj, before wrapping up this podcast, would you like to tell us about Abstract 618? This is titled “Prospective COTRIMS (Cologne trial of retroperitoneal lymphadenectomy in metastatic seminoma) trial: Final results.” Dr. Neeraj Agarwal: Sure, Peter. I would be delighted to. Dr Heidenrich from the University of Cologne in Germany presented the COTRIMS data evaluating retroperitoneal LN dissection in patients with clinical stage 2A/B seminomas. Seminomas are classified as 2A or B when the disease spreads to the retroperitoneal lymph nodes of up to 2 cm (CS IIA) or of more than 2 cm to up to 5 cm (CS 2B) in maximum diameter, respectively. They account for 10-15% of seminomas and they are usually treated with radiation and chemotherapy. However, radiation and chemo can be associated with long-term toxicities such as cardiovascular toxicities, diabetes, solid cancers, leukemia, particularly for younger patients. From this standpoint, Dr Heidenrich and colleagues evaluated unilateral, modified template, nerve-sparing retroperitoneal lymph node dissection as a less toxic alternative compared to chemo and radiation. They included 34 patients with negative AFP, beta-HCG, and clinical stage 2A/B seminomas. At a median follow-up of 43.2 months, the trial demonstrated great outcomes: a 99.3% treatment-free survival rate and 100% overall survival, with only four relapses. Antegrade ejaculation was preserved in 88% of patients, and severe complications such as grade 3 and 4 were observed in 12% of patients. Pathological analysis revealed metastatic seminoma in 85% of cases, with miR371 being true positive in 23 out of 24 cases and true negative in 100% of cases. It appears to be a valid biomarker for predicting the presence of lymph node metastases. These findings highlight retroperitoneal lymph node dissection is feasible; it has low morbidity, and excellent oncologic outcomes, avoiding overtreatment in 80% of patients and sparing unnecessary chemotherapy or radiotherapy in 10-15% of cases. Dr. Peter Hoskin: Great summary and important data on retroperitoneal lymphadenectomy in metastatic seminoma. These findings will help shape clinical practice. Any final remarks before we conclude today's podcast? Dr. Neeraj Agarwal: Before wrapping up this podcast, I would like to say that we have reviewed several abstracts addressing prostate, bladder, kidney cancers, and seminoma, which are impacting our medical practices now and in the near future. Peter, thank you for sharing your insights with us today. These updates are undoubtedly exciting for the entire GU oncology community, and we greatly appreciate your valuable contribution to the discussion and your leadership of the conference. Many thanks. Dr. Peter Hoskin: Thank you, Neeraj. Thank you for the opportunity to share this information more widely. I'm aware that whilst we have nearly 6,000 delegates, there are many other tens of thousands of colleagues around the world who need to have access to this information. And it was a great privilege to chair this ASCO GU25. So, thank you once again, Neeraj, for this opportunity to share more of this information that we discussed over those few days. Dr. Neeraj Agarwal: Thank you, Peter. And thank you to our listeners for joining us today. You will find links to the abstracts discussed today on the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.  Find out more about today's speakers:   Dr. Neeraj Agarwal    @neerajaiims    Dr. Peter Hoskin Follow ASCO on social media:      @ASCO on Twitter      ASCO on Bluesky  ASCO on Facebook      ASCO on LinkedIn      Disclosures: Dr. Neeraj Agarwal: Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, AstraZeneca, Pfizer, Merck, Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences Research Funding (Institution): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, Crispr Therapeutics, Arvinas Dr. Peter Hoskin: Research Funding (Institution): Varian Medical Systems, Astellas Pharma, Bayer, Roche, Pfizer, Elekta, Bristol Myers  

Dr. Neeraj Agarwal and Dr. Rana McKay discuss promising studies in GU cancers featured at the 2024 ASCO Annual Meeting that highlighted improved outcomes in urothelial carcinoma, improved survival in renal cell carcinoma, and the role of ctDNA as a potential biomarker for predicting outcomes.   TRANSCRIPT Dr. Neeraj Agarwal: Hello and welcome to the ASCO Daily News Podcast. I'm Dr. Neeraj Agarwal, your guest host of the ASCO Daily News Podcast today. I am the director of the Genitourinary Oncology Program, a professor of medicine at the University of Utah's Huntsman Cancer Institute, and editor-in-chief of the ASCO Daily News.  I am delighted to welcome Dr. Rana McKay, a GU medical oncologist and associate professor at the University of California San Diego. Today, we'll be discussing some key GU abstracts featured at the 2024 ASCO Annual Meeting. Our full disclosures are available in the transcript of this episode. Rana, we're thrilled to have you on the podcast today to share your insights on key advances in GU oncology from ASCO24. Dr. Rana McKay: Thank you so much, Neeraj; it's a pleasure to be here. Dr. Neeraj Agarwal: So, Rana, let's start with some bladder cancer abstracts. Could you tell us about Abstract 4503, titled “Impact of exposure on outcomes with enfortumab vedotin in patients with locally advanced or metastatic urothelial cancer”? Dr. Rana McKay: Of course, I would be delighted to. First, I would like to remind our listeners that enfortumab vedotin (EV) was approved as a monotherapy for the treatment of locally advanced or metastatic urothelial cancer based on the results of EV-201 and EV-301 trials. In these pivotal studies, EV was initiated at a dose of 1.25 mg/kg, and dose modifications, such as reductions and interruptions, were used to manage adverse events. In the abstract presented at ASCO 2024, Dr. Daniel Petrylak and colleagues conducted a post-hoc exploratory analysis to evaluate the association between EV plasma exposure and outcomes. They used multiple pharmacokinetic samples collected during the first two cycles and pre-dose samples from 3 EV monotherapy studies, namely EV-101, EV-201, and EV-301, that were conducted in patients with previously treated locally advanced or metastatic urothelial carcinoma. Dose reductions to 1 mg/kg were required in 42.1% and 35.1% of patients in the EV-201 and EV-301 trials, respectively, and reductions to 0.75 mg/kg were required in 13.6% and 11.1% in the EV-201 and EV-301 trials, respectively. Higher EV exposure during the first two cycles was associated with a higher objective response rate. The ORR was 21.4% for the dose of 0.75 mg/kg, while it was 18.5% for the dose of 1.0 mg/kg. Interestingly, increasing the dosage to 1.25 mg/kg improved the ORR, which ranged from 40 to 51.1% across various studies. In the EV-301 trial, when comparing the efficacy of EV to chemotherapy, EV improved PFS and OS across all dose quartiles, and there was no evidence that recommended dose modifications impacted long-term efficacy outcomes. Dr. Neeraj Agarwal: Thank you, Rana, for this great summary. I would like to add that the meticulously conducted pharmacokinetic studies demonstrated that serum levels of EV correlated with responses. Importantly, patients who had to decrease the dose did not experience compromised outcomes as EV improved PFS and OS outcomes vs chemotherapy in across all exposure quartiles in the EV-301 trial where EV was compared with chemotherapy. These findings highlight the need to start at the recommended dose of 1.25 mg/kg and reduce it, if necessary, however, clinicians should not start at a lower dose.  Dr. Rana McKay: I totally agree with you, Neeraj. Now, moving on to a different setting in bladder cancer, what can you tell us about LBA4517, titled “Perioperative sacituzumab govitecan alone or in combination with pembrolizumab for patients with muscle-invasive urothelial bladder cancer: SURE-01/02 interim results”? Dr. Neeraj Agarwal: Of course! So, SURE was a multicohort, open-label, phase 2 study in patients with muscle-invasive bladder cancer assessing sacituzumab govitecan as a neoadjuvant therapy either alone in SURE-01 or as a combination with pembrolizumab followed by adjuvant pembro in SURE-02 in a flexible design allowing a bladder-sparing approach. In the abstract presented at ASCO 2024, Dr. Antonio Cigliola and colleagues report interim results of the SURE-01 study. Patients with cT2-4N0M0 urothelial carcinoma who were ineligible for or refused cisplatin-based neoadjuvant chemotherapy were planned to receive 4 cycles of neoadjuvant sacituzumab govitecan at a dose of 10 mg/kg followed by radical cystectomy.  An extensive assessment was performed at baseline and after the 4 cycles for response assessment. Patients with clinical complete response defined with negative MRI, cystoscopy and ctDNA assays refusing radical cystectomy were offered redo transurethral resection of the bladder tumor or repeat TURBT followed by observation in the absence of viable high-grade tumor in the bladder. The primary endpoint was pathological complete response rate, while secondary endpoints included pathological downstaging rate and safety. After the first 8 patients were enrolled, the protocol was amended due to the occurrence of grade 3 and 4 neutropenia and diarrhea in 75% and 50% of patients, respectively, and 2 deaths – one of which was deemed to be treatment-related due to sepsis. Key protocol changes included the reduction of the dose of sacituzumab govitecan to 7.5 mg/kg, the introduction of G-CSF as primary prophylaxis, and the exclusion of patients at high risk of febrile neutropenia per ASCO guidelines.  Among 21 patients who received at least one cycle of sacituzumab govitecan and included in the intention-to-treat population, 47.6% had a complete pathological response, and 52.4% had pathological downstaging. 11 patients underwent radical cystectomy, while 7 received repeat-TURBT due to complete clinical response or patient preference. Regarding the safety profile, grade 3 or more adverse events occurred in 42.5% of patients. Treatment-related adverse events leading to dose interruptions or discontinuations were more common before the protocol amendment. It is noteworthy that 3 patients died after treatment discontinuation, with one deemed treatment-related, as previously mentioned. Dr. Rana McKay: Thank you, Neeraj, for a great summary. The pathological complete responses observed show promising activity for sacituzumab govitecan as a neo-adjuvant therapy and a window for bladder-sparing approaches, which is definitely exciting news for our patients! However, although the 3 deaths encountered in a neo-adjuvant setting could be concerning, the improvement of the safety profile after protocol amendments is reassuring and supports the continuation of the study. Dr. Neeraj Agarwal: Before wrapping up the bladder cancer section, would you like to share your insights with our listeners on Abstract 4518, titled “Quantitative circulating tumor DNA (ctDNA) assessment in patients with advanced urothelial carcinoma treated with pembrolizumab or platinum-based chemotherapy from the phase 3 KEYNOTE-361 trial”?  Dr. Rana McKay: Sure. So, the KEYNOTE-361 trial was a randomized phase 3 study with 3 arms that included pembrolizumab plus chemotherapy, pembrolizumab monotherapy, or chemotherapy alone in patients with previously untreated advanced urothelial carcinoma. The results showed that neither the combination of pembrolizumab plus chemotherapy nor pembrolizumab monotherapy improved survival outcomes compared to the chemotherapy arm. So, in this exploratory analysis presented at ASCO24, Dr. Tom Powles and colleagues sought to assess the role of ctDNA as a potential biomarker between the pembrolizumab monotherapy arm and the chemotherapy arm. Tumor tissue mutations were evaluated using whole exome sequencing, and plasma ctDNA was assessed with the Guardant 360 assay. Changes in ctDNA from pre-treatment cycle 1 to on-treatment cycle 2, so 3 weeks post-baseline assessment, were quantified by the maximum variant allele frequency of tumor tissue-specific mutations.  Results showed that lower baseline ctDNA levels were associated with improved clinical outcomes of response in the pembrolizumab arm but not in the chemotherapy arm. This improvement in the pembrolizumab arm was also robust to adjustment for tumor mutational burden and PD-L1. Additionally, chemotherapy led to a ctDNA clearance rate of 41% compared to 11% in the pembrolizumab arm. Patients who had a large ctDNA reduction with pembrolizumab had significantly improved outcomes compared to those achieving a large reduction with chemotherapy with a hazard ratio of 0.25. However, this did not replicate in patients who did not achieve a large reduction, as these patients had similar outcomes across both arms. Let's switch gears to kidney cancer and start with Abstract 4508, reporting the final OS analysis from the JAVELIN Renal-101 trial. Neeraj, what would you like to tell us about this abstract? Dr. Neeraj Agarwal:  Well, as a quick reminder, the JAVELIN Renal-101 was a randomized phase 3 trial where patients with previously untreated advanced or metastatic clear cell renal cell carcinoma were randomized to receive either the combination of avelumab plus axitinib or sunitinib. In previous analyses, the combination of avelumab and axitinib significantly improved PFS compared to sunitinib and was subsequently approved by the FDA for the first-line treatment of patients with advanced RCC in 2019. This superiority in PFS was maintained across the different analyses; however, OS data remained immature. In the abstract presented at ASCO24 by Dr. Robert Motzer from Memorial Sloan Kettering Cancer Center and colleagues, the authors reported OS results at a median follow-up of around 73 months and a minimum of 68 months for all patients, which is the longest follow-up for any ICI-TKI combination in RCC. The final analysis in the overall population favored the combination of avelumab plus axitinib with a median OS of 44.8 months compared to 38.9 months with sunitinib, however, this did not reach statistical significance with a hazard ratio of 0.88. The PFS results and safety profile were consistent with previous analyses.  Dr. Rana McKay: Thank you, Neeraj, for such a nice overview of this abstract. These new data could make this regimen less optimal than other ICI-TKI combinations in the first-line mRCC setting.   Dr. Neeraj Agarwal: I concur, Rana. Moving on to perhaps one of the most exciting GU abstracts featured, Abstract 4506, titled “Circulating kidney injury molecule-1 biomarker analysis in IMmotion010: A randomized phase 3 study of adjuvant atezolizumab vs placebo in patients with renal cell carcinoma at increased risk of recurrence after resection.” Rana, what are your thoughts on this abstract? Dr. Rana McKay: Well, first, I would like to take a step back and remind our audience that in the IMmotion010 trial, patients with resected intermediate to high-risk RCC with clear cell and/or sarcomatoid component were randomized in a 1:1 ratio to receive either atezolizumab or placebo. Investigator-assessed disease-free survival, which was the primary endpoint, favored the atezolizumab arm but did not reach statistical significance. In the abstract featured at ASCO24, Dr. Laurence Albiges and colleagues build on data previously reported in the ASSURE and CheckMate 914 trials and report provocative findings regarding a molecule known as kidney injury molecule 1 or KIM-1, which is a type 1 membrane glycoprotein that has been identified as a minimally invasive potential peripheral blood circulating biomarker. The KIM-1 level of 86 pg/ml was identified as the optimized threshold for defining post-nephrectomy KIM-1 high vs KIM-1 low subgroups in the IMmotion010 trial. KIM-1 levels were measured at baseline or pre-treatment, at cycle 4 day 1, and at disease recurrence or discontinuation without disease recurrence. Baseline characteristics were balanced between the KIM-1 high and KIM-1 low groups, except perhaps for a slightly higher pathological stage in the KIM-1 high subgroup.  I would like to highlight 3 key takeaways from this abstract. First, KIM-1 high level was associated with significantly worse DFS with a hazard ratio of 1.75. Second, patients in the KIM-1 high subgroup receiving atezolizumab had a 28% reduction in the risk of recurrence or death compared to those receiving placebo, while those in the KIM-1 low subgroup had comparable outcomes across both treatment arms. Third, patients in the KIM-1 high subgroup receiving atezolizumab were significantly less likely to experience an on-treatment increase in KIM-1 levels, which was associated with worse DFS in both high and low KIM-1 subgroups, regardless of treatment arm. Thus, these findings support the use of KIM-1 as both a predictive and prognostic biomarker in patients with RCC. Dr. Neeraj Agarwal: Yes, Rana, this is amazing data! I would like to add that these results warrant larger and, ideally, prospective studies to validate the utility of KIM-1 as a noninvasive biomarker for identifying minimal residual disease after nephrectomy and for predicting outcomes to immune checkpoint inhibitors. Dr. Rana McKay: Also, in the field of biomarkers, 2 abstracts interrogating different biomarkers in a different setting, so in patients with advanced or metastatic RCC were presented. Neeraj, could you tell us more about these abstracts? Dr. Neeraj Agarwal: Of course! I think you are referring to Abstracts 4504 and 4505. In abstract 4504, Dr. Toni Choueiri and colleagues sought to assess the clinical implications of different biomarkers in the CLEAR trial, which was a randomized phase 3 trial that led to the approval of the combination of pembrolizumab plus lenvatinib in the first-line mRCC setting. On the other hand, in abstract 4505, Dr. Brian Rini presented biomarker results in KEYNOTE-426, which was also a randomized phase 3 trial based on which the combination of pembrolizumab plus axitinib was approved in patients with mRCC. The authors in both trials sought to investigate the role of biomarkers in predicting treatment outcomes from 3 different angles. Starting with PD-L1 expression, the superiority of the combination arms over sunitinib was not impacted by PD-L1 status in both trials. Moving on to RCC driver gene mutations on whole exome sequencing, such as VHL, SETD2, PBRM1, and BAP1, ICI combination therapies improved outcomes regardless of mutation gene status, and this improvement was statistically significant with PBRM1 mutations in KEYNOTE-426 compared to wild-type PBRM1, but this did not replicate in the CLEAR trial. Finally, using transcriptomic signatures derived from RCC trials, especially the IMmotion 151 and JAVELIN Renal 101 trials, where 7 clusters or molecular subtypes were identified, the combination arms outperformed sunitinib in all clusters in both trials and the magnitude of this benefit differed across clusters.  Dr. Rana McKay: Thank you for this very interesting summary and comparison of the results of these 2 abstracts. These findings support the use of ICI-based combinations in all patients with mRCC as a first-line option. Although these abstracts could not identify specific biomarkers that could guide us clinicians in treatment selection, they provide very interesting biological insights on these molecular biomarkers that are, however, not yet clinically actionable. Dr. Neeraj Agarwal: Very interesting point, Rana. Moving on to prostate cancer, let's start with abstract LBA5000 titled, “Cabazitaxel with abiraterone versus abiraterone alone randomized trial for extensive disease following docetaxel: The CHAARTED2 trial of the ECOG-ACRIN Cancer Research Group (EA8153).” Rana, what is your takeaway on this abstract? Dr. Rana McKay: As a reminder to our audience, the CHAARTED2 trial was a randomized open-label phase 2 study that compared the combination of cabazitaxel and abiraterone to abiraterone alone in patients with mCRPC previously treated with ADT plus docetaxel in the hormone-sensitive setting. The primary endpoint was progression-free survival. After a median follow-up of 47.3 months, Dr. Christos Kyriakopoulos and colleagues reported in LBA5000 that patients receiving the combination of cabazitaxel plus abiraterone had a 27% reduction in the risk of progression or death. However, there was no significant difference in overall survival between the two arms, with a median OS of 25 months in the cabazitaxel+abiraterone arm and 26.9 months in the abiraterone arm, although the study was underpowered for this endpoint. Regarding the toxicity profile, the combination of cabazitaxel and abiraterone was overall well tolerated with more cytopenias, as expected.  Dr. Neeraj Agarwal: Very nice summary of this abstract, Rana. I would like to add that the treatment landscape of patients with mHSPC has evolved since the design of the study and now includes combination therapies of ADT + ARPI with or without docetaxel, and ADT + docetaxel is no longer a standard of care, which limits the applicability of these results in clinical practice today.  Dr. Rana McKay: Excellent point, Neeraj. Let's discuss Abstract 5001, titled “CYCLONE 2: A phase 3 study of abemaciclib with abiraterone in patients with metastatic castration-resistant prostate cancer”. Dr. Neeraj Agarwal: Sure! In the abstract featured at ASCO24, Dr. Matthew Smith and colleagues report the primary results of the CYCLONE 2 trial, which was a randomized phase 2/3 study that investigated the combination of abemaciclib plus abiraterone versus abiraterone monotherapy in patients with mCRPC. Stratification factors included radiographic progression at study entry, presence of measurable disease, and prior docetaxel for mHSPC. Part 1 of the study established the recommended phase 2 dose of abemaciclib at 200 mg twice daily. In part 2, patients were randomized to placebo or abemaciclib, and an adaptive interim analysis using prespecified criteria was performed and recommended the expansion of the study to part 3. The primary endpoint was investigator-assessed radiographic progression-free survival by RECIST 1.1 and PCWG3 criteria in the intention-to-treat population. At the time of the primary analysis, adding abemaciclib to abiraterone did not improve rPFS, with a hazard ratio of 0.83. The median rPFS was 22 months for the combination arm and 20.3 months for the abiraterone arm. The combination was well tolerated, and the safety profile was consistent with the known adverse events. Dr. Rana McKay: So, the addition of abemaciclib to abiraterone did not improve outcomes in patients with mCRPC. These findings suggest that no further investigation is warranted for abemaciclib or CDK4/6 inhibitors in biomarker-unselected patients with prostate cancer.  Dr. Neeraj Agarwal: Rana, what's your take-home message on Abstract 5006, titled “Health-related quality of life results from PRESTO (AFT-19), a phase 3 randomized trial of intensification of androgen blockade in patients with high-risk biochemically relapsed castration sensitive prostate cancer”? Dr. Rana McKay: So, as a reminder to our audience, the PRESTO trial was a randomized phase 3 study that assessed the effects of intensified androgen receptor blockade in patients with biochemically recurrent prostate cancer following local therapies. Patients with a PSA doubling time of less than 9 months and no evidence of metastatic disease were randomized to receive either 52 weeks of ADT alone, ADT plus apalutamide, or ADT plus apalutamide plus abiraterone. In their paper published earlier this year in the Journal of Clinical Oncology, the authors showed that patients receiving ADT plus apalutamide with or without abiraterone had significantly longer PSA-progression-free survival than those receiving ADT alone. In the oral presentation featured at ASCO24, Dr. Ronald Chen and colleagues report health-related quality of life outcomes that were assessed using various questionnaires or scales at baseline, at cycle 7, which is around 6 months on treatment, and at the end of treatment. Results showed that this intensified approach with apalutamide did not significantly increase severe adverse events, did not lengthen the time to testosterone recovery, and did not meaningfully increase common treatment-related symptoms such as hormonal symptoms, sexual dysfunction, hot flash interference, and fatigue. Importantly, additional intensification with abiraterone did not further improve PSA-PFS but did increase the rate of serious adverse events, lengthened the time to testosterone recovery, and increased hot flash interference.  Dr. Neeraj Agarwal: So, in conclusion, the PRESTO trial supports using intensified androgen blockade with apalutamide to improve PSA-PFS in patients with high-risk biochemically recurrent prostate cancer without compromising health-related quality of life. However, adding abiraterone did not offer additional benefits and increased side effects.  Dr. Rana McKay: Let's move on to LBA5002 titled, “A randomized, double-blind, placebo-controlled trial of metformin in reducing progression among men on expectant management for low-risk prostate cancer: The MAST (Metformin Active Surveillance Trial) study.” Would you like to share your insights on this abstract with our listeners? Dr. Neeraj Agarwal: Absolutely. MAST was a randomized, double-blinded, placebo-controlled trial that investigated the impact of metformin on the progression of low-risk localized prostate cancer in patients choosing to undergo active surveillance. Eligible patients had biopsy-proven, low-risk, localized prostate cancer diagnosed within the past 6 months, characterized by a Gleason score of less than 6 observed in less than one-third of the total cores, less than 50% positivity in any one core, a PSA level of less than 10 ng/ml, and a clinical-stage between T1c and T2a. Patients were randomized in a 1:1 ratio to receive either metformin 850 mg twice daily or placebo for three years. All patients underwent repeat prostate biopsy at 18 and 36 months. The primary endpoint was time to progression, defined as the earliest occurrence of primary prostate cancer therapy, such as prostatectomy, radiation, hormonal therapy, or pathological progression on subsequent biopsies, which was defined as more than 1/3 of total cores involved, at least 50% of any one core involved, or Gleason pattern 4 or higher. The study included 407 patients, with 204 receiving metformin and 203 receiving a placebo. Results presented by Dr. Anthony Joshua showed no statistically significant difference in progression-free survival, including therapeutic and pathologic progression, with an unadjusted hazard ratio of 1.08.  Interestingly, there was a signal that patients with a BMI more than 30 had a detriment to taking metformin with a higher risk of progression compared to those receiving placebo with an unadjusted HR of 2.39 and a p-value of 0.01. Dr. Rana McKay: I would like to add that this study showed that metformin use does not prevent the progression of low-risk localized prostate cancer on active surveillance and could represent a potential detriment for patients with high BMI at study entry. Dr. Neeraj Agarwal: Yes, Rana, I concur. Any final remarks before we conclude today's podcast? Dr. Rana McKay:  Thank you, Neeraj; it's been wonderful being here with you today and you having me on the podcast to highlight these important advances and the amazing work that many investigators are conducting and the patients who were involved in the context of these trials. It's really excellent to see these updated results.   Dr. Neeraj Agarwal: Before we wrap up this podcast, I would like to say that we have reviewed a selection of abstracts addressing prostate, bladder, and kidney cancer, which are significantly impacting our medical practices now and in the near future. Rana, thank you for sharing your insights today. These updates are undoubtedly exciting for the entire GU oncology community, and we greatly appreciate your valuable contribution to the discussion. Many thanks. And thank you to our listeners for joining us today. You will find links to the abstracts discussed today on the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts.   Find out more about today's speakers:    Dr. Neeraj Agarwal   @neerajaiims   Dr. Rana McKay  @DrRanaMcKay     Follow ASCO on social media:      @ASCO on Twitter      ASCO on Facebook      ASCO on LinkedIn         Disclosures:        Dr. Neeraj Agarwal:         Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, AstraZeneca, Pfizer, Merck, Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences     Research Funding (Institution): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, Crispr Therapeutics, Arvinas      Dr. Rana McKay:   Consulting or Advisory Role: Janssen, Novartis, Tempus, Exelxis, Pfizer, Bristol-Myers Squibb, Astellas Medivation, Dendreon, Bayer, Sanofi, Merck, Vividion, Calithera, AstraZeneca, Myovant, Caris Life Sciences, Sorrento Therapeutics, AVEO, Seattle Genetics, Telix, Eli Lilly, Pfizer, Bayer, Tempus

Dr. Neeraj Agarwal and Dr. Jeanny Aragon-Ching discuss promising combination therapies and other compelling advances in genitourinary cancers in advance of the 2024 ASCO Annual Meeting. TRANSCRIPT Dr. Neeraj Agarwal: Hello and welcome to the ASCO Daily News Podcast. I'm Dr. Neeraj Agarwal, your guest host of the ASCO Daily News Podcast today. I'm the director of the Genitourinary Oncology Program and a professor of medicine at the University of Utah Huntsman Cancer Institute, and editor-in-chief of the ASCO Daily News. I'm delighted to be joined by Dr. Jeanny Aragon-Ching, a GU medical oncologist and the clinical program director of genitourinary cancers at the Inova Schar Cancer Institute in Virginia. Today, we will be discussing some key abstracts in GU oncology that will be featured at the 2024 ASCO Annual Meeting.  Our full disclosures are available in the transcript of this episode. Jeanny, it's great to have you on the podcast. Dr. Jeanny Aragon-Ching: Thank you so much, Dr. Agarwal. It's a pleasure to be here. Dr. Neeraj Agarwal: So, Jeanny, let's start with some bladder cancer abstracts. Could you tell us about the Abstract 4509 titled, “Characterization of Complete Responders to Nivolumab plus Gemcitabine Cisplatin versus Gemcitabine Cisplatin Alone in Patients with Lymph Node Only Metastatic Urothelial Carcinoma from the CheckMate 901 Trial.”  Dr. Jeanny Aragon-Ching: Of course, Neeraj, I would be delighted to. First, I would like to remind our listeners that the CheckMate 901 trial was a randomized, open-label, phase 3 study, in which this particular sub-study looked at cisplatin-eligible patients with previously untreated, unresectable, or metastatic urothelial carcinoma who were assigned to receive the combination of gemcitabine and cisplatin, followed by up to 2 years of nivolumab or placebo. Based on the data presented at ESMO 2023 and subsequently published in the New England Journal of Medicine, which shows significantly improved progression-free survival and overall survival in patients receiving the combination of gemcitabine, cisplatin, and nivolumab, this regimen was approved in March 2024 as a first-line therapy for patients with unresectable or metastatic urothelial carcinoma.  In the abstract that will be featured at ASCO this year, Dr. Matt Galsky and colleagues present a post-hoc analysis that aims to characterize a subset of patients with complete response as well as those with lymph node-only metastatic disease. In patients receiving the experimental treatment, 21.7% achieved a complete response, while 11.8% of the patients in the control arm achieved a complete response.  Among these complete responders, around 52% had lymph- node-only disease in both arms. Furthermore, when characterizing the subgroup of patients with lymph-node-only disease, those receiving the combination of gemcitabine-cisplatin plus nivolumab had a 62% reduction in the risk of progression or death and a 42% reduction in the risk of death compared to those treated with gemcitabine-cisplatin alone.  The median overall survival in the experimental arm in this subgroup was around 46.3 months, while it was only 24.9 months in the control arm. The ORR in patients with lymph-node-only disease receiving gem-cis plus nivo was about 81.5% compared to 64.3% in those treated with gem-cis alone. Dr. Neeraj Agarwal: Thank you, Jeanny, for the excellent summary of this abstract. We can say that nivolumab plus gemcitabine-cisplatin induced durable disease control and clinically meaningful improvements in OS and PFS compared to gem-cis alone in patients with lymph- node-only metastasis, and deserves to be considered as one of the options for these patients.  In a similar first-line metastatic urothelial carcinoma setting, Abstract 4502, also reported data on a recently approved combination of enfortumab vedotin and pembrolizumab. Can you tell us more about this abstract, Jeanny? Dr. Jeanny Aragon-Ching: Sure, Neeraj. So, as quick reminder to our audience, this regimen was tested in the EV-302 phase 3 trial, where patients with previously untreated, locally advanced or metastatic urothelial carcinoma were randomized to receive enfortumab vedotin, plus pembrolizumab or gemcitabine plus either cisplatin or carboplatin. These data were also first presented at ESMO 2023 and subsequently published in the New England Journal of Medicine. They showed that this immune based combination significantly improved both progression free survival and overall survival, which were the primary endpoints compared to chemotherapy. In this abstract, Dr. Shilpa Gupta from the Cleveland Clinic and colleagues present the results of patient reported outcomes based on quality-of-life questionnaires in this trial.  Time to pain progression and time to confirm deterioration were numerically longer in patients treated with EV plus pembro, and patients with moderate to severe pain at baseline receiving this combination had a meaningful improvement in the Brief Pain Inventory Short-Form worst pain from week 3 through 26. Dr. Neeraj Agarwal: Thank you, Jeanny. This means that patients treated with EV plus pembro did not only have improved survival compared with platinum-based chemotherapy, but also improvement in their quality-of-life and functioning, further supporting the value of this combination for patients with locally advanced or metastatic urothelial carcinoma. This is terrific news for all of our patients.   Before we wrap up the bladder cancer section, would you like to tell our listeners about Abstract 4565, which provides the data on the efficacy of trastuzumab deruxtecan in patients with bladder cancer? Dr. Jeanny Aragon-Ching: Yes, Neeraj; this is timely given the recent FDA approval, which we will talk about. The abstract is titled, “Efficacy and Safety of Trastuzumab Deruxtecan in Patients with HER2 Expressing Solid Tumors: Results from the Bladder Cohort of the DESTINY-PanTumor02 Study.” And as a quick reminder, the DESTINY-PanTumor02 was a phase 2 open-label study where trastuzumab deruxtecan, an antibody-drug conjugate targeting HER2 expression on cancer cells, was evaluated in patients with HER2-expressing locally advanced or metastatic disease who previously received systemic treatment or who had no other treatment options. The expression of HER2 was evaluated on immunohistochemistry by local or central testing.   The primary endpoint was confirmed objective response rate by investigator assessment. Secondary endpoints included duration of response, progression free survival, disease control rate, and safety. The primary analysis, which was published in the Journal of Clinical Oncology, showed an ORR of 37.1% and responses across all cohorts and the median duration of response was 11.3 months. Based on these results, fam-trastuzumab deruxtecan-nxki was just granted accelerated FDA approval for unresectable or metastatic HER2-positive solid tumors in April 2024.  So, back to this abstract; Dr. Wysocki and colleagues report the results of the bladder cancer cohort. This study included 41 patients with urothelial cancer and at a median follow up of around 12.6 months, the objective response rate among these patients was 39%, the median PFS was 7 months, and the duration of response median was 8.7 months. The disease control rate at 12 weeks was around 71%. Regarding the safety profile, 41.5% of patients experienced grade ≥3 drug related adverse events and interstitial lung disease or pneumonitis did occur in about 4 patients. Although there was no statistical comparison between different groups, the ORR was numerically highest among the HER2 3+ group with 56.3%.  Dr. Neeraj Agarwal: Thank you, Jeanny. So, these data support consideration of trastuzumab deruxtecan as a salvage therapy option for pre-treated patients with HER2 expressing urothelial cancers and show that we are extending our treatment options to include therapies with novel mechanisms of action. This is definitely exciting news for patients with bladder cancer. Dr. Jeanny Aragon-Ching: Yes, absolutely, Neeraj. Now, let's switch gears a bit to prostate cancer. Could you tell us about Abstract 5005 which is titled, “EMBARK Post Hoc Analysis of Impact of Treatment Suspension on Health Quality-of-Life?” Dr. Neeraj Agarwal: Of course, I'd be happy to. So, enzalutamide was recently granted FDA approval for the treatment of patients with non-metastatic castration-sensitive prostate cancer with biochemical recurrence at high-risk of metastasis, based on the results of the EMBARK trial, which was a phase 3 study where patients with high-risk biochemical recurrence were randomized to receive either enzalutamide with leuprolide, enzalutamide monotherapy, or placebo plus leuprolide. The primary endpoint was metastasis-free survival with secondary endpoints including overall survival and safety.  Results showed that patients receiving enzalutamide alone or enzalutamide plus leuprolide had significantly improved metastasis-free survival compared to those treated with leuprolide alone while preserving health-related quality-of-life.   One important aspect in the design of the trial was that patients who achieved undetectable PSA at week 37 underwent treatment suspension. The treatment was resumed if PSA rose to more than 2 ng/ml for patients who underwent radical proctectomy or when PSA rose to more than 5 ng/ml for those who did not undergo surgery.  In this abstract, Dr. Stephen Freedland and colleagues present a post-hoc analysis of health-related quality-of-life outcomes after treatment suspension between weeks 37 and 205. They found that treatment was suspended in 90.9% of patients receiving enzalutamide plus leuprolide, 85.9% of those receiving enzalutamide monotherapy, and 67.8% of those receiving leuprolide monotherapy. Among those patients who stayed on treatment suspension, a trend toward numerical improvement in health-related quality-of-life after week 37 was seen in all 3 arms and this reached clinically meaningful threshold at week 205 in pain questionnaires, physical well-being, urinary and bowel symptoms. For hormonal treatment side effects, all arms reached clinically meaningful improvement at the subsequent assessments of week 49 to week 97. However, patients slowly deteriorated, with clinically meaningful deterioration at week 205 relative to week 37 in patients receiving the combination of enzalutamide and leuprolide and those treated with leuprolide.    Concerning sexual activity, a clinically meaningful improvement was reported only in patients receiving enzalutamide plus leuprolide, possibly because sexual function was better preserved prior to suspension in the enzalutamide monotherapy arm and thus there was less opportunity for “improvement” while on suspension.  Dr. Jeanny Aragon-Ching: Thank you, Neeraj, for this great summary. This analysis confirms that treatment suspension in good responders might lead to a clinically meaningful improvements in health-related quality-of-life.   Now, moving on to patients with metastatic castration-resistant prostate cancer, what can you tell us, about Abstract 5008 titled, “Baseline ctDNA analyses and associations with outcomes in taxane-naive patients with mCRPC treated with 177Lu-PSMA-617 versus change of ARPI in PSMAfore”?  Dr. Neeraj Agarwal: Sure, Jeanny. The PSMAfore trial was a phase 3 study that compared the efficacy of 177Lu-PSMA-617 versus an ARPI switch in patients with mCRPC and prior progression on a first ARPI, and not previously exposed to docetaxel chemotherapy. The primary endpoint was rPFS and OS was an important secondary endpoint. The primary analysis presented at ESMO 2023 showed a significantly prolonged rPFS in patients receiving lutetium. In the abstract that will be featured at the 2024 ASCO Annual Meeting, Dr. Johann De Bono and colleagues present an exploratory analysis regarding the associations between baseline circulating tumor DNA and outcomes.  ctDNA fraction was evaluated in all samples as well as alterations in key prostate cancer drivers prevalent in more than 10% of participants.  The investigators sought to interrogate the association of ctDNA fraction or alterations with rPFS, PSA response, and RECIST response at data cutoff. They showed that median rPFS was significantly shorter in patients with a ctDNA fraction >1% compared to those with a fraction < 1% regardless of the treatment arm. Furthermore, ctDNA fraction >1% was also associated with worst RECIST response and PSA50 response. Regarding prostate cancer drivers, median rPFS was significantly shorter in patients with alterations in the AR, TP53 or PTEN in both treatment arms. There was no significant association between ctDNA alterations and PSA or objective responses. Dr. Jeanny Aragon-Ching: Thank you, Neeraj. So, these results show that the presence of a ctDNA fraction >1% or alterations in AR, P53 and PTEN were all associated with worse outcomes regardless of treatment with lutetium or change in the ARPI. These data are definitely important for counseling and prognostication of patients in the clinic and may guide the design of future clinical trials. Let's move on to kidney cancer. Neeraj, do you have any updates for us?  Dr. Neeraj Agarwal:  Sure. In Abstract 4512 titled, “A Multi-institution Analysis of Outcomes with First-Line Therapy for 99 Patients with Metastatic Chromophobe Renal Cell Carcinoma,” Dr. Sahil Doshi and colleagues present a retrospective, multi-institutional study comparing survival outcomes, including time-to-treatment failure and overall survival, between different first-line treatment options in patients with metastatic chromophobe renal cell carcinoma, where limited clinical trial data exists to guide systemic therapy. They categorized patients into 4 treatment groups: and immune checkpoint inhibitors + targeted therapy doublets (such as ICI VEGF TKI); pure immune checkpoint inhibitor monotherapy and doublets (such as ipilimumab plus nivolumab); targeted therapy doublets (such as lenvatinib plus everolimus), and targeted monotherapy (such as sunitinib).  They identified 99 patients, of whom 54 patients received targeted monotherapy, 17 received ICI VEGF-TKI, 14 received targeted doublet, and 14 patients received only ICI therapies. So the patients treated with any doublet containing a targeted agent had a 52% decrease in the risk of treatment failure and a 44% decrease in the risk of death compared to those treated with targeted monotherapy. The median time to treatment failure was 15 months with IO-targeted doublet, and the median overall survival was 56 months. Dr. Jeanny Aragon-Ching: Thank you, Neeraj. So, these results show that targeted doublet regimens resulted in a longer time to treatment failure and overall survival compared to any monotherapy in patients with chromophobe metastatic RCC and definitely provides valuable insights on treatment selection, albeit I would say there's still a small number of patients that were included in this retrospective analysis. Dr. Neeraj Agarwal: I completely agree this is a relatively small number of patients, but I decided to highlight the abstract given how rare the cancer is, and it is highly unlikely that we'll see large randomized clinical trials in patients with metastatic chromophobe renal cell carcinoma.  So, before we wrap up the podcast, what would you like to tell us about Abstract 5009 which is titled, “A Phase II Trial of Pembrolizumab Platinum Based Chemotherapy as First Line Systemic Therapy in Advanced Penile Cancer: HERCULES (LACOG 0218) Trial.” Dr. Jeanny Aragon-Ching: I'm glad you brought this up, Neeraj. As our listeners may know, advanced penile squamous cell carcinoma has a poor prognosis with limited treatment options. From this perspective, the results of the LACOG 0218 trial are very important. As you mentioned, this was a phase 2 single-arm study evaluating the addition of pembrolizumab to platinum-based chemotherapy as first-line treatment in patients with metastatic or locally advanced penile squamous cell carcinoma not amenable to curative therapy. Patients enrolled received chemotherapy, namely 5-Fluorouracil with cisplatin or carboplatin and pembrolizumab 200 mg IV every 3 weeks for 6 cycles, followed by pembrolizumab 200 mg IV every 3 weeks up to 34 cycles. The primary endpoint was confirmed overall response rate by investigator assessment.  In the 33 patients eligible for the efficacy analysis, the confirmed ORR by investigator assessment was 39.4% and included one complete response and 12 partial responses. The confirmed ORR was 75% in patients with high TMB and 55.6% in patients positive for HPV16, making TMB and HPV16 potential predictive biomarkers for efficacy in this study. Concerning the toxicity profile, any grade treatment-related adverse events were reported in around 92% of patients, and grade 3 or more treatment-related adverse events occurred in 51% of patients. 10.8% of patients discontinued treatment due to adverse events.  Dr. Neeraj Agarwal: Thank you, Jeanny. I would like to add that HERCULES is the first trial to demonstrate the efficacy of an immune checkpoint inhibitor in advanced penile squamous cell carcinoma with a manageable safety profile. Thus, the combination of ICI with platinum-based chemotherapy is a promising treatment for advanced penile squamous cell carcinoma and warrants further investigation.  Dr. Jeanny Aragon-Ching: I agree, Neeraj. Any final remarks before we conclude today's podcast? Dr. Neeraj Agarwal: Jeanny, I really want to thank you for your participation and valuable insights. Your contributions are always appreciated, and I sincerely thank you for taking the time to join us today. Dr. Jeanny Aragon-Ching: Thank you, Neeraj. It was a pleasure.  Dr. Neeraj Agarwal:  As we bring this podcast to an end, I would like to acknowledge the significant advances happening in the treatment of patients with genitourinary cancers. During our upcoming 2024 ASCO Annual Meeting, there will be an array of different studies featuring practice-changing data presented by researchers and physicians from around the globe. I urge our listeners to not only participate in this event to celebrate these achievements, but to also play a role in sharing these cutting-edge data with healthcare professionals worldwide. Through our collective efforts, we can surely optimize the benefits of patients on a global scale.   And thank you to our listeners for joining us today. You will find links to the abstracts discussed today on the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcast. Thank you very much.   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Find out more about today's speakers:  Dr. Neeraj Agarwal  @neerajaiims  Dr. Jeanny Aragon-Ching    Follow ASCO on social media:   @ASCO on Twitter     ASCO on Facebook     ASCO on LinkedIn       Disclosures:    Dr. Neeraj Agarwal:     Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, AstraZeneca, Pfizer, Merck, Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences    Research Funding (Institution): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, Crispr Therapeutics, Arvinas     Dr. Jeanny Aragon-Ching:  Honoraria: Bristol-Myers Squibb, EMD Serono, Astellas Scientific and Medical Affairs Inc., Pfizer/EMD Serono  Consulting or Advisory Role: Algeta/Bayer, Dendreon, AstraZeneca, Janssen Biotech, Sanofi, EMD Serono, MedImmune, Bayer, Merck, Seattle Genetics, Pfizer, Immunomedics, Amgen, AVEO, Pfizer/Myovant, Exelixis,   Speakers' Bureau: Astellas Pharma, Janssen-Ortho, Bristol-Myers Squibb, Astellas/Seattle Genetics. 

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME/MOC/NCPD/CPE/AAPA/IPCE information, and to apply for credit, please visit us at PeerView.com/HGE865. CME/MOC/NCPD/CPE/AAPA/IPCE credit will be available until February 16, 2025.From Resistance to Resilience in R/R CLL: Sequencing Strategies for Achieving Effective Continuous Care In support of improving patient care, this activity has been planned and implemented by PVI, PeerView Institute for Medical Education, and CLL Society. PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by an educational grant from Lilly.Disclosure PolicyAll relevant conflicts of interest have been mitigated prior to the commencement of the activity.Faculty/Planner DisclosuresCo-Chair/PlannerMeghan C. Thompson, MD, has a financial interest/relationship or affiliation in the form of:Consultant and/or Advisor for AstraZeneca; Lilly/Loxo Oncology, Inc.; and Pharmacyclics LLC/Janssen Pharmaceuticals, Inc.Grant/Research Support from AbbVie; AstraZeneca; BeiGene, Inc.; Genentech, Inc.; Genmab; and Nurix Therapeutics. Research funding goes to Institution.Co-Chair/PlannerCatherine C. Coombs, MD, has a financial interest/relationship or affiliation in the form of:Consultant and/or Advisor for AbbVie Inc.; Allogene Therapeutics; AstraZeneca; BeiGene, Inc.; Genentech, Inc.; Janssen Pharmaceuticals, Inc.; Lilly; MEI Pharma, Inc.; Mingsight Pharmaceuticals, Inc.; and Octapharma USA, Inc.Grant/Research Support from Lilly.Speaker for AbbVie Inc.; AstraZeneca; BeiGene, Inc.; and Genentech, Inc.Planning Committee and Reviewer DisclosuresPlanners, independent reviewers, and staff of PVI, PeerView Institute for Medical Education, do not have any relevant financial relationships related to this CE activity unless listed below.

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME/MOC/NCPD/CPE/AAPA/IPCE information, and to apply for credit, please visit us at PeerView.com/HGE865. CME/MOC/NCPD/CPE/AAPA/IPCE credit will be available until February 16, 2025.From Resistance to Resilience in R/R CLL: Sequencing Strategies for Achieving Effective Continuous Care In support of improving patient care, this activity has been planned and implemented by PVI, PeerView Institute for Medical Education, and CLL Society. PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by an educational grant from Lilly.Disclosure PolicyAll relevant conflicts of interest have been mitigated prior to the commencement of the activity.Faculty/Planner DisclosuresCo-Chair/PlannerMeghan C. Thompson, MD, has a financial interest/relationship or affiliation in the form of:Consultant and/or Advisor for AstraZeneca; Lilly/Loxo Oncology, Inc.; and Pharmacyclics LLC/Janssen Pharmaceuticals, Inc.Grant/Research Support from AbbVie; AstraZeneca; BeiGene, Inc.; Genentech, Inc.; Genmab; and Nurix Therapeutics. Research funding goes to Institution.Co-Chair/PlannerCatherine C. Coombs, MD, has a financial interest/relationship or affiliation in the form of:Consultant and/or Advisor for AbbVie Inc.; Allogene Therapeutics; AstraZeneca; BeiGene, Inc.; Genentech, Inc.; Janssen Pharmaceuticals, Inc.; Lilly; MEI Pharma, Inc.; Mingsight Pharmaceuticals, Inc.; and Octapharma USA, Inc.Grant/Research Support from Lilly.Speaker for AbbVie Inc.; AstraZeneca; BeiGene, Inc.; and Genentech, Inc.Planning Committee and Reviewer DisclosuresPlanners, independent reviewers, and staff of PVI, PeerView Institute for Medical Education, do not have any relevant financial relationships related to this CE activity unless listed below.

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME/MOC/NCPD/CPE/AAPA/IPCE information, and to apply for credit, please visit us at PeerView.com/HGE865. CME/MOC/NCPD/CPE/AAPA/IPCE credit will be available until February 16, 2025.From Resistance to Resilience in R/R CLL: Sequencing Strategies for Achieving Effective Continuous Care In support of improving patient care, this activity has been planned and implemented by PVI, PeerView Institute for Medical Education, and CLL Society. PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by an educational grant from Lilly.Disclosure PolicyAll relevant conflicts of interest have been mitigated prior to the commencement of the activity.Faculty/Planner DisclosuresCo-Chair/PlannerMeghan C. Thompson, MD, has a financial interest/relationship or affiliation in the form of:Consultant and/or Advisor for AstraZeneca; Lilly/Loxo Oncology, Inc.; and Pharmacyclics LLC/Janssen Pharmaceuticals, Inc.Grant/Research Support from AbbVie; AstraZeneca; BeiGene, Inc.; Genentech, Inc.; Genmab; and Nurix Therapeutics. Research funding goes to Institution.Co-Chair/PlannerCatherine C. Coombs, MD, has a financial interest/relationship or affiliation in the form of:Consultant and/or Advisor for AbbVie Inc.; Allogene Therapeutics; AstraZeneca; BeiGene, Inc.; Genentech, Inc.; Janssen Pharmaceuticals, Inc.; Lilly; MEI Pharma, Inc.; Mingsight Pharmaceuticals, Inc.; and Octapharma USA, Inc.Grant/Research Support from Lilly.Speaker for AbbVie Inc.; AstraZeneca; BeiGene, Inc.; and Genentech, Inc.Planning Committee and Reviewer DisclosuresPlanners, independent reviewers, and staff of PVI, PeerView Institute for Medical Education, do not have any relevant financial relationships related to this CE activity unless listed below.

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME/MOC/NCPD/CPE/AAPA/IPCE information, and to apply for credit, please visit us at PeerView.com/HGE865. CME/MOC/NCPD/CPE/AAPA/IPCE credit will be available until February 16, 2025.From Resistance to Resilience in R/R CLL: Sequencing Strategies for Achieving Effective Continuous Care In support of improving patient care, this activity has been planned and implemented by PVI, PeerView Institute for Medical Education, and CLL Society. PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by an educational grant from Lilly.Disclosure PolicyAll relevant conflicts of interest have been mitigated prior to the commencement of the activity.Faculty/Planner DisclosuresCo-Chair/PlannerMeghan C. Thompson, MD, has a financial interest/relationship or affiliation in the form of:Consultant and/or Advisor for AstraZeneca; Lilly/Loxo Oncology, Inc.; and Pharmacyclics LLC/Janssen Pharmaceuticals, Inc.Grant/Research Support from AbbVie; AstraZeneca; BeiGene, Inc.; Genentech, Inc.; Genmab; and Nurix Therapeutics. Research funding goes to Institution.Co-Chair/PlannerCatherine C. Coombs, MD, has a financial interest/relationship or affiliation in the form of:Consultant and/or Advisor for AbbVie Inc.; Allogene Therapeutics; AstraZeneca; BeiGene, Inc.; Genentech, Inc.; Janssen Pharmaceuticals, Inc.; Lilly; MEI Pharma, Inc.; Mingsight Pharmaceuticals, Inc.; and Octapharma USA, Inc.Grant/Research Support from Lilly.Speaker for AbbVie Inc.; AstraZeneca; BeiGene, Inc.; and Genentech, Inc.Planning Committee and Reviewer DisclosuresPlanners, independent reviewers, and staff of PVI, PeerView Institute for Medical Education, do not have any relevant financial relationships related to this CE activity unless listed below.

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME/MOC/NCPD/CPE/AAPA/IPCE information, and to apply for credit, please visit us at PeerView.com/HGE865. CME/MOC/NCPD/CPE/AAPA/IPCE credit will be available until February 16, 2025.From Resistance to Resilience in R/R CLL: Sequencing Strategies for Achieving Effective Continuous Care In support of improving patient care, this activity has been planned and implemented by PVI, PeerView Institute for Medical Education, and CLL Society. PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by an educational grant from Lilly.Disclosure PolicyAll relevant conflicts of interest have been mitigated prior to the commencement of the activity.Faculty/Planner DisclosuresCo-Chair/PlannerMeghan C. Thompson, MD, has a financial interest/relationship or affiliation in the form of:Consultant and/or Advisor for AstraZeneca; Lilly/Loxo Oncology, Inc.; and Pharmacyclics LLC/Janssen Pharmaceuticals, Inc.Grant/Research Support from AbbVie; AstraZeneca; BeiGene, Inc.; Genentech, Inc.; Genmab; and Nurix Therapeutics. Research funding goes to Institution.Co-Chair/PlannerCatherine C. Coombs, MD, has a financial interest/relationship or affiliation in the form of:Consultant and/or Advisor for AbbVie Inc.; Allogene Therapeutics; AstraZeneca; BeiGene, Inc.; Genentech, Inc.; Janssen Pharmaceuticals, Inc.; Lilly; MEI Pharma, Inc.; Mingsight Pharmaceuticals, Inc.; and Octapharma USA, Inc.Grant/Research Support from Lilly.Speaker for AbbVie Inc.; AstraZeneca; BeiGene, Inc.; and Genentech, Inc.Planning Committee and Reviewer DisclosuresPlanners, independent reviewers, and staff of PVI, PeerView Institute for Medical Education, do not have any relevant financial relationships related to this CE activity unless listed below.

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME/MOC/NCPD/CPE/AAPA/IPCE information, and to apply for credit, please visit us at PeerView.com/HGE865. CME/MOC/NCPD/CPE/AAPA/IPCE credit will be available until February 16, 2025.From Resistance to Resilience in R/R CLL: Sequencing Strategies for Achieving Effective Continuous Care In support of improving patient care, this activity has been planned and implemented by PVI, PeerView Institute for Medical Education, and CLL Society. PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by an educational grant from Lilly.Disclosure PolicyAll relevant conflicts of interest have been mitigated prior to the commencement of the activity.Faculty/Planner DisclosuresCo-Chair/PlannerMeghan C. Thompson, MD, has a financial interest/relationship or affiliation in the form of:Consultant and/or Advisor for AstraZeneca; Lilly/Loxo Oncology, Inc.; and Pharmacyclics LLC/Janssen Pharmaceuticals, Inc.Grant/Research Support from AbbVie; AstraZeneca; BeiGene, Inc.; Genentech, Inc.; Genmab; and Nurix Therapeutics. Research funding goes to Institution.Co-Chair/PlannerCatherine C. Coombs, MD, has a financial interest/relationship or affiliation in the form of:Consultant and/or Advisor for AbbVie Inc.; Allogene Therapeutics; AstraZeneca; BeiGene, Inc.; Genentech, Inc.; Janssen Pharmaceuticals, Inc.; Lilly; MEI Pharma, Inc.; Mingsight Pharmaceuticals, Inc.; and Octapharma USA, Inc.Grant/Research Support from Lilly.Speaker for AbbVie Inc.; AstraZeneca; BeiGene, Inc.; and Genentech, Inc.Planning Committee and Reviewer DisclosuresPlanners, independent reviewers, and staff of PVI, PeerView Institute for Medical Education, do not have any relevant financial relationships related to this CE activity unless listed below.

Drs. Neeraj Agarwal and Todd Morgan discuss CONTACT-02, KEYNOTE-564, CheckMate-67T, and other notable studies featured at the 2024 ASCO Genitourinary Cancers Symposium, as well as additional key abstracts in prostate, kidney, and bladder cancers that will significantly influence clinical practice. TRANSCRIPT Dr. Neeraj Agarwal: Hello, and welcome to the ASCO Daily News Podcast. I'm Dr. Neeraj Agarwal, the director of the Genitourinary Oncology Program and professor of medicine at the Huntsman Cancer Institute at the University of Utah, and editor-in-chief of ASCO Daily News. Today, we'll be discussing practice-changing abstracts and other key advances in GU oncology featured at the 2024 ASCO Genitourinary Cancers Symposium. Joining me for this discussion is Dr. Todd Morgan, the chair of this year's ASCO GU. Dr. Morgan is a urologic surgeon, chief of urologic oncology at Michigan Medicine, and a professor of urology at the University of Michigan. Our full disclosures are available in the transcript of this episode, and the disclosures of all guests on the podcast can be found at asco.org/DNpod. Todd, thank you for joining us today. Dr. Todd Morgan: Thanks so much, Neeraj. It's an honor to be here and I'm just thrilled to be able to do this with you. Dr. Neeraj Agarwal: Thank you. So, the GU meeting showcased significant advancements across the spectrum of GU malignancies. Can you tell us about the hot topics that captured the headlines this year? What did you find exciting this year at the ASCO GU Symposium? Dr. Todd Morgan: The theme of this year's meeting was "20 Years of Advancing Science and Transforming Patient Care," and this reflected ASCO GU's incredible milestone in GU cancer research over the last 2 decades. We were thrilled to welcome over 5,200 attendees from over 70 countries, and, believe it or not, there were more than 875 abstract submissions, compared to more than 300 in the meeting's first year. Most of the participants were present in person and that was fantastic. It enabled great networking opportunities and opportunities for experts, trainees, and mentees to exchange knowledge and ideas. Without a doubt, ASCO GU remains the annual meeting in our field, and it's amazing to hear the breadth and depth of the state-of-the-art science that's presented at this meeting, and so much of it impacts patient care the second that you return home. Additionally, the meeting's focus on diversity and interactivity, networking, multidisciplinary collaboration, and evidence-based care were absolutely phenomenal from my standpoint. We had a lunch session for women's networking that was a huge success—the first time we've done that. The keynote lecture by Dr. Cheryl Lee that talked about ensuring adequate representation in clinical trials was a huge hit, and we had tremendous positive feedback from that lecture. There were also multiple featured sessions on different diagnostic and therapeutic challenges in localized, recurrent, and advanced GU cancers. And, Neeraj, my personal favorite during the symposium is always the Trainee and Early-Career Networking Luncheon on the first day and then the additional networking luncheons on the 2 following days. I had great conversations with a ton of trainees and junior faculty, and I feel so fortunate for the opportunity to get to know the future superstars in our field. So I'd like to kick it back to you for a second because the first day started with a focus on prostate cancer and some of the key clinical trials. A great example is Abstract 17, which was the second oral presentation delivered, and really congratulations to you, Neeraj, on sharing the exciting data from the CONTACT-02 trial which we were eagerly awaiting. And I'd love to get your thoughts on the data that you presented. Could you tell us more about that trial? Dr. Neeraj Agarwal: Yes, Todd, I agree with you. It was such an exciting conference overall, and thank you for your leadership of this conference. So let's talk about the CONTACT-02 trial. It was a phase 3 randomized trial assessing the combination of cabozantinib and atezolizumab versus a second NHT in patients with metastatic castration-resistant prostate cancer after progression on one NHT. This patient population had to have extrapelvic soft tissue metastases, which could be liver metastases, lung metastases, or lymph nodal metastases, and about up to a quarter of patients had liver metastases. And overall, this was a high-risk patient population which was randomized to, as I said, cabozantinib plus atezolizumab versus a second line NHT. And these patients had received a prior NHT, mostly in the mCRPC setting.  The co- or dual primary endpoints were overall survival and progression-free survival (PFS). And a unique thing was that PFS was assessed only by RECIST 1.1 because, as per our discussions with regulatory authorities, the trial was focused on soft tissue metastases because of questions in the past that cabozantinib can affect bone lesions in an artifactual fashion, possibly concerns. That's why the PCWG 3 criteria were not used as the primary endpoint, but, of course, indeed used as another key endpoint, so we have information on both. Anyway, coming back to the endpoint 1:1 randomization. The randomization was stratified by presence or absence of liver metastases, prior docetaxel chemotherapy, and the setting in which NHT was given (mCSPC or CRPC). The PFS or primary endpoint was significantly improved with a 35% reduction in risk of progression or death with the cabozantinib-atezolizumab combination versus second NHT. And there was a trend for overall survival, with a hazard ratio of 0.79 favoring the cabozantinib-atezolizumab combination. Interestingly, all subgroups benefitted, regardless of age, region, site of metastases, but we decided to choose three clinical subgroups of interest such as patients with liver metastases, patients with prior docetaxel chemotherapy in the castration-sensitive setting, and bone metastases, and all these subgroups seemed to be benefitting with the strongest signal in the liver metastasis subgroup, with a 57% reduction in risk of progression or death, which I would argue we have never seen with any combination or any regimen in the metastatic prostate cancer setting yet, barring some targeted therapies in very selected patients. But overall, across the non-biomarker-selected patients, we have never seen this kind of signal. Toxicity — no discussion is complete without discussing toxicity, so I would like to highlight that. Safety signal — there were no new safety signals. The most common grade 3-4 adverse events were hypertension in 7%, anemia in 6%, which were similar in both arms, and, of course, diarrhea and fatigue in 4% each. And if we look at the secondary endpoints, such as time to chemotherapy and time to symptomatic skeletal events, they tended to favor the cabozantinib-atezolizumab. To sum it up, cabozantinib-atezolizumab showed a significant PFS benefit, with a 35% reduction in risk of progression or death, with a trend for overall survival in this patient population with an unmet need. So thank you so much, Todd, for allowing me to summarize the results of this trial. Dr. Todd Morgan: Yeah, wow. That's so impressive, and not surprising that you could so fluidly go right through all that data. Amazing. We heard some discussion of the NHT control arm in this trial. Could you discuss that for a bit? Because it obviously has implications on the similar control arm of other ongoing trials in this setting. Dr. Neeraj Agarwal: Absolutely. Pretty much all trials, every trial which has recently been reported or started in metastatic castrate-resistant prostate cancer have a similar second NHT arm. Whether there were multiple immunotherapy trials which we have just reported, or new trials which are starting or just started enrolling patients. And the reason for that is no randomized trial has ever shown superiority of docetaxel chemotherapy over a second NHT after failure of prior NHT in the mCRPC setting. That's number one. If you look at NHT as a control, it is accepted by health authorities globally with multiple recent trials which are just starting also having NHDR and it would not have been possible without the approval of global regulatory authorities across the world.  Then, if you look at the recently reported trial in the mCRPC setting with prior treatment with an NHT, there is an indication that chemotherapy may not be superior to NHT. For example, in the KEYNOTE-641 trial in patients with mCRPC with prior NHT, randomizing patients to enzalutamide plus pembrolizumab versus enzalutamide, the median PFS with enzalutamide was 9 months. This is very similar with docetaxel in patients randomized to docetaxel plus pembrolizumab versus docetaxel; the median PFS with docetaxel is 8 months or 8.3 months. And lastly, if you really want to have a comparison of chemotherapy with NHT which has been done after progression on NHT and docetaxel chemotherapy, so later line of mCRPC setting, that is the CARD trial, as you can imagine, cabazitaxel versus NHT, especially in patients with visceral metastasis, which was the point of discussion. For example, people may not feel comfortable randomizing patients to NHT compared to taxane. The hazard ratio for PFS supporting cabazitaxel was 0.79, so almost a 0.80 PFS hazard ratio, which we have never seen turning out to be a clinically significant benefit. So, if you combine all these data together, I think it was absolutely acceptable to us as investigators to have a second NHT as the control arm. And of course, when we are consenting the patient, we have to keep alternatives in mind, and we do talk about those alternatives with the patients. And if alternatives seem more applicable, we should not be talking to patients about those clinical trials or a given clinical trial in the clinic. I'm glad you brought this up, Todd, because this control NHT arm is not an issue with this trial, but all trials which should be presented in GU ASCO in the future meetings in the coming years. So, thank you. Dr. Todd Morgan: Yeah, thank you. It's such an important topic and controversy at some level, but it's a difficult problem to think about and obviously highly relevant to all the trials that we're looking at. Congrats again on that trial, that's tremendous. There was another important randomized phase 3 trial and it covers radiotherapy in patients with high-risk localized prostate cancer. Can you give us your insights on that one? Dr. Neeraj Agarwal: Yeah, Todd, I think you are referring to LBA259, titled "Long-term Results of Dose Escalation of Radiation Therapy from 70 Gy to 80 Gy Combined with Long-term Androgen Deprivation Therapy in High-risk Prostate Cancer: The GETUG-AFU 18 Randomized Trial." As you mentioned, in this randomized phase 3 trial, Dr. Christophe Hennequin and colleagues randomized patients with high-risk prostate cancer, which means they had to have either clinical stage T3 or T4 disease, or PSA ≥20 nanograms per milliliter, or a Gleason score between 8 and 10. These patients were randomized to receive ADT for 3 years combined with either dose-escalated intensity-modulated radiotherapy. So, I'd like to highlight, this was in the context of IMRT in the dose of 80 Gy or a conventional dose of 70 Gy. Now, you can argue that more people are using more than 70 Gy nowadays, but across the world, the conventional dose is still considered 70 Gy. So, 80 Gy versus 70 Gy were tested. Patients also had to have negative lymph node status on CT scans and MRI. The primary endpoint was biochemical progression-free survival or clinical progression-free survival at 5 years following the ASTRO Phoenix definition. Secondary endpoints – and these are quite important secondary endpoints – include overall survival, acute and late toxicity, and quality of life. The best part is that this trial met its primary endpoint with a 44% reduction in risk of biochemical or clinical progression or death in the dose-escalation radiotherapy arm compared with the conventional radiotherapy arm. Interestingly, a significant 52% improvement in prostate cancer-specific survival and a 39% improvement in overall survival was observed in the dose-escalated arm. So, 80 Gy continued to be superior to 70 Gy IMRT across the primary and secondary endpoints. Now, the best part is, regarding the toxicity profile, there was no significant difference between the 2 arms, with 78% of patients in the higher dose arm and 76% of patients in the conventional arm experiencing grade 2 or more toxicities. Dr. Todd Morgan: Great summary and really important, great news for our patients. Of course, it's a slightly different setting as it's high-risk localized prostate cancer. I checked in with our radiation oncologists at the University of Michigan after that [presentation] because I couldn't remember exactly where we are in terms of dose on these patients. And they were like, “Yeah, we've been doing 80 to 90 Gy for several years,” so it's great having this data to support that. And I think, as you said, the field at many centers has already moved that way. And again, the key takeaway from this abstract would be that IMRT, in combination with long-term androgen deprivation therapy, is effective and safe and increases not only the biochemical or clinical PFS rate, but also the cancer-specific survival and overall survival, again, in high-risk localized prostate cancer patients. And it does not appear to increase long-term toxicity. So really important. It'd be great to switch gears and discuss kidney cancer, if that's okay, and talk about some key abstracts in that field. What do you think? Dr. Neeraj Agarwal: There were so many exciting data in all cancers, which is amazing. So, Todd, could tell us about the LBA359, which I thought was one of the most impactful abstract presentations in the ASCO GU this year. It was titled, “Overall Survival Results from the Phase 3 KEYNOTE-564 Study of Adjuvant Pembrolizumab Versus Placebo for Treatment of Clear Cell Renal Cell Carcinoma (ccRCC)."   Dr. Todd Morgan: Yeah, this was a really big moment in our field, complete with a mid-presentation round of applause that was well deserved. And so this abstract was presented by Dr. Toni Choueiri from Dana-Farber Cancer Institute, and it included patients with clear cell renal cell carcinoma at intermediate high or high risk of recurrence, meaning that they had positive nodal disease or negative nodal disease with PT 2 and grade 4, or sarcomatoid features, or stage PT 3 or 4. These patients underwent nephrectomy with or without metastasectomy less than 12 weeks before randomization and had not received prior systemic therapy for clear cell RCC. Patients were randomized to receive either pembrolizumab 200 milligrams or placebo IV every three weeks for at least 17 cycles, or until disease recurrence, intolerable toxicity, or withdrawal of consent. Disease-free survival by investigator assessment was the primary endpoint, and overall survival was a key secondary endpoint. In this abstract, Dr. Choueiri and colleagues report results of the third prespecified interim analysis with a median follow-up of around 57 months in 496 patients receiving pembrolizumab and 498 patients receiving placebo. So, just as a reminder to the audience here, the first interim analysis reported at a median follow-up of 24 months and showed a significant reduction of 32% in the risk to recurrence or death in patients in the pembrolizumab arm. Then subsequently in November of 2021, the FDA approved pembrolizumab for the adjuvant treatment of patients with RCC who are at intermediate high or high risk of recurrence following nephrectomy or following nephrectomy and resection of metastatic lesions. At that time, though, overall survival data were still immature. So, at the third prespecified interim analysis with a median follow-up of around 57 months, pembrolizumab showed, for the first time in an adjuvant RCC setting, improved overall survival with a 38% reduction in the risk of death. The estimated OS rate at 48 months was 91.2% with pembrolizumab and 86% with placebo. Furthermore, the OS benefit was observed across key subgroups, including patients with non-metastatic disease, patients with metastatic but no evidence of disease, patients with PDL-1 combined positive score less than or greater than or equal to one, and patients with presence or absence of sarcomatoid features. In each of these subgroups, the forest plot looks really impressive. And the DFS benefit was similar to previously reported interim analyses with a hazard ratio of 0.72. Also, no new safety signals with pembrolizumab were observed so just tremendous data. Dr. Neeraj Agarwal: Thank you, Todd, for such a great summary of these very important results. So the key message from this abstract, as you said, is that after a median follow-up of around 57 months, which is a long follow-up, adjuvant pembrolizumab demonstrates a statistically significant and clinically meaningful improvement in overall survival versus placebo in patients with RCC at high risk of disease recurrence after surgery. And this is, by the way, the first phase 3 study to show improved overall survival with any adjuvant therapy in RCC. Basically, this means we should continue to use adjuvant pembrolizumab or at least bring it up in our discussion with our patients who are in a similar situation with high-risk RCC after surgery. So this is great news overall. Todd, there was another kidney cancer abstract, LBA360, which compared, interestingly, subcutaneous nivolumab with intravenous nivolumab in patients with metastatic renal cell carcinoma. Could you please give us your insight about this abstract?   Dr. Todd Morgan: Sure. Really interesting study. Really interesting data that were presented. So as you mentioned, CheckMate 67T was a multicenter, randomized, open-label phase three study led by Dr. Saby George and colleagues that evaluated pharmacokinetics and objective response rate non-inferiority of subcutaneous nivolumab versus IV nivolumab in patients with locally advanced or metastatic clear cell RCC. So patients with measurable disease that progressed during or after 1 to 2 prior systemic regimens and who did not receive a prior immuno-oncology treatment were randomized 1-1 to receive either subcutaneous nivolumab 1200 milligrams every 4 weeks or IV nivolumab 3 milligrams per kilogram every two weeks until disease progression, unacceptable toxicity, withdrawal of consent, completion of two years of treatment, or death. The coprimary pharmacokinetics endpoints for non-inferiority testing were time-average serum concentration over the first 28 days and minimum serum concentration at steady state determined by a population pharmacokinetics analysis. A key secondary endpoint was objective response rate by independent review. So in 248 patients receiving subcutaneous nivolumab and 247 patients receiving IV nivolumab, non-inferiority for the coprimary pharmacokinetics and key-powered secondary objective response rate endpoints were met. The relative risk ratio for objective response rate was 1.33. The median PFS by independent review was 7.23 months in the subcutaneous group and 5.65 months in the IV group. Treatment-related serious adverse events occurred in 6.5% of patients in each group, and study drug toxicity led to 3 deaths in the subcutaneous group and 1 death in the IV group. These results could support using subcutaneous nivolumab as a new option to improve healthcare efficiency, especially since the average injection time with subcutaneous nivolumab was less than 5 minutes. I think we all know what issues are going on in infusion beds across the country, including, I'm sure, your center and mine. Dr. Neeraj Agarwal: Yes, absolutely. I think this is great news for our patients, Todd. Thank you. This shows that we are not only improving therapeutic options and diagnostic tools, but maybe we're also on the right track towards more practical administration routes, assisting in addressing the treatment burden and improving the efficiencies of healthcare systems. We love to have this option available for our patients, especially those who are pressed for time. So, Todd, would you like to move on to bladder cancer now?  Dr. Todd Morgan: Yeah, Neeraj, that'll be fantastic. I'm sure listeners would love to hear more about LBA530. Could you tell us more about this one, Neeraj? Dr. Neeraj Agarwal: Of course. I think this abstract is titled "Enfortumab Vedotin in Combination with Pembrolizumab Versus Chemotherapy in Previously Untreated, Locally Advanced or Metastatic Urothelial Carcinoma: Subgroup Analysis Results from EV-302," which was a global phase three study and was presented by Dr. Michiel Van Der Heijden. As our audience may recall, the EV-302 trial was presented at the ESMO 2023 meeting by Dr Tom Powles and the results were very exciting where, for the first time, a combination outperformed traditional gemcitabine-cisplatin chemotherapy. In this trial, patients with previously untreated with metastatic advanced urothelial carcinoma were randomized 1-1 to receive a 3-week cycle of a combination of enfortumab vedotin, which, as we know, is an antibody-drug conjugate targeting nectin-4 expressed on the cancer cells and pembrolizumab, which is a PD-1 inhibitor, versus gemcitabine and cisplatin or carboplatin, which were, until recently, the standard of care in this setting, and continue to be so in many countries in the world. The combination of enfortumab and pembrolizumab reduced the risk of progression or death by 55% and reduced the risk of death by 53% in the overall population. So consistent decrease in the hazard ratios for PFS and OS, and consistent improvement in overall survival and PFS in that previously reported presentation in the ESMO 2023. Now, based on these results, this combination was recently approved by the FDA in December 2023 for patients with advanced or metastatic urothelial carcinoma. So now the abstract, which was presented at the ASCO GU 2024 meeting, reported the results of a prespecified subgroup analysis. Select secondary endpoints included objective responses, duration of response, and safety. In 442 patients receiving the combination of enfortumab vedotin plus pembrolizumab, and a similar number of patients receiving chemotherapy both PFS and OS were higher for the combination of EV and pembro among prespecified subgroups such as race, platinum eligibility, PDL-1 expression, metastatic site, involvement of the liver or kidney function. Interestingly, the combination of EV and pembro reduced the risk of death by 53% in patients with visceral metastasis and 54% in patients with node-only metastasis. The improvement in PFS seems to be consistent regardless of the site of metastasis. In patients with moderate to severe renal function, the risk of death was reduced by 50% in patients receiving combination therapy. This is one of the best findings of these results because we always face challenges in treating patients with suboptimal kidney function and we cannot use cisplatin. Overall, EV plus pembro continues to show superior efficacy compared to platinum-based regimens across subgroups across the subgroups across the site of metastasis regardless of kidney function and so on. Dr. Todd Morgan: Yeah, just amazing data. I love hearing you spell it out like that. So, thank you again for the opportunity for me to sit here with you and listen to you talk about these data. It's impressive that we have been able to expand our therapeutic arsenal for urothelial carcinoma with an immune-targeting regimen that can spare our patients potential side effects of chemotherapy. What would your final takeaway on this abstract be? Dr. Neeraj Agarwal: I agree with you, Todd. I would add that the OS benefit was consistently observed across these select prespecified subgroups, including those historically associated with poor prognosis. The results of this new analysis support the finding of primary results, which indicate that EV plus pembro is a potentially new standard of care for patients with newly diagnosed, locally advanced, or metastatic urothelial carcinoma. Before we wrap up the bladder cancer session and the podcast, Todd, could you please give us insights about LBA531? Dr. Todd Morgan: Yeah, absolutely. I loved getting to hear this abstract presented. This one is titled “Ambassador,” known as the AMBASSADOR trial aligns A031501, a phase 3 randomized adjuvant study of pembrolizumab in muscle-invasive and locally advanced urothelial carcinoma versus observation, that was presented by Dr. Andrea Apolo. It's an open-label, randomized, phase 3 trial that included patients with muscle-invasive urothelial carcinoma of the bladder, upper tract, or urethra. Eligible patients had pathologic tumor stage T2 or greater and/or positive pathologic nodal disease or positive margins at surgery following neoadjuvant chemotherapy, or patients with pathologic tumor stage T3 or greater and/or positive pathologic nodal disease or positive margins at surgery without prior neoadjuvant chemotherapy, and who were cisplatin ineligible or declined adjuvant cisplatin-based therapy. These patients were randomized one to one to either receive pembrolizumab 200 milligrams every 3 weeks for 1 year or observation. The dual primary endpoints were disease-free survival and overall survival. Secondary objectives included evaluation of DFS and OS in PDL-1 positive and negative patients and assessing safety. A total of 354 patients were enrolled to receive pembrolizumab and 348 to the observation arm, and 21% of the patients in the observation arm received a subsequent immune checkpoint inhibitor. At a median follow-up of 22.3 months for DFS, the median disease-free survival in the pembrolizumab arm was 29 months, while it was only 14 months in the observation arm with a hazard ratio of 0.69. At the interim analysis, OS data showed only a trend toward better outcomes in the pembrolizumab arm, which did not, however, reach statistical significance, with a median of 50.9 months in the pembrolizumab arm and 55.8 months in the observation arm with a hazard ratio of 0.98. These results could nevertheless have been impacted by the subsequent treatment of patients in the observation arm with an immune checkpoint inhibitor, especially after the FDA approval of nivolumab in 2021 for patients with muscle-invasive urothelial carcinoma, based on results of the CheckMate 274 trial. In terms of the safety profile, grade three or more adverse events occurred in 48.4% of patients in the pembrolizumab arm and 31.8% of patients in the observation arm. Dr. Neeraj Agarwal: That's great, Todd. This is such a great summary of this trial, and this is exciting news for our patients with muscle-invasive urothelial carcinoma. I'm hoping that pembrolizumab will be another option for our patients when we are discussing adjuvant immunotherapy in the clinic, moving forward very soon. With that, we have covered several abstracts addressing prostate, bladder, and kidney cancer, significantly influencing our medical practices, at least at the current moment or in the near future. Todd, thank you for sharing your insights today. These are undoubtedly exciting updates for all members of the GU oncology community, and we are grateful for your valuable contribution to the discussion. Many thanks. Dr. Todd Morgan: Thanks, for having me, Neeraj; this was really fun. I'm just really proud and excited to still be part of this field, to be part of the GU oncology field, and it continues to be exciting for all the folks who are coming up. Dr. Neeraj Agarwal: Indeed. And thank you to our listeners for joining us today. You will find links to the abstracts discussed today on the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Thank you very much.   Disclaimer: The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Find out more about today's speakers:   Dr. Neeraj Agarwal @neerajaiims   Dr. Todd Morgan @wandering_gu   Follow ASCO on social media:   @ASCO on Twitter     ASCO on Facebook     ASCO on LinkedIn       Disclosures:    Dr. Neeraj Agarwal:    Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, AstraZeneca, Pfizer, Merck, Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences    Research Funding (Institution): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, Crispr Therapeutics, Arvinas   Dr. Todd Morgan: Consulting or Advisory Role: Myriad Genetics, MDxHealth, TerumoBCT Research Funding (Institution): Prostate Cancer Foundation, National Institutes of Health, Department of Defence, GenomeDX Biosciences, Myriad Genetics, MDxHealth  

Drs. Neeraj Agarwal and Jeanny Aragon-Ching discuss several key abstracts to be presented at the 2024 ASCO GU Cancers Symposium, including sequencing versus upfront combination therapies for mCRPC in the BRCAAway study, updates on the CheckMate-9ER and CheckMate-214 trials in ccRCC, and a compelling real-world retrospective study in mUC of patients with FGFR2 and FGFR3 mutations. TRANSCRIPT Dr. Neeraj Agarwal: Hello, everyone, and welcome to the ASCO Daily News Podcast. I'm Dr. Neeraj Agarwal, your guest host of the podcast today. I am the director of the Genitourinary Oncology Program and a professor of medicine at the University of Utah's Huntsman Cancer Institute, and editor-in-chief of ASCO Daily News. I am delighted to welcome Dr. Jeanny Aragon-Ching, a genitourinary oncologist and the clinical program director of Genitourinary Cancers at the Inova Schar Cancer Institute in Virginia. Today, we will be discussing key posters and oral abstracts that will be featured at the 2024 ASCO Genitourinary Cancer Symposium, which is celebrating 20 years of evolution in GU oncology this year.  You will find our full disclosures in the transcript of this podcast, and disclosures of all guests on the podcast at asco.org/DNpod.  Jeanny, it's great to have you on the podcast today to highlight some key abstracts for our listeners ahead of the GU meeting. Dr. Jeanny Aragon-Ching: Thank you so much, Neeraj. It's an honor to be here. Dr. Neeraj Agarwal: Jeanny, as you know, this year we are celebrating the 20th anniversary of the ASCO GU Cancers Symposium, and judging from this year's abstracts, it's clear that this meeting continues to play a major role in advancing GU cancer research. Dr. Jeanny Aragon-Ching: Indeed, Neeraj. This year's abstracts reflect the important strides we have made in GU cancers. So, let's start with the prostate cancer abstracts. What is your takeaway from Abstract 19 on BRCAAway, which will be presented by Dr. Maha Hussein, and of which you are a co-author? As our listeners know, several PARP inhibitor combinations with second-generation androgen receptor pathway inhibitors, or ARPIs, have recently been approved as first-line treatment for patients with metastatic castrate-resistant prostate cancer, or metastatic CRPC, and the question of sequencing PARP inhibitors and ARPIs instead of combining them has emerged. From that perspective, the results of the BRCAAway trial are very important. Can you tell us a little bit more about this abstract, Neeraj?  Dr. Neeraj Agarwal: I totally agree with you, Jeanny. The BRCAAway study attempts to answer the crucial questions regarding sequencing versus upfront combination of therapies in the mCRPC setting. It is a phase 2 trial of abiraterone versus olaparib versus abiraterone with olaparib in patients with mCRPC harboring homologous recombination repair mutations. Enrolled patients had mCRPC disease and no prior exposure to PARP inhibitors or ARPIs or chemotherapy in the mCRPC setting and had BRCA1 or BRCA2 or ATM mutations. As previously mentioned, these patients were randomized to 3 arms: abiraterone monotherapy at 1000 milligrams once daily, or olaparib monotherapy at 300 milligrams twice daily, or the combination of abiraterone and olaparib. The primary endpoint was progression-free survival per RECIST 1.1 or Prostate Cancer Working Group 3-based criteria or clinical assessment or death, so, whichever occurred first was deemed to be progression.   Secondary endpoints included measurable disease response rates, PSA response rate, and toxicity. This was a relatively small trial with 21 patients in the combination arm, 19 patients in the abiraterone monotherapy arm, and 21 patients in the olaparib monotherapy arm. It should be noted that 26% of patients had received docetaxel chemotherapy in the hormone-sensitive setting, and only 3% of patients had any prior exposure to an ARPI, and these were darolutamide or enzalutamide or in the non-metastatic CRPC setting.  The results are very interesting. The median progression-free survival was 39 months in the combination arm, while it was 8.4 months in the abiraterone arm and 14 months in the olaparib arm. An important finding that I would like to highlight is that crossover was also allowed in the monotherapy arms. Of the 19 patients receiving abiraterone, 8 crossed over to receive olaparib, and of the 21 patients receiving olaparib, 8 crossed over to the abiraterone arm. The median PFS from randomization was 16 months in both groups of patients who received abiraterone followed by olaparib or those who received olaparib followed by abiraterone. This is striking when compared to 39 months in patients who started therapy with the combination therapy of abiraterone with olaparib. Dr. Jeanny Aragon-Ching: Thank you so much for that wonderful summary, Neeraj. So the key message from this abstract is that combining olaparib and abiraterone upfront seems to be associated with improvement in PFS compared to just sequencing those agents. Dr. Neeraj Agarwal: Exactly, Jeanny. I would like to add that these results are even more important given that in real-world practice, only half of the patients with mCRPC receive a second-line treatment. Based on these results, upfront intensification with a combination of an ARPI plus a PARP inhibitor in the first-line mCRPC setting seems to have superior efficacy compared to sequencing of these agents. Dr. Jeanny Aragon-Ching: Thank you so much. Now, moving on to a different setting in prostate cancer, there were a couple of abstracts assessing transperineal biopsy compared to the conventional transrectal biopsy for the detection of prostate cancer. So let's start with Abstract 261. Neeraj, can you tell us a little bit more about this abstract? Dr. Neeraj Agarwal: Sure, Jeanny. So, in Abstract 261 titled "Randomized Trial of Transperineal versus Transrectal Prostate Biopsy to Prevent Infection Complications," Dr. Jim Hugh and colleagues led a multicenter randomized trial comparing these 2 approaches, so, transperineal biopsy without antibiotic prophylaxis with transrectal biopsy with targeted prophylaxis in patients with suspected prostate cancer. The primary outcome was post-biopsy infection. Among the 567 participants included in the intention-to-treat analysis, no infection was reported with the transperineal approach, while 4 were detected with the transrectal approach, with a p-value of 0.059. The rates of other complications, such as urinary retention and significant bleeding, were very low and similar in both groups. The investigators also found that detection of clinically significant cancer was similar between the 2 techniques and concluded that the transperineal approach is more likely to reduce the risk of infection without antibiotic prophylaxis. Dr. Jeanny Aragon-Ching: So the key takeaway from this abstract sounds like office-based transperineal biopsy is well-tolerated and does not compromise cancer detection, along with better antibiotic stewardship and health care cost benefits.  Moving on to Abstract 273, also comparing these two approaches, what would be your key takeaway message, Neeraj?  Dr. Neeraj Agarwal: In this Abstract 273, titled "Difference in High-Risk Prostate Cancer Detection between Transrectal and Transperineal Approaches," Dr. Semko and colleagues found that the transperineal biopsy based on MRI fusion techniques was also characterized by a higher possibility of detecting high-risk prostate cancer and other risk factors as well, such as perineural and lymphovascular invasion or the presence of cribriform pattern, compared to the conventional transrectal method. Dr. Jeanny Aragon-Ching: Thank you, Neeraj. So we can see that the transperineal approach is gaining more importance and could be associated with more benefits compared to the conventional methods.   Let's now switch gears to kidney cancer, Neeraj. Dr. Neeraj Agarwal: Sure, Jeanny. Let's start by highlighting Abstract 361, which discusses patient-reported outcomes of the LITESPARK-005 study. So what can you tell us about this abstract, Jeanny?  Dr. Jeanny Aragon-Ching: Thank you, Neeraj. So as a reminder to our listeners, based on the LITESPARK-005 trial, it was a Phase 3 trial looking at belzutifan, which is an inhibitor of hypoxia inducible factor 2 alpha or I'll just call HIF-2 alpha for short, was very recently approved by the FDA as a second-line treatment option for patients with advanced or metastatic clear cell renal cell carcinoma after prior progression on immune checkpoint and antiangiogenic therapies. The title of Abstract 361 is "Belzutifan versus Everolimus in Patients with Previously Treated Advanced RCC: Patient-Reported Outcomes in the Phase 3 LITESPARK-005 Study," and this will be presented by Dr. Tom Pells at the meeting. At a median follow-up of 25.7 months, the median duration of treatment with belzutifan was 7.6 months, while it was only 3.9 months with everolimus. At the time of data cutoff date for the second interim analysis, 22.6% of patients remained on belzutifan while only 5% remained on everolimus. In the quality of life questionnaires, the time of deterioration to various quality of life scores, as assessed by standardized scales, was significantly longer in patients randomized to the belzutifan arm compared to those in the everolimus arm. Also, patients in the everolimus arm had worse physical functioning scores. Dr. Neeraj Agarwal: Yes, Jeanny. In addition to the improved outcomes associated with belzutifan, patient-reported outcomes indicate better disease-specific symptoms and better quality of life among patients treated with belzutifan compared to everolimus. This is great news for patients with advanced renal cell carcinoma.  Now, Jeanny, can you please tell us about the two abstracts that reported longer follow-up of CheckMate 9ER and CheckMate 214 trials in untreated patients with advanced or metastatic renal cell carcinoma? Dr. Jeanny Aragon-Ching: Yes, Neeraj. So you are referring to Abstracts 362 and 363. Let's start with Abstract 362. This abstract reports the results after a median follow-up of 55 months in the CheckMate 9ER trial, comparing the combination of nivolumab and cabozantinib to sunitinib in patients with advanced RCC without any prior treatment, so first-line therapy. The primary endpoint was PFS per RECIST 1.1 as assessed by an independent central review. So there were key secondary outcomes including overall survival (OS), objective response rates, and safety. Consistent with prior analysis at a median follow-up time of 18.1 and 44 months, the combination of nivolumab and cabozantinib at a median follow up of 55.6 months continues to show a significant reduction in the risk of progression or death by 42% and in the risk of death by 23% compared to sunitinib.  Dr. Neeraj Agarwal: And Jeanny, what can you tell us about the efficacy results of this combination by IMDC risk categories? Dr. Jeanny Aragon-Ching: Similar to prior results in patients with intermediate to poor risk IMDC risk category, the combination treatment maintained significant efficacy and reduced the risk of progression or death by 44% and the risk of death by 27%. To put it simply, the update now shows a 15-month improvement in overall survival with the cabozantinib-nivolumab combination compared to sunitinib, which is amazing. Also, in patients with favorable IMDC risk group, which represented truly a small number of patients in the trial, there was a strong trend for improvement of outcomes as well. I would like to point out that no new safety concerns were identified. Dr. Neeraj Agarwal: So, it looks like the key message from this abstract is that with longer follow-up, the combination of nivolumab and cabozantinib maintains a meaningful long-term efficacy benefit over sunitinib, supporting its use for newly diagnosed patients with advanced or metastatic renal cell carcinoma.   Let's move on to Abstract 363, which compares nivolumab with ipilimumab to sunitinib in first-line advanced renal cell carcinoma. What would you like to tell us about this abstract, Jeanny? Dr. Jeanny Aragon-Ching: Yes, Neeraj. The title of this abstract is "Nivolumab plus Ipilimumab versus Sunitinib for the First-Line Treatment of Advanced RCC: Long-Term Follow-Up Data from the Phase 3 CheckMate 214 Trial." In this abstract, Dr. Tannir and colleagues report outcomes with the longest median follow-up in first-line advanced RCC setting for any clinical trial. So the median follow-up now is about 18 months. The primary endpoints were OS, PFS, and objective response rates, as assessed by an independent review according to RECIST 1.1 criteria in the intermediate to poor risk IMDC risk group, which is the intent-to-treat (ITT) analysis, while secondary outcomes included the same outcomes in the ITT population of patients. Although the progression-free survival was similar in both arms, the combination of nivolumab-ipilimumab reduced the risk of death by 28% compared to sunitinib in the ITT population of patients. When stratifying the results by IMDC risk groups, the combination arm of nivolumab-ipilimumab showed significant improvement in the intermediate to poor risk group, but there was no difference in the favorable risk group. But in the study, no new safety signals were identified. Dr. Neeraj Agarwal: Thank you, Jeanny, for such a comprehensive description of the results of these two studies. I'd like to add that the median overall survival of patients with metastatic renal cell carcinoma in the ITT population in the CheckMate 214 trial has now reached 53 months, which would have been unimaginable just a decade ago. This is wonderful news for our patients. So the key takeaway from these two abstracts would be that immune checkpoint inhibitor-based combinations remain the backbone of first-line advanced renal cell carcinoma treatment.  Dr. Jeanny Aragon-Ching: Absolutely, Neeraj. This is wonderful news for all of our patients, especially for those who are being treated for first-line therapy.  Now, let's move on to the bladder cancer abstracts. We have two exciting abstracts from the UNITE database. What are your insights on Abstract 537, titled "Outcomes in Patients with Advanced Urethral Carcinoma Treated with Enfortumab Vedotin After Switch-Maintenance of Avelumab in the UNITE Study"? Dr. Neeraj Agarwal: As our listeners know, enfortumab vedotin is an antibody-drug conjugate that binds to a protein called Nectin 4 expressed on bladder cancer cells. In this abstract, Dr. Amanda Nizam and colleagues describe outcomes in 49 patients receiving third-line enfortumab vedotin after prior progression on platinum-based therapy and maintenance avelumab. At a median follow-up of 8.5 months, the median progression-free survival was 7 months and the median overall survival was 13.3 months with enfortumab vedotin in this treatment-refractory setting, the objective response rates were 54%. The message of this study is that enfortumab vedotin is an effective salvage therapy regimen for those patients who have already progressed on earlier lines of therapies, including platinum-based and immunotherapy regimens. Dr. Jeanny Aragon-Ching: Thank you, Neeraj, for that comprehensive review.  I want to focus on another patient population in the UNITE database, which is the use of fibroblast growth factor receptor (FGFR) alterations. Can you tell us more about the sequencing now of erdafitinib and enfortumab vedotin in these patients with metastatic urothelial cancer, as discussed in Abstract 616? Dr. Neeraj Agarwal: Sure, Jeanny. As a reminder, erdafitinib is a fibroblast growth factor receptor kinase inhibitor approved for patients with locally advanced or metastatic urothelial carcinoma harboring FGFR2 or FGFR3 alterations after progression on platinum-based chemotherapy. However, the optimal sequencing of therapies in these patients is unclear, especially with enfortumab vedotin being approved in the salvage therapy setting and now in the frontline therapy setting.  So in this retrospective study, all patients with metastatic urothelial carcinoma had FGFR2 or FGFR3 alterations. Dr. Cindy Jiang and colleagues report outcomes in 24 patients receiving enfortumab vedotin after erdafitinib, 15 patients receiving erdafitinib after enfortumab vedotin, and 55 patients receiving enfortumab vedotin only. This is a multicenter national study. Interestingly, patients receiving both agents had a longer overall survival in a multivariate analysis, regardless of the treatment sequencing, than patients receiving enfortumab vedotin alone or only with a hazard ratio of 0.52. The objective response rate of enfortumab vedotin in the enfortumab vedotin monotherapy arm was 49%. When these agents were sequenced, the objective response with enfortumab vedotin was 32% after erdafitinib and 67% when used before erdafitinib. Dr. Jeanny Aragon-Ching: Thank you so much, Neeraj. I think these are important real-world data results, but I would like to point out that larger and prospective studies are still needed to confirm these findings, especially regarding the outcome of erdafitinib after enfortumab vedotin, particularly when the latter is used in the first-line setting. Dr. Neeraj Agarwal: I totally agree, Jeanny. Now, let's discuss some abstracts related to disparities in the management of patients with genitourinary cancers.  Dr. Jeanny Aragon-Ching: Sure, actually, I would like to discuss 2 abstracts related to disparities in patients with prostate cancer. So the first one, Abstract 265, titled "Patient-Provider Rurality and Outcomes in Older Men with Prostate Cancer." In this study, Dr. Stabellini, Dr. Guha and the team used a SEER Medicare-linked database that included more than 75,000 patients with prostate cancer. The primary outcome was all-cause mortality, with secondary outcomes included prostate cancer-specific mortality. The investigators showed that the all-cause mortality risk was 44% higher in patients with prostate cancer from rural areas who had a provider from a non-metropolitan area compared to those who were in a metropolitan area and had a provider also from a metropolitan area. Dr. Neeraj Agarwal: Those are very important data and highlight the healthcare disparities among the rural population with prostate cancer that still exist.  So what is your key takeaway from Abstract 267, titled "Rural-Urban Disparities in Prostate Cancer Survival," which is a population-based study? Dr. Jeanny Aragon-Ching: Of course. This abstract discusses, actually, a very similar issue regarding access to healthcare among rural versus urban patients. In this study, Dr. Hu and Hashibe and colleagues and team at the Huntsman Cancer Institute assessed all-cause death and prostate cancer-related death risk in a retrospective study in which patients with prostate cancer based on rural versus urban residencies looked at 18,000 patients diagnosed with prostate cancer between 2004 and 2017. 15% lived in rural counties. Similar to the prior abstract we talked about, patients living in rural areas had about a 19% higher risk of all-cause mortality and a 21% higher risk of prostate cancer-specific mortality in comparison to patients living in urban areas. Dr. Neeraj Agarwal: So Jeanny, we can say that both of these abstracts, led by different groups of investigators, highlight that patients with prostate cancer living in rural areas have inferior survival outcomes compared to those living in urban areas, and it is time to focus on the disparities experienced by the rural population with prostate cancer.  Dr. Jeanny Aragon-Ching: Yeah, absolutely Neeraj. I concur with your thoughts.  So, any final thoughts before we wrap up the podcast today? Dr. Neeraj Agarwal: Yes, before concluding, Jeanny, I want to express my gratitude for your participation and the valuable insights you have shared today. Your contributions are always appreciated, and I sincerely thank you for taking the time to join us today.   As we bring this podcast to a close, I would like to highlight the significant advances happening in the treatment of patients with genitourinary cancers during our upcoming 2024 ASCO GU meeting. Many studies featuring practice-impacting data will be presented by investigators from around the globe. I encourage our listeners to not only participate at this event to celebrate these achievements, but to also play a role in disseminating these cutting-edge findings to practitioners worldwide. By doing so, we can collectively maximize the benefit for patients around the world.  And thank you to our listeners for joining us today. You will find links to the abstracts discussed today in the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Thank you very much.  Disclaimer: The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guest speakers express their own opinions, experience, and conclusions. Guest statements on the podcast do not necessarily reflect the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  Find out more about today's speakers:     Dr. Neeraj Agarwal  @neerajaiims  Dr. Jeanny Aragon-Ching    Follow ASCO on social media:     @ASCO on Twitter     ASCO on Facebook     ASCO on LinkedIn       Disclosures:      Dr. Neeraj Agarwal:       Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, AstraZeneca, Pfizer, Merck, Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences    Research Funding (Institution): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, Crispr Therapeutics, Arvinas     Dr. Jeanny Aragon-Ching:    Honoraria: Bristol-Myers Squibb, EMD Serono, Astellas Scientific and Medical Affairs Inc., Pfizer/EMD Serono  Consulting or Advisory Role: Algeta/Bayer, Dendreon, AstraZeneca, Janssen Biotech, Sanofi, EMD Serono, MedImmune, Bayer, Merck, Seattle Genetics, Pfizer, Immunomedics, Amgen, AVEO, Pfizer/Myovant, Exelixis,   Speakers' Bureau: Astellas Pharma, Janssen-Ortho, Bristol-Myers Squibb, Astellas/Seattle Genetics. 

Dr. John Sweetenham and Dr. Neeraj Agarwal discuss advances across the spectrum of malignancies, including key studies in precision oncology and disparities in cancer care in advance of the 2023 ASCO Annual Meeting.  TRANSCRIPT Dr. John Sweetenham: Hello, I'm Dr. John Sweetenham, now the associate director for cancer network clinical affairs at UT Southwestern's Harold C. Simmons Comprehensive Cancer Center, and host of the ASCO Daily News Podcast. I'm delighted to welcome Dr. Neeraj Agarwal, director of the Genitourinary Oncology Program and a professor of medicine at the University of Utah Huntsman Cancer Institute, who is editor-in-chief of the ASCO Daily News.  Today we'll be discussing some key advances across the spectrum of malignancies, as well as novel approaches in precision medicine and cancer disparities that will be featured at the 2023 ASCO Annual Meeting.  Our full disclosures are available in the transcript of this episode, and disclosures of all guests on the podcast can be found on our transcripts at asco.org/DNpod.  Neeraj, it's great to have you back on the podcast today. Dr. Neeraj Agarwal: Thank you so much, John, for having me. Dr. John Sweetenham: Neeraj, let's begin by discussing some practice-changing phase 3 trials, starting with Abstract 5500, the KEYNOTE-826 study. This study reports the final overall survival results from a randomized, double-blind, phase 3 study of pembrolizumab plus chemotherapy versus placebo plus chemotherapy for first-line treatment of persistent, recurrent, or metastatic cervical cancer, which will be presented by Dr. Bradley Monk.  Dr. Neeraj Agarwal: I'd be happy to. The initial analysis of the KEYNOTE-826 study revealed that first-line pembrolizumab plus chemotherapy provided significant improvements in the overall survival and progression-free survival compared to placebo plus chemotherapy in patients with metastatic, persistent, or recurrent cervical cancer who had not previously received systemic chemotherapy and were not candidates for curative treatments such as surgery or radiation. In this study, patients were randomly assigned in a 1:1 ratio to receive pembrolizumab or placebo at 200 milligrams every three weeks for up to 35 cycles, along with chemotherapy with paclitaxel, plus a platinum therapy with or without bevacizumab.   From November 2018 to January 2020, 617 patients were enrolled with 308 receiving pembrolizumab plus chemotherapy and 309 patients receiving placebo plus chemotherapy. At the data cutoff of October 3, 2022, the median follow-up was 39 months. At this protocol-specified final overall survival analysis, pembrolizumab plus chemotherapy treatment continues to show a significant improvement in overall survival and progression-free survival, regardless of whether patients receive bevacizumab or not. The incidence of grade 3 or more adverse events was higher in the pembrolizumab plus chemotherapy arm than the placebo plus chemotherapy arm, with the most common adverse event being anemia, neutropenia, and hypertension. Dr. John Sweetenham: These are exciting data, Neeraj. So the main message from this trial is that pembrolizumab plus chemotherapy, with or without bevacizumab, can now be considered as standard of care for first-line treatment of persistent, recurrent, or metastatic cervical cancer. Dr. Neeraj Agarwal: Yes, I agree, John. Now, moving on to a different common type of cancer, let's discuss Abstract 1001, titled “Second-Line Endocrine Therapy with or without Palbociclib Maintenance in Patients with Hormone Receptor-Positive/HER2-Negative Advanced Breast Cancer: Results from the PALMIRA Trial,” which will be discussed by Dr. Antonio Llombart-Cussac. So, John, based on this abstract, can you please tell us about the role of palbociclib after prior progression on this drug? Dr. John Sweetenham: Yes. In this study, the authors aimed to determine if palbociclib maintenance with an alternative endocrine therapy improves the anti-tumor activity of second-line treatment in patients with endocrine-sensitive hormone receptor-positive and HER2-negative advanced breast cancer who had disease progression to first-line treatment with palbociclib in combination with endocrine therapy. After including 198 patients in the trial with a 2:1 randomization, 136 patients received palbociclib with endocrine therapy and 62 patients received endocrine therapy alone. And at a median follow-up of 8.7 months, the primary endpoint of progression-free survival was not met with a median progression-free survival of 4.2 months in the palbociclib-containing combination versus 3.6 months in the control arm. Also, higher grade 3 to 4 adverse events were reported in patients treated in the palbociclib arm. Dr. Neeraj Agarwal: Thanks, John. So you are saying that continuing the CDK4/6 inhibitor palbociclib after prior disease progression on palbociclib, even when the primary endocrine therapy has been changed, doesn't seem to be beneficial, therefore, this practice may be discouraged in the clinical setting? Dr. John Sweetenham: Yes, that's correct. Neeraj, I think that's the conclusion from this study. Dr. Neeraj Agarwal: So, John, now let's switch gears and highlight some precision oncology studies.  Dr. John Sweetenham: Well, Abstract 3602, titled “Real World Rates of FDA-Approved Targeted Therapy and Immunotherapy Prescriptions for Metastatic Colorectal Cancer Patients in the VA's National Precision Oncology Program” will be presented by Dr. Alice Nono Djosta. Can you tell us more about this abstract, Neeraj? Dr. Neeraj Agarwal: Well, comprehensive genomic profiling has the potential to guide the administration of FDA-approved biomarker-directed therapies and improve outcomes among patients with metastatic colorectal cancer. So, in this study, Abstract 3602, investigators sought to determine the rates of actionable biomarkers and prescription of associated FDA-approved therapies among veterans in the National Precision Oncology Program. Patients with metastatic colorectal cancer who had undergone comprehensive genomic profiling via tissue or liquid biopsy were included between 2019 and 2022 and had 1 of the following 5 actionable biomarker profiles including: NRAS, KRAS, BRAF wild-type, BRAF V600E mutation, MSI-high, TMB-high, NTRK fusion or rearrangements.  Prescription data for seven FDA-approved biomarker-directed therapies were extracted and rates of comprehensive genomic profiling (CGP)-directed therapy prescriptions were assessed by the investigators. A total of 908 patients with metastatic colorectal cancer underwent comprehensive genomic profiling, with 80% patients having colon adenocarcinoma and 20% with rectal adenocarcinoma. The combined rates of any actionable variants were 47% in patients with colon adenocarcinoma and 45% in patients with rectal adenocarcinoma. After including 424 eligible patients for FDA-approved biomarker therapy, only 70% patients with MSI-high, 48% patients with TMB-high, 38% patients with NRAS, KRAS, and BRAF wild-type, and only 17% of patients with BRAF V600E mutation received FDA-approved CGP-directed therapies.  Dr. John Sweetenham: Very important data, Neeraj. What's the main conclusion of this study? Dr. Neeraj Agarwal: So, in conclusion, this study found that almost 30% of patients with MSI-high metastatic colorectal cancer did not receive effective immune checkpoint inhibitors. And overall, a significant number of eligible patients did not receive FDA-approved biomarker-directed therapies. So, it is crucial that we evaluate the barriers to prescribing comprehensive genomic profiling-directed therapies in our patients with metastatic colorectal cancers.  So, John, let's move on to lung cancer, where the use of single-gene testing is still common in the community practice. Can you please tell us about Abstract 6506, titled “The Impact of Single-Gene Testing on Subsequent Comprehensive Genomic Profiling Success in Community Oncology Practice for Advanced Non–small Cell Lung Cancer”? These are results from a prospective observational reference laboratory testing program and these results will be presented by Dr. Mary Nesline. Dr. John Sweetenham: Yes, definitely. In this study, researchers aim to investigate the impact of prior single-gene testing on comprehensive genomic profiling success and therapeutic opportunities for patients with non–small cell lung cancer in community settings. They included patients who underwent at least 1 single gene testing for guideline recommending genomic variants in non–small cell lung cancer such as BRAF, EGFR, KRAS, MET exon 14 skipping mutations, ALK, RET, and ROS1 rearrangements as well as PD-L1 immunohistochemistry.  And they offered comprehensive genomic profiling either before or after receipt of a negative single gene test. Of 580 patients with non–small cell lung cancer with the comprehensive genomic profiling ordered between 2021 and 2022, around 30% of the patients had at least 1 single-gene testing ordered prior to the comprehensive testing, with a median of 5 prior single-gene tests. Compared to CGP-only cases. CGP per cases with prior negative single gene testing was canceled twice as often at tissue review, had a higher DNA extraction failure, and a lower DNA sequencing success. CGP also identified guideline-recommended variants in genes with no single-gene testing offered during the study period, such as ERBB2 mutations, or NTRK2/3 fusions, as well as variants targeted in ongoing clinical trials in 28% of patients. Dr. Neeraj Agarwal: Very interesting. So John, what is your key takeaway message from this? Dr. John Sweetenham: The main message is that in a community oncology setting, the practice of ordering single gene testing prior to comprehensive genomic profiling for patients with non–small cell lung cancer is common. Prior negative single-gene testing led to a higher rate of CGP test cancellation due to tissue insufficiency and increased CGP DNA extraction failures. The practice of single-gene testing does not align with practice guideline recommendations and may negatively impact the potential benefits of CGP testing for patients with non–small cell lung cancer.  Now, let's move on to another important abstract that our fellow clinicians should hear about. This is Abstract 1534 titled “Real-World Experience of an In-House Dihydropyrimidine Dehydrogenase Genotype Test to Guide Fluoropyrimidine Dosing at a Multi-Site Cancer Hospital” that will be presented by Dr. Jai Patel. Can you tell us more about this abstract, Neeraj? Dr. Neeraj Agarwal: Sure. Fluoropyrimidines, such as 5-fluorouracil and capecitabine, are commonly used to treat solid tumor cancers such as gastrointestinal and breast cancers. We know that severe toxicity occurs in one-third of patients, which delays the timely completion of treatments and result in prolonged hospitalization of these patients. These toxicities may be due in part to genetic variation in the DPYD gene. Five variants are known to have moderate to strong evidence according to the Clinical Pharmacogenetics Implementation Consortium. So, in this observational study, the authors describe the implementation of an in-house DPYD test and its impact on the dosing of these fluoropyrimidines, which include capecitabine and 5-fluorouracil.  From March 2020 to December 2022, 491 patients received DPYD genotyping testing, and 90% of them had gastrointestinal cancers. The median lab turnaround time was only 3 days. Pre-treatment testing was ordered in 80% of patients, and 93% of patients had results before starting cycle 1. Overall, 6% of patients were heterozygous carriers. Fluoropyrimidine dose was reduced, avoided, or discontinued in 90% of these patients. Moreover, in pre-treatment carriers, 90% of patients received an upfront dose reduction, avoidance, or they even declined chemotherapy. Dr. John Sweetenham: Thanks, Neeraj. So what do you think is the key takeaway message here? Dr. Neeraj Agarwal: So, DPYD genotype-guided dosing of fluoropyrimidine, including 5-fluorouracil and capecitabine, is logistically feasible with a rapid turnaround time and can result in treatment dose modifications for most carriers, potentially avoiding or mitigating severe toxicities, especially in those patients who received pre-treatment testing. Dr. John Sweetenham: Thanks again. Now let's transition to studies that focus on disparities in cancer care. Dr. Neeraj Agarwal: Definitely. Let's discuss Abstract 6530, titled “Impact of Free Hospital-Provided Rideshare Service on Radiation Therapy Completion Rates: A Matched Cohort Analysis.” In this study, Dr. Eric Chen and colleagues assess the potential of rideshare services in facilitating timely radiation therapy for patients facing barriers, such as limited transportation, financial constraints, and lack of adequate social support. So the authors analyzed data from about 2,900 patients who underwent radiation therapy and found that 58 of them utilized a free hospital-provided rideshare service.  These free hospital-provided rideshare service utilizers had a lower median age and were more likely to identify as Black or African American compared to those who did not utilize these services. They also had higher socioeconomic disadvantages and traveled shorter distances for treatment. Interestingly, more rideshare utilizers underwent radiation therapy with curative intent, had longer treatment course duration, and a higher number of fractions prescribed. In the matched-cohort analysis, the study found that radiation therapy completion rates were significantly higher for rideshare utilizers compared to non-rideshare utilizers, especially for patients who were undergoing radiation therapy with curative intent.  Dr. John Sweetenham: So what's the key take-home message from this abstract? Dr. Neeraj Agarwal: This study highlights the potential benefit of utilizing hospital-provided free ride-share services, particularly for patients facing barriers to timely treatment. So, using these services were associated with higher radiation therapy completion rates, especially in the curative setting.  So, John, there is another study, Abstract 1606, titled “Trends and Disparities in Oncology Telehealth after the Initial Pandemic Era” that will be presented by Dr. Michael Lee and colleagues. They evaluated whether telehealth utilization continued after the pandemic and if demographic differences in its users persist. So John, please tell us more about this abstract. Dr. John Sweetenham: Yes, the authors conducted a retrospective cohort study in 22 Kaiser Permanente Northern California hematology and oncology clinics between October 1, 2020, and June 1, 2022. The study investigated the use of office, video, and telephone visits, analyzing more than 340,000 hematology oncology visits with MD or DO providers. Of these visits, 25% were in-office, 37% were video visits, and 39% were telephone visits. Monthly telehealth visits peaked in January 2021, representing around 86% of total visits, and decreased to 69% of the total visits by June 2022. Video visits were more common for new appointments, whereas telephone visits were more common for return appointments. Moving to the post-pandemic period, telehealth visits remained popular, with video visits being the most commonly utilized. However, telehealth use varied among demographic populations. Video visits were a significantly higher proportion of all visits among individuals less than 45 years old, primary English speakers, patients with commercial insurance, non-Hispanic Whites and Asians, compared with Hispanic, Whites, and Blacks, and patients living in the deprived neighborhoods. Dr. Neeraj Agarwal: Interesting data, John. So what is the key takeaway message from this abstract? Dr. John Sweetenham: Well, overall, it's encouraging to see that even after the pandemic, telehealth continued to be widely used. However, the concerning issue is that telehealth is less utilized in patients who may need it most. The next step, in my view, will be to work on barriers to access telehealth by underprivileged populations.   And that brings our discussion to a close today. Before we wrap up the podcast, Neeraj, do you have any final thoughts to share? Dr. Neeraj Agarwal: Yes, thanks, John. I would urge our listeners to come and join us at the ASCO Annual Meeting, not only to celebrate these successes but also to help disseminate these cutting-edge data to practitioners and patients across the world. Dr. John Sweetenham: Absolutely. I'd like to thank our listeners for joining us today, and thank you, Neeraj, for sharing your insights with us as well.  You will find links to the abstracts discussed today on the transcripts of this episode. Finally, if you value the insights that you hear on ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts.  Disclaimer:  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  Find out more about today's speakers: Dr. John Sweetenham Dr. Neeraj Agarwal @neerajaiims Follow ASCO on social media:   @ASCO on Twitter  ASCO on Facebook  ASCO on LinkedIn   Disclosures: Dr. John Sweetenham: Consulting or Advisory Role: EMA Wellness Dr. Neeraj Agarwal:  Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, AstraZeneca, Pfizer, Merck, Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences   Research Funding (Institution): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, Crispr Therapeutics, Arvinas

Dr. Neeraj Agarwal and Dr. Jeanny Aragon-Ching discuss the CLEAR study in renal cell carcinoma, a new exploratory analysis combining the TheraP and VISION trials in metastatic urothelial cancer, and compelling advances in prostate cancer and across GU oncology in advance of the 2023 ASCO Annual Meeting.  TRANSCRIPT Dr. Neeraj Agarwal: Hello and welcome to the ASCO Daily News Podcast. I'm Dr. Neeraj Agarwal, your guest host for the ASCO Daily News Podcast today. I'm the director of the Genitourinary Oncology Program and a professor of medicine at the University of Utah Huntsman Cancer Institute, and editor-in-chief of the ASCO Daily News. I'm delighted to welcome Dr. Jeanny Aragon-Ching, a GU medical oncologist and the clinical director of the Genitourinary Cancers Program at the Inova Schar Cancer Institute in Virginia.   Today, we'll be discussing some key abstracts in GU oncology that will be featured at the 2023 ASCO Annual Meeting.  Our full disclosures are available in the show notes and disclosures of all guests on the podcast can be found on our transcript at asco.orgDNpod.   Jeanny, it's great to have you on the podcast today. Dr. Jeanny Aragon-Ching: Thank you so much, Dr. Agarwal, for having me. Dr. Neeraj Agarwal: Jeanny, let's begin with Abstract 4502 regarding long-term updated results on the CLEAR study. The abstract reports the final, prespecified overall survival analysis of the CLEAR trial, a four-year follow-up of lenvatinib plus pembrolizumab versus sunitinib in patients with advanced renal cell carcinoma. Dr. Jeanny Aragon-Ching: Yes, I would be happy to. So, just as a reminder, the combination of lenvatinib and pembrolizumab was initially approved by the FDA in August 2021 for first-line treatment of adult patients with advanced renal cell carcinoma. So, this was based on significant benefits that were seen in progression-free survival, which was a primary endpoint, but also showed improvement in the overall response rates compared with sunitinib in first-line advanced renal cell carcinoma.   So this abstract reports on longer-term follow-up now at a median of 49.8 months, and PFS favored the combination lenvatinib and pembrolizumab compared to sunitinib across all MSKCC risk groups, and PFS benefit versus lenvatinib and pembro compared to sunitinib was maintained with a hazard ratio of 0.47. And even overall survival was also maintained with the combination with a hazard ratio of 0.79, and the overall survival favored the combination across all risk groups. If we look at the CR rate, it was 18.3% for the combination compared to 4.8% with sunitinib, unless patients in the combination arm received subsequent anticancer therapies, and that's intuitive. And the PFS2 was also longer with the combination at 43 months compared to 26 months. Now, it is important to note that grade III or more treatment-related adverse events did occur in about 74% of the patients in the combination of lenvatinib and pembro, compared to 60.3% in patients with sunitinib. Dr. Neeraj Agarwal: Jeanny, this is good news. So the main message from the abstract is that sustained results from this combination of lenvatinib plus pembrolizumab are being seen even after a longer follow-up of more than four years.  Dr. Jeanny Aragon-Ching: Yes, I agree. So now, moving on, Neeraj, to a different setting in the RCC space, let's look at Abstract 4519, which is titled “Efficacy of First-line Immunotherapy-based Regimens in Patients with Sarcomatoid and/or Rhabdoid Metastatic Non-Clear Cell RCC: Results from the IMDC,” which will be discussed by Dr. Chris Labaki. So, Neeraj, based on this abstract, can you tell us a little bit more about the impact of these adverse pathologic risk features in non-clear cell RCC?  Dr. Neeraj Agarwal: Of course. So, using real-world patient data, the IMDC investigators compared the outcomes of patients with metastatic non-clear cell RCC who were treated with immunotherapy-based combination regimens versus those who were treated with VEGF-TKIs alone. They also assessed the impact of sarcomatoid and rhabdoid features on response to IO-based combinations versus VEGF-TKIs. Of 103 patients with metastatic non-clear cell RCC who had rhabdoid or sarcomatoid features, 32% of patients were treated with immunotherapy-based combinations.   After adjusting for confounding factors, the authors show that those treated with a combination of two immune checkpoint inhibitors or an immune checkpoint inhibitor with a VEGF-TKI combination had significantly improved overall survival, which was not reached in the immunotherapy combination group versus seven months within the VEGF-TKI group. Time to treatment failure and objective responses were also prolonged, significantly higher, and better in the immunotherapy groups compared with patients who were treated with VEGF-TKIs alone. Interestingly, if you look at those 430 patients with metastatic non-clear cell RCC who did not have sarcomatoid or rhabdoid features, they didn't seem to benefit with immunotherapy-based combinations.  Dr. Jeanny Aragon-Ching: This is an exciting update, Neeraj. What are the key takeaways from this abstract? Dr. Neeraj Agarwal: So the main takeaway is if you see a patient with advanced non-clear cell RCC who has sarcomatoid and rhabdoid features, there appears to be a rather substantial and selective benefit with IO-based combinations. And in this context, I would like to highlight the ongoing SWOG 2200 trial also known as PAPMET2 trial, which is comparing the combination of cabozantinib plus atezolizumab. So immuno-therapy-based combinations versus cabozantinib alone in advanced papillary renal cell carcinoma setting. So this trial is being led by Dr. Benjamin Maughan and Dr. Monty Pal. And I like to encourage our listeners to consider referring their patients for involvement in this federally funded trial so that we can validate the data from this retrospective study in a prospective way. So, Jeanny, let's now move on to another important disease type which is urothelial carcinoma. There is a very recent accelerated FDA approval of the drug combination of enfortumab vedotin and pembrolizumab for cisplatin-ineligible metastatic urothelial carcinoma patients. This is Abstract 4505, which is being presented by Dr. Shilpa Gupta and colleagues. Can you please tell us more about this update? Dr. Jeanny Aragon-Ching: Yeah, absolutely. So, as you mentioned, Neeraj, the FDA just granted accelerated approval in April 2023 for this combination of enfortumab vedotin or EV, which is and ADC, antibody drug conjugate against nectin-4 and the PD-1 inhibitor pembroluzimab. So it's a combination for patients with locally advanced or metastatic urothelial carcinoma who are considered cisplatin ineligible. So this is nearly a four-year follow-up.   So as a reminder, this was a phase 1b/2 trial that included 45 patients and it had a primary endpoint of safety and tolerability although the key secondary endpoints included confirmed overall responses, duration of response, progression-free survival, and the resist criteria was investigated via investigator and BICRs which is in a blinded independent central review. Even overall survival was a key secondary endpoint.  So, the bottom line was the confirmed overall response by BICR was 73.3%, the disease control rate was about 84%, and the CR rate was 15.6% with a PFS of close to 13 months, and a 12-month overall survival rate of 83%. However, it is important to cite that there were treatment-related adverse events including skin reactions in 66%, neuropathy occurred in 62%, and ocular disorders in 40%. And there was a little bit of pneumonitis in close to 9%, colitis, and hypothyroidism, so there are side effects to watch out for.  Dr. Neeraj Agarwal: So, Jeanny this is great. What is the key takeaway from this trial?  Dr. Jeanny Aragon-Ching: So I think the most important thing is we now have a new combination of EV and pembro which shows very promising responses and survival in part which led to the FDA accelerated approval in the cisplatin-ineligible population of patients. However, we must note that the phase 3 trial of EV302 will ultimately establish which approach is really beneficial for all of our cisplatin-ineligible patients, either a carboplatin-based chemotherapy regimen or a non-platinum-based regimen such as EV and pembro. Dr. Neeraj Agarwal: Thanks Jeanny, would you like to discuss any other study in the bladder cancer space? Dr. Jeanny Aragon-Ching: Absolutely. I think Abstract 4508 from Dr. Seth Lerner and colleagues will be very relevant to our colleagues. This abstract is SWOG S1011, which is a phase 3 surgical trial to evaluate the benefit of a standard versus an extended lymphadenectomy performed at the time of radical cystectomy for muscle-invasive bladder cancer.  Dr. Neeraj Agarwal: Yes. So this trial, as you said, is an important trial which randomized in a one-on-one fashion 618 patients with muscle-invasive bladder cancer undergoing radical cystectomy, and these patients were randomized to either standard lymph node dissection or an extended lymph node dissection. And standard lymph node dissection included, as we know, external and internal iliac and operative lymph node. The extended lymph node dissection included lymph nodes up to aortic bifurcation which included common iliac, presciatic, and presacral lymph nodes. At a median follow-up of approximately 6 years, there was no disease-free survival or overall survival benefit in patients undergoing an extended lymph node dissection compared to standard lymph node dissection. And extended lymph node dissection was also associated with greater morbidity and preoperative mortality. Dr. Jeanny Aragon-Ching: Very interesting data, Neeraj. So these results, I think, will be very useful for a lot of our surgical colleagues in both academia and the community who may still be inclined to perform extended lymphadenectomy during cystectomy. This study shows that it's actually not necessary. Dr. Neeraj Agarwal: Absolutely. So now let's move on to another disease type, which is very important - prostate cancer. There are several practice-informing abstracts that are worthwhile discussing. The first of these involves Abstract 5002, which looks at the impact of the PSA nadir as a prognostic factor after radiation therapy for localized prostate cancer, which will be presented by Dr. Praful Ravi and  colleagues. Jeannie, can you please tell us more about this abstract? Dr. Jeanny Aragon-Ching: Yeah, definitely. So this abstract, as you mentioned, Neeraj, is a prognostic impact of PSA nadir of more than or equal to 0.1 nanogram per ml within six months after completion of radiotherapy for localized prostate cancer - an individual patient data analysis of randomized trials from the ICECaP Collaborative. Basically, it refers to an attempt to evaluate early surrogate measures to predict for long term outcomes such as prostate cancer-specific survival, metastases-free survival, and overall survival. So they looked at a big registry from the ICECaP collaboration that included 10,415 patients across 16 randomized controlled trials. And those men underwent treatment for intermediate risk and high risk prostate cancer treated with either radiation therapy alone in about a quarter of patients, or they got RT with short-term ADT in about 58% of patients, and 17% of them got RT with long-term ADT.  So, after a median follow-up of ten years, what they found was, if you had a PSA nadir that is over or equal to 0.1 nanogram per ml within six months after completion of radiation therapy, it was associated with worse prostate cancer-specific survival, metastases-free survival, and overall survival. For instance, the five-year metastases-free survival for those who achieved a PSA nadir of less than 0.1 was 91% compared to those who did not, which was 79%. Therefore, they concluded that if you achieve a bad PSA of 0.1 or above within six months after you completed radiation, you had worse outcomes.  Dr. Neeraj Agarwal: Jeanny, what is the key takeaway message from this study? Dr. Jeanny Aragon-Ching: The key takeaway from this ICECaP analysis is that this information would be very important to augment a signal-seeking endpoint, especially for clinical trial development, so that we can develop further strategies to de-escalate for those who don't need systemic intensification or therapy intensification versus escalation for those who really do. Dr. Neeraj Agarwal: So, my radiation oncology colleagues need to watch out for those patients who do not achieve a PSA of less than 0.1 nanogram per ml within the first six months of finishing radiation therapy. Very interesting data.  Dr. Jeanny Aragon-Ching: Yes, absolutely. So. Neeraj another important abstract for our fellow clinicians, switching gears a little bit now, is Abstract 5011, which is titled “Do Bone Scans Overstage Disease Compared to PSMA PET?” This was an international, multicenter retrospective study with blinded, independent readers. Can you tell us more about this abstract? Dr. Neeraj Agarwal: Yes, a relatively small retrospective study, but still pertinent to our practice. So I'll summarize it. This study by Dr. Wolfgang Fendler and colleagues evaluated the ability of bone scans to detect osseous metastasis using PSMA PET scan as a reference standard. So in this multicenter retrospective study, 167 patients were included, of which 77 patients were at the initial staging of prostate cancer, 60 had biochemical recurrence after definitive therapy, and 30 patients had CRPC or castor-resistant disease.  These patients had been imaged with a bone scan and a PSMA PET scan within 100 days. And in all patients, the positive predictive value, negative predictive value and specificity for bone scan were evaluated at different time points. They had bone scan and PSMA PET scan and both were compared. And what they found was interesting. All these three values - positive predictive value, negative predictive value, and specificity for bone scan were 0.73, 0.82 and 0.82 in all patients, and in initial staging, it was even lower at 0.43 and 0.94 and 0.80.  So, without getting into too much detail regarding these numbers, I want to highlight the most important part of the study, that at the initial staging, 57% patients who had a positive bone scan had false positive bone scans. The interreader agreement for bone disease was actually moderate for bone scans and quite substantial for the PSMA PET scan.  Dr. Jeanny Aragon-Ching: So, Neeraj, what do you think is the key takeaway message here for our audience?   Dr. Neeraj Agarwal: The key takeaway message is that positive predictive value of bone scan was low in prostate cancer patients at initial staging, with the majority of positive bone scans being false positive. This suggests that a large proportion of patients which we consider to have low-volume metastatic disease by bone scan actually have localized disease. So in the newly diagnosed patients with prostate cancer, patients should ideally have a PSMA PET scan to rule out metastatic disease.   So, let's move on to another abstract I would like to discuss, which has important implications in treatment, especially now that lutetium 177 is approved, but frankly not available widely. Dr. Jeanny Aragon-Ching: Yeah, that's actually very timely. So the abstract you're referring to is 5045, which is being presented by Dr. Yu Yang Sun and colleagues entitled “Effects of Lutetium PSMA 617 on Overall Survival in TheraP Versus VISION Randomized Trials: An Exploratory Analysis.” So, Neeraj, can you tell us more about the relevance of this exploratory analysis? Dr. Neeraj Agarwal: Definitely. In this abstract, Dr. Yang Sun and colleagues assess the effect of lutetium PSMA on overall survival in two different trials, TheraP and VISION trials. So, just for our listeners' recollection, the phase 2 TheraP trial compared lutetium PSMA and cabazitaxel in patients with mCRPC who had progression on docetaxel and had significant PSMA avidity on gallium PSMA pet scan, which was defined as a minimum uptake of SUV max of 20 at least one site of disease and SUV max of more than 10 at all sites of measurable disease.  In this trial, 20 of 101 patients in the cabazitaxel arm crossed over to lutetium PSMA, and 32 of 99 patients in the lutetium PSMA arm crossed over to cabazitaxel. In the VISION trial, patients with mCRPC who previously progressed on at least one ARPI and one taxane-based therapy and had a positive gallium PSMA scan, and here, positivity was not stringently pre-specified as it was done in the context of TheraP trial. So, positive gallium pet scans were randomly assigned in two to one fashion to receive either lutetium PSMA plus best supportive care or standard of care versus standard of care.  And I'd like to highlight that the standard of care comprised ARPIs and bone protecting agents and these patients were not allowed to have cytotoxic chemotherapy such as cabazitaxel in the standard of care arm. Now, overall survival was similar in the lutetium PSMA group regardless of whether they got lutetium PSMA in the VISION trial or TheraP trial. There was no difference in overall survival with lutetium in the lutetium arms of VISION and TheraP trial with a hazard ratio of 0.92. And there was no difference in the overall survival between the lutetium PSMA and the cabazitaxel group in the TheraP trial if you use counterfactual analysis, assuming crossover had not occurred. So, quite interesting in my view. Dr. Jeanny Aragon-Ching: Yeah, thanks Neeraj for that wonderful synopsis and discussion. So, what is the key take home message then? Dr. Neeraj Agarwal: The main message in this new exploratory analysis, which combined both the TheraP and VISION trials, is that lutetium PSMA and cabazitaxel seem to be associated with similar overall survival benefit in these highly selected patients with PSMA positivity. Additionally, the difference in the observed effect of lutetium PSMA and overall survival in the TheraP and VISION trials may be actually better explained by the use of different treatments in the respective control arms of these trials. And these results, in my view, are quite pertinent for those patients and providers who do not have access to lutetium-177 therapy.  Let's go to another abstract that is currently relevant to our practice, given many patients with advanced prostate cancer who have concurrent diabetes; I'm talking about Abstract 5066. Jeanny, can you please tell us more about this abstract?  Dr. Jeanny Aragon-Ching: Certainly, Neeraj. So this abstract will be presented by Dr. Amy Shaver and colleagues. So it's also very relevant, since many men who are diagnosed with prostate cancer frequently also have a concomitant diagnosis of type 2 diabetes mellitus. So, this was a SEER-Medicare population database analysis that looked at men who were treated with either abiraterone or enzalutamide and also had concomitant diagnosis of type 2 diabetes mellitus (DM). And they were identified using ICD-9 and ICD-10 codes and they were all tied in to acute care utilization. So they looked at CMS research data codes and ER hospitalization visits six months after treatment initiation was recorded. So all in all, they took a sample of 11,163 men, of whom close to 62% were treated with abiraterone and about 38% were treated with enzalutamide.  So, of these, about 27% of them had type 2 DM, of whom 59% received abiraterone and about 41% had enzalutamide. So, the bottom line is, compared to those without diabetes mellitus, those who had type 2 diabetes had worse acute care utilization, which was 43% higher than those who got abiraterone compared to enzalutamide, and also had higher overall mortality. Therefore, the bottom line is, having type 2 diabetes mellitus, unfortunately, portends worse outcomes in men with prostate cancer, so careful attention needs to be paid to those who are starting out already with such comorbidities. So Neeraj, any final thoughts you have regarding this abstract and overall before we wrap up on the podcast today?  Dr. Neeraj Agarwal: Absolutely. So it looks like, based on this very important pertinent Abstract 5066, which talks about the impact of diabetes on our patients, I think we need to be very watchful regarding the impact of diabetes on our patients who are being treated with abiraterone or enzalutamide, especially drugs which are known to make the metabolic syndrome and diabetes worse. I think close monitoring and close attention to control of diabetes is very important. So with that, I would urge the listeners to come and join us at the Annual Meeting, not only to celebrate these successes but also to help disseminate this cutting-edge data to practitioners and maximize the benefit to our patients across the globe.   And thank you to our listeners for joining us today. You will find links to the abstracts we discussed today on the transcript of this episode. Finally, if you value the insights that you hear on our ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcast.  Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Find out more about today's speakers:  Dr. Neeraj Agarwal @neerajaiims Dr. Jeanny Aragon-Ching Follow ASCO on social media:   @ASCO on Twitter   ASCO on Facebook   ASCO on LinkedIn     Disclosures:  Dr. Neeraj Agarwal:   Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, AstraZeneca, Pfizer, Merck, Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences  Research Funding (Institution): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, Crispr Therapeutics, Arvinas  Dr. Jeanny Aragon-Ching: Honoraria: Bristol-Myers Squibb, EMD Serono, Astellas Scientific and Medical Affairs Inc., Pfizer/EMD Serono Consulting or Advisory Role: Algeta/Bayer, Dendreon, AstraZeneca, Janssen Biotech, Sanofi, EMD Serono, MedImmune, Bayer, Merck, Seattle Genetics, Pfizer, Immunomedics, Amgen, AVEO, Pfizer/Myovant,  Exelixis, Speakers' Bureau: Astellas Pharma, Janssen-Ortho, Bristol-Myers Squibb, Astellas/Seattle Genetics.

Guest host Dr. Neeraj Agarwal and Dr. Christian Kollmannsberger discuss practice-changing abstracts that were presented at the 2023 ASCO Genitourinary Cancers Symposium, including results from the TALAPRO-2, PROpel, TRITON3, ARASENS, KEYNOTE-057, CheckMate 274, and CheckMate 9ER studies. TRANSCRIPT Dr. Neeraj Agarwal: Hello and welcome to the ASCO Daily News Podcast. I'm Dr. Neeraj Agarwal, the director of the Genitourinary Oncology Program, and professor of Medicine at the Huntsman Cancer Institute at the University of Utah, and editor-in-chief of the ASCO Daily News.  Today, we will be discussing practice-changing abstracts and other key advances in GU Oncology featured at the 2023 ASCO Genitourinary Cancers Symposium. Joining me for this discussion is Dr. Christian Kollmannsberger, the chair of this year's ASCO GU. Dr. Kollmannsberger is a GU medical oncologist at the BC Cancer Vancouver Cancer Center and a clinical professor at the University of British Columbia.  Our full disclosures are available in the transcript of this episode, and the disclosures of all guests on the podcast can be found on our transcripts at asco.org/DNpod.  Christian, thank you for joining us on the podcast today.  Dr. Christian Kollmannsberger: Thank you very much, Neeraj. It's a real pleasure to be here and have this discussion. Dr. Neeraj Agarwal: Thank you. So, Christian, the GU meeting featured remarkable progress in various GU malignancies. Could you please share some of the prominent topics that made the headlines this year and give us an overall feel of ASCO GU this year? Dr. Christian Kollmannsberger: Absolutely. I think it was a great meeting with over 5,800 attendees from more than 70 countries. And most of the attendees were in person, so it was a great event. ASCO GU is truly the premier global event to feature the very best of GU cancer research and treatment. The theme of this year's meeting was "Today's Science, Tomorrow's Treatment," and that was reflected in the novel scientific and clinical findings that were presented and will potentially lead to changes in our daily clinical practice. It also reminds us how quickly the development today is and how quickly novel scientific progress is immediately translated into clinical practice, particularly oncology.   I was very impressed by the meeting's emphasis on diversity, interactivity, networking, multidisciplinary collaboration, and evidence-based care. We introduced several new features such as a “Meet the Professor session, a women's networking event, etc. And the first day really kicked off with a very rich focus on prostate cancer and much attention given to PARP inhibitors in our first session. As an example, LBA 17 was the first late-breaking abstract presented. And congratulations to you, Neeraj, on delivering this exciting data on the TALAPRO-2 trial, which were eagerly awaited. Let's start with that. Can you tell us about this trial? Dr. Neeraj Agarwal: Yes, of course. So the TALAPRO-2 trial was a phase 3 randomized trial where patients in newly diagnosed metastatic CRPC settings were randomized to standard of care enzalutamide plus placebo versus enzalutamide plus talazoparib PARP inhibitor. And as we know, Christian, the rationale has been that dual inhibition of PARP and AR may enhance the efficacy of each. And there's a laboratory preclinical rationale and based on which other studies have been done in the past. So, without getting into too much detail into the rationale for the trial, I'll come right to the results of the trial. So, this was the first-line mCRPC setting where rPFS was the primary endpoint as assessed by the independent radiology assessment. And in this trial, patients were recruited regardless of the homologous recombination repair gene alterations. So, patients were recruited and they were prospectively tested for whether they had these HRR gene alterations or not, but all comer population was included in this trial. And after a median follow-up of approximately 23 months, the trial read out, and we found that trial made the primary endpoint was improved radiographic progression-free survival with the rPFS being about 22 months in the enzalutamide arm and not reached in the combination arm with a 37% reduction in risk of progression or death.  If you look at the subgroup analysis of patients who were HRR+, there was a 54% reduction risk of progression or death. If you look at patients who were stratified in HRR- or unknown group, there was a 30% reduction risk of progression or death. If you specifically look at an exploratory analysis we did to look for patients who were HRR- by prospective tumor tissue testing; there was a 34% reduction in risk of death with a hazard ratio of 0.66 favoring the combination arm. So overall, the rPFS primary endpoint was met in all groups. We also see significant delay in PSA progression in the combination arm by more than nine months. We also see delays in the time to cytotoxic chemotherapy. We saw delay in progression or death on subsequent neoplastic therapy after the protocol treatment. We saw delays in deterioration of quality of life and global health status. All these were significant and happened on the talazoparib plus enzalutamide arm.  So overall, if you look at the totality of the data, these all favored the combination of talazoparib plus enzalutamide compared to enzalutamide alone. I want to highlight that overall survival is immature at 31% maturity with a hazard issue of 0.89, currently favoring enzalutamide plus talazoparib. But we'll have to look at more mature data as time passes.  Dr. Christian Kollmannsberger: Wow. Thank you, Neeraj. So, it sounds like that was a very positive trial, and it's potentially practice-changing. One of the concerns is always safety and toxicity. So can you tell us whether there were any new safety signals, and can you tell us more about the common adverse events that were noticed in TALAPRO-2? Dr. Neeraj Agarwal: No discussion is complete without talking about safety results, so I'm glad you asked me, Christian. The most common dose-affecting toxicity, if you will - so toxicities which led to dose modification and dose discontinuation of talazoparib were cytopenias, as we expect from this class of agents. So anemia, neutropenia, thrombocytopenia, these were the common toxicities. In fact, rate with anemia was 46.5%. Neutropenia and cytopenia were much less common.  I would like to highlight one fact which also came up during the discussion section after our oral presentation. The qualifying criteria for entry in this trial was a hemoglobin of 9-gram percent. And 49% of patients had grade 1 to 2 anemia at baseline, that is before starting treatment with talazoparib. So, we knew that if you mandate dose reduction, a lot of patients will not get adequate dosing of talazoparib. So, we waited for grade 3 anemia and then instituted dose reduction. And that I thought personally was a good strategy because the grade 3 anemia happened after a median duration of three months, 3.3 months to be more precise. And then, these patients underwent protocol-mandated dose reduction, following which the dose discontinuations were quite low actually. Only 8.3% patients discontinued talazoparib because of anemia, and the median dose intensity or median relative dose intensity of talazoparib in the talazoparib arm remained quite high at more than 80%, which translates to a talazoparib dose of 0.4 milligram daily when the starting dose was 0.5 milligram. So those were the hallmark of toxicities.   I do like to mention that those grade 3, 4 toxicities which are more known to affect the quality of life of our patients, such as grade 3, 4 anorexia, fatigue, nausea and vomiting, they were quite rare, happening in 1 to 4% patients who were on talazoparib. So overall, regarding the side effects, they were manageable, there were no new safety signals, and we could maintain adequate talazoparib dosing with dose reduction, which happened quite early during the protocol treatment.  Dr. Christian Kollmannsberger: Thank you, Neeraj. Very impressive results indeed. The patient population included in TALAPRO-2 was very similar to those included in the PROpel phase 3 trial, which tested the combination of abiraterone and olaparib in the first-line mCRPC setting. So, I'd like to just mention that we also saw LBA16 on the PROpel study, which was the final overall survival in PROpel, which was presented by Noel Clarke. So PROpel, as you know, was a randomized phase 3 trial evaluating efficacy and safety of olaparib plus abiraterone versus placebo plus abiraterone as first-line therapy for mCRPC in the first-line metastatic castration resistance setting. The enrollment in that study was independent of known defects in the homologous recombination repair gene pathway in contrast to other studies, such as MAGNITUDE, which tested the biomarker upfront. A total of 796 patients were randomly assigned to either olaparib plus abiraterone or placebo plus abiraterone. And we saw similar results, significant radiographic progression-free survival with olaparib plus abiraterone in PROpel, which was the primary endpoint similar to TALAPRO-2, and that was published last year in the New England Journal of Medicine Evidence.  Now, this abstract presented here at ASCO GU reported on overall survival with an overall survival majority of 47.9% and showed that with the addition of the PARP inhibitor olaparib to abiraterone, a statistically non-significant but clinically meaningful improvement in overall survival of about seven months were achieved compared to standard of care in abiraterone alone. The numbers were 42.1 versus 34.7 months in the all-comers population of patients in the first-line mCRPC setting. Importantly, I think the median overall survival of more than 42 months really represents the longest reported median overall survival thus far in a phase III trial for first-line metastatic castration-resistant prostate cancer. Although the median overall survival for the non-HRR group remains not statistically significant, with a hazard ratio of 0.89. Dr. Neeraj Agarwal: Such a great synopsis of the PROpel result data. Thank you, Christian, for highlighting these results. As we know, the combination is already approved by the EMA, the European Medical Agency, for patients in the first-line mCRPC setting who are not candidates for docetaxel chemotherapy. If this combination is approved by the FDA, we may have one more therapeutic option for our patients in first-line mCRPC.  So, just continuing on the PARP inhibitors, there was one more oral presentation with PARP inhibitor rucaparib by Dr. Alan Bryce from the Mayo Clinic, Arizona. This was Abstract 18 on the primary result of the TRITON3 trial. So to complete our PARP inhibitor section, I would like to summarize the result of the TRITON3 trial, which was a randomized phase III trial evaluating rucaparib versus physician choice, which notably included docetaxel in addition to abiraterone or enzalutamide in patients with chemotherapy-naive mCRPC with BRCA1, BRCA2 or ATM alterations. These patients had disease progression after having one novel hormonal therapy, or we call them second-generation androgen pathway inhibitors in any setting. So these patients had to have disease progression on a novel hormonal therapy.   In the BRCA subgroup and the subsequent intention to treat the population, the primary endpoint tested first was radiographic progression-free survival, and overall survival was the key secondary endpoint. The subgroup of patients with BRCA-altered disease had a median rPFS of 11.2 months with rucaparib compared to 6.4 months with physician choice of treatment - looks like almost doubling of the rPFS with the rucaparib. In the overall ITT population, median rPFS was 10.2 months with rucaparib and 6.4 months with the physician's choice of treatment. Although the overall survival data are immature, we still see a trend for improved overall survival with rucaparib. Regardless, the study clearly demonstrates the value of rucaparib for treating BRCA1 and BRCA2-altered mCRPC after disease progression on an androgen receptor pathway inhibitor. So these were the impressive results from the TRITON3 trial.  But before we switch to non-prostate abstract, I would like to complete the prostate cancer discussion by talking about the Abstract 15, which was based on the results of the ARASENS trial presented by Dr. Maha Hussain. As we know, ARASENS is a randomized phase 3 trial evaluating the efficacy and safety of darolutamide plus androgen deprivation therapy plus docetaxel versus androgen deprivation therapy or ADT plus docetaxel. So the triplet of ADT plus darolutamide plus docetaxel being compared to ADT plus docetaxel chemotherapy in patients with newly diagnosed metastatic castration-sensitive prostate cancer. A total of 1,300 patients were randomly assigned to the doublet versus triplet. As presented in the last ASCO GU meeting exactly one year ago, the primary endpoint of the study was met with a significant improvement in overall survival and a 32% reduction in risk of death for patients on the triplet therapy with ADT plus docetaxel plus darolutamide versus ADT plus docetaxel chemotherapy. So triplet therapy was already approved based on these data.  The abstract presented by Dr. Hussain this year is a post-talk analysis where Dr. Hussain and colleagues investigated the impact of triplet therapy across patients with high volume versus low volume per chartered criteria and higher risk versus low risk using latitude trial criteria. And investigators knew that these results would be highly attractive to practicing oncologists who are now choosing treatment based on volume of disease or risk of disease, more commonly, volume of disease.  So, let's come to what was presented this ASCO GU. So, after 1,305 patients in ARASENS, the majority had high-volume disease and high-risk disease. Among patients with high-volume disease, the addition of darolutamide reduced the risk of death by 30% compared with ADT and docetaxel, with a hazard ratio of 0.69. In the risk groups, the addition of darolutamide seems to favor both high-risk and low-risk groups. Among patients with low-volume disease, there was a trend towards improvement in overall survival with the addition of darolutamide, but it did not reach statistical significance. The great news was that there was no new safety signal. So, to summarize these data, the triplet of darolutamide plus ADT plus docetaxel showed superior overall survival compared to doublet of ADT plus docetaxel, with an important caveat that triplet was not compared with any of the modern doublets of ADT plus a second generation androgen receptor pathways inhibitor such as abiraterone, apalutamide, or enzalutamide, or even darolutamide. So, I wish there was a third arm of ADT plus darolutamide.  Having said that, triplet can be considered a standard of care now based on these data for patients with metastatic hormone sensory prostate cancer, where we would be using ADT plus docetaxel chemotherapy. And from this meeting data, this efficacy of triplet can be applied to high-volume disease and all risk disease. And we just need more time to see how the data pans out in low-volume patients with metastatic hormone-sensitive prostate cancer.  Dr. Christian Kollmannsberger: Yes, I completely agree, Neeraj. I think all the data presented in these abstracts are really impressive and will impact our daily clinical practice and our patients more or less immediately. I think the use of PARP inhibitors, whether as a monotherapy or in combination with androgen receptor pathway inhibitors, as well as now the option of triplet therapy in the metastatic castration sensitive setting really offer patients with metastatic prostate cancer new treatment strategies and most importantly, improved survival outcomes. And it is impressive to see how we have pushed the prognosis and the outcomes for our patients with prostate cancer, I would say, in the last five to ten years. And similar to last year, I think the entire Prostate Cancer Day at ASCO GU 2023 was full with impressive data and featured dynamic content throughout the day. Dr. Neeraj Agarwal: Indeed. So, let's move on to bladder cancer. Christian, what are your key takeaways from the bladder cancer studies presented at the meeting? Dr. Christian Kollmannsberger: I think there were interesting abstracts in both the non-muscle-invasive and the muscle-invasive setting and the metastatic setting. So, for example, Abstract 442 was presented by Dr. Andrea Necchi on the cohort B of the phase 2 KEYNOTE-057 trial. As a background here, the standard treatment for high-risk non-muscle-invasive bladder cancer involves transurethral resection of the bladder tumor, a TURBT, followed by intravesical BCG therapy to eradicate any residual disease. And patients who fail to adequately respond to BCG are usually recommended to undergo radical cystectomy. So in the cohort B of the phase 2  KEYNOTE-057 trial that investigated the safety and efficacy of pembrolizumab as a single agent for patients with BCG-unresponsive, high-risk non-muscle-invasive bladder cancer who were ineligible or declined to undergo radical cystectomy, enrolled patients received standard-dose pembrolizumab of 200 milligrams every three weeks for up to 35 cycles. So very common as we do it with other disease sites. And at a median follow-up of 45.4 months, the primary endpoints of disease-free survival at twelve months was 43.5%. The median disease-free survival duration was 7.7 months. These are encouraging results, and we should keep in mind that a radical cystectomy has immense impact on our patients' quality of life. So I think it is important that we do these trials.  Now in order to address potential biases in this phase II trial, such as the underlying heterogeneity of transurethral resection of bladder tumor quality, and to obtain a more comprehensive understanding of pembrolizumab's efficacy relative to a particular control group, we need further evaluation of pembrolizumab in a randomized trial before we can really go for regulatory approval. But overall, I think for the first time in a long time that we seem to be able to move the needle in non-muscle-invasive bladder cancer. Dr. Neeraj Agarwal: Thank you, Christian, for this great overview. Could you please also share the findings presented by Dr. Matt Galsky on Abstract 443? Dr. Christian Kollmannsberger: Of course, Neeraj. Abstract 443, presented by Matt Galsky, reported the extended follow-up results from the CheckMate 274 trial, which looked at another very important field where we haven't made that much progress, which is the adjuvant setting. And CheckMate 274 examined adjuvant nivolumab compared to placebo for patients with high-risk resected muscle-invasive urothelial carcinoma. In this trial, nivolumab was given at 240 milligrams every two weeks or placebo every two weeks for up to one year of treatment. After following up with patients for a median of 36.1 months, the study found that those who received nivolumab had a median DFS of 22 months compared to only 10.9 months for those who received placebo among the ITT patients. So basically, a doubling of the DFS with the addition of adjuvant nivolumab.  The results were particularly notable for patients with high PD-L1 expressions or PD-L1 expression of 1% or more, as those who are treated with nivolumab had a median DFS of 52.6 months, which was six times higher than the DFS in the control group where patients received placebo, which was only 8.4 months. And I think that is truly impressive. One year of adjuvant therapy with nivolumab continues to show a sustained disease-free survival benefit over a period of three years in both the ITT and the PD-L1-high patient population. In my view, these results reinforce the utility of nivolumab in the adjuvant urothelial carcinoma setting after surgery. And it will be interesting to see how the overall survival pans out in this study.  So, Neeraj, moving on to kidney cancer, what were your key takeaways from these studies on kidney cancer presented in this meeting?  Dr. Neeraj Agarwal: So, there were exciting results presented from multiple studies in this area as well. For example, Abstract 603 presented by Dr. Mauricio Burotto, senior author was, Dr. Toni Choueiri on the three-year follow-up from the phase 2 CheckMate-9ER trial. So, in this trial, patients were randomized one-to-one to nivolumab 240 milligrams every two weeks, plus cabozantinib 40 milligrams daily versus sunitinib 50 milligrams daily for four weeks, and it was a six-week cycle for sunitinib until disease progression or unacceptable toxicity. So this was the design of the phase 3 CheckMate-9ER trial. And after a median follow-up of three years, the benefit of nivolumab plus cabozantinib remained consistent with previous follow-ups. So, as we know, these data have been presented in the past, also published in the New England Journal of Medicine. But this meeting was a clear follow-up of these data.  Notably, the median overall survival of patients treated with cabozantinib plus nivolumab in the ITT population, which included all favorable intermediate and poor IMDC score patients, was significantly improved at 49.5 months compared to 35.5 months in the sunitinib arm. It is so heartening to see that median overall survival breaching the four-year mark in our patients with metastatic RCC in a consistent fashion. We saw similar data with the combination of ipilimumab plus nivolumab recently. And as these trials are maturing, we are probably going to see more combinations breaching this four-year mark. So importantly, no new safety signals emerged with the additional follow-up in either arm. And I think these results provide further support for the use of cabozantinib plus nivolumab as a first-line treatment option for patients with metastatic or advanced renal cell carcinoma. Dr. Christian Kollmannsberger: Indeed, I think it is extremely impressive what we've seen over the last 15 years in metastatic kidney cancer, going from a median overall survival of about a year to now more than four years. I think that is a great achievement, and we can see it on a daily basis in our clinical practice.  Now, before we wrap up, I would like to highlight another potentially practice-changing trial, LBA602, which titled, “Results from Phase 3 Study of 89Zr-DFO-Girentuximab for PET/CT Imaging of Clear Cell Renal Cell Carcinoma: The ZIRCON Trial” presented by Dr. Brian Shuch. The background of this is that the detection of renal masses poses a challenge due to the limitations of diagnostic options such as imaging and biopsy. And we often, in clinical practice, are confronted with "What exactly is this?" And what's even more importantly, “What's the histology of this?” And a non-invasive, accurate method is needed for pre-treatment risk stratification. Girentuximab, a monoclonal antibody that targets carbonic anhydrase IX expressed on clear cell renal cell carcinoma, can obviously now aid in the differentiation between clear cell renal cell carcinomas and other renal lesions when radiolabeled with this new agent.  The ZIRCON trial was open-label and designed to include patients with renal masses up to 7 cm in size or clear tumor stage cT1 who were scheduled for partial nephrectomy within 90 days of planned TLX250-CDx administration. The enrolled patients received a single intravenous dose of girentuximab on day 0 and underwent FDG PET/CT imaging on day 5 before their scheduled surgery. And the co-primary endpoints were to assess the sensitivity and specificity of girentuximab PET/CT imaging for detecting clear cell renal cell carcinoma in patients with indeterminate renal masses, with histology as the reference standard, which I think is a great way to test these agents because you get 100% validation.  In the primary analysis of 284 patients, the average sensitivity and specificity across all three central readers were 86% and 87%, respectively, exceeding the prespecified thresholds. The positive and negative predictive values were 93.4% and 78%, respectively. And with very few related adverse events reported, the study affirms that girentuximab PET/CT is safe and effective in identifying clear cell renal cell carcinoma in patients with indeterminate renal masses. And the findings hold potential for developing optimal management strategies for patients with indeterminate renal masses. I think this is important that we add a non-invasive method to this because we are confronted on a regular basis with patients who either cannot tolerate a biopsy or where the biopsy is indeterminate. And this could potentially be a great tool to help us with our pre-treatment planning of our treatment strategy. Dr. Neeraj Agarwal: Wow. So, it looks like a new PET scan using a unique tracer and antibody to detect the clear cell renal cell carcinoma with high specificity and sensitivity. It reminds me of drawing a crude analogy from the PSMA PET scan in prostate cancer. And hopefully, we will be able to use these newer scans that we call TLX250-CDx PET/CT scan. I hope they have a simpler name for this very soon. Or maybe follow up for patients who had kidney cancer, localized kidney cancer taken out by radical surgery, and then we are following them. And sometimes, we don't know if a small lung nodule is metastatic or not. And these kinds of imaging studies may help us down the line in monitoring those patients as well. So indeed, very exciting progress not only in the therapeutic area now but also in diagnostic fields at this GU ASCO.   So with that, we have seen multiple abstracts on prostate, bladder, and kidney cancer with real impact on how we practice medicine. Thank you, Christian, for sharing your insight with us today. It is an exciting time in GU Oncology, and we appreciate you taking the time to contribute to the discussion. Thank you so much.   Dr. Christian Kollmannsberger: Thank you, Neeraj, thank you for having me. And I completely agree it remains an exciting time in GU oncology.   Dr. Neeraj Agarwal: And thank you to our listeners for joining us today. You will find links to the abstracts discussed today on the transcripts of this episode.  Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts.   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Find out more about today's speakers:   Dr. Neeraj Agarwal  @neerajaiims Dr. Christian Kollmannsberger Follow ASCO on social media:    @ASCO on Twitter    ASCO on Facebook    ASCO on LinkedIn    Disclosures:   Dr. Neeraj Agarwal:    Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, AstraZeneca, Pfizer, Merck, Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences   Research Funding (Institution): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, crispr therapeutics, Arvinas   Dr. Christian Kollmannsberger: None disclosed  

Guest host Dr. Neeraj Agarwal and Dr. Jeanny Aragon-Ching discuss several crucial studies that will be presented at the 2023 ASCO Genitourinary Cancers Symposium, including ARASENS, TRITON3, and others in prostate cancer, as well as novel therapies in mRCC and urothelial carcinoma. TRANSCRIPT Dr. Neeraj Agarwal: Hello, and welcome to the ASCO Daily News Podcast. I'm Dr. Neeraj Agarwal, your guest host of the ASCO Daily News Podcast today. I'm the director of the Genitourinary Oncology Program, a professor of medicine at the University of Utah Huntsman Cancer Institute, and editor-in-chief of the ASCO Daily News. I'm delighted to welcome Dr. Jeanny Aragon-Ching, a medical oncologist and the clinical program director of the Genitourinary Cancers Program at the Inova Schar Cancer Institute in Virginia.   Today we will be discussing key abstracts in genitourinary oncology that will be featured at the 2023 ASCO Genitourinary Cancers Symposium.   Our full disclosures are available in the show notes, and disclosures for all guests on the podcast can be found on our transcripts at asco.org/podcasts. Jeanny, it is great to have you on the podcast today.   Dr. Jeanny Aragon-Ching: Thank you so much, Dr. Agarwal, for having me.  Dr. Neeraj Agarwal: So Jeanny, let's begin with Abstract 15 on the update on the ARASENS trial, which Dr. Maha Hussain will present [at the meeting]. In March ‘22, as we know, almost a year ago, the results of the ARASENS trials were published in the New England Journal of Medicine. Darolutamide, which is an AR signaling inhibitor plus androgen deprivation therapy plus docetaxel chemotherapy, significantly reduced the risk of death by 32.5% versus placebo plus ADT plus docetaxel. The effect of triplet therapy, including darolutamide on overall survival, was consistent across prespecified subgroups. However, survival outcomes by disease volume were not reported at the time. Can you please tell us about Abstract 15?  Dr. Jeanny Aragon-Ching: Yeah, thank you so much, Neeraj, I would be happy to. So, this new data is actually very crucial for all clinicians. The title of this abstract is “Efficacy and Safety of Darolutamide in Combination with ADT and Docetaxel by Disease Volume and Disease Risk in the Phase 3 ARASENS Study.” So, as a quick reminder, in this trial, patients were randomized 1:1 to the standard dose of darolutamide 600 milligrams twice daily or placebo with ADT and docetaxel in the metastatic hormone-sensitive prostate cancer setting.    Now remember, too, high volume disease was defined per the charted criteria, which is visceral metastases and/or four or more bone lesions, of which at least one or more has to be beyond the vertebral column or pelvis. 8And high-risk disease was actually defined per the LATITUDE criteria, which is any two or more of the following three factors: Gleason scores eight or more, bone lesions that are three or more, and the presence of measurable visceral metastases. Of all the 1,305 patients, 77% of them were actually classified as having high-volume disease, and 70% of them had high-risk disease. So, in both of these high-volume and low-volume disease patients, the triplet therapy darolutamide, ADT, and docetaxel actually improved overall survival and hazard ratio was 0.69 and 0.68, respectively. Compared to the placebo and ADT, and docetaxel arm. So overall survival improvement was also significant in patients across all risk, high-risk, or low-risk disease.   Dr. Neeraj Agarwal: So, Jeanny, this is great news. So, the main message from this abstract for our audience is that triplet therapy of darolutamide plus docetaxel plus ADT is more efficacious than the doublet of ADT plus docetaxel chemotherapy, regardless of disease volume or risk status.   One important caveat I would like to note is that triplet therapy with the darolutamide was not compared with the doublet therapy of ADT plus darolutamide or any androgen receptor signaling inhibitor such as abiraterone or apalutamide or enzalutamide, all of which have shown benefit consistently, regardless of volume status, and in the case of abiraterone, also in the context of high-risk disease setting, as we saw in the LATITUDE trial.  Dr. Jeanny Aragon-Ching: Absolutely. I agree with that, Neeraj. Those are important points to consider.   Now, moving on to a different setting in prostate cancer across the disease continuum, let's discuss Abstract 18, titled “Rucaparib for Metastatic Castrate-Resistant Prostate Cancer.” This is TRITON3 entering overall survival and efficacy of rucaparib versus docetaxel or second-generation engine pathway inhibitor therapy, which will provide us with some additional data regarding overall survival. Neeraj, based on this new abstract, can you tell us more about TRITON3, which will be presented by Dr. Alan Bryce and colleagues from the Mayo Clinic Arizona?  Dr. Neeraj Agarwal: Of course. So TRITON3 is a randomized multicenter open-label phase 3 trial where rucaparib was compared with the physician choice of docetaxel chemotherapy or abiraterone or enzalutamide in those patients who had not received chemotherapy in the metastatic castration-resistant prostate cancer setting, and they had to be progressing on a prior androgen receptor signaling inhibitor in any setting prior. So, they just had to have disease progression either in the hormone-sensitive setting or CRPC setting on one of the AR inhibitors, and they had to have a BRCA1, BRCA2, or ATM alteration.   So, in this context, these patients were randomized to rucaparib versus physician's choice of agent, which could again be docetaxel chemotherapy, abiraterone, or enzalutamide. So, OS maturity is 54% in BRCA group and 59% in the intention to treat population. In BRCA1 and BRCA2 populations, radiographic PFS, which was the primary endpoint, was 11.2 months in rucaparib group and 6.4 months in the physician choice arm. In the intention to treat population where you include all patients BRCA plus ATM patients, ATM positive patients. Radiographic PFS was 10 months almost versus 6.4 months with standard of care. And both were statistically significant as well as clinically meaningful improvement in the radiographic progression-free survival with rucaparib over physician's choice of either docetaxel or enzalutamide, or abiraterone. I would like to note that most frequent toxicity which we see with this group of agents is most frequent grade III or more toxicity was anemia, which was present in approximately 24% patients treated with rucaparib.  Dr. Jeanny Aragon-Ching: Yeah. This is a really exciting update, Neeraj. What do you think is the key takeaway from this abstract?  Dr. Neeraj Agarwal: The key takeaway is that TRITON3 trial met its primary endpoint, and rucaparib significantly improves radiographic progression-free survival in BRCA mutation-positive patients or BRCA ATM-positive patients. Overall survival is still immature, and these results further establish rucaparib as one of the standard of care options in those patients who have metastatic CRPC with prior treatment with the AR signaling inhibitor and who harbor one of the BRCA mutations or BRCA NAT mutations.   So, Jeanny, before moving on to the renal cell carcinoma section in this podcast, there is an Abstract in prostate cancer talking about correlation between the source of funding and disparities among patients with advanced prostate cancer. So, I'm referring to that Abstract 40, titled “Source of Funding and Enrollment Disparity in Prostate Cancer Clinical Trials.” I thought this was an interesting abstract. Could you please tell us more about this abstract?  Dr. Jeanny Aragon-Ching: Absolutely, Neeraj. So, in Abstract 40, Dr. Riaz and Dr. Bryce, and colleagues actually looked at phase II and III clinical trials that involved prostate cancer patients that reported on patients with age by 65 years, and they got the data from the MEDLINE and Embase databases. Trials recruiting from the United States were considered eligible for analysis by race and ethnicity. So, in terms of race and ethnic enrollment, they found that black patients were significantly underrepresented in the industry's funded trials. Notably, no significant disparity was observed in the US government-funded trials, but Hispanics were also significantly underrepresented in industry-funded clinical trials. However, no significant disparity was seen in terms of older adults overall and by funding sources. Remarkably, Black patients' representation in industry-funded prostate cancer trials has actually decreased over the last three decades.  Dr. Neeraj Agarwal: That's concerning. So, what is your key takeaway from this trial, Jeanny?  Dr. Jeanny Aragon-Ching: The key message here is that Black and Hispanic men with prostate cancer are significantly less likely to be included in industry-sponsored clinical trials. A bigger concern is that black patients' representation actually continues to decline over time. So these results warrant a really more proactive role by regulatory bodies to ensure that a proportional representation of minorities in the industry trials, which in turn will make these results more applicable to a wider entire population of men with prostate cancer.  Dr. Neeraj Agarwal: Thanks, Jeanny. Let's move on to renal cell carcinoma. I saw some innovative research correlating the efficacy of immune checkpoint inhibitors with the time of the day these checkpoint inhibitors were administered. So, interestingly, there were two studies from two different groups of investigators showing very similar results. Please tell us about this innovative research correlating outcomes with immune checkpoint inhibitors with the time of the day these medicines or these drugs were infused into the patients.   Dr. Jeanny Aragon-Ching: Absolutely, Neeraj. I think they're very exciting and interesting. So there's actually two abstracts, so Abstract 681 and 678, which we, of course, can discuss separately. So, let's probably start first with Abstract 678. Neeraj, do you want to explain to us further about this abstract?  Dr. Neeraj Agarwal: Yes. When our center participated in that abstract, which was led by Dr. Nazli Dizman from Yale University, Dr. Dizman and colleagues examined the relationship between the time of the administration of immune checkpoint inhibitors, or ICIs, as we call them, during the time of the day, and outcomes in patients with metastatic renal cell carcinoma. So, I'd like to point out that previously Dr. Qian and colleagues reported an association between the time of day of immunotherapy infusion and survival outcomes in patients with metastatic melanoma.   In this study, Dr. Dizman and colleagues, which included our center also, patients with metastatic RCC who received nivolumab with or without ipilimumab– so these patients all received either nivolumab alone or without ipilimumab. And patients who received less than 25% of infusion after 4:30 pm. were assigned to the early-time of infusion group. So, if they have received less than 25% infusion of these immunotherapies after 04:30 pm in the evening, they belong to the early infusion group, and the rest were assigned to the late infusion group.  In the univariate analysis, numerically higher objective responses and time to treatment failure were observed in the early infusion group compared to the late infusion group. So, differences were 33% versus 25% in objective responses in early versus late infusion group. If you look at time to treatment failure, 8.3 months versus 4.4 months in early versus late infusion group. In the multivariate models, which took into account the clinical characteristics such as age, gender, line of treatment, IMDC risk category, histological subtypes, there was a trend towards improved outcomes in those who received these infusions with ICIs early in the day. So, Dr. Dizman concluded that larger randomized and controlled investigations are warranted to examine the impact of this chronal modulation, if you will, on the efficacy of immune checkpoint inhibitors in metastatic RCC sets.  Dr. Jeanny Aragon-Ching: Yeah, this is very interesting data, Neeraj. And that actually resonates closely with this other abstract by Fernandez Manias and colleagues in Abstract 681. So, in this abstract, the primary outcome was overall survival, but they did look at other secondary endpoints like time on treatment, time to the next treatment, and overall response rates. Now, because of the small number of events, the authors actually focused on just patients who received second-line immune checkpoint inhibitors. And what they did was they looked at patients who received overall more than 20% of their infusions after 04:30 pm, and they found that those who did receive actually fewer infusions had a significantly shorter time on treatment and had a worse overall survival. And similar results were seen when they looked at those who got more than 50% of their dose of checkpoint inhibitors that were administered after 04:30 pm, so interestingly enough, there was a 16% increase in the risk of death for each 10% increment of checkpoint infusion after 04:30 pm. So the key message here is that administration of checkpoint inhibitors after 04:30 pm is associated, unfortunately, with inferior outcomes. Now, these results should, of course, be further considered in the organization overall of the outpatient clinic as it can impact patient survival and outcomes.  Dr. Neeraj Agarwal: Very interesting. So similar results from two independent groups of investigators from two different continents obviously made this research area very appealing and pertinent. Ideally, I think these results should be validated prospectively, but that will take time. But investigators who have already lagged multiple phase III trials should explore validating these results in the last phase 3 trials which have already been reported and where the data on the timing of infusion is available. Once validated, I think these results may profoundly influence how we organize, as you said, Jeanny, the outpatient scheduling of these checkpoint therapy infusions compared to those who are not checkpoint inhibitors. I think this is going to have very interesting data overall, no doubt.   Before moving onto bladder cancer, I would like to discuss an important abstract related to testicular cancer patients titled “Longitudinal Evaluation of Plasma MicroRNA-371 to Detect Minimal Residual Disease and Early Relapse of Germ Cell Tumors.” Could you please tell us more about this abstract?  Dr. Jeanny Aragon-Ching: Yeah, absolutely, Neeraj. So this is a very interesting up-and-coming Abstract, it's number 407, which will be presented by Dr. Lucia Nappi and colleagues. In this study, clinical patients with stage I germ cell tumor with available plasma samples after they underwent radical orchiectomy were all included. So, they looked at sensitivity, specificity, negative, positive predictive values, an area under the curve in predicting tumor recurrence, and they evaluated the microRNA-371, I'll just call it and truncate it as miR-371, and compared the same operating characteristics of current gold standard diagnostic tests. Relapse-free survival was correlated to post-orchiectomy miR-371 status, which could be either positive or negative.   So, at a median follow-up of 41 months, 101 patients with clinical stage one germ cell tumor were included. About 35% of them experienced a disease relapse during that time of follow-up. Now, what they found was miR-371 was positive in about 63% of the relapsed patients, and the miR-371 positivity preceded clinically evident disease by a median of about three months. The specificity and positive predictive values were 100%, sensitivity was like 63%, and negative predictive value was 83.5%, so very high. No false positive results were seen. And, the authors reported that the recurrence-free survival of the patients who had positive post-orchiectomy miR-371 was significantly shorter compared to those patients who had a negative biomarker for the miR-371. So, they concluded that the miR-371 sensitivity correlated with the tumor burden, time between tumor relapse, the microRNA testing, and histology. It was notably a little bit more sensitive in non-seminomas compared to those who had seminoma.  Dr. Neeraj Agarwal: Interesting findings, indeed. So, Jeanny, what is the take-home message from this abstract?   Dr. Jeanny Aragon-Ching: Yeah, so I think the key takeaway is that microRNA-371 seems to be a good test, like a biomarker for predicting disease relapse in patients with early-stage germ cell tumor. So, additionally, its high specificity and positive predictive value in predicting relapse could really be used and utilized to guide adjuvant therapy, selections, and decisions after orchiectomy. Further validation in other studies, such as swab 1823, are currently ongoing or planned to validate its clinical utility.   So Neeraj, moving on to bladder cancer, the last abstract I'd like to mention before we wrap up the podcast is Abstract 563, titled “Utility of ctDNA in Predicting Outcome and Pathological Complete Response in Patients with Bladder Cancer as a Guide for Selective Bladder Preservation Strategies.” Neeraj, can you tell us more about this abstract?  Dr. Neeraj Agarwal: Sure. So, this study was led by Dr. Lars Dyrskjøt. He and colleagues evaluated the prognostic value of circulating tumor DNA, or ctDNA, in predicting recurrence in a cohort of 68 patients with muscle-invasive bladder cancer who received new adjuvant chemotherapy prior to cystectomy. So ctDNA was analyzed two times at baseline before new adjuvant chemotherapy and then before surgery or before cystectomy. So, patients had ctDNA assessed before neoadjuvant chemotherapy and then before cystectomy after completion of new adjuvant chemotherapy. At baseline, of the 64 patients, around 60% were ctDNA negative, and 40% were positive for ctDNA. So of those patients who were ctDNA negative, 84% achieved pathologic complete response, while in those who tested ctDNA positive, only 35% achieved their pathologic complete response after surgery.   Prior to surgery, 84% of patients were ctDNA negative, and 81% achieved pathologic complete response. While none of the ctDNA-positive patients who were positive before surgery and after neoadjuvant chemotherapy, none of them achieved pathologic complete response, which translates into a positive predictive value of 100% and a negative predictive value of 81% for this test. So based on both ctDNA time points, the probability of ctDNA negative patients to achieve a pathologic complete response was significantly higher than ctDNA positive patients.   At a median follow-up of 59 months, ctDNA-positive patients without pathologic complete response demonstrated significantly lower recurrence-free survival and overall survival compared to those who were ctDNA negative. So, I want to repeat that, at a longer follow-up, which Dr. Dyrskjøt will be presenting, ctDNA positive patients without pathologic complete response had significantly lower recurrence-free survival and overall survival compared to ctDNA negative patients. Furthermore, ctDNA status at baseline, which is before neoadjuvant chemotherapy and before cystectomy, was a better predictor of recurrence-free survival compared to pathologic complete response, which is a remarkable finding here, although it's a smaller data set.  Dr. Jeanny Aragon-Ching: Agree completely, Neeraj. So, I think the importance here, too, is upon prospective validation in larger data sets, we will find that a negative ctDNA test would help in identifying patients who can benefit more from bladder-sparing strategies.   Neeraj, any final thoughts before we wrap up the podcast today?  Dr. Neeraj Agarwal: Before I share my final thoughts, Jeanny, I would like to thank you for joining us and sharing your insights. I always find them very valuable. So, thank you so much for taking the time.   I would like to wrap up the podcast by saying we are seeing an explosion in the development of novel therapeutic approaches for our patients with genitourinary cancers. At the 2023 ASCO GU meeting, we will have multiple studies with practice-impacting data presented by investigators from around the world. I urge our listeners to come and join us in the meeting not only to celebrate these successes but also to help disseminate these cutting-edge data to practitioners and maximize the benefit for our patients across the globe.   I would like to thank our listeners for joining us today. You will find links to the abstracts which we discussed today on the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcasts. Thank you so much.    Disclaimer:   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.    Guests on this podcast express their own opinions, experiences, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.     Find out more about today's speakers:   Dr. Neeraj Agarwal  @neerajaimms  Dr. Jeanny Aragon-Ching  Follow ASCO on social media:    @ASCO on Twitter    ASCO on Facebook    ASCO on LinkedIn      Disclosures:   Dr. Neeraj Agarwal:    Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, AstraZeneca, Pfizer, Merck, Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences   Research Funding (Institution): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, crispr therapeutics, Arvinas   Dr. Jeanny Aragon-Ching:    Honoraria: Bristol-Myers Squibb, EMD Serono, Astellas Scientific and Medical Affairs Inc   Consulting or Advisory Role: Algeta/Bayer, Dendreon, AstraZeneca, Janssen Biotech, Sanofi, EMD Serono, AstraZeneca/MedImmune, Bayer, Merck, Seattle Genetics, Pfizer, Immunomedics, Amgen, AVEO, Pfizer/Myovant, Exelixis   Speakers' Bureau: Astellas Pharma, Janssen-Ortho, Bristol-Myers Squibb , Astellas/Seattle Genetics   Travel, Accommodations, Expenses: Dendreon, Algeta/Bayer, Bristol Myers Squibb, EMD Serono, Astellas Pharma    

Dr. Charles Ryan, president and CEO of the Prostate Cancer Foundation (PCF), joins ASCO Daily News Editor-in-Chief Dr. Neeraj Agarwal, of the University of Utah Huntsman Cancer Institute, to assess impactful prostate cancer research from the PCF's recent conference and discuss Dr. Ryan's vision for the future, including increasing access to cutting-edge care. TRANSCRIPT Dr. Neeraj Agarwal: Welcome, to the ASCO Daily News Podcast. I'm Dr. Neeraj Agarwal, the editor-in-chief of the ASCO Daily News, and director of the Genitourinary Cancers Program at the University of Utah Huntsman Cancer Institute. Today, we'll be discussing compelling research that was featured at the recent Prostate Cancer Foundation Scientific Retreat, and I'm very pleased to welcome Dr. Charles Ryan, the president, and CEO of the Prostate Cancer Foundation. Our full disclosures are available on the transcript of this episode, and disclosures relating to all episodes of the ASCO Daily News Podcast are available on our transcripts at: asco.org/podcasts. Dr. Ryan, thank you for taking the time to be with us today. Dr. Charles Ryan: Dr. Agarwal, thank you. It's my pleasure to be with you. Dr. Neeraj Agarwal: So, Dr. Ryan, before I discuss the PCF meeting, I would like to ask you, what made you move to the PCF as the president and CEO when you had a flourishing career as a division chief of a large academic program, and as one of the top and internationally recognized investigators in prostate cancer? Dr. Charles Ryan: Well, thanks. That's a fair question, I guess. And it took me about three minutes to make the decision when I was offered the position, simply because the Prostate Cancer Foundation has been one of my intellectual homes for my entire career. I've been at the University of Wisconsin, Memorial Sloan Kettering Cancer Center, UCSF, and the University of Minnesota, and all those institutions were affected by the Prostate Cancer Foundation, or previously, CaP CURE. So, I was involved in their research during my time at all those institutions. In addition to my own personal legacy with the PCF, but more importantly, is the fact that it is an organization that funds the deepest scientific inquiry into prostate cancer and the ways that it can cause suffering and death for men with the disease and has made tremendous progress in identifying factors that lead to that lethality. It's also a community of scholars, a community of researchers, that is a platform really for collaboration. And it's also an organization with a world reach - we fund research in 28 countries around the world, and we fund research going from the scope of very basic research to correlative research, to quality of life, and health services research. Dr. Neeraj Agarwal: That is truly impressive and inspiring. So, what is the mission of the Prostate Cancer Foundation formally? Dr. Charles Ryan: Formally, it's pretty simple. The mission of the Prostate Cancer Foundation is to reduce the death and suffering from prostate cancer. Dr. Neeraj Agarwal: So, the 29th PCF Scientific Retreat was recently held on October 27 to October 29th in Carlsbad, California. What were the goals and objectives of this meeting? Dr. Charles Ryan: The meeting, we call it the retreat, it's an annual event and it always has several goals. One is, it's where we announce and hand out, if you will, our awardees of our various awards that we give. It's also a reporting-in process where those who have been using PCF funding are called to come and discuss their work. We also want it to be an open forum for individuals to come and interact - it's really a collaboration and an interaction vehicle as much as anything. So, when you come to our scientific retreat, we all stay at the same hotel, we all share meals together, nobody goes out for dinner. You don't leave the campus, essentially, of the hotel where we are. We have many, many round tables set out, it's designed to be interactive. We have a big room where people are giving their talks, but if you step outside of the room, there are likely to be many, many conversations happening, and those conversations range from collaborations being formed to people looking for jobs, to people getting advice and mentoring, and even people sharing, as I've done over the years, compelling and challenging patient stories around prostate cancer, and really engaging in what communities do - which is, share ideals, share a mission, and share a passion for what they do. Dr. Neeraj Agarwal: Very interesting. Very inspiring. Please tell us some of the highlights of the meeting. Dr. Charles Ryan: Sure. Well, there are many highlights. There are many things happening in prostate cancer research. Most notably, there are a number of papers and investigators that are looking at how prostate cancer evolves, and probably the most significant set of observations that have been made in the field in the last decade, have been understanding the diverse and numerous mechanisms that underlie the evolution of prostate cancer from a disease that responds to hormonal manipulation, to one that becomes resistant to hormonal manipulation. And so, a lot of the work that's happening now is identifying, for example, the evolution of neuroendocrine prostate cancer, or mixed types of prostate cancer, or this sort of evolution of it under constant therapy. And that is allowing the exposure of new targets that we can exploit for new therapy development, and that feeds into some of the grant-making process that's going on in the background. And so, you have a lot of individuals who are looking at this or that mechanism pathway related to disease resistance that they can exploit, and whether they can create small molecules to do that, or antibodies to do that, et cetera. At the same time, we have a strong component of discussion of how prostate cancer affects different populations. So, we had some really nice talks looking at healthcare disparities and different populations across the world, and how they're affected by prostate cancer, and how care delivery may be impacted in those groups of patients. And then you have topics ranging around survivorship and other factors that are looking at what is life like for a man with advanced prostate cancer, which is in many cases, you know, men who get prostate cancer, who have recurrent disease, who end up going on systemic therapy are frequently on the treatment for 5, 10, 15 years. And so, survivorship, and how they live their life, and what the complications are of that treatment, is tremendously important because it's such a daily experience for these men undergoing treatment. Dr. Neeraj Agarwal: So, how does the Prostate Cancer Foundation support and build the next generation of prostate cancer researchers? Dr. Charles Ryan: Right. So, the PCF supports the next generation in a very specific way, in addition to the informal way of bringing people together and inducing collaborations. We have a program called the Young Investigator Program. It started formally in 2008, but before that, there were one-off, if you will, Young Investigator Awards being given. So, our Young Investigator Awardees receive $75,000 per year to support their work, and we awarded 34 of those this year. The range is somewhere from 25 to 34 per year. We get over 100 applications for them every year. It's a straightforward application - they need to have a project that's going to be about three years in length, they need to be mentored, and they are best served by describing a mentorship plan for themselves and how that mentorship relationship will help them grow in their careers. Now, once you become a Young Investigator, it's not that we just write you a check and wish you well, we do that, but we also have annual check-ins. So, we try to visit the sites of our Young Investigators, see them in their home institution, and meet with their colleagues and their mentors. And that's one of the things I do, or Howard Soule does-- Howard Soule, is our chief scientific officer, one of those things we try to do. We also bring them to the scientific retreat that we just had last week, and we have them present their data. So, a vast number of the individuals who are presenting at the scientific retreat are in fact, Young Investigators, or they were Young Investigators when they started the projects that they are presenting. And then, the other thing we do is we have another retreat specifically for the Young Investigators, and that's called the Coffey-Holden Retreat, and that's named after Don Coffey, the late researcher from Johns Hopkins, who is really considered to be one of the grandfathers of prostate cancer research, and Stuart or Skip Holden, who is one of the founders of the Prostate Cancer Foundation, and a urologist at UCLA. So, that event that we do is designed for people to come to give highlights of the work that they're doing; it's designed to be incredibly interactive. In fact, we have 15 or so minutes of presentation, followed by sometimes 25 minutes of questions for each presenter. There's always a line of people who are waiting to ask questions, and it's designed to engage and have that dialogue with the Young Investigators, to make their science better, and to get it known. And so, the Young Investigator Program, it's about 30 individuals per year on average, and the average age is about 30. Many of these are postdoctoral PhDs, and many of them are fellows, or early-stage faculty, MDs. And I like to think that if somebody's going to work until the age of 70, we're stimulating, or launching a 40-year career with these Young Investigator awards. So, I like to think that if we give 25 out, times 40 years, that's 1,000 years of research that we're sort of stimulating with this Young Investigator program. And I bring that up for the reason that we're very proud of the fact that many of our Young Investigators may start out in prostate cancer, and their ideas, their science, takes them elsewhere. And that's what science does. And we, of course, are very, very focused on solving the problem of prostate cancer, and we want people to do that. But we also understand that by launching a scientist, by launching a scientific career, you may end up with people going off in different directions. And so, we have many examples of that. And in my talk this year, I actually highlighted a person who, let's say she won an investigator award when she was young, it was before the formal Young Investigator Award was named, and this was a person who is creating conjugates for the delivery of chemotherapy to prostate cancer cells. And this was Carolyn Bertozzi up at UC Berkeley, and she just won the Nobel Prize. She didn't win the Nobel Prize for research she did on prostate cancer, but at some point, at one point in her career, this was a direction she was going, and she got two grants from us in 1999 and 2000, that helped her work continue on and go the direction that it did. Dr. Neeraj Agarwal: Yeah. And congratulations. Dr. Charles Ryan: Sure. I'll take credit for that one. Dr. Neeraj Agarwal: Being the President and the CEO, you deserve the credit. Dr. Charles Ryan: Sure. That's my job. Dr. Neeraj Agarwal: So, we are coming to the end of the interview, but let me ask you this; the prostate cancer field is so constantly evolving. What is your vision for PCF going forward? Dr. Charles Ryan: Well, my vision for the organization is that we are going to continue on our mission to reduce the death and suffering from prostate cancer. But that's a fairly general statement, and one of the ways you can do that is you can research cancer at a molecular level, and you could try to develop new therapies - we're going to continue to do that. But there's also a real problem, especially, in the United States, and actually globally, with individuals with prostate cancer who are not receiving the cutting-edge care, not receiving the cutting-edge therapy. We have some data that in the United States, maybe upwards of 50% of men with metastatic hormone-sensitive prostate cancer are not getting the therapies that are supported by the latest findings from randomized phase III trials. And this may be for economic reasons, it may be communications or an education deficit with their treating clinicians, and there may be other factors as well. So, as we think about the vision of this, we need to be mindful of that, because if we only focus on studying the cancer molecularly, and we don't address what's happening on the other end, then we're not completing the story, and we're not completing the mission. And so, I've started calling Prostate Cancer Foundation the Global Public Square of Prostate Cancer, because I think of four sides of that square - funding research, as of what we just got done talking about, education and communication, is another one, and we do that in the same way that you are doing this today - through podcasts, and web content, and in-person meetings, as well as applied discovery, which is helping our researchers take their discoveries or their findings out into the clinic. Now, you might think, "Well, that's a small molecule, becoming a company going into a phase I clinical trial." Certainly, that's part of it, but it's also the epidemiologist who is making observations about diet and exercise, who is then empowered to do a clinical trial of exercise and diet intervention. It's also the health services researcher who is able to use their data to go talk to payers or talk to organizations about how care may be delivered differently. So, that's applied discovery. And then finally, supporting the patient is part of what we do. So, we also hold patient webinars every month, we've held patient summits at various points around the country where we bring patients together and talk to them about the latest research or about the factors we've discussed, such as survivorship, or quality of life after treatment, or treatment complications, and things like that. Dr. Neeraj Agarwal: That's wonderful. Thank you so much for sharing your insights. Any final remarks, Dr. Ryan? Dr. Charles Ryan: Dr. Agarwal, thank you so much. It's always a pleasure to speak to another Genitourinary Oncologist, of course, about the field, and the opportunity to talk about the Prostate Cancer Foundation and what we're doing, and the directions we are trying to grow. We've had a great collaboration with ASCO over the years, and I hope that that continues as well. I hope anybody who is interested would come and visit us at: pcf.org, and they can also check us out on: urotoday.com, where we have a lot of content that might be of interest to them. Dr. Neeraj Agarwal: Thank you, Dr. Ryan, for taking the time to be with us on the ASCO Daily News Podcast today. And thank you to our listeners for joining us today. If you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe, wherever you get your podcast. Thank you very much. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy, should not be construed as an ASCO endorsement. Follow today's Speakers: Dr. Neeraj Agarwal @neerajaimms Dr. Charles Ryan @charlesryanmd Want more related content? Listen to our podcast on therapeutic advances in prostate cancer and other GU cancers.   Advances in Genitourinary Cancers at #ASCO22 Follow ASCO on social media: @ASCO on Twitter ASCO on Facebook ASCO on LinkedIn   Disclosures: Dr. Neeraj Agarwal:  Consulting or Advisory Role: Pfizer, Medivation/Astellas, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, AstraZeneca, Pfizer, Merck, Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, Gilead Sciences  Research Funding (Inst.): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck , Lilly, Nektar, ORIC Pharmaceuticals, crispr therapeutics, Arvinas   Dr. Charles Ryan: Honoraria: Janssen Oncology, Bayer Consulting or Advisory Role: Bayer, Dendreon, AAA, Myovant Sciences, Roivant, Clovis Oncology  

Host Dr. John Sweetenham, of the UT Southwestern's Harold C. Simmons Comprehensive Cancer Center, and Dr. Bridgette Thom, of the Memorial Sloan Kettering Cancer Center, discuss a novel intervention to address financial toxicity and social need using the Electronic Medical Record.   TRANSCRIPT Dr. John Sweetenham: Hello. I'm Dr. John Sweetenham, the associate director for clinical affairs at UT Southwestern Harold C. Simmons Comprehensive Cancer Center and host of the ASCO Daily News podcast. My guest today is Dr. Bridgette Thom, a researcher at Memorial Sloan Kettering (MSK) Cancer Center. We'll be discussing a novel approach to address financial toxicity that uses the electronic medical record to streamline referrals to financial assistance and counseling for high-risk patients. Our full disclosures are available in the show notes, and disclosures of all guests on the podcast can be found on our transcripts at asco.org/podcasts. Dr. Thom, it's great to have you on the podcast today. Dr. Bridgette Thom: Thanks so much for having me. Dr. John Sweetenham: Dr. Thom, the high costs of cancer care have caused major financial distress for many patients and their families. And this, of course, has been the subject of a great deal of literature in recent years. As you noted in your poster presentation at the recent ASCO Annual Meeting, there are limited interventions, despite a need for patient level and system-based solutions (Abstract 6596). Listeners to our podcast will remember a previous discussion that we had with Dr. Derek Raghavan from the Levine Cancer Institute, where they had instituted financial toxicity grand rounds to partially address this problem. Can you tell us about the novel approach that you and your colleagues explored using the electronic medical record to streamline referrals for financial assistance and counseling? Dr. Bridgette Thom: I first have to credit our team for this work. Dr. Emeline Aviki, who is a gynecological surgical oncologist with keen interest in affordability and payment models, founded the MSK affordability working group several years ago. The first priority of the group was to determine the scope of financial hardship at our institution. At the time, we were absent a systematic screening process. So she, our data analysts, and representatives from our Patient Financial Services Program, developed proxy measures to figure out which patients might be having financial issues. Looking through the medical record, we found those patients who had used one of our Patient Financial Services assistance programs, those who had billing issues, and those who had been referred specifically to social work for a financial issue. And in doing so, we found out that about 25% of our patients over a 2-year period were facing some sort of financial issue. Looking closer at that data, patients experiencing financial hardship weren't necessarily being connected to the resources that we had available, which include copay assistance programs, financial assistance programs, and support for non-medical essential needs. So, for example, we had about 1 in 6 patients who had some sort of payment issue, but only about 20% of them had applied for financial assistance. And we wanted to figure out why this was happening and review the process. In doing so, we discovered that too much burden was being placed on already burdened social workers who had to triage all those issues. So Dr. Aviki in her wisdom realized that care providers, physicians, advanced practice providers (APP), nurses needed to make direct referrals to the resources that we had. So we had a place for patients to go, we just needed an easier mechanism for them to get there. And that was the birth of the financial toxicity order set. And she and her team really powered through the developmental and testing phases working with IT, our strategy administration groups, clinical end users, our PFS team, that's Patient Financial Services. We built this order set that allows clinicians directly to refer to our resources. So clinicians, either through their discussions with patients or if patients bring up an issue, through the order set they can select a reason for a referral, the urgency of referral, the clinical location, etc. And then those orders go directly to our Patient Financial Services staff who then contact patients. We piloted this program in late 2020, early 2021 on 1 service, and then used that feedback to roll out the program first to our outpatient clinics and then to inpatient. That process involved a lot of educational efforts, getting the word out, and working with IT and our strategy team to stay on top of the data and monitor referrals over time. Dr. John Sweetenham: Thanks. Could you say just a little bit more about the educational process that you use? I noticed in looking at your poster that the bulk of referrals came either from the clinic nurse or from the APP. Did you tailor your education in any way to the specific provider that was involved? How did you do that piece? Dr. Bridgette Thom: Our affordability working group is an interdisciplinary team and we have nurses, social workers, physicians. So we did a lot of grand rounds work tailored to the audience be it by disease type or clinical role. Dr. John Sweetenham: Great, thank you. This is clearly great work. There's a lot of useful and helpful information in your abstract and in your poster. What would you say are the key takeaways from the intervention? What would you say about the scalability of this approach into community practice as opposed to a very large institution such as yours? Dr. Bridgette Thom: One key takeaway from a process perspective was the need, like I said, for an interdisciplinary approach to handling the issues. That might seem obvious, but it was really crucial to the success of the project to engage key departmental stakeholders and decision makers very early in the process and keep them informed throughout the development of the order set. That definitely helped us to smooth a potentially bumpy road when we're dealing with big systems change. From an outcomes perspective, a key takeaway is the importance of having actionable items to empower the care providers. So while our institution has this amazing program, our Patient Financial Services program which provides counseling, and connects patients to tangible resources, this type of intervention I think could be scalable or applicable to a community practice or smaller hospital, provided there's somebody, a social worker, patient navigator, [or] nurse, that can be a connection for patients and those potential resources that do exist out there. For us going forward, we're going to continue to evaluate the order set, both from the clinical end user and then also the Patient Financial Services staff to learn more about their perspectives and what can be adapted in the order. We also, of course, want to learn from our patients about their experience with the process, and so we have projects, both research and program evaluation, in the works to consider their perspective. Dr. John Sweetenham: Great, thank you. And I guess 1 of the other aspects of this where there is obviously substantial opportunity is that, of course, currently, you're still reliant upon the provider to place the order. And I wonder whether you feel that some form of screening for social need and financial hardship could be embedded within the electronic health record as a key next step, so that you proactively identify those high-risk patients. Dr. Bridgette Thom: Definitely. And that is, in fact, our next step. We are currently piloting our financial hardship screening tool on 4 large services at our institution. The objective here is to, like you said, proactively identify patients who might be at risk and connect them to resources, be it tangible resources, or just counseling or insurance guidance, [and] do that before the hardship can occur. And the goals of our pilot phase are to (1) develop and refine a tool that's both predictive, but also feasible to administer within a busy clinic setting. And then also (2) to work with our interdisciplinary team to adapt the workflow. We can have a great tool, but if we don't have a way to administer it in a clinic, it's not going to do us any good. So for us, that means listening to feedback from, first and foremost, our patients and then the key stakeholders in the process. Our nurses have been integral to this process. We also, of course, our Patient Financial Services, staff, the clinical operations staff, obviously, IT, social work. And once we have these processes figured out and we have our tool solid, we will hopefully expand the screening to all services, and then use data to figure out the optimal screening interviews by disease and treatment type because we feel that this could vary by a patient's treatment trajectory. Dr. John Sweetenham: You note in your poster that additional multilevel interventions are needed to address the problem of financial toxicity at a systems level, and of course, what you have done here is a really great and important step in helping to identify those patients. But identifying those patients who are at particular risk is only beginning of addressing the issue. Could you elaborate a little bit more on other areas that you're exploring in terms of the interventions that you're using? Dr. Bridgette Thom: Sure. And this idea of multi-level interventions comes from my social work training, where there's an emphasis on viewing the individual as being part of a series of dynamic and interconnected relationships and systems: the social ecological theory. So if we think of concentric circles with the patient at the center, there are cascading relationships that are going to impact the course of their care. We radiate out to families and caregivers, a patient's workplace if they're employed, the hospital and the providers there, and then look to bigger systems where a patient lives, their town. If it's in an urban setting or a rural setting, the type of insurance that they have, if it comes from their employer, or if it's a different insurance system, their community and then of course, broader, social, societal, more macro issues. My point and that of many others who work in this space is that we have to consider the context. We can't just build and test interventions that focus on a patient because the patient isn't existing in a bubble. They're existing in relationships with their caregivers, their health care providers, their health care system. And all of that exists in, for lack of a better word, a broken system of structural inequality, systemic racism, and conflicting values about health care as a right. Patient-level interventions are indeed important, but we can't place the burden solely on the patient. And we, as researchers and clinicians in this space, really need solutions that are going to reach across systems. I think, like you said, this project demonstrates that and this is something that I hear from patients in other work that I'm doing. For example, I'm working on a digital intervention to help young adult cancer survivors to build their financial capability and build their understanding of the health care system and insurance systems and financing and all of that. As I co-develop this intervention with patients and survivors, I'm hearing, 'This is great. I'm glad I'm learning these things, but at the same time, my co-pays are unmanageable,' Or, 'I might have to skip my survivorship appointment because I can't afford to take off work that day.' I think we have to really think about, like I said, the context and the bigger picture of the scope of the problem and build and develop interventions that acknowledge that. Dr. John Sweetenham: Well, as you say, very complex, multi-level problem and many interventions needed. But congratulations and kudos to you and your colleagues for addressing one component of this. And we're really looking forward to seeing how this develops and progresses in the coming years. And I'd like to thank you, again, for sharing your insights with us today on the ASCO Daily News podcast and telling us a little bit more about this great work. Dr. Bridgette Thom: Thank you so much for having me. I want to just acknowledge all of the work of our team. It has really been a team effort. We're looking forward to our next steps. Dr. John Sweetenham: And thank you to our listeners for joining us today. You'll find links to the poster discussed today on the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. You can hear more about the MSK Affordability Working Group's efforts on the podcast, Cancer Straight Talk from MSK.   Disclosures: Dr. John Sweetenham: Consulting or Advisory Role: EMA Wellness Dr. Bridgette Thom: Stock and Other Ownership Interests (Immediate Family Member): Caladrius Biosciences, Mediwound, Sierra Oncology, Lipocine, MEI Pharma, Oncternal Therapeutics, Avadel Pharmaceuticals, Chimerix, Avidity Biosciences, Sutro Biopharma, Adma Pharma, Concert Pharmaceuticals, Processa Pharmaceuticals, Curis           An, IMV, Arcus Biosciences, Iovance Biotherapeutics, Qiagen, Revance Therapeutics, DermTech, Zimmer BioMet, Axonics Modulation, Halozyme, Autolus, Pavmed Inc       , Mereo BioPharma, and AADi Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    

Dr. Neeraj Agarwal, of the University of Utah Huntsman Cancer Institute, tells host Dr. John Sweetenham, of the UT Southwestern Harold C. Simmons Comprehensive Cancer Center, about the first study to examine the quality of diagnosis and treatment of breast cancer in sex and gender minority patients and other key studies on disparities associated with access to clinical trials and rising drug costs.  Transcript Dr. John Sweetenham: Hello, I'm John Sweetenham, the associate director for Clinical Affairs at UT Southwestern Harold C. Simmons Comprehensive Cancer Center and host of the ASCO Daily News podcast.  I'm delighted to welcome my friend and colleague Dr. Neeraj Agarwal, the director of the Genitourinary Cancers Program and a professor of medicine at the University of Utah's Huntsman Cancer Institute. Dr. Agarwal also serves as editor-in-chief of the ASCO Daily News.  Today, he'll be sharing his insights on compelling studies that will be featured at the 2022 ASCO Annual Meeting, addressing access to clinical trials, disparities associated with high deductible health plans, rising drug costs, and more.  Our full disclosures are available in the show notes and disclosures of all guests on the podcast can be found on our transcripts at asco.org/podcasts.  Neeraj, it's great to have you back on the podcast.  Dr. Neeraj Agarwal: Thanks, John.  Dr. John Sweetenham: Neeraj, let's begin with Abstract 6503. This study looks at the impacts of high deductible health plans on delays in metastatic cancer diagnosis. What do you think about this study and why should it be on our radar?  Dr. Neeraj Agarwal: Well, John, in high deductible health plans, patients are liable for the cost of all cancer-related care, with the exception of screening tests, until their annual deductible is met. Due to increased out-of-pocket costs, patients may postpone seeing a physician for concerning symptoms or diagnostic testing, leading to delayed diagnosis.  So, in this study, Mr. Nicholas Trad and J. Frank Wharam assessed the impact of high deductible health plans on the timing of metastatic cancer detection.  The authors leveraged a nationally representative cohort of more than 340,000 privately insured members whose employers mandated a switch from a low deductible of less than $500 plan to a high deductible plan of more than $1,000.  So, the group consisted of more than 1 million individuals in a contemporary time frame, whose employers offered only low deductible plans. Participants were matched based on multiple baseline characteristics, time to metastatic cancer diagnosis, and the before and after switching to high deductible health plans was investigated using a weighted Cox proportional-hazards model.  After matching, there were no systematic differences between the 2 groups with regards to baseline characteristics, and there were no differences in time to metastatic cancer diagnosis prior to the switch to high deductible health plans.  However, after the employer-mandated switch to the high deductible health plans, these participants had lower odds of metastatic cancer diagnosis, which was significant, statistically speaking, and indicates delayed detection of metastatic cancer diagnosis relative to the control group.  Dr. John Sweetenham: This is certainly concerning data, Neeraj. What's your key takeaway from this study?  Dr. Neeraj Agarwal: So, the key takeaway from the study is that compared with conventional health plans, high deductible health plans are associated with delayed detection of metastatic cancer, implying that patients postpone seeking care for concerning symptoms or even defer diagnostic testing when they're exposed to high-cost sharing.  Dr. John Sweetenham: Thanks, Neeraj. So, let's continue with this theme of the financial burden of cancer care for our patients. Of course, we're all aware of the rising costs of targeted oral therapies, and this was addressed in Abstract 6504, where the study looks at the rising costs of targeted oral treatments among Medicare beneficiaries. And the study reported a substantial increase in the total cost and out-of-pocket costs of these medicines. Can you tell us more about this abstract?  Dr. Neeraj Agarwal: Yes! So, due to the rapidly rising cost of targeted oral anticancer medicines, Drs. Meng Li and Ya-Chen T. Shih examined recent trends and the financial burden of these oral medicines among patients with cancer with Medicare Part D insurance. So, eligible patients in the SEER-Medicare database had to be 65 years and older and had to have one primary cancer diagnosis.  The investigators estimated the trends in the share of patients who used targeted oral anticancer medicines, the percentage of users reaching catastrophic coverage, and the total and patient out-of-pocket spending on these medicines in the catastrophic phase in a year.  So, from 2011 to 2016, the uptake of these oral anti-cancer medicines increased from approximately 4% to 9%. The percentage of those who reached catastrophic coverage increased from 55% to 60%.  Among those who reached the catastrophic phase, the mean total annual gross spending on oral anti-cancer medicine increased 4-fold from approximately $16,000 to $64,000. And the mean out-of-pocket spending for the patients rose from approximately $600 to $2600.  Dr. John Sweetenham: Yes, this is more evidence that the financial toxicity generated from an increase in spending and out-of-pocket costs is going to have serious impacts on our patients. Would you agree with that, Neeraj?  Dr. Neeraj Agarwal: Yes, John. The key takeaway from this study is that the financial burden of these oral anti-cancer medicines continues to increase. In the relatively short period of time, we see here, 5 years from 2011 to 2016, there was a 4-fold increase in the total cost and out-of-pocket cost of these medicines. And in my view, these findings warrant immediate actions to rein in drug prices and cap out-of-pocket spending for our patients.  Dr. John Sweetenham: Absolutely. It's very difficult to know where this will end unless we see some kind of slowdown in these rising costs. I'm going to change gears just a little bit now to address the access to clinical trials, which is the subject of Abstract 6505.  This study looks at the implementation of the Affordable Care Act Medicaid expansion, which was associated with an almost threefold increase in the proportion of patients using Medicaid in cancer clinical trials by early 2020. What are your thoughts on this study?  Dr. Neeraj Agarwal: As you said, the Affordable Care Act Medicaid expansion resulted in increased use of this platform across the nation. However, its impact on access to clinical trials has not been examined.  So, in this study, Dr. Joseph Unger and Dr. Dawn Hershman examined the number and proportion of patients insured by Medicaid at enrollment over time using data from the SWOG Cancer Research Network.  In addition, they also examined all patients, 18 to 64 years old, enrolled in treatment trials between 1992 to 2020 using Medicaid versus private insurance.  So, the implementation of the Affordable Care Act Medicaid expansion was associated with a nearly threefold increase from 7% to 21% in the proportion of patients using Medicaid in cancer clinical trials by early 2020.  The increase per year of Medicaid uses for patients in these treatment trials from states that implemented the Affordable Care Act Medicaid expansion was 27% compared to 7% for patients from other states who did not implement this platform of Affordable Care Act Medicaid expansion.  So, the key takeaway from the study is that better access to clinical trials for more vulnerable patients is critical to improving confidence in how generalizable these trial findings are. In addition, these results suggest that the recently enacted Cancer Treatment Act may continue to improve access to clinical trials for those with Medicaid insurance or those who are vulnerable patients.  Dr. John Sweetenham: Yes, I think this is a really important study which adds to the growing literature on the benefits of the Affordable Care Act and Medicaid expansion on cancer care in general, in this case, specifically related to clinical trials. So, so important, I think.  On that theme of equity, I think the next 2 abstracts we're going to discuss address specific aspects of equity, which I think are both interesting and really important. So, Abstract 6510 has interesting research which conveys an urgent need to ensure equitable patient-reported access and implementation and to address the greater reported symptom burden among minority patients. Why do you think this study is important?  Dr. Neeraj Agarwal: The routine collection of patient-reported outcomes for patients with cancer is an evidence-based practice and a critical component of high-quality cancer care, but the real-world adherence and reporting patterns are poorly understood.  In this study, Dr. Samuel Takvorian and Dr. Ravi Parikh examined differences in adherence to the collection of patient-reported outcomes and reported symptoms by race and ethnicity.  This was a retrospective cross-sectional study using de-identified electronic health record data from an National Cancer Institute (NCI)-designated Comprehensive Cancer Center. The participants included adults seen in follow-up at 1 of the 2 medical oncology practices—one was in academics and one was in the community—from June 2019 to February 2020. Using ordinary least-squares regression, the authors modeled patient adherence as a function of race or ethnicity, and this was adjusted for age, sex, insurance, median area income, ECOG, performance status, and many other patient-related characteristics.  The results show that adjusted mean PRO adherence and reported symptoms varied by race and ethnicity, with Black and Hispanic patients being less likely to complete PRO questionnaires, but reporting significantly higher symptom burden compared to the White patients.  Dr. John Sweetenham: Right. So, it seems that more work is needed to ensure equitable access and adherence to PRO questionnaires so we can better address the symptom burden of our minority patients.  Dr. Neeraj Agarwal: Correct, John. In this large cohort reflecting real-world PRO collection patterns, Black and Hispanic patients were less likely than White patients to complete these PRO questionnaires, but more likely to report more severe symptoms. And I think there is an urgent need to ensure equitable PRO access and implementation and to address the greater reported symptom burden among minority patients.  Dr. John Sweetenham: Let's continue the theme of health equity and cancer care equity into the use of telemedicine. Of course, we saw a massive expansion of telemedicine for patients with cancer during the COVID-19 pandemic.  But studies are emerging now to show that there have been substantial disparities among the Black, uninsured, non-urban, and less affluent patients who are less likely to use telemedicine services.  Abstract 6511 reminds us that telemedicine may expand access to specialty care, but the proliferation of these services may widen cancer care disparities if vulnerable populations don't have equitable access. Can you tell us more about this abstract?  Dr. Neeraj Agarwal: These are indeed very interesting findings, John. The COVID-19 pandemic was associated with declines in in-person clinical visits, with a concurrent increase in the use of telemedicine.  In this study, Dr. Gregory S. Calip assessed demographic and socioeconomic factors associated with telemedicine use among patients initiating treatment for 21 common cancers at community oncology clinics.  This was a retrospective study and made use of the nationwide Flatiron electronic health record derived de-identified database of patients with cancer. The authors focused on differences in telemedicine use across race and ethnicity, insurance coverage, rural versus urban areas, and socioeconomic status.  They used logistic regression models for this analysis, which was adjusted for clinical characteristics to examine differences in telemedicine use among these different cohorts.  Results indicate Black patients were significantly less likely to use telemedicine services compared to White patients. Telemedicine use was also significantly lower among patients without documented insurance than well-insured patients. It was also lower in patients from rural and suburban areas versus patients who were living in urban areas. Lastly, telemedicine use was significantly lower in patients in the least affluent areas than those in the most affluent areas.  So, during the COVID-19 pandemic, nearly one-fifth of patients initiating cancer treatment using telemedicine services—among these patients, we see substantial disparities. So, Black, uninsured, non-urban, and less affluent patients were less likely to use telemedicine services.  So, the take home message from this study is that while telemedicine may expand access to care, the proliferation of these services may actually widen cancer care disparities if vulnerable populations do not have equitable access to these services.  Dr. John Sweetenham: Thanks, Neeraj. So, the final study that we'll discuss today also looks at another aspect of disparities, and that's Abstract 6517. It's a case-controlled study of health care disparities in sex and gender minority patients with breast cancer. What are the key takeaways from this study?  Dr. Neeraj Agarwal: Disparities and the quality of diagnosis and treatment of breast cancer in sex and gender minority populations are largely undefined. Only 24% of studies funded by the National Cancer Institute capture data on sexual orientation and only 10% capture data on gender identity.  In this case-control study, Drs. Eric Eckhert and Allison W. Kurian matched sex and gender minority patients with breast cancer to cisgender heterosexual controls in the Stanford University health care database. Ninety-two sex and gender minority patients were identified who were then matched by year of diagnosis, age, stage of cancer, presence of estrogen receptor (ER), and HER-2/neu receptor status to cisgender heterosexual controls within this database.  Additional data on demographics, diagnosis, treatment, and relapse were then manually abstracted from the electronic health care records. The sex and gender minority cohort were comprised of 80% lesbians, 13% bisexuals, and 6% transgender men.  One of the most pertinent findings was a significant, almost twice as much delay in time to diagnosis from the onset of symptoms in these minority patients versus control. Although there was no difference in the receipt of surgery or surgical radiation or new adjuvant therapy, sex, and gender minority patients were significantly less likely to undergo chest reconstruction surgery, and if they were estrogen receptor-positive, they were significantly less likely to complete at least 5 years of ER directed therapy.  Please also note that sex and gender minority patients used more alternative medicine, had a higher rate of documented refusal of recommended oncology treatments, and they experienced a higher recurrence rate.  So, the key takeaway from this study is that—this is the first study, I really want to congratulate the investigators who examined the quality of diagnosis and treatment of breast cancer in sex and gender minority patients. Several novel potential health care disparities are identified in these patients, which should be further evaluated in population-based studies to inform further interventions.  Dr. John Sweetenham: Neeraj, it's always a pleasure to talk with you and have an opportunity to spend some time with you. Thanks very much for sharing your insights on these compelling studies today. Our listeners will find the links to these abstracts in the transcripts of this episode.  Dr. Neeraj Agarwal: Thanks, John.  Dr. John Sweetenham: And thanks to our listeners for your time today. If you're enjoying the content on the ASCO Daily News podcast, please take a moment to rate, review and subscribe wherever you get your podcasts.    Disclosures:  Dr. John Sweetenham  Consulting or Advisory Role: EMA Wellness  Dr. Neeraj Agarwal:  Consulting or Advisory Role: Pfizer, Medivation/Astellas, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, AstraZeneca, Merck, Novartis, lily, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences    Research Funding (Institution): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, ORIC Pharmaceuticals, CRISPR therapeutics, and Arvinas     Disclaimer:   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. 

Guest host Dr. Neeraj Agarwal, of the University of Utah Huntsman Cancer Institute and the ASCO Daily News editor-in-chief, discusses key therapeutic advances in mRCC and mUC, as well as new research that proposes periodic scans to monitor patients with mCSPC for disease progression, with Dr. Jeanny-Aragon-Ching of the Inova Schar Cancer Institute.  Transcript:  Dr. Neeraj Agarwal: Hello and welcome to the ASCO Daily News podcast. I'm Dr. Neeraj Agarwal, the director of the Genitourinary Oncology Program, a professor of medicine at the University of Utah Huntsman Cancer Institute, and editor-in-chief of the ASCO Daily News.  My guest today is Dr. Jeanny Aragon-Ching, who is a medical oncologist and the Clinical Program Director of Genitourinary Cancers at the Inova Schar Cancer Institute in Virginia.  Today, we will be discussing key posters in genitourinary (GU) oncology that will be featured at the 2022 ASCO Annual Meeting. Our full disclosures are available in the show notes and disclosures of all guests on the podcast can be found on our transcripts at asco.org/podcast.  Jeanny, it is great to have you on the podcast today.  Dr. Jeanny Aragon-Ching: Thanks, Neeraj. It's a pleasure for me to be here as well.  Dr. Neeraj Agarwal: Jeanny, let's begin with Abstract 4510. This is a trial that represents a growing interest among researchers worldwide in the microbiome and how it is impacted by antibiotics and how it modulates immune checkpoint inhibitor response. Can you tell us about this study?  Dr. Jeanny Aragon-Ching: Thanks, Neeraj, I would be happy to. So, the title of the abstract is, “Characterization of the Microbial Resistome in a Prospective Trial of CBM 588 in Metastatic Renal Cell Carcinoma Offers Mechanism for Interplay Between Antibiotic Use and Immune Checkpoint Inhibitor Activity.”  So, this is an interesting abstract that originated likely from the observation that getting antibiotics while on checkpoint inhibitors typically results in worse outcomes, perhaps because antibiotics can clear the normal gut flora and thereby increase these pathogenic antibiotic-resistant bacteria.  Now, on the other hand, there were some retrospective studies using a live microbial product called CBM 588, which seems to improve outcomes in patients on checkpoint inhibitors and getting antibiotics.  So, the idea, therefore, is that shifting the genes encoding antimicrobial resistance could result in a better checkpoint inhibitor response. So, this Abstract 4510 is a small study conducted by Dr. Nazli Dizman and Dr. Sumanta (Monty) Kumar Pal, and colleagues, and enrolled 29 metastatic clear cell RCC patients with intermediate or poorest disease. And they were stratified into receiving either nivolumab or ipilimumab compared to nivo/IPI with CBM 588.  Now stool samples were collected at baseline in week 12. And they did this whole metagenome sequencing to analyze a stool microbiome composition, and they also looked at the antibiotic resistance genes for the most common classes of antibiotics.  The results showed an astounding improvement in objective responses. So, 58%, for instance, in nivo/IPI and the CBM 588 arm compared to only 20% in the nivo/IPI arm. And it seems like also the antibiotics resistance genes were also decreased in those getting the CBM 588 alongside nivo/IPI. Therefore, responses were improved by shifting the gut microbiome alone. So, these findings were published actually recently by these authors in Nature Medicine. So, in case anyone wants to take a deep dive, it would be a good interesting read for this dataset.  Dr. Neeraj Agarwal: Very interesting, indeed. Jeanny, what is the main message here for our colleagues?  Dr. Jeanny Aragon-Ching: I think, Neeraj, the key takeaway message is that this is a very provocative proof of concept trial that suggests shifting the gut microbiome has the potential to improve responses to checkpoint inhibitors and outcomes. So, this is a very up-and-coming trial and is seen also across the board in other cancers.  Dr. Neeraj Agarwal: Thanks, Jeanny. Moving on to urothelial cancer, there is a poster that I think is a must-see for our colleagues. This is Abstract 4577 titled, “Defining Platinum Ineligible Patients with Metastatic Urothelial Carcinoma.”  Dr. Jeanny Aragon-Ching: So, Neeraj, what can you tell us about this abstract?  Dr. Neeraj Agarwal: So, over the past few years, there has been a tremendous evolution in the treatment landscape for patients with metastatic urothelial carcinoma. For over 40 years the standard of care for these patients has been cisplatin-based chemotherapy.  However, approximately 50% of patients are cisplatin-ineligible, due to underlying comorbidities, and are offered carboplatin as an alternative. So, although the checkpoint inhibitors pembrolizumab and atezolizumab were approved as first-line therapy for these patients in 2017, the U.S. Food and Drug Administration (FDA) has now restricted the use of first-line pembrolizumab to platinum ineligible patients with metastatic urothelial carcinoma.  The challenge we face as oncologists since the FDA restriction is the absence of a formal definition of platinum ineligibility and the inclusion of this definition in the guidelines. So, in Abstract 4577, Drs. Shilpa Gupta and Jonathan Rosenberg, along with the team present an updated consensus definition for platinum ineligibility based on an online survey of 60 genitourinary oncologists in the United States.  Based on the results from this survey, any patient with metastatic urothelial carcinoma, meeting 1 of the following 5 clinical and or laboratory parameters should be considered platinum ineligible, and these are 1 of the following: an ECOG performance status of 3 or more, creatinine clearance of fewer than 30 mils per minute, or peripheral neuropathy of grade 2 or more, or heart failure class of 3 or more—so, this is NYHA heart failure class of 3 or more—and lastly, the combination of performance status of 2 or more, plus a creatinine clearance of less than 30 mils per minute.  Dr. Jeanny Aragon-Ching: Well, this is a timely update, Neeraj. So, what do you think is a key takeaway from this abstract?  Dr. Neeraj Agarwal: These criteria based on simple and easily available clinical and or laboratory parameters will now allow us to readily define platinum ineligibility in our patients with metastatic urothelial carcinoma, which is a need in busy clinics, both in academic and community settings.  So, I think once published and obviously once endorsed by guidelines, we really would like to be able to use this criterion to quickly define platinum ineligibility in our clinics.  Dr. Jeanny Aragon-Ching: Agree. Yeah.  Dr. Neeraj Agarwal: So, Jeanny, let me switch the gears. PSMA testing is a hot topic this year. And there is an abstract that could potentially have an impact on future guidelines, and how we will practice further down the road.  So, I'm referring to the Abstract 5088 titled, “Predictive Value of Extra Prostatic Disease Detection by Preoperative PSMAPET for Biochemical Recurrence-free Survival in Patients with Otherwise Localized Prostate Cancer and Who are Treated with Radical Prostatectomy.”  So, this is a follow-up analysis of a multicenter prospective phase 3 imaging trial. So, could you please tell us more about this abstract where they are using PSMA PET scan in the preoperative localized prostate cancer setting?  Dr. Jeanny Aragon-Ching: Absolutely, Neeraj. So, you may recall that the multicenter prospective phase 3 imaging trial that garnered gallium PSMA approval by the FDA was actually based on this study that looked at the intermediate and high-risk patients with prostate cancer undergoing radical prostatectomy and lymph node dissection, and they underwent prior gallium PSMA PET scanning for pelvic nodal metastases prior to surgery.  So, this was actually previously reported by Dr. Calais and group. Now they are reporting on Abstract 5088 as a post hoc analysis of the same population and group of patients looking for extraprostatic disease. And the final pathology was also correlated to look at nodal disease in these patients in order to predict biochemical recurrence, so they follow these patients for biochemical recurrence occurrence.  So, of the 36% of patients who did undergo radical prostatectomy after they underwent PSMA PET scan, about 41% of them recurred with biochemical recurrence, and 40% of them underwent some kind of salvage therapy or some treatment.  What was very interesting was when they looked at the biochemical recurrence-free survival. It was better in those who were PSMA negative, and that recurrence-free survival was easily about 33 months, compared to only about 7.3 months in those who were PSMA-positive scans.  Furthermore, the ones who had the longest and the highest biochemical recurrence-free survival, intuitively, were those who were node-negative and PSMA PET-negative, so probably not surprisingly. And that rate was about 46 months—close to 4 years. Whereas those who are node-positive on final pathology and their PSMA PET was also positive, they only had about 3 months of biochemical recurrence-free survival.  Dr. Neeraj Agarwal: Very interesting. So, it looks like the PSMA PET scan is predicting biochemical recurrence-free survival in localized prostate cancer settings. So, Jeanny, what is the key takeaway from this trial?  Dr. Jeanny Aragon-Ching: I think, Neeraj, the bottom line is that patients with extraprostatic disease that is detected by their preoperative PSMA PET scan does predict strongly a high risk of biochemical relapse, and this can really be an additional tool that clinicians can use to help inform and guide future therapy.  Dr. Neeraj Agarwal: Thanks, Jeanny. The research on preoperative PSMA testing and its implications on future treatment strategies in the setting is going to be really interesting to watch in the very near future.  Dr. Jeanny Aragon-Ching: Yes, absolutely. I really think we should also discuss Abstract 5072, along those lines, the importance really of radiographic monitoring for disease progression in patients with metastatic hormone-sensitive prostate cancer.  Dr. Neeraj Agarwal: Yes, thanks for reminding and this is Abstract 5072. This is a post hoc analysis of the ARCHES trial, titled, “Radiographic Progression in the Absence of PSA Progression in Patients with Metastatic Hormone-sensitive Prostate Cancer.”  During the last several years, we have seen many of these agents typically given for gastric resistant prostate cancer moving upfront to the castration-sensitive prostate cancer setting. This is especially true for androgen receptor access targeting agents such as abiraterone, enzalutamide, and apalutamide, all being now approved for patients with metastatic castration-sensitive prostate cancer.  What is noteworthy from all these trials, and is reported in Abstract 5072, is the use of imaging studies to evaluate disease progression. So, in Abstract 5072, Dr. Andrew Armstrong and Dr. Arun Azad performed a post hoc analysis of the ARCHES trial to investigate the concordance between radiographic progression and the PSA Progression as defined by PCWG2 criteria, or between radiographic progression and any rise in the PSA above nadir, in patients who were being treated with this novel hormonal therapies, in this case, enzalutamide for metastatic castration sensitive prostate cancer.  And as a quick reminder, ARCHES was a phase 3 trial that showed a significant reduction and radiographic progression-free survival and improved overall survival for patients with metastatic castration sensitive prostate cancer treated with enzalutamide plus androgen deprivation therapy (ADT) versus those treated with placebo plus androgen deprivation therapy.  So, very interestingly, the findings from this study indicate that 67% of patients on the enzalutamide plus ADT arm did not have [Prostate Cancer Clinical Trials Working Group 2 criteria] PCWG2-defined prostate-specific antigen (PSA) progression at the time of radiographic progression. And discordance was present in the ADT-only arm as well, where they found 42% of patients on the ADT-only arm had radiographic progression but did not have PCWG2-defined PSA progression.  Interestingly, this discordance of radiographic disease progression was also seen with any rise in the PSA above nadir. And I personally found this information to be very clinically relevant when we are seeing the majority of patients actually experiencing radiographic disease progression, not experiencing PSA progression at the same time.  Dr. Jeanny Aragon-Ching: Yeah, absolutely. I agree with that, Neeraj. So, very interesting data. So, what do you think is the key takeaway message for the clinicians listening to us?  Dr. Neeraj Agarwal: I'll make the message very simple. I think the message is that patients with metastatic castration-sensitive prostate cancer need to be monitored for disease progression with periodic scans, and PSA monitoring alone is not sufficient in the majority of these patients.  Again, we cannot undervalue the role of periodic imaging studies in these patients so that we can timely diagnose them to have disease progression.  Dr. Jeanny Aragon-Ching: I agree with that.  Dr. Neeraj Agarwal: Jeanny, the last abstract I would like to mention before we wrap up the podcast is Abstract 4509, the results from the phase1 live SPARC 001 study. So, can you please tell us more about this study titled, “Phase-1 Live SPARC 001: The Study of Belzutifan in Advanced Solid Tumors,” which is an update of the renal cell carcinoma cohort with more than 3 years of total follow up?  Dr. Jeanny Aragon-Ching: Thanks, Neeraj. So, while the current therapeutic landscape for patients with metastatic clear cell renal cell carcinoma (RCC) has changed dramatically over the past several years, with significant improvement in patient outcomes. Most patients unfortunately still experience disease progression on current treatments.  So, in-depth molecular profiling of clear cell RCC has revealed recurrent loss of function mutations in VHL in actually greater than 90% of patients. So, the VHL protein, as you will recall, is part of the oxygen-sensing pathway, regulating levels of HIF which is hypoxia-inducible factor protein, it's a transcriptional activator that mediates the response to hypoxic conditions. So, HIF-2α is a key oncogenic driver in RCC.  So, previous data you may recall from the phase-1 Live SPARC 001 trial was designed to evaluate belzutifan so, this was a novel HIF-2α inhibitor which showed durable anti-tumor activity and acceptable safety profile in patients with metastatic clear cell RCC.  So, in Abstract 4509, Drs. Jonasch and Toni Choueiri presented updated results from this trial after more than 3 years of follow-up. Of the 55 patients enrolled 16% of patients remained in treatment. And 62% of patients had discontinued treatment because of, unfortunately, disease progression.  The median progression-free survival (PFS) for the total cohort was 14.5 months. And the overall disease control rate was 80%. Forty percent of patients experienced grade 3 treatment-related adverse events with the most frequent ones being anemia and hypoxia.  There were no great 4 or 5 treatment-related adverse events. And these results, therefore, show that belzutifan monotherapy continues to show a high rate of disease control and a safety profile in a heavily treated population of patients with metastatic RCC. So, it is great to see that there were no new safety signals.  Dr. Neeraj Agarwal: Very nice data indeed. So, Jeanny, what is the key takeaway message here for our listeners?  Dr. Jeanny Aragon-Ching: Yeah, I think the message here is that the use of belzutifan monotherapy continues to show efficacy and safety in patients with metastatic clear cell RCC, which have progressed on multiple prior contemporary therapies, and there are phase 3 trials currently underway.  Dr. Neeraj Agarwal: Jeanny, any final thoughts before we wrap up the podcast today?  Dr. Jeanny Aragon-Ching: Thanks, Neeraj. I think it's a really exciting time to be in genitourinary (GU) oncology, and I'm truly looking forward to seeing some great sessions at the 2022 ASCO Annual Meeting.  Dr. Neeraj Agarwal: Thank you, Jeanny, for sharing your insight with us today. It was a great conversation. And thank you to our listeners for joining us today. You will find links to the abstracts discussed today on the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News podcast, please take a moment to rate, review, and subscribe wherever you get your podcast.    Disclosures:   Dr. Neeraj Agarwal:   Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, AstraZeneca, Pfizer, Merck, Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences  Research Funding (Institution): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, crispr therapeutics, Arvinas  Dr. Jeanny Aragon-Ching:   Honoraria: Bristol-Myers Squibb, EMD Serono, Astellas Scientific and Medical Affairs Inc  Consulting or Advisory Role: Algeta/Bayer, Dendreon, AstraZeneca, Janssen Biotech, Sanofi, EMD Serono, AstraZeneca/MedImmune, Bayer, Merck, Seattle Genetics, Pfizer, Immunomedics, Amgen, AVEO, Pfizer/Myovant, Exelixis  Speakers' Bureau: Astellas Pharma, Janssen-Ortho, Bristol-Myers Squibb , Astellas/Seattle Genetics  Travel, Accommodations, Expenses: Dendreon, Algeta/Bayer, Bristol Myers Squibb, EMD Serono, Astellas Pharma  Disclaimer:   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast expressed their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.       

Dr. Neeraj Agarwal, ASCO Daily News editor-in-chief, and director of the Genitourinary Cancers Program at the University of Utah's Huntsman Cancer Institute, highlights key studies on disparities in GU cancers featured at the 2022 ASCO Genitourinary Cancers Symposium. Transcript:   ASCO Daily News: Hello and welcome to the ASCO Daily News Podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. In today's episode, Dr. Neeraj Agarwal, the ASCO Daily News editor in chief, will highlight compelling studies on disparities in GU cancers featured at the 2022 ASCO Genitourinary (GU) Cancers Symposium. Dr. Agarwal has no conflicts relating to the topic of this episode and his full disclosures are available in the show notes. Disclosures of all guests on the podcast can be found in our transcripts at asco.org/podcasts.  Dr. Neeraj Agarwal: Hello and welcome to the ASCO Daily News Podcast. I'm Dr. Neeraj Agarwal, the director of the Genitourinary Cancers Program and professor of medicine at the University of Utah Huntsman Cancer Institute. So, I'd like to start with Abstract 20 presented by Dr. Alicia Morgans from the Dana-Farber Cancer Institute. Multiple population-based studies have reported a higher incidence of prostate cancer in Black men. [This disease] usually presents with aggressive features, at an earlier age, and is associated with higher mortality rates compared to White men. In contrast, multiple reports suggest that Black men with advanced prostate cancer also have better survival outcomes to novel hormonal therapies compared to White men. Using electronic medical records retrieved from a urology specialty database, Dr. Alicia Morgans investigated whether improved survival outcomes in Black men treated with enzalutamide are due to better responses compared to White men. So eligible patients, who are chemotherapy and abiraterone naive and included 214 Black men and 1,332 White men with advanced prostate cancer.    Reserves from a multivariate analysis were adjusted for baseline characteristics and indicated a statistically significant delay in clinical progression-free survival for Black men treated with enzalutamide compared to White men. This supports the argument that given equal access to care, Black men may respond similarly or better than White men to treatment for advanced prostate cancer. The next abstract addressing disparities in GU cancers was Abstract 444 presented by Dr. Samuel Washington from UCSF School of Medicine. Radical cystectomy remains the gold standard for muscle-invasive bladder cancer, yet confers significant health care costs. Prior work on the impact of cost commonly relied on comparisons by insurance status and income. Few studies have examined the relationship between the net worth of the household and the encounter type, such as outpatient versus inpatient encounters. As we also know, outpatient encounters are usually cheaper or less expensive than more expensive inpatient encounters.    So, in this intriguing and novel study, Dr. Samuel Washington presented a real-world analysis of demographics, household net worth, health plan cost, out-of-pocket cost, and total health care cost accrued from the day of admission to 90 days after radical cystectomy for muscle-invasive bladder cancer. This was the largest study of its kind and included more than 140,000 commercially insured patients to examine variations in health care utilization by net worth in 90 days after radical cystectomy. Results are very interesting and indicate that patients with lower household net worth were at a greater risk for an acute inpatient encounter and thus higher medical cost, while patients with greater household net worth had greater odds of office visits or outpatient encounters, which are associated with lower cost. So, these findings indicate that a lower household network continues to be a significant factor in health care utilization and higher health care costs, even within a commercially insured patient population. So very interesting findings indeed and these findings definitely should pay for further future studies involving or looking at this aspect of disparities. Thank you very much for your kind attention.    ASCO Daily News: That was Dr. Neeraj Agarwal of the University of Utah's Huntsman Cancer Institute. If you've enjoyed this series, please take a moment to rate and review us wherever you get your podcasts.     Disclosures:   Dr. Neeraj Agarwal:   Consulting or Advisory Role: Pfizer, Medivation/Astellas, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, AstraZeneca, Merck, Novartis, lily, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences      Research Funding (Institution): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, ORIC Pharmaceuticals, CRISPR therapeutics, and Arvinas      Disclaimer: The purpose of this podcast is to educate and to inform this is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    

Dr. Neeraj Agarwal, ASCO Daily News editor-in-chief, and director of the Genitourinary Cancers Program at the University of Utah's Huntsman Cancer Institute, shares key takeaways from the practice-changing ARASENS trial in mHSPC, featured at the 2022 ASCO Genitourinary Cancers Symposium.   Transcript: ASCO Daily News: Hello, and welcome to the ASCO Daily News podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. Today in our continuing coverage of the 2022 ASCO Genitourinary (GU) Cancer Symposium. Dr. Neeraj Agarwal, the editor in chief of the ASCO Daily News will share key takeaways from the practice-changing ARASENS trial, which showed promising results in metastatic hormone-sensitive prostate cancer. Dr. Agarwal has no conflicts relating to the topic of this episode and his full disclosures are available in this show notes. Disclosures of all guests on the podcast can be found in our transcripts at asco.org/podcasts. Dr. Neeraj Agarwal: Hello and welcome to the ASCO Daily News podcast. I'm Dr. Neeraj Agrawal, the director of the Genitourinary Cancers Program and professor of medicine at the University of Utah Huntsman Cancer Institute. Let's discuss the results of the practice-changing ARASENS trial in patients with metastatic castration-sensitive prostate cancer as presented at the 2022 ASCO GU Symposium. This abstract, Abstract 13, was presented by Dr. Matthew Smith from the Massachusetts General Hospital and Hartford Medical School. ARASENS is a randomized phase 3 trial evaluating the efficacy and safety of darolutamide, a novel hormonal therapy, plus ADT (antiandrogen therapy) plus docetaxel versus placebo plus ADT plus docetaxel in patients with metastatic castration-sensitive prostate cancer. Randomization was stratified by the extent of disease and alkaline phosphatase levels, below versus upper limit of normal or above. It is important to know that this study only included patients that were eligible for ADT and docetaxel chemotherapy, to begin with. The primary endpoint was overall survival with multiple secondary endpoints, including time to CRPC (castration-resistant prostate cancer), time to pain progression, time to first symptomatic skeletal event, and time to start off the next anti-neoplastic therapy, and safety. A total of 1,306 patients were randomly assigned to triplet therapy with darolutamide plus ADT plus docetaxel versus placebo plus ADT plus docetaxel. Baseline characteristics were well balanced between the treatment arms. Analysis of the primary endpoint was pre-specified. After, 533 events had occurred results show the primary endpoint of this study was met with a significant improvement in overall survival and a 32.5% reduction in risk of death for patients on the triplet therapy on for darolutamide plus ADT plus docetaxel versus placebo plus ADT plus docetaxel. It is important to know that the triplet therapy improved overall survival, despite 76% of patients in the control arm having received the next life-prolonging therapy. Subgroup analysis indicates consistent benefit across the 3 specified groups. Secondary endpoints also were favored by the triplet therapy combination over the control arm. While this study offers an additional excellent option for our patients with metastatic cancer-sensitive prostate cancer in older populations, the use of docetaxel may be a significant limitation to this triplet combination. In addition, and importantly, this study did not answer the question of whether adding docetaxel chemotherapy to the ADT plus novel hormonal therapy backbone will also improve survival. With the advent of multiple doublets and triplet combinations in recent years, as we saw in the form of ADT plus enzalutamide ADT plus apalutamide in the recent years, it is very important to find biomarkers that may predict response to these treatment options, which will allow personalization of therapy with that. I would like to conclude this podcast on the ARASENS trial. Thank you very much for your kind attention. ASCO Daily News: You've been listening to Dr. Neeraj Agarwal of the University of Utah's Huntsman Cancer Institute. Thanks for joining us today. If you're enjoying the content on the podcast, please take a moment to rate and review us wherever you get your podcasts. Disclosures: Dr. Neeraj Agarwal: Consulting or Advisory Role: Pfizer, Medivation/Astellas, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, AstraZeneca, Merck, Novartis, lily, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences Research Funding (Institution): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, ORIC Pharmaceuticals, CRISPR therapeutics, and Arvinas Disclaimer: The purpose of this podcast is to educate and to inform this is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Dr. Neeraj Agarwal, ASCO Daily News editor-in-chief, and director of the Genitourinary Cancers Program at the University of Utah's Huntsman Cancer Institute, shares key takeaways from the PROpel and MAGNITUDE trials in mCRPC, featured at the 2022 ASCO Genitourinary Cancers Symposium.   Transcript: ASCO Daily News: Hello and welcome to the ASCO Daily News Podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. Today, in our continuing coverage of the 2022 ASCO Genitourinary (GU) Cancers Symposium, Dr. Neeraj Agarwal, the editor-in-chief of the ASCO Daily News will highlight promising advances in metastatic castration-resistant prostate cancer. Dr. Agarwal has no conflicts relating to the topic of this episode, and his full disclosures are available in the show notes. Disclosures of all guests on the podcast can be found in our transcripts at asco.org/podcasts.   Dr. Neeraj Agarwal: Hello and welcome to the ASCO Daily News Podcast. I'm Dr. Neeraj Agarwal, the director of the Genitourinary Cancer Program, and professor of medicine at the University of Utah Huntsman Cancer Institute, and editor in chief of the ASCO Daily News. I'd like to start with the PROpel trial followed by a discussion on the MAGNITUDE trial. So, Abstract 11 was on the results of the PROpel trial and presented by Dr. Fred Saad from the University of Montreal. PROpel is a randomized phase 3 trial, which evaluated the efficacy and safety of olaparib, a PARP inhibitor plus abiraterone versus this placebo plus abiraterone in the first-line metastatic castration-resistant prostate cancer setting. Patients were allowed to have docetaxel chemotherapy is given in a metastatic castration-sensitive prostate cancer setting. Enrollment in the study was independent of the effects in the homologous recombination repair pathway. The primary endpoint was investigator-assessed radiographic progression-free survival (PFS) with multiple secondary endpoints, including overall survival and safety.   Approximately 800 patients were randomly assigned to the novel combination of olaparib plus abiraterone or placebo plus abiraterone. Baseline characteristics were well-balanced between the treatment arms, including homologous recombination repair or HRR mutation status. At the pre-planned interim analysis results show the trial meets its primary endpoint with significant improvement in radiographic PFS for all patients receiving the combination therapy versus control, regardless of the presence of homologous recombination repair gene mutations. Median PFS was 24.8 months versus 16.6 months for patients receiving olaparib plus abiraterone versus placebo plus abiraterone respectively with the hazard ratio of 0.66, and a P < 0.0001. This translates into a 34% reduction in risk of progression or death. Overall survival results are still immature with only 29% [of patients experiencing events] thus far. It is interesting that even patients deemed negative for homologous recombination repair gene mutations showed significant improvement in radiographic PFS when treated with the combination of olaparib plus abiraterone versus placebo plus abiraterone.   Regarding the adverse effects, they were what you would expect from the combination of a PARP inhibitor, such as olaparib and abiraterone. We saw a higher sequence of all great events of anemia, fatigue, and nausea in the combination arm. While anemia was the only grade 3-4 adverse event observed at a significantly high frequency in the combination arm. It is also important [that] we get a better understanding of the molecular mechanism by which patients who are homologous recombination repair mutation-negative are benefiting from the combination treatment as well.   The next trial in this context, or this team, was the MAGNITUDE trial. Abstract 12 was presented by Dr. Kim Chi from British Columbia Cancer Center in Vancouver, Canada. MAGNITUDE is a randomized phase 3 trial evaluating the efficacy and safety of niraparib plus abiraterone plus placebo plus abiraterone in the first-line metastatic castration-resistant prostate cancer setting. The study population was slightly different from what we saw in PROpel trial. Taxane chemotherapy, as well as novel hormonal therapy, was allowed in metastatic castration-sensitive prostate cancer, as well as a prior novel hormonal therapy was allowed in the non-metastatic castration-resistant prostate cancer.   Also, patients were allowed up to 4 months of treatment with abiraterone in the first-line metastatic castrate-resistant prostate cancer. Prospective selection of patients with, and without homologous recombination repair (HRR) gene mutations were required. The primary endpoint was radiographic PFS by central review with multiple secondary endpoints, including overall survival and safety. A pre-specified fertility analysis was planned after enrolling 233 patients who were randomly assigned to niraparib plus abiraterone or placebo plus abiraterone. Evaluation of fertility was based on the composite PFS of PSA or radiographic progression, whichever occurred first. The pre-planned fertility analysis showed no benefit in the biomarker negative cohort. And thus the trial did not pursue further enrollment of those patients who were not positive for homologous recombination repair gene mutations.   Coming to the HRR positive cohort, 423 patients were randomly assigned to either niraparib plus abiraterone or placebo plus abiraterone. At the pre-planned interim analysis primary endpoint was met with a significant improvement in radiographic PFS for BRCA1 and BRCA2 and all patients who are homologous recombination repair mutation-positive, receiving the novel combination of niraparib plus abiraterone. Overall survival results are still immature. It is important to note that in the patients who are HRR positive, approximately 50% were BRCA1 and 2 positive. And these patients clearly derived the most benefit with a combination with an approximate 47% reduced risk of death. And if you look at other patients who are biomarker positive, there was a clear benefit and a significant improvement in median PFS (radiographic progression-free survival) with a hazard ratio of 0.73, which translates to a 27% reduction in the risk of death or progression. With the caveat of subgroup analysis, being underpowered following groups of patients seem to derive less benefit with the combination than the overall cohort with the combination of niraparib plus abiraterone. And these patients included patients who were age 65 or younger, or less than age 65, patients with visceral metastatic disease, patients with prior abiraterone or taxane chemotherapy, [and] patients who had a PSL level below the median, and patients with non-BRCA homologous recombination repair mutations.   In conclusion, the combination of niraparib plus abiraterone shows a significant improvement in the radiographic PFS for patients who are HRR positive in the first-line metastatic CRPC. Based on the available data in the public domain, without any doubt that both PROpel and MAGNITUDE trials established a combination of a PARP inhibitor with abiraterone in the first-line metastatic CRPC setting for patients who are positive for HRR mutation improve radiographic progression-free survival. Even though overall survival data are immature for both trials, I expect both combinations will be approved by the U.S. Food and Drug Administration in the near future and will be available to our patients. Regarding the HRR negative cohort in the PROpel trial, which also seems to derive significant benefit with the combination of abiraterone plus olaparib, I'm looking forward to the data on confirmation of HRR negative status by tissue-based genomic profiling results in the full-length publication which we expect to be published soon. If indeed confirmed by the tissue-based genomic profiling, I see the combination of abiraterone plus olaparib to be a reasonable option in the patients who are HRR negative in the first-line metastatic CRPC setting.   With this, I would like to conclude my discussion on the 2 practice-changing trials presented in the 2022 ASCO GU meeting, which were the PROpel and MAGNITUDE trials. Thank you very much for your kind attention. ASCO Daily News: That was Dr. Neeraj Agarwal of the University of Utah's Huntsman Cancer Institute. Thanks for joining us today. If you're enjoying the content on the podcast, please take a moment to rate and review us wherever you get your podcast.   Disclosures: Dr. Neeraj Agarwal: Consulting or Advisory Role: Pfizer, Medivation/Astellas, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, AstraZeneca, Merck, Novartis, lily, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences Research Funding (Institution): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, ORIC Pharmaceuticals, CRISPR therapeutics, and Arvinas Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

Guest host, Dr. Neeraj Agarwal, editor-in-chief of ASCO Daily News and director of the Genitourinary Cancers Program at the University of Utah's Huntsman Cancer Institute, and Dr. Jason Efstathiou, chair of the 2022 ASCO Genitourinary Cancers Symposium, discuss key abstracts and innovations in GU oncology featured at #GU22. Dr. Efstathiou is professor at Harvard Medical School and director of the Genitourinary Division in Radiation Oncology at Massachusetts General Hospital.   Transcript Dr. Neeraj Agarwal: Hello, and welcome to the ASCO Daily News Podcast. I am Dr. Neeraj Agarwal, the director of the Genitourinary Program and professor of medicine at the University of Utah Huntsman Cancer Institute and editor in chief of the ASCO Daily News. Today we'll be discussing key advances in GU oncology featured at the 2022 ASCO Genitourinary (GU) Cancers Symposium. I'm delighted to welcome Dr. Jason Efstathiou, who was the chair of this year's GU ASCO meeting. Dr. Efstathiou is the professor at Harvard Medical School and the director of Genitourinary Division in Radiation Oncology and clinical co-director of The Claire and John Bertucci Center for GU Cancers at the Massachusetts General Hospital. Our full disclosures are available in the show notes and the disclosure of all guests on the podcast can be found on our transcript at asco.org/podcast. Jason, thank you for coming on the podcast today.   Dr. Jason Efstathiou: Thank you very much, Neeraj. It's a real pleasure to be with you.   Dr. Neeraj Agarwal: So, Jason, the GU meeting showcased some fantastic advances across the spectrum of GU malignancies, can you please tell us about some of the hot topics that made the headlines this year?   Dr. Jason Efstathiou: Absolutely. This certainly was a dynamic and interactive hybrid ASCO GU meeting for all those attending in person, live streaming, or accessing the content on demand. With over 5,200 registrants this year, that's an actual record for this meeting and over 70 countries represented. This meeting truly serves as the premier global event for all those who diagnose, treat and study GU cancers. The meeting highlighted novel scientific and clinical findings that were high impacted. [And] in many cases will lead to practice changing care. The meeting had a real focus on diversity, global perspectives, enhanced interactivity, networking, multidisciplinary, collaborative, and evidence-based care. As you know, this year's theme was “World Class Science, Patient-Centered Care,” and this theme was highlighted throughout the program. The meeting kicked off with a rich day focusing on prostate cancer, lots on PSMA imaging, such as Abstract 9 and a very, very excellent session on PSMA targeting and beyond which explored opportunities and challenges with PSMA novel therapeutics, including biomarkers of response and mechanisms of resistance.   Then Abstract 10 looked at PSMA PET and FDG PET as predictors of response and prognosis in a randomized phase 2 trial of Lutetium PSMA (177Lu-PSMA-617) vs cabazitaxel and metastatic castration-resistant prostate cancer (CRPC) progressing after docetaxel. And it suggested that Lutetium PSMA be prioritized in men with high PSMA expression. And this could actually be predictive. We had some awesome abstracts. Abstracts 222 and 223 suggested that a nozzle digital pathology-based biomarker developed using artificial intelligence is more effective than clinical prognostic markers for predicting long term outcomes in patients with prostate cancer. And that this AI tool can actually successfully guide the use of androgen deprivation therapy in men with intermediate risk localized prostate cancer. And then of course, there were some very exciting results in discussion with the primary results of 3 potentially practice-changing phase 3 trials in the setting of metastatic prostate cancer that were presented in the oral prostate session. These were: PROpel (Abstract 11), MAGNITUDE (Abstract 12), and the ARASENS trials (Abstract 13). Neeraj, as a practicing medical oncologist, what did you think of these 3 abstracts?   Dr. Neeraj Agarwal: I agree with you, Jason. These are indeed practice-impacting, practice-changing abstracts, which was a record for a prostate oral session, all 3 abstracts. In fact, the results of the phase 3 trials are [likely] going to influence or impact our practice in coming months. I would like to start with Abstract 11 on the results of the PROpel trial. So, PROpel is a randomized phase 3 trial evaluating the efficacy and safety of olaparib plus abiraterone vs placebo plus abiraterone. In the first-line metastatic cast of resistant cluster cancer, docetaxel therapy was allowed for these patients if given in the metastatic castration sensitive prostate cancer setting. Enrollment in the study was independent of the defects in the homologous recombination repair gene pathway. The primary endpoint was investigator assessed radiographic progression-free survival with multiple secondary endpoints, including overall survival and safety. A total of 796 patients were randomly assigned to olaparib plus abiraterone or placebo plus abiraterone at the pre-plant interim analysis.   Results show that with a significant improvement in the radiographic progression-fee survival for all patients receiving the combination therapy, regardless of the presence of homologous recombination repair gene mutations. Overall survival analysis is still immature with only 29% event having occurred thus far. It is interesting that even patients deemed a negative for homologous recombination repair gene mutations showed significant improvement in video graphic progression-free survival when treated with the combination of olaparib plus abiraterone versus placebo plus abiraterone. I would like to mention the MAGNITUDE trial, which is Abstract 12, in the same context, as these have very similar populations and combination regimens.   So, MAGNITUDE is a randomized phase 3 trial evaluating the efficacy and safety of niraparib plus abiraterone vs placebo plus abiraterone in the first-line metastatic castrate resistant prostate cancer setting. The eligible patient population was slightly different from that in the PROpel trial—prior attacks in therapy or novel hormonal therapy in the metastatic castration sensitive prostate cancer or non-metastatic castrate resistant prostate cancer were allowed. Also, patients were eligible if they had received up to 4 months of abiraterone in the first-line metastatic CRPC setting. Prospective selection of the patients with, and without homologous recombination repair gene mutations was required.   So, the primary endpoint was radiographic progression-free survival by central with multiple secondary endpoints, including overall survival and safety. A pre-specified early fragility analysis was planned after enrolling 200 patients who are [homologous recombination repair] (HRR) negative and who were randomly assigned to receive either niraparib plus abiraterone or placebo plus abiraterone. The pre-planned fertility analysis showed no benefit in the biomarker negative cohort. Four hundred and twenty-three patients who were HRR positive were randomly assigned to receive either the combination of niraparib plus abiraterone or placebo plus niraparib at the pre-planned interim analysis. The results show that trial method—primary endpoint with a significant improvement in the radiographic progression-free survival for BRCA1 and 2 patients—and all patients who are homologous recombination repair mutation positive [were] receiving the combination of niraparib plus abiraterone versus placebo plus niraparib. Overall survival reserve is still immature.   My combined take on the PROpel and the MAGNITUDE trial, based on the data presented so far or available in the public domain so far, is that both trials establish that combination of a PARP inhibitor plus abiraterone on in the first-line settings for me, for [patients with] HRR mutation positive metastatic castration resistant prostate cancer [will] improve radiographic progression-free survival. Even though overall survival data immature for both trials, I expect both combinations will be approved by the U.S. Food and Drug Administration in the near future and will be available to our patients. The HRR negative in the PROpel trial also seemed to benefit with the combination of abiraterone plus olaparib.   I'm looking forward to data on confirmation of HRR negative status by tissue-based genomic profiling results in the full-length publication, which we expect to be published soon. If indeed confirmed, I see the combination of abiraterone plus olaparib to be reasonable option for patients who are HRR negative in the first metastatic castration prostate cancer set. The last practice changing abstract in the oral prostate session was Abstract 13 on the results of the ARASENS trial. ARASENS is a randomized phase 3 trial evaluating the efficacy and safety of darolutamide plus ADT or androgen deprivation therapy plus docetaxel versus placebo plus ADT plus docetaxel in patients with metastatic castration sensitive prostate cancer or mCSPC.   It is important to note that this study only included patients that were eligible for ADT plus docetaxel chemotherapy. The primary endpoint was overall survival with multiple secondary endpoints, including time to casted resistance, time to pain progression, time to first symptomatic skeletal event, and time to start of next antineoplastic therapy and of course, safety. A total of 1,300 patients were randomly assigned to the darolutamide plus ADT plus docetaxel vs placebo plus ADT plus docetaxel.   Results show the primary endpoint of the study was met with a significant improvement in overall survival and a 32% reduction in risk of death for patients on the triplet therapy with thalidomide plus ADT plus docetaxel. While this study offers an additional excellent option for our patients with metastatic castration sensitive prostate cancer, in an older patient population [the] use of docetaxel may be a significant limitation to this combination. In addition, this study did not answer the question [of] if adding docetaxel to ADT plus a novel hormonal therapy backbone will also improve survival with the advent of multiple doublets and triplet combinations. In the recent years, it is very important to find biomarkers which may predict response to these treatments and personalized therapy.   Dr. Jason Efstathiou: Well, Neeraj, it certainly is a mic drop moment. Isn't it? When you can announce that the New England Journal of Medicine has just released the publication of your ARASENS trial, as you're presenting it at ASCO GU don't you think (DOI: 10.1056/NEJMoa2119115)?   Dr. Neeraj Agarwal: Indeed, I think this is one of the most exciting ASCO GU meetings I've seen ever from GU ASCO. This is not an exaggeration.   Dr. Jason Efstathiou: I totally agree. It was a phenomenal meeting and a very dynamic rich prostate day.   Dr. Neeraj Agarwal: So, let's move on to the bladder cancer. Jason, what are your key takeaways from the studies of bladder cancer presented in this meet?   Dr. Jason Efstathiou: Thanks, Neeraj. Yeah, the sessions on urothelial cancer were phenomenal and there were great sessions on novel therapies, such as antibody drug conjugates in advanced urothelial cancer and management of toxicities. There were abstracts such as [Abstract] 440 suggesting that neoadjuvant gemcitabine and cisplatin produced a favorable pathologic response rate and was well tolerated in patients with high grade upper tract urothelial carcinoma, and thus should be potentially deemed a new standard. Abstract 442 was a phase 2 trial that suggested that maintenance treatment with niraparib plus best supportive care did not improve outcomes compared to best supportive care alone, in patients with advanced urothelial carcinoma that did not progress after first-line chemotherapy.   There was Abstract 435, which was an earlier face study suggesting that neoadjuvant treatment with enfortumab demonstrated promising activity among patients who are cisplatin ineligible with muscle invasive bladder cancer. And then there was a lot of focus in the meeting on trimodality therapy and optimizing bladder preservation. Dr. Alexandre R. Zlotta presented Abstract 433, which was a large multi-institutional match comparison of radical cystectomy to trimodality therapy for patients with muscle-invasive bladder cancer. And it suggested equivalent oncologic outcomes for select patients, and that trimodality therapy should be offered as an effective alternative for these patients. So Neeraj, moving on to kidney cancer, what were your key takeaways from these studies on kidney cancer presented in this meeting?   Dr. Neeraj Agarwal: Yes, Jason, thank you. There were exciting results presented from multiple studies in kidney cancer as well. For example, Abstract 290 presented by Dr. Toni K. Choueiri from the Dana-Farber Cancer Institute on the 30-month follow-up of the KEYNOTE-564, which showed continued and strong disease-free survival benefit with adjuvant pembrolizumab in the context of localized or completely dissected renal cell carcinoma. I would like to highlight that highest benefit was seen in those patients who had oligometastatic disease, who on different surgery to remove those metastatic foresight and then were randomly assigned to receive pembrolizumab vs placebo in this trial. Abstract 291, presented by Dr. Matthew Zibelman from Fox Chase Cancer Center, showed the combination of axitinib with nivolumab was associated with close to 70% objective responses. Abstract 300 on kidney cancer on more than 1,000 patients—and on the International Metastatic Renal Cell Carcinoma Consortium, or IMDC Consortium—show that in the context of first-line immunotherapy regimens, presence of lung metastasis, CT nephrectomy and better MDC risk scores correlated with improved objective responses on this novel immunotherapy regimens.   Abstract 350 on the update of the cabozantinib nivolumab was a sunitinib trial in metastatic renal cell carcinoma in the first-line setting. And it showed that the combination of cabozantinib nivolumab continues to be associated with an improved survival with the 30% reduction risk of death, even after this longer follow up—approximately 3 years. So, indeed, multiple abstracts on kidney cancer with real impact on how we practice medicine. So, Jason, let me switch gears here and talk about the education session. For example, there was a compelling keynote addressed by Dr. Karen Knudsen, the CEO of the American Cancer Society, about disparities in GU cancers in the United States. Are there any key messages that you would like to highlight briefly before we wrap up the podcast today?   Dr. Jason Efstathiou: Thanks, Neeraj. Absolutely. The educational sessions were phenomenal. There was a must-see session, by the way, on management of rare variants in GU cancers. They made management of nuanced, rare variants and rare situations, very practical. And then there was an exciting prostate focus session called “Regulating the Wild West: PET-Based Imaging in Trials and the Clinic.” This session was planned with representatives from the U.S. Food and Drug Administration as we have done for the past 3 years. But this year it looked at how often PET based imaging affects clinical decision making and prostate cancer and how the integration of novel molecular based imaging like PET informs clinical trial design and endpoints, including regulatory considerations. And yes, of course, as you noted this year's program also focused on identifying and addressing disparities in cancer care and research with sessions each day, focused on this topic (Abstract 225, 446, 472, and 26). There were great oral presentations and there was a phenomenal Virtual Poster Walk with Dr. Ahmedin Jemal from the American Cancer Society. He, by the way, is an author that we have all quoted. So, please check that out. But we were thrilled, absolutely thrilled to have Dr. Karen Knudsen, the CEO of the American Cancer Society (ACS) as our keynote speaker to address this important topic in her phenomenal and frankly, inspiring talk called “A Path Forward: Addressing Disparities in Genitourinary Cancers.” This talk was especially poignant because as you know, there is a new and robust collaboration between ASCO and the ACS that was announced earlier this month on February 1, regarding equity, diversity, and inclusion in cancer care. ASCO's work aims to address all of the important differences that can impact access to cancer care and outcomes, including age, gender, race, sexual orientation, and geography, both in the U.S. and internationally. ASCO has clearly aligned its equity, diversity, and inclusion (EDI) goals within the mission pillars of research, education, and quality.   Dr. Neeraj Agarwal: Thank you, Jason, for sharing your insights with us today. It is really an exciting time in GU oncology. Thank you.   Dr. Jason Efstathiou: Thank You, Neeraj. I totally agree.   Dr. Neeraj Agarwal: And thank you to our listeners for joining us today. You will find links to the abstracts discussed today on the transcript of this episode. Finally, if you like what you're hearing on the ASCO Daily News podcast, please take a moment to rate, review and subscribe wherever you get your podcast. Thank you so much.   Disclosures: Dr. Neeraj Agarwal: Consulting or Advisory Role: Pfizer, Medivation/Astellas, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, AstraZeneca, Merck, Novartis, lily, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences Research Funding (Institution): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, ORIC Pharmaceuticals, crispr therapeutics, and Arvinas   Dr. Jason Efstathiou: Consulting or Advisory Role: Blue Earth Diagnostics, AstraZeneca, Boston Scientific, Roivant Pharma, Merck, and Myovant Sciences   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guests' statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

Dr. Karim Fizazi, medical oncologist at Gustave Roussy and professor in Oncology at the University of Paris-Saclay in France, tells guest host, Neeraj Agarwal, editor-in-chief of ASCO Daily News and director of the Genitourinary Cancers Programs at the University of Utah's Huntsman Cancer Institute, about the practice-changing PEACE-1 trial, an ongoing phase 3 trial among men diagnosed with de novo metastatic castration-sensitive prostate cancer.   Transcript: Dr. Neeraj Agarwal: Hello and welcome to the ASCO Daily News Podcast. I'm Dr. Neeraj Agarwal, the director of Genitourinary Oncology Program and professor of medicine at the University of Utah Huntsman Cancer Institute and editor-in-chief of the ASCO Daily News. Our topic today is the practice-changing PEACE-1 trial, an ongoing phase 3 trial among men with de novo metastatic castration-sensitive prostate cancer.   Joining me today to discuss the results of this trial is Dr. Karim Fizazi, who is a world-renowned medical oncologist practicing at Gustave Roussy and a full professor in Oncology at the University of Paris-Saclay in Villejuif, France. Dr. Fizazi has led multiple practice-changing trials in advanced prostate cancer and is also the founder of the Prostate Cancer Consortium in Europe known as PEACE Consortium. Our full disclosures are available in the show notes, and disclosures related to all episodes of the podcast can be found on our transcripts at the asco.org podcasts. Welcome, Karim. It is so great to have you on the podcast today, and thank you so much for taking time to be with us.   Dr. Karim Fizazi: Thank you very much, Neeraj. It's a pleasure and an honor.   Dr. Neeraj Agarwal: You recently presented the primary results of the phase 3 PEACE-1 trial in men with de novo metastatic castration-sensitive prostate cancer in the ESMO 2021 meeting. Could you please tell us more about the design of this study and why you did this study?   Dr. Karim Fizazi: Sure, yes, happy to do so. So, PEACE-1 is a large academic European phase 3 trial, which is enrolling patients with de novo metastatic prostate cancer. And it is basically asking 2 questions. Number 1, should we add abiraterone acetate on top of standard of care for these men? And in most of them, standard of care consisted in androgen prevention therapy plus chemotherapy with docetaxel. So, this is the number 1 question—in other words, 3 drugs instead of just 2.   And the second question is whether we should use radiation therapy directed to the primary cancer in these men who are treated with intensive systemic treatments? And we're doing that because we already know the answer regarding the radiation question, and it's a yes answer for men who received androgen deprivation therapy (ADT) alone, but we don't really know whether this applies when intensified treatment is being used.   So, it's a 2x2 design, and we were able to enroll almost 1,200 men in the trial. We completed the inclusion in the trial back in 2018, so the patients or at least those who are alive are on follow-up. And this year, 2021, we have analyzed the co-primary endpoints of radiographic progression-free survival and overall survival for the abiraterone equation. In probably 1 or 2 years from now, we will be able to do the same thing regarding the radiation therapy equations when we have sufficient number of events for these patients.   Dr. Neeraj Agarwal: Very interesting trial design and massive effort at the multinational level in Europe. So please tell us about the results of the study and how it will affect the current treatment paradigm of our patients with de novo metastatic castration-sensitive prostate cancer.   Dr. Karim Fizazi: Sure. So, as I said, right now, we have data regarding the abiraterone question. And again, the question is whether we should use ADT plus docetaxel with or without abiraterone acetate and prednisone. At ASCO [Annual Meeting] this year, we reported the radiographic progression-free survival data, which is a co-primary endpoint of the trial, and this is clearly positive (Abstract 5000). If patients received 3 agents—ADT, docetaxel, and abiraterone—they will enjoy 4.5 years without radiographic progression or death in the experimental arm versus only 2 years in the control arm. So, in other words, this mean 2 and a half year of additional life without problems, if you will, without a significant progression or death for this patient, which is big.   I think many people were already convinced with this data and thought this could be practice changing. I remember our discussion, you and me, Neeraj, at this time. But some others were not necessarily convinced and request the overall survival data before making their decision. Or if it's possible to collect the events, and of course, in the COVID-19 times, this has been challenging. But I think we made it, and we were able to show the data for overall survival at ESMO this year in September. And of course, this was planned—pre-planned and dependent on a pre-planned number of events, which was reached. The news here is good again. And actually, patients receiving ADT plus docetaxel plus abiraterone clearly have an improvement significantly by overall survival as compared to those who received just 2 treatments. The reduction in the risk of death was approximately 25% for these patients receiving the triplet treatment, and it's even greater for men with what we call high-volume disease, so those with multiple bone metastases, at least 4, or visceral metastases, of course, men with a poor outcome. For these men, the reduction in the risk of death achieved by the triplet treatment was 28% in reduction of risk of death and was translated in a marked difference in medians, 3.5 years in the control arm with ADT plus docetaxel, and this was actually what we were expecting for this population of men, as compared to 5.1 years for patients receiving the triplet treatment. So, in other words, it's more than 1 and a half additional year of life for these men receiving 3 treatments up front.   I think what is very unique also in this trial is that men in the control arm were treated very aggressively when they progressed. And actually, more than 80% of them received at least one next-generation hormonal agents, and basically, 85% of them received at least 1 drug associated with proven life prolongation. Again, this is in marked contrast to what we saw in previous pharma industry-sponsored trial conducted in the past, where patients in the control arm were not necessarily very aggressively treated. This is clearly showing us that—   Dr. Neeraj Agarwal: Yeah. This is very interesting. I was really impressed by the fact that patients in control arm and as well as experimental arm—so basically patient on ADT plus docetaxel versus ADT plus docetaxel plus abiraterone—more than 80% patients were receiving subsequent life prolonging therapies, which is in marked contrast to other trials we have seen in the recent past. And despite that, you were able to show a remarkable, clinically meaningful improvement in overall survival with the triplet therapy. I think that is the most important message I got from the updated presentation in ESMO 2021. Would you agree?   Dr. Karim Fizazi: Absolutely. I think it's truly a demonstration that early intensification is better than use—a subsequent use of these agents when the cancer is already more heterogeneous, more aggressive, and harder to treat. We should intensify treatment up front. I think this is very important, especially those with predicted poor outcome.   Dr. Neeraj Agarwal: So, Karim, these data are obviously very impressive, in my view, practice changing. Many of my community oncology colleagues have asked me about the potential side effects of this combination versus chemotherapy with docetaxel or abiraterone therapy alone in addition to ADT. Any tips for our colleagues and friends out there in the community on how to manage side effects or what should we be looking for as a community? What should we be telling the patients and any tips on managing the side effects?   Dr. Karim Fizazi: Absolutely. I think this is a key question, and also, this was great news from the trial. We couldn't find basically synergistic toxicity between docetaxel and abiraterone in the trial. So, in other words, what we saw was the expected toxicity from docetaxel, and we expected toxicity from abiraterone, but nothing additional or nothing worse, if you will. For example, the neutropenic fever incidence was exactly the same in the two arms. The GI toxicity from docetaxel was not increased, and actually, it was even a bit less, numerically speaking at least.   And regarding the abiraterone toxicity, what we saw mainly was an excess in hypertension, usually of lower grade, and an excess in transaminase increase, which was actually rare, approximately 6% if I recall well, which is really in line with what you would expect with the general use of this agent. And of course, this is something you can monitor, and you should monitor. We know how to handle toxicity with abiraterone, and the same also applies to the hypertension management with this agent.   Dr. Neeraj Agarwal: Got it. So, say a patient is hesitant, and of course, this was not addressed by the clinical trial. But given compelling survival benefit, if I'm talking to a patient in the clinic tomorrow morning and the patient is hesitant to start all 3 drugs at the same time, do you think it would be reasonable to start chemotherapy with docetaxel, finish 4 to 6 cycles, and then start abiraterone? With the caveat that this was not addressed by the trial, but I'm just asking a very practical question.   Dr. Karim Fizazi: Again, this is a difficult question you're asking. And I'm saying that because, as you rightly said, in PEACE-1 we combined abiraterone with docetaxel. So, in other words, abiraterone was given concomitantly with docetaxel and then was continued when docetaxel was stopped. So, we don't really know whether giving abiraterone as a maintenance strategy, if you will, in your example, post docetaxel would be associated with the same benefit. It's probably reasonable to think it does, but it's not a given. So, my preference would be actually to combine up front, if possible, of course.   Dr. Neeraj Agarwal: Absolutely. And as I said, this was not tested or addressed by the trial. So final message is, as far as combination therapy is concerned, there is no synergy—there is synergy with the efficacy, but we are not seeing synergy, if you will, from the side effect perspective. And if we are deciding to start triplet therapy, we should be starting all drugs at the same time. At least docetaxel and abiraterone should be started together and not sequenced. Any final message for our friends and colleagues in the community by you, Karim?   Dr. Karim Fizazi: Well, maybe just 1 or 2 final messages. The 1 is a hurrah message because I'm happy, of course, with the data. And just to put this into perspective, back in 2015, before we had all of the recent trials in M1 castration-sensitive disease, men with high-volume disease had approximately 3 years of life expectancy. And now just 5 or 6 years afterwards, thanks to all clinical research we conducted during this time frame, in PEACE-1, these patients can live more than 5 years, which I think is remarkable.   I think the second and last message is that we should soon have more data for these men regarding the triplet combination with ADT, docetaxel, and a next-generation hormonal agent. Specifically, the ARASENS trial (NCT02799602), which is testing darolutamide randomly in this setting, is to release its data probably very soon. And the same applies to the enzalutamide trial with ENZAMET, which should be updated specifically for these men receiving the triplet treatment. So, we should see even more data than what I was fortunate enough to report this year with PEACE-1.   Dr. Neeraj Agarwal: Thank you. So, thank you, Karim, again, for sharing these exciting data from the PEACE-1 trial. Congratulations for conducting this massive trial and coming out with such great news for our patients. I wish you all the best.   Dr. Karim Fizazi: Thank you very much, Neeraj. It was a pleasure. Thank you so much.   Dr. Neeraj Agarwal: And thank you to our listeners for your time today. If you enjoyed this podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Thank you very much.   Disclosures: Dr. Neeraj Agarwal: Consulting or Advisory Role: Pfizer, Medivation/Astellas, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Exelixis, Pfizer, Merck, Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Foundation Medicine, Gilead Sciences Research Funding (inst.): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, ORIC Pharmaceuticals, crispr therapeutics, and Arvinas   Dr. Karim Fizazi: Honoraria (inst.): Janssen, Sanofi, Astellas Pharma, Bayer Consulting or Advisory Role (inst.): Janssen Oncology, Astellas Pharma, Sanofi, AstraZeneca, ESSA, Amgen, Bristol-Myers Squibb, Clovis Oncology Consulting or Advisory Role: Curevac, Orion Pharma GmbH, Bayer Travel, Accommodations, Expenses: Janssen, MSD   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guests' statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

Dr. Dan Gold is the President and CEO of MEI Pharma and is tackling non-Hodgkin's B cell lymphoma to bring a therapy to patients minimizing the toxicities that are associated with current treatments. Their drug candidate zandelisib is a P13K delta inhibitor. It is being studied in lymphoma in B cells to determine if this is a way to block signaling and diminish the malignant capacity of the B cell. Dan explains, "We sort of think of lymphoma in two flavors. it's either a more chronic disease, or it's a more aggressive disease, and then there is sort of a spectrum that spans that. In the less aggressive, we call it indolent diseases, the patients will live with these cancers for many, many years. " "So for the cancers that we treat most commonly or that we're studying most commonly, they're more of the indolent variety. It is interesting because the fact that it's indolent, the patients will respond to therapies. But, eventually, the efficacy of that therapy will wane, and they'll need something else. But there are a number of options that can be staged over the years, again, to keep that cancer at bay, or at least minimally invasive and minimally problematic for many, many years. That's the area that we're focusing all of our energies on currently." "What we have done, and what we have strived to do is to diminish those toxicities so that the patient will stay on the drug as long as possible. So what we've kind of pioneered for this class of drugs, because of the properties of zandelisib, is that we initially give the patient the drug on a daily basis for a couple of months to get that tumor at bay and shrink it as much as we can." @MEI_Pharma $MEIP #Lymphoma #BloodCancer #P13K #P13KDelta #OptimizedDosing #SanDiego meipharma.com Download the transcript here

Dr. Dan Gold is the President and CEO of MEI Pharma and is tackling non-Hodgkin's B cell lymphoma to bring a therapy to patients minimizing the toxicities that are associated with current treatments. Their drug candidate zandelisib is a P13K delta inhibitor. It is being studied in lymphoma in B cells to determine if this is a way to block signaling and diminish the malignant capacity of the B cell. Dan explains, "We sort of think of lymphoma in two flavors. it's either a more chronic disease, or it's a more aggressive disease, and then there is sort of a spectrum that spans that. In the less aggressive, we call it indolent diseases, the patients will live with these cancers for many, many years. " "So for the cancers that we treat most commonly or that we're studying most commonly, they're more of the indolent variety. It is interesting because the fact that it's indolent, the patients will respond to therapies. But, eventually, the efficacy of that therapy will wane, and they'll need something else. But there are a number of options that can be staged over the years, again, to keep that cancer at bay, or at least minimally invasive and minimally problematic for many, many years. That's the area that we're focusing all of our energies on currently." "What we have done, and what we have strived to do is to diminish those toxicities so that the patient will stay on the drug as long as possible. So what we've kind of pioneered for this class of drugs, because of the properties of zandelisib, is that we initially give the patient the drug on a daily basis for a couple of months to get that tumor at bay and shrink it as much as we can." @MEI_Pharma $MEIP #Lymphoma #BloodCancer #P13K #P13KDelta #OptimizedDosing #SanDiego meipharma.com Listen to the podcast here

Guest host, Dr. Neeraj Agarwal, ASCO Daily News editor-in-chief and director of the Genitourinary Cancers Program at the University of Utah's Huntsman Cancer Institute, discusses the practice-changing KEYNOTE-564 and SWOG 1500 trials with Drs. Toni Choueiri and Sumanta "Monty" Pal. Dr. Choueiri is director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute and Dr. Pal is co-director of City of Hope's Kidney Cancer Program and associate editor of Cancer.Net. (This episode was recorded on 11/18/2021) Transcript Dr. Neeraj Agarwal: Hello, and welcome to the ASCO Daily News podcast. I am Dr. Neeraj Agarwal, the director of the Genitourinary Oncology Program, and the professor of Medicine at the University of Utah Huntsman Cancer Institute, and editor-in-chief of the ASCO Daily News. I'm delighted to welcome two internationally recognized leaders in the field, Dr. Toni Choueiri and Dr. Sumanta (Monty) Pal, for a discussion about two practice-changing studies in kidney cancer published this year-- KEYNOTE-564 and SWOG 1500. As a quick introduction, Dr. Choueiri is the director of Lank Center of Genitourinary Oncology at the Dana-Farber Cancer Institute. He's also the Jerome and Nancy Kohlberg Chair, and professor of medicine at the Harvard Medical School. Dr. Sumanta "Monty" Pal is a professor in oncology, and co-director of City of Hope's Kidney Cancer Program, and he is an associate editor of cancer.net of ASCO. Our full disclosures are available in the show notes. And disclosures relating to all episodes of podcasts can be found on our transcripts at ASCO.org/podcast. Toni and Monty, what a day it has been for our patients with kidney cancer. I woke up with the news of the U.S. Food and Drug Administration (FDA) approval of the first ever adjuvant immunotherapy for patients with renal cell carcinoma. It is so great to have you both on the podcast today.   Dr. Monty Pal: Glad to be here. Thanks, Neeraj.   Dr. Toni Choueiri: Thank you, Neeraj. So glad to be here.   Dr. Neeraj Agarwal: So, let me start by asking questions to you first, Toni. So, you recently published the primary results of the phase 3 KEYNOTE-564 study, showing the efficacy of adjuvant therapy with pembrolizumab and immune checkpoint inhibitor in patients with renal cell carcinoma. And this study led to the approval of pembrolizumab this morning. So, please tell us more about the study design and why did you do this study.   Dr. Toni Choueiri: Thank you, Neeraj. And thank you, really, ASCO for this wonderful podcast series. And a big hit, I always listen to them when I'm driving or jogging. And really, thanks for this opportunity because kidney cancer adjuvant therapy has been something like a holy grail we're trying to find for a long, long time. The first adjuvant trial, a randomized trial, in renal cell cancer was in 1973 with radiation therapy. And since that time, all the trials except for one have been a complete failure in a way. And the first adjuvant immunotherapy trial was with old immunotherapy cytokine that we don't use much anymore and was in 1992. I was not done with medical school. I was not actually done with high school at that time, let alone medical school. And now that we have, as we all know, a revolution in the oncology field through these immune checkpoint inhibitors that reinvented immunotherapy in cancer, and now that pembrolizumab has shown activity in patients with more advanced disease, we thought about taking this into the adjuvant setting, a setting of patients where they were subjected to surgery. But on the pathology report, we knew that their risk of this cancer coming back, of recurrence, is somewhat intermediate high or high. These are patients that have stage 2 but grade 4, stage 3, D3, D4. These are patients that had node-positive resected. And we took even patients where the kidney is out, but, also, they had a removal of a metastatic site--let's say a lung metastasis--within a year of removing the kidney. And we know these patients we refer to as M1NED are at quite high risk of recurrence. And we randomly assigned 994 patients to receive pembrolizumab for a year versus placebo. And after a median follow-up of only 2 years--so I want to insist here that this is short for any trial in general--we saw a decrease in the risk of recurrence or death. The hazard ratio for disease-free survival was 0.68. So, a 32% decrease in the risk of recurrence or death. We looked at safety, and we already are familiar in the field of GU oncology with pembrolizumab. And we didn't see when we looked at the safety profile any surprises, any enhanced toxicity. Of course, immune-related adverse events are the number one concern with pembrolizumab. There were no deaths on trial related to pembrolizumab. We saw around 7% of patients needing high dose steroid to medicate these immune-related adverse event, and some patients had to come off therapy for that. We also took a look, Neeraj, an early look, at overall survival. We only had 25% of events, 51 deaths. And we did not meet the very rigorous statistical significance that is needed to say that study is positive for overall survival. But the hazard ratio was 0.54, a 46% decrease in the risk of death, which is kind of encouraging. And after a year, the curve starts to separate. Before a year, they're not separating. And that is consistent with prior studies in general.   Dr. Neeraj Agarwal: This is a very interesting point you just raised, that DFS, disease-free survival, is strongly positive. And even overall survival is trending in the right direction, right?   Dr. Toni Choueiri: Correct.   Dr. Neeraj Agarwal: That's great. So obviously, I would like to raise another point here. When we talk about adjuvant study, we usually think about a localized kidney cancer, which is removed by the surgeon, and then [the] patient is coming to see us for treatment in adjuvant setting. But this study, I would like to highlight, as you said, also included patients who had oligometastatic disease, had successful surgical removal of the oligometastatic disease, and they were also eligible for this trial.   Dr. Toni Choueiri: Yes, absolutely. And I think this is somewhat on the recent side in clinical trials in kidney cancer. The reason for that is that, in practice, we see those patients. And we even had two small trials in the TKI era with sorafenib and pazopanib, small studies, were also completely negative. So, we thought here that we should not exclude these patients. They end up being 6%, 7% of all participants, but this remains an area of unmet medical need.   Dr. Neeraj Agarwal: So, how is the hazard ratio in those patients who had metastatic disease removed and then treated with pembrolizumab?   Dr. Toni Choueiri: Yeah, it was very low. It was 0.2, so 0.29. And this was great to see. I don't want to go into really over-interpreting these results. All the hazard ratio--when you look at subgroup analysis or in the forest plot, all the hazard ratio are less than 1. We didn't see something--let's say 1.5--in favor of pembrolizumab. Now you go into a smaller subgroup, then your confidence intervals are very large and hard to interpret, except that to say, look, on average there could be a significant benefit here, but we can't tell.   Dr. Neeraj Agarwal: Sure, absolutely. I agree with you. So, how this is going to affect the current treatment paradigm, which is for patients with newly diagnosed metastatic RCC, where combination of VEGF-TKI plus immunotherapies (IOs) or IO/IO combinations have become standard of care or treatment paradigm?   Dr. Toni Choueiri: I do believe it will be a standard of care currently in the right population. There are a lot of unanswered questions, but that will be answered hopefully with more follow up. We have already, beside these results, reported--so these results were reported in the plenary session at the 2021 ASCO [Annual Meeting]. But later on, another analysis dealing with patient-reported outcome and quality of life was reported at ESMO and also showed no detriment in quality of life--that's the voice of the patient--no detriment with pembrolizumab (pembro). There is a lot still to do and a lot of unanswered questions, such as the non-clear cell histology, those patients who had surgery of their metastatic disease more than a year. But most important, I think, two questions. One, how can you know from the get-go who are the patients that need adjuvant pembrolizumab? We do not have any valid ctDNA. And I know Dr. Pal was involved with a lot of these type of research. We don't have any ctDNA test that is really that faithful and sensitive in the MRD space in renal cell. Many of us are working, so we don't know. We may end up over-treating patients that need surgery only. And actually, we may end up under-treating patients that need, perhaps, pembro, and another drug. And the second thing in those patients--and I hope it does not happen, but unfortunately, it will to some extent--whose tumor progress on adjuvant pembrolizumab, what do you do? What's the treatment paradigm? And actually, there is no data. This is a data-free zone. And I would think somebody whose tumor progressed, tumor continued to grow or grows, while they're actively on pembrolizumab, on IO, is way different than someone whose tumor comes back after 2 or 3 years from stopping the drug. Should we treat them with the same drug? Should we treat them with the TKI plus IO? Luckily, there are trials that are ongoing in patients whose tumor progressed after PD-1/PD-L1 inhibitor to give them a TKI as a control arm, or a TKI plus an immune checkpoint inhibitor. And I know Dr. Pal is very heavily involved with such trials. So, hopefully, we will answer this question, but not anytime soon.   Dr. Neeraj Agarwal: Very interesting, and definitely new results are posing new challenges in how we practice medicine here in the coming future. So, Monty, you are leading a trial with a very similar trial with atezolizumab. And I'm really hoping, we are all really hoping, that we see the other trial being positive, so we have more treatment options for our patients.   Dr. Monty Pal: I couldn't agree with you more. I mean, I definitely think that Toni's study really adds a lot of fuel to the fire suggesting that this strategy of adjuvant immunotherapy may be successful in localized renal cell.   Dr. Neeraj Agarwal: And I'm not going to really delve into the side effects of pembrolizumab and atezolizumab because these drugs are used quite often. They are in widespread use for different types of cancer. But just a quick question, any safety signal, Toni? Did you see any safety signal with pembrolizumab in this patient population?   Dr. Toni Choueiri: Yeah, this is an excellent question. So, nothing that would be different than using pembrolizumab overall knowing in other diseases as a single agent. So, this drug not first in human, as you know, and it's been approved in combination or as a single agent in many diseases. A tumor that the three of us treat is bladder cancer, and we know from another study how to use pembrolizumab. I think that the use of corticosteroid is somewhat of an objective way, at least to me, in looking at immune-related adverse event. And it has been between 5% to 10%, so we're not way off here. But there is no doubt that there are patients that we had no death on trial attributed to drug that may have, with pembrolizumab, some serious toxicities. We had patients that had autoimmune diabetes, hypophysitis, pneumonitis--quite uncommon, but not impossible.   Dr. Neeraj Agarwal: We'll still need to keep an eye for that, basically.   Dr. Toni Choueiri: No doubt.   Dr. Neeraj Agarwal: Yes. So, changing gears, let's talk to you, Monty. You recently presented the primary results of the SWOG 1500 trial in patients with metastatic non-clear cell renal cell carcinoma. Could you please tell us why you did this study and how this study's design was unique compared to similar studies in this setting?   Dr. Monty Pal: Yeah. No, absolutely. Toni did a great job of outlining areas that are sort of free of data in the adjuvant space, particularly with immunotherapy. I think that data-free area for us in kidney cancer for a long time has been non-clear cell histology. We just don't really know how to treat them. And I actually got advice from Toni when I was devising SWOG 1500. We planned it out as a very simple study comparing sunitinib and cabozantinib. And Toni will remember this history well. It sort of went through several iterations. The study blossomed into a six-arm trial. Ultimately, it turned into a four-arm study, looking at sunitinib versus cabozantinib versus two other MET inhibitors--savolitinib and crizotinib. And ultimately, the study was boiled down to essentially what we'd originally proposed. Two of the MET inhibitors--savolitinib and crizotinib--failed to surpass that initial analysis for PFS. So, ultimately, we demonstrated a superiority with cabozantinib over sunitinib for progression-free survival.   Dr. Neeraj Agarwal: So, what is the current treatment paradigm for patients who have newly diagnosed metastatic papillary RCC now?   Dr. Monty Pal: I think for patients who don't have genomic selection, I think that cabozantinib remains the standard. I really want to champion- and maybe Toni can talk a little bit more about this--a study that Toni is leading called the SAMETA trial, which I think has a really innovative design. And it's going to be genomically characterizing patients and randomizing to savolitinib with durvalumab or sunitinib. Tell me, Toni, if I have the design right there.   Dr. Toni Choueiri: Yes. Actually, this is a specific study in a specific population. It's not in papillary RCC as much as in those 30%, 40% of papillary RCC that have MET-driven tumors, so MET alteration, whether through chromosome 7 duplication, through chromosome 7 trisomy, through mutation or amplification. These patients will get either control arm or they will get savolitinib, which is a pure MET inhibitor that is devoid of VEGF-related toxicities, savolitinib plus durvalumab, or durvalumab alone. So, two experimental arms and one control. And the reason for this is we saw activity and quite a good toxicity profile with savolitinib, a pure MET inhibitor, over sunitinib in an earlier trial that was sunitinib against savolitinib in selected patient populations. The study had to close early. So, despite the numerical difference, this was not statistically significant. And then in another study led by Dr. Powles and colleagues, there was also some interesting activity how durvalumab could augment that activity. So, we're launching a phase 3 trial with three arms that you described very well.   Dr. Neeraj Agarwal: That's wonderful. So, what are the next steps, Monty? I mean, this is amazing to see you designing an investigator-initiated trial. This was your concept. You designed it. You built this to be a huge multicenter trial, which was open across the country, funded by the National Cancer Institute. And congratulations for making that happen. It's rare for us to see these trials going from a concept stage to a national trial, and then changing the standard of care. So, what are the next steps now for you and your team in SWOG for papillary RCC or metastatic papillary RCC? How do you build out further with the backbone of cabozantinib?   Dr. Monty Pal: I really appreciate the question, Neeraj. It's so critical to understand that we're just not quite done yet. Toni's study, as I've mentioned, is incredibly innovative. I'm also really thrilled to be working with someone who you've mentored so well, Ben Maughan, at the Huntsman Cancer Institute in Utah. And he's actually designed a brilliant study, which we're going to be leading together, which looks at cabozantinib with or without atezolizumab. Recently, in a study that you and I and Toni were a part of that we just published in JCO, we actually saw quite impressive response rates with the combination of cabozantinib and atezolizumab in patients with papillary RCC, around 47%. Those response rates were actually replicated in a separate study run by Joe Lee at Memorial Sloan Kettering. In the context of papillary disease response rates were again above a threshold of around 40%. So, I think there's something to it. But until we really subject this to randomization, I think we're not going to know whether or not cabo plus IO is standard. So, I encourage everyone to consider Toni's study. I encourage everyone to look out for our trial of cabo plus or minus atezo, which should be rolling out next year.   Dr. Neeraj Agarwal: What is the name of the trial, or the number, for our audience?   Dr. Monty Pal: Yeah, we lucked out with another great number. We got 1500 for the first trial. This is going to be SWOG 2200. So SWOG 2200, and I think it's due to open maybe in the first quarter of 2022.   Dr. Neeraj Agarwal: That's fantastic news. Any new signal? We know cabozantinib is already approved for our patients with metastatic RCC, courtesy METEOR trial led by Dr. Choueiri. Toni, it's amazing to see how many times you have changed standard of care for our patients with metastatic RCC. So, any new safety signal of cabozantinib in this patient population with metastatic papillary RCC?   Dr. Monty Pal: Nothing that appreciated. The toxicity profile was pretty much on par with what you'd anticipate for cabozantinib in the setting. Major side effects were hypertension, hand-foot syndrome, [and] diarrhea. Nothing that really sort of stood out relative to what we would expect in a clear cell population of patients.   Dr. Neeraj Agarwal: That's great. Any final messages for our patients, for our audience, for our listeners?   Dr. Toni Choueiri: Well, let me start, and maybe Monty can add. It's been, and it hopefully will continue to be, this humbling experience, where median survival from metastatic RCC in mid-2000--not long time ago during our training--has been 1 year. And now in metastatic disease, it's 4 to 5 years. And that is only going to get better. And then it's even more humbling to be in a time where you can talk about adjuvant treatment in this disease, renal cell cancer, that continues every year to kill, unfortunately, 14,000 Americans. That's just in the U.S. alone. So, we have to continue in getting more targets, more drugs, more reasonable combination, and the right patient, whether through specific biomarker that are tissue or blood-based or specific liquid biopsies that can tell you who has and who doesn't have cancer at the microscopic levels.   Dr. Neeraj Agarwal: Thank you. How about you, Monty? Any final message for our audience?   Dr. Monty Pal: I couldn't have summarized it better than Toni, just such a wonderful statement around optimism for what we've achieved so far and what's yet to come. And if I could emphasize to anyone in the audience today the need to keep progressing the field further with clinical trials, I think that would be my underlying message.   Dr. Neeraj Agarwal: Thank you again, Toni, Monty, for your valuable insights and thoughts. Thank you for all the inspiration. This is indeed so inspiring to see your work, which is changing the lives of our patients on a daily basis. Our listeners will find links to your studies in the transcript of this episode. I wish you all the best.   Dr. Toni Choueiri: Thank you.   Dr. Neeraj Agarwal: And thank you to our listeners for your time today. If you enjoyed this episode, please take a moment to rate, review, and subscribe wherever you get your podcasts. Thank you so much.   Disclosures: Dr. Neeraj Agarwal: Consulting or Advisory Role: Pfizer, Medivation/Astellas, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Exelixis, Pfizer, Merck    , Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Foundation Medicine, Gilead Sciences Research Funding (inst.): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, ORIC Pharmaceuticals, crispr therapeutics, and Arvinas   Dr. Sumanta (Monty) Pal: Consulting or Advisory Role: F. Hoffmann LaRoche, F. Hoffman Research Funding (inst.): Eisai, Genentech, Roche, Exelixis, Pfizer Travel, Accommodations, Expenses: Genentech, Seattle Genetics   Dr. Toni Choueiri: Employment: Dana Farber Cancer Hospital Leadership: Dana Farber Cancer Hospital, NCCN, KidneyCan, ASCO, ESMO Stock and Other Ownership Interests: Pionyr, TEMPEST Honoraria: NCCN, UpToDate, Michael J. Hennessy Associates, ASCO, Harborside Press, Analysis Group,                AstraZeneca, Alexion Pharmaceuticals, Sanofi/Aventis, Bayer, Bristol-Myers Squibb, Genentech/Roche, GlaxoSmithKline, Merck          , Novartis, Peloton Therapeutics , Pfizer, Corvus Pharmaceuticals, Ipsen,                 Foundation Medicine, Eisai, PlatformQ Health, Clinical Care Options, Navinata Healthcare, Kidney Cancer Journal, Exelixis, Prometheus, Lpath, NEJM, Lancet Oncology, Cerulean Pharma, alligent, EMD Serono, HERON, Lilly, Janssen Oncology, IQvia, Aveo, and NCI. Consulting or Advisory Role: Pfizer, Bayer, Novartis, GlaxoSmithKline, Merck, Bristol-Myers Squibb, Roche/Genentech, Eisai, Foundation Medicine, Cerulean Pharma, AstraZeneca, Exelixis, Prometheus Laboratories, alligent, Ipsen, Corvus Pharmaceuticals, Lpath, Alexion Pharmaceuticals, Sanofi/Aventis, Peloton Therapeutics, UpToDate, NCCN, Michael J. Hennessy Associates, Analysis Group, Kidney Cancer Journal, Clinical Care Options, Paltform Q, Navinata Healthcare, Harborside Press, ASCO, NEJM, Lancet Oncology, EMD Serono, HERON, Lilly, ESMO, NiKang Therapeutics, Kanaph Therapeutics, Infinity Pharmaceuticals, and Aravive Research Funding (inst.): Pfizer, Novartis, Merck, Exelixis               , TRACON Pharma, GlaxoSmithKline, Bristol-Myers Squibb, AstraZeneca, Peloton Therapeutics, Roche/Genentech, Celldex, Agensys, Eisai, Takeda, Prometheus, Ipsen, Corvus Pharmaceuticals, Cerulean Pharma, Seattle Genetics/Astellas, Bayer, Foundation Medicine, Roche, Calithera Biosciences, Analysis Group, NCI, GATEWAY for Cancer Research, and Congressionally Directed Medical Research Programs (DOD) Patents, Royalties, Other Intellectual Property (inst.): International Patent Application No. PCT/US2018/058430, entitled “Biomarkers of Clinical Response and Benefit to Immune Checkpoint Inhibitor Therapy, International Patent Application No. PCT/US2018/12209, entitled “PBRM1 Biomarkers Predictive of Anti-Immune Checkpoint Response Patents, Royalties, Other Intellectual Property: ctDNA technologies Travel, Accommodations, Expenses: Pfizer, Bayer, Novartis, GlaxoSmithKline, Merck, Bristol-Myers Squibb, Roche/Genentech, Eisai, Foundation Medicine, Cerulean Pharma, AstraZeneca, Exelixis, Prometheus, alligent, Ipsen, Corvus Pharmaceuticals, Lpath, Alexion Pharmaceuticals, Sanofi/Aventis, UpToDate, Peloton Therapeutics, NCCN, Michael J. Hennessy Associates, Analysis Group, Kidney Cancer Journal, Clinical Care Options, PlatformQ Health, Harborside Press, Navinata Healthcare, NEJM, Lancet Oncology, EMD Serono, HERON, Lilly, and ESMO Other Relationship: Medical writing and editorial assistance support may have been funded by Communications companies funded by pharmaceutical companies such as ClinicalThinking, Health Interactions, Envision Pharma Group, Fishawack Group of Companies, Parexel   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    

Guest host Dr. Neeraj Agarwal, editor-in-chief of ASCO Daily News and director of the Genitourinary Cancers Program at the University of Utah Huntsman Cancer Institute, interviews Dr. Oliver Sartor, medical director of the Tulane Cancer Center in New Orleans, on the practice-changing VISION trial and its impact on the current treatment paradigm for mCRPC. Transcript ASCO Daily News: Welcome to the ASCO Daily News Podcast. Our topic today is the practice-changing VISION trial, a phase III trial of radioligand therapy in patients with metastatic castration-resistant prostate cancer. Our guest host, Dr. Neeraj Agarwal, the editor-in-chief of the ASCO Daily News and director of the Genitourinary Cancers Program at the University of Utah's Huntsman Cancer Institute, will speak with one of the trial's investigators, Dr. Oliver Sartor, the medical director of the Tulane Cancer Center and Laborde Professor for Cancer Research. Their full disclosures are available on the transcript of this episode, and disclosures relating to all episodes of the Daily News Podcast are available on our transcripts at asco.org/podcasts.   Dr. Neeraj Agarwal: Hi, my name is Dr. Neeraj Agarwal. I am with Dr. Oliver Sartor. Today, we are going to discuss one of the practice-changing trials in the context of metastatic castration-resistant prostate cancer. Welcome to the ASCO Daily News Podcast, Dr. Sartor. Thanks for taking the time to be with us today.   Dr. Oliver Sartor: Thank you, Neeraj. A pleasure to be here.   Dr. Neeraj Agarwal: You recently published the primary results of the phase III VISION trial, which tested the efficacy of a novel radioligand therapy, Lutetium-177-PSMA-617, in men with metastatic castrate-resistant prostate cancer. Could you please tell us more about this compound and why you did this study?   Dr. Oliver Sartor:  So I'll start off with the compound itself. Radioligand therapy is a therapy that has a little warhead, and that warhead in this case is Lutetium-177. But it's guided by binding to PSMA. Now, PSMA is prostate-specific membrane antigen, and many of us are familiar with it, but some may not be. So PSMA is a protein expressed on the surface of most prostate cancer cells. Not all patients have it, but most do. And the ability of the PSMA Lutetium-177 to target the cancer was indicated in some preliminary studies, but they have not been to phase III. So the purpose of the phase III VISION trial was really to design a definitive study to look at overall survival, in particular, to determine whether or not this agent was truly active. And the good news is, it is truly active. And in the VISION trial, we were able to not only extend life with an overall survival benefit, haz ratio 0.62, but there was also a time-to-progression image-based radiographic progression-free survival. It was also much in favor of the PSMA Lutetium with a haz ratio of 0.4. So whether or not you look at time to cancer progression or whether or not you look at overall survival, this is an effective therapy. It, of course, does have some adverse side effects. We can talk more about that, but it's reasonably well tolerated. And I do anticipate that there'll be an FDA approval as a consequence of these pivotal findings.   Dr. Neeraj Agarwal: These are wonderful results and news for our patients. Please tell me how it will affect the current treatment paradigm of our patients with mCRPC. As we know, you selected patients who had disease progression on chemotherapy with taxanes and novel hormonal therapy. But real-world studies, many of which were published by you, have shown that docetaxel is received by a minority of patients with metastatic prostate cancer. So how do you envision treating your patients who do not want to be treated with chemotherapy as many of my patients do? How will you apply Lutetium-177 in their treatment?   Dr. Oliver Sartor:  Well, Neeraj, I think that we're going to be restricted in accordance with the label that the FDA provides. And I fully expect that the label will include a progression after treatment with docetaxel or at least one taxane-based therapy because that's the way the VISION trial was constructed. Now, you're raising a very critical point, and that is, what about the individuals that do not want to receive or are ineligible to receive a chemotherapy such as docetaxel? And for those individuals, we now have a new trial called PSMA4, and that trial is going to be testing the Lutetium-177-PSMA-617 in the context of chemotherapy-naive patients. So I think we're going to have to wait until we have more results, more clinical trials completed, prior to the application of PSMA-617 into the more general population of chemotherapy-naive patients. But those clinical trials are now underway.   Dr. Neeraj Agarwal: That's great. So, Oliver, in the VISION trial, you did mandate a diagnostic PSMA PET scan, and patients who were positive on the diagnostic PSMA PET scan were deemed to be eligible for enrollment on the VISION trial. Do you expect FDA to include diagnostic PSMA scan for eligibility for treatment with the Lutetium-177 in the real-world setting? If it doesn't or if it does, how it is going to affect the treatment of our patients, that availability of treatment for our patients?   Dr. Oliver Sartor:  That's really a great question. And I do expect that PSMA PET imaging will be a criteria given that it was used for patient selection. Now, as it turned out, about 87% of the patients actually did qualify after getting a PSMA PET scan. And given that that was part of the inclusion criteria, I anticipate that the FDA will also incorporate such imaging. Now, it does get to be a bit of an issue because it turns out that PSMA PET is just now coming into more widespread use. We did have, in May of this year, the approval by the FDA for the PSMA PET imaging agent and-- I shouldn't say "the"-- a PSMA PET imaging agent. Prior to that, in December of last year, there was both UCLA and UCSF approval by the FDA for yet another PSMA PET imaging agent. As we move forward, I anticipate that PET imaging is going to be more widely available. And of course, we don't have the approval as of yet today for the PSMA-617-Lutetium-177. And when we do get the anticipated approval, which likely will be in 2022, then I also anticipate that PSMA PET will be more widely available. Now, there are still issues with reimbursement for PSMA PET, and we've encountered those in our own practice. But that's a rapidly changing area, and we're working with the insurance companies in an effort to ensure that patients will get the imaging that they need.   Dr. Neeraj Agarwal:  Got it. And obviously, I asked this question because many of my community friends and colleagues have asked me this question.  Before we talk about the side effects of Lutetium-177, would you have any message for our friends and colleagues in the community who are bracing themselves for treating their patients with the Lutetium-177, whether they should be proactive in establishing contacts and relationships with the nuclear medicine facilities and so on?   Dr. Oliver Sartor:  That's a great question, Neeraj, because I think you're raising a very important point. This is going to be the type of therapy that involves multidisciplinary care. We can see that there'll be diagnostic PET imaging as being a component of the study. There'll be the necessity of licensed physicians, typically either nuclear medicine or radiation oncology, to actually administer the drug. And then, quite frankly, the medical oncologists or those urologists who are trained in advanced prostate cancer are going to need to manage the patient. This is a lot more than just getting an injection. Many of these patients are ill. They need to have symptom management. They need to manage their bone health. They need to manage their hormonal manipulations. They need management with regard to pain. So this is not just about giving an injection. And I encourage those people who are interested to involve multidisciplinary teams starting now. And I realize that the therapy is not available now, but you have to anticipate that it will be. And I think it will be a game changer of a therapy, and many patients are going to want it. So that means it's incumbent upon the physicians to be prepared, and that means multidisciplinary care.   Dr. Neearj Agarwal:  Excellent point. So basically, we should be ready. We should start establishing relationships with nuclear medicine facilities or radiation oncologists who are going to deliver Lutetium-177. Overall, when I was reading the New England Journal paper, the side effect profile seemed very reasonable. I did not see any red flags. To me, it sounded like a pretty well-tolerated drug. So what is your take on the side effects of Lutetium-177?   Dr. Oliver Sartor: I think the side effects are quite manageable. One of the unique side effects is that of dry mouth and that's because the PSMA can actually be expressed in the salivary glands and that there is some potential for salivary gland binding in the PSMA-617-Lutetium. And that means that you can have damage to the salivary glands, and that means dry mouth. It turns out that a little over 40% of the patients actually did complain of a dry mouth, and that needs to be managed typically with fluid intake or various ways of mouth moisturizers. Fatigue is a potential issue. It was raised, as well as some bone marrow suppression. And if you look at the grade 3/4 toxicities, anemia was present a little more than 10% of the time. And that, of course, needs to be monitored. There is some potential collateral damage to the bone marrow. So these patients need to have their counts monitored. They need to have their symptoms assessed. And they need to be managed as they go through the process. It's not just about giving an injection, but clearly, the licensed individuals, including nuclear medicine and radiation oncology, need to be engaged, because without them, there is no injection. So this is a complex multidisciplinary care paradigm. And emphasizing the point, symptom management, yes; adverse event management, yes. But you have to deliver the drug, and that means multidisciplinary care.   Dr. Neeraj Agarwal:  Those are fantastic points. Thank you very much, Dr. Sartor, for taking time to be with us. And I'm really hoping that this podcast will be very enriching to our listeners. Thank you very much.   Dr. Oliver Sartor: Thank you, Neeraj. Glad to be here.   ASCO Daily News:  You've been listening to Dr. Neeraj Agarwal of the Huntsman Cancer Institute and Dr. Oliver Sartor of the Tulane Cancer Center. Our listeners will find a link to the VISION study in the transcript of this episode. Thank you to our listeners for joining us today. If you enjoyed this episode, please take a moment to rate, review, and subscribe wherever you get your podcasts.   Disclosures: Dr. Neeraj Agarwal Consulting or Advisory Role: Pfizer, Medivation/Astellas, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Exelixis, Merck, Novartis, Eisai,    Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences   Research Funding (Inst.): Bayer Your Institution, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen,    AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, crispr therapeutics, and Arvinas     Disclosures: Dr. Oliver Sartor Stocks & Other Ownership Interests: Lilly, GlaxoSmithKline, Abbvie, Cardinal Health, United Health Group, PSMA Therapeutics, Clarity Pharmaceuticals, Noria Therapeutics, Inc., Clovis Consulting or Advisory Role: Bayer, Sanofi, AstraZeneca, Dendreon, Constellation Pharmaceuticals, Advanced Accelerator Applications, Pfizer, Bristol-Myers Squibb, Bavarian Nordic, EMD Serono, Astellas Pharma, Progenics, Blue Earth Diagnostics, Myovant, Myriad Genetics, Novartis, Clarify Pharmaceuticals, Fusion, Istopen Technologien Meunchen, Janssen, Noxopharm, Clovis, Noria Therapeutics, Point Biopharma, TeneoBio, Telix, Theragnostics Research Funding (Inst): Sotio, Janssen, Progenics, Bayer, Sanofi, Endocyte, Merck, Invitae, Constellation Pharmaceuticals, Advanced Accelerator Applications, Dendreon, AstraZeneca Expert Testimony: Sanofi Travel, Accommodations, Expenses: Bayer, Johnson & Johnson, Sanofi, AstraZeneca, Progenics   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Dr. Oliver Sartor on the VISION Trial and Improving Care for Patients With mCRPC       ASCO Daily News: Welcome to the ASCO Daily News Podcast. Our topic today is the practice-changing VISION trial, a phase III trial of radioligand therapy in patients with metastatic castration-resistant prostate cancer. Our guest host, Dr. Neeraj Agarwal, the editor-in-chief of the ASCO Daily News and director of the Genitourinary Cancers Program at the University of Utah's Huntsman Cancer Institute, will speak with one of the trial's investigators, Dr. Oliver Sartor, the medical director of the Tulane Cancer Center and Laborde Professor for Cancer Research. Their full disclosures are available on the transcript of this episode, and disclosures relating to all episodes of the Daily News Podcast are available on our transcripts at asco.org/podcasts.   Dr. Neeraj Agarwal: Hi, my name is Dr. Neeraj Agarwal. I am with Dr. Oliver Sartor. Today, we are going to discuss one of the practice-changing trials in the context of metastatic castration-resistant prostate cancer. Welcome to the ASCO Daily News Podcast, Dr. Sartor. Thanks for taking the time to be with us today.   Dr. Oliver Sartor: Thank you, Neeraj. A pleasure to be here.   Dr. Neeraj Agarwal: You recently published the primary results of the phase III VISION trial, which tested the efficacy of a novel radioligand therapy, Lutetium-177-PSMA-617, in men with metastatic castrate-resistant prostate cancer. Could you please tell us more about this compound and why you did this study?   Dr. Oliver Sartor:  So I'll start off with the compound itself. Radioligand therapy is a therapy that has a little warhead, and that warhead in this case is Lutetium-177. But it's guided by binding to PSMA. Now, PSMA is prostate-specific membrane antigen, and many of us are familiar with it, but some may not be. So PSMA is a protein expressed on the surface of most prostate cancer cells. Not all patients have it, but most do. And the ability of the PSMA Lutetium-177 to target the cancer was indicated in some preliminary studies, but they have not been to phase III. So the purpose of the phase III VISION trial was really to design a definitive study to look at overall survival, in particular, to determine whether or not this agent was truly active. And the good news is, it is truly active. And in the VISION trial, we were able to not only extend life with an overall survival benefit, haz ratio 0.62, but there was also a time-to-progression image-based radiographic progression-free survival. It was also much in favor of the PSMA Lutetium with a haz ratio of 0.4. So whether or not you look at time to cancer progression or whether or not you look at overall survival, this is an effective therapy. It, of course, does have some adverse side effects. We can talk more about that, but it's reasonably well tolerated. And I do anticipate that there'll be an FDA approval as a consequence of these pivotal findings.   Dr. Neeraj Agarwal: These are wonderful results and news for our patients. Please tell me how it will affect the current treatment paradigm of our patients with mCRPC. As we know, you selected patients who had disease progression on chemotherapy with taxanes and novel hormonal therapy. But real-world studies, many of which were published by you, have shown that docetaxel is received by a minority of patients with metastatic prostate cancer. So how do you envision treating your patients who do not want to be treated with chemotherapy as many of my patients do? How will you apply Lutetium-177 in their treatment?   Dr. Oliver Sartor:  Well, Neeraj, I think that we're going to be restricted in accordance with the label that the FDA provides. And I fully expect that the label will include a progression after treatment with docetaxel or at least one taxane-based therapy because that's the way the VISION trial was constructed. Now, you're raising a very critical point, and that is, what about the individuals that do not want to receive or are ineligible to receive a chemotherapy such as docetaxel? And for those individuals, we now have a new trial called PSMA4, and that trial is going to be testing the Lutetium-177-PSMA-617 in the context of chemotherapy-naive patients. So I think we're going to have to wait until we have more results, more clinical trials completed, prior to the application of PSMA-617 into the more general population of chemotherapy-naive patients. But those clinical trials are now underway.   Dr. Neeraj Agarwal: That's great. So, Oliver, in the VISION trial, you did mandate a diagnostic PSMA PET scan, and patients who were positive on the diagnostic PSMA PET scan were deemed to be eligible for enrollment on the VISION trial. Do you expect FDA to include diagnostic PSMA scan for eligibility for treatment with the Lutetium-177 in the real-world setting? If it doesn't or if it does, how it is going to affect the treatment of our patients, that availability of treatment for our patients?   Dr. Oliver Sartor:  That's really a great question. And I do expect that PSMA PET imaging will be a criteria given that it was used for patient selection. Now, as it turned out, about 87% of the patients actually did qualify after getting a PSMA PET scan. And given that that was part of the inclusion criteria, I anticipate that the FDA will also incorporate such imaging. Now, it does get to be a bit of an issue because it turns out that PSMA PET is just now coming into more widespread use. We did have, in May of this year, the approval by the FDA for the PSMA PET imaging agent and-- I shouldn't say "the"-- a PSMA PET imaging agent. Prior to that, in December of last year, there was both UCLA and UCSF approval by the FDA for yet another PSMA PET imaging agent. As we move forward, I anticipate that PET imaging is going to be more widely available. And of course, we don't have the approval as of yet today for the PSMA-617-Lutetium-177. And when we do get the anticipated approval, which likely will be in 2022, then I also anticipate that PSMA PET will be more widely available. Now, there are still issues with reimbursement for PSMA PET, and we've encountered those in our own practice. But that's a rapidly changing area, and we're working with the insurance companies in an effort to ensure that patients will get the imaging that they need.   Dr. Neeraj Agarwal:  Got it. And obviously, I asked this question because many of my community friends and colleagues have asked me this question.  Before we talk about the side effects of Lutetium-177, would you have any message for our friends and colleagues in the community who are bracing themselves for treating their patients with the Lutetium-177, whether they should be proactive in establishing contacts and relationships with the nuclear medicine facilities and so on?   Dr. Oliver Sartor:  That's a great question, Neeraj, because I think you're raising a very important point. This is going to be the type of therapy that involves multidisciplinary care. We can see that there'll be diagnostic PET imaging as being a component of the study. There'll be the necessity of licensed physicians, typically either nuclear medicine or radiation oncology, to actually administer the drug. And then, quite frankly, the medical oncologists or those urologists who are trained in advanced prostate cancer are going to need to manage the patient. This is a lot more than just getting an injection. Many of these patients are ill. They need to have symptom management. They need to manage their bone health. They need to manage their hormonal manipulations. They need management with regard to pain. So this is not just about giving an injection. And I encourage those people who are interested to involve multidisciplinary teams starting now. And I realize that the therapy is not available now, but you have to anticipate that it will be. And I think it will be a game changer of a therapy, and many patients are going to want it. So that means it's incumbent upon the physicians to be prepared, and that means multidisciplinary care.   Dr. Neearj Agarwal:  Excellent point. So basically, we should be ready. We should start establishing relationships with nuclear medicine facilities or radiation oncologists who are going to deliver Lutetium-177. Overall, when I was reading the New England Journal paper, the side effect profile seemed very reasonable. I did not see any red flags. To me, it sounded like a pretty well-tolerated drug. So what is your take on the side effects of Lutetium-177?   Dr. Oliver Sartor: I think the side effects are quite manageable. One of the unique side effects is that of dry mouth and that's because the PSMA can actually be expressed in the salivary glands and that there is some potential for salivary gland binding in the PSMA-617-Lutetium. And that means that you can have damage to the salivary glands, and that means dry mouth. It turns out that a little over 40% of the patients actually did complain of a dry mouth, and that needs to be managed typically with fluid intake or various ways of mouth moisturizers. Fatigue is a potential issue. It was raised, as well as some bone marrow suppression. And if you look at the grade 3/4 toxicities, anemia was present a little more than 10% of the time. And that, of course, needs to be monitored. There is some potential collateral damage to the bone marrow. So these patients need to have their counts monitored. They need to have their symptoms assessed. And they need to be managed as they go through the process. It's not just about giving an injection, but clearly, the licensed individuals, including nuclear medicine and radiation oncology, need to be engaged, because without them, there is no injection. So this is a complex multidisciplinary care paradigm. And emphasizing the point, symptom management, yes; adverse event management, yes. But you have to deliver the drug, and that means multidisciplinary care.   Dr. Neeraj Agarwal:  Those are fantastic points. Thank you very much, Dr. Sartor, for taking time to be with us. And I'm really hoping that this podcast will be very enriching to our listeners. Thank you very much.   Dr. Oliver Sartor: Thank you, Neeraj. Glad to be here.   ASCO Daily News:  You've been listening to Dr. Neeraj Agarwal of the Huntsman Cancer Institute and Dr. Oliver Sartor of the Tulane Cancer Center. Our listeners will find a link to the VISION study in the transcript of this episode. Thank you to our listeners for joining us today. If you enjoyed this episode, please take a moment to rate, review, and subscribe wherever you get your podcasts.   Disclosures: Dr. Neeraj Agarwal Consulting or Advisory Role: Pfizer, Medivation/Astellas, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Exelixis, Merck, Novartis, Eisai,    Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences   Research Funding (Inst.): Bayer Your Institution, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen,    AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, crispr therapeutics, and Arvinas     Disclosures: Dr. Oliver Sartor Stocks & Other Ownership Interests: Lilly, GlaxoSmithKline, Abbvie, Cardinal Health, United Health Group, PSMA Therapeutics, Clarity Pharmaceuticals, Noria Therapeutics, Inc., Clovis Consulting or Advisory Role: Bayer, Sanofi, AstraZeneca, Dendreon, Constellation Pharmaceuticals, Advanced Accelerator Applications, Pfizer, Bristol-Myers Squibb, Bavarian Nordic, EMD Serono, Astellas Pharma, Progenics, Blue Earth Diagnostics, Myovant, Myriad Genetics, Novartis, Clarify Pharmaceuticals, Fusion, Istopen Technologien Meunchen, Janssen, Noxopharm, Clovis, Noria Therapeutics, Point Biopharma, TeneoBio, Telix, Theragnostics Research Funding (Inst): Sotio, Janssen, Progenics, Bayer, Sanofi, Endocyte, Merck, Invitae, Constellation Pharmaceuticals, Advanced Accelerator Applications, Dendreon, AstraZeneca Expert Testimony: Sanofi Travel, Accommodations, Expenses: Bayer, Johnson & Johnson, Sanofi, AstraZeneca, Progenics   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Dr. Oliver Sartor on the VISION Trial and Improving Care for Patients With mCRPC       ASCO Daily News: Welcome to the ASCO Daily News Podcast. Our topic today is the practice-changing VISION trial, a phase III trial of radioligand therapy in patients with metastatic castration-resistant prostate cancer. Our guest host, Dr. Neeraj Agarwal, the editor-in-chief of the ASCO Daily News and director of the Genitourinary Cancers Program at the University of Utah's Huntsman Cancer Institute, will speak with one of the trial's investigators, Dr. Oliver Sartor, the medical director of the Tulane Cancer Center and Laborde Professor for Cancer Research. Their full disclosures are available on the transcript of this episode, and disclosures relating to all episodes of the Daily News Podcast are available on our transcripts at asco.org/podcasts.   Dr. Neeraj Agarwal: Hi, my name is Dr. Neeraj Agarwal. I am with Dr. Oliver Sartor. Today, we are going to discuss one of the practice-changing trials in the context of metastatic castration-resistant prostate cancer. Welcome to the ASCO Daily News Podcast, Dr. Sartor. Thanks for taking the time to be with us today.   Dr. Oliver Sartor: Thank you, Neeraj. A pleasure to be here.   Dr. Neeraj Agarwal: You recently published the primary results of the phase III VISION trial, which tested the efficacy of a novel radioligand therapy, Lutetium-177-PSMA-617, in men with metastatic castrate-resistant prostate cancer. Could you please tell us more about this compound and why you did this study?   Dr. Oliver Sartor:  So I'll start off with the compound itself. Radioligand therapy is a therapy that has a little warhead, and that warhead in this case is Lutetium-177. But it's guided by binding to PSMA. Now, PSMA is prostate-specific membrane antigen, and many of us are familiar with it, but some may not be. So PSMA is a protein expressed on the surface of most prostate cancer cells. Not all patients have it, but most do. And the ability of the PSMA Lutetium-177 to target the cancer was indicated in some preliminary studies, but they have not been to phase III. So the purpose of the phase III VISION trial was really to design a definitive study to look at overall survival, in particular, to determine whether or not this agent was truly active. And the good news is, it is truly active. And in the VISION trial, we were able to not only extend life with an overall survival benefit, haz ratio 0.62, but there was also a time-to-progression image-based radiographic progression-free survival. It was also much in favor of the PSMA Lutetium with a haz ratio of 0.4. So whether or not you look at time to cancer progression or whether or not you look at overall survival, this is an effective therapy. It, of course, does have some adverse side effects. We can talk more about that, but it's reasonably well tolerated. And I do anticipate that there'll be an FDA approval as a consequence of these pivotal findings.   Dr. Neeraj Agarwal: These are wonderful results and news for our patients. Please tell me how it will affect the current treatment paradigm of our patients with mCRPC. As we know, you selected patients who had disease progression on chemotherapy with taxanes and novel hormonal therapy. But real-world studies, many of which were published by you, have shown that docetaxel is received by a minority of patients with metastatic prostate cancer. So how do you envision treating your patients who do not want to be treated with chemotherapy as many of my patients do? How will you apply Lutetium-177 in their treatment?   Dr. Oliver Sartor:  Well, Neeraj, I think that we're going to be restricted in accordance with the label that the FDA provides. And I fully expect that the label will include a progression after treatment with docetaxel or at least one taxane-based therapy because that's the way the VISION trial was constructed. Now, you're raising a very critical point, and that is, what about the individuals that do not want to receive or are ineligible to receive a chemotherapy such as docetaxel? And for those individuals, we now have a new trial called PSMA4, and that trial is going to be testing the Lutetium-177-PSMA-617 in the context of chemotherapy-naive patients. So I think we're going to have to wait until we have more results, more clinical trials completed, prior to the application of PSMA-617 into the more general population of chemotherapy-naive patients. But those clinical trials are now underway.   Dr. Neeraj Agarwal: That's great. So, Oliver, in the VISION trial, you did mandate a diagnostic PSMA PET scan, and patients who were positive on the diagnostic PSMA PET scan were deemed to be eligible for enrollment on the VISION trial. Do you expect FDA to include diagnostic PSMA scan for eligibility for treatment with the Lutetium-177 in the real-world setting? If it doesn't or if it does, how it is going to affect the treatment of our patients, that availability of treatment for our patients?   Dr. Oliver Sartor:  That's really a great question. And I do expect that PSMA PET imaging will be a criteria given that it was used for patient selection. Now, as it turned out, about 87% of the patients actually did qualify after getting a PSMA PET scan. And given that that was part of the inclusion criteria, I anticipate that the FDA will also incorporate such imaging. Now, it does get to be a bit of an issue because it turns out that PSMA PET is just now coming into more widespread use. We did have, in May of this year, the approval by the FDA for the PSMA PET imaging agent and-- I shouldn't say "the"-- a PSMA PET imaging agent. Prior to that, in December of last year, there was both UCLA and UCSF approval by the FDA for yet another PSMA PET imaging agent. As we move forward, I anticipate that PET imaging is going to be more widely available. And of course, we don't have the approval as of yet today for the PSMA-617-Lutetium-177. And when we do get the anticipated approval, which likely will be in 2022, then I also anticipate that PSMA PET will be more widely available. Now, there are still issues with reimbursement for PSMA PET, and we've encountered those in our own practice. But that's a rapidly changing area, and we're working with the insurance companies in an effort to ensure that patients will get the imaging that they need.   Dr. Neeraj Agarwal:  Got it. And obviously, I asked this question because many of my community friends and colleagues have asked me this question.  Before we talk about the side effects of Lutetium-177, would you have any message for our friends and colleagues in the community who are bracing themselves for treating their patients with the Lutetium-177, whether they should be proactive in establishing contacts and relationships with the nuclear medicine facilities and so on?   Dr. Oliver Sartor:  That's a great question, Neeraj, because I think you're raising a very important point. This is going to be the type of therapy that involves multidisciplinary care. We can see that there'll be diagnostic PET imaging as being a component of the study. There'll be the necessity of licensed physicians, typically either nuclear medicine or radiation oncology, to actually administer the drug. And then, quite frankly, the medical oncologists or those urologists who are trained in advanced prostate cancer are going to need to manage the patient. This is a lot more than just getting an injection. Many of these patients are ill. They need to have symptom management. They need to manage their bone health. They need to manage their hormonal manipulations. They need management with regard to pain. So this is not just about giving an injection. And I encourage those people who are interested to involve multidisciplinary teams starting now. And I realize that the therapy is not available now, but you have to anticipate that it will be. And I think it will be a game changer of a therapy, and many patients are going to want it. So that means it's incumbent upon the physicians to be prepared, and that means multidisciplinary care.   Dr. Neearj Agarwal:  Excellent point. So basically, we should be ready. We should start establishing relationships with nuclear medicine facilities or radiation oncologists who are going to deliver Lutetium-177. Overall, when I was reading the New England Journal paper, the side effect profile seemed very reasonable. I did not see any red flags. To me, it sounded like a pretty well-tolerated drug. So what is your take on the side effects of Lutetium-177?   Dr. Oliver Sartor: I think the side effects are quite manageable. One of the unique side effects is that of dry mouth and that's because the PSMA can actually be expressed in the salivary glands and that there is some potential for salivary gland binding in the PSMA-617-Lutetium. And that means that you can have damage to the salivary glands, and that means dry mouth. It turns out that a little over 40% of the patients actually did complain of a dry mouth, and that needs to be managed typically with fluid intake or various ways of mouth moisturizers. Fatigue is a potential issue. It was raised, as well as some bone marrow suppression. And if you look at the grade 3/4 toxicities, anemia was present a little more than 10% of the time. And that, of course, needs to be monitored. There is some potential collateral damage to the bone marrow. So these patients need to have their counts monitored. They need to have their symptoms assessed. And they need to be managed as they go through the process. It's not just about giving an injection, but clearly, the licensed individuals, including nuclear medicine and radiation oncology, need to be engaged, because without them, there is no injection. So this is a complex multidisciplinary care paradigm. And emphasizing the point, symptom management, yes; adverse event management, yes. But you have to deliver the drug, and that means multidisciplinary care.   Dr. Neeraj Agarwal:  Those are fantastic points. Thank you very much, Dr. Sartor, for taking time to be with us. And I'm really hoping that this podcast will be very enriching to our listeners. Thank you very much.   Dr. Oliver Sartor: Thank you, Neeraj. Glad to be here.   ASCO Daily News:  You've been listening to Dr. Neeraj Agarwal of the Huntsman Cancer Institute and Dr. Oliver Sartor of the Tulane Cancer Center. Our listeners will find a link to the VISION study in the transcript of this episode. Thank you to our listeners for joining us today. If you enjoyed this episode, please take a moment to rate, review, and subscribe wherever you get your podcasts.   Disclosures: Dr. Neeraj Agarwal Consulting or Advisory Role: Pfizer, Medivation/Astellas, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Exelixis, Merck, Novartis, Eisai,    Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences   Research Funding (Inst.): Bayer Your Institution, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen,    AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, crispr therapeutics, and Arvinas     Disclosures: Dr. Oliver Sartor Stocks & Other Ownership Interests: Lilly, GlaxoSmithKline, Abbvie, Cardinal Health, United Health Group, PSMA Therapeutics, Clarity Pharmaceuticals, Noria Therapeutics, Inc., Clovis Consulting or Advisory Role: Bayer, Sanofi, AstraZeneca, Dendreon, Constellation Pharmaceuticals, Advanced Accelerator Applications, Pfizer, Bristol-Myers Squibb, Bavarian Nordic, EMD Serono, Astellas Pharma, Progenics, Blue Earth Diagnostics, Myovant, Myriad Genetics, Novartis, Clarify Pharmaceuticals, Fusion, Istopen Technologien Meunchen, Janssen, Noxopharm, Clovis, Noria Therapeutics, Point Biopharma, TeneoBio, Telix, Theragnostics Research Funding (Inst): Sotio, Janssen, Progenics, Bayer, Sanofi, Endocyte, Merck, Invitae, Constellation Pharmaceuticals, Advanced Accelerator Applications, Dendreon, AstraZeneca Expert Testimony: Sanofi Travel, Accommodations, Expenses: Bayer, Johnson & Johnson, Sanofi, AstraZeneca, Progenics   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    

Doniel Jackson, MD is a 24+ year Drug Safety and PV veteran in the pharmaceutical industry. Dr. Jackson and I discuss aspects of Drug Safety and Pharmacovigilance and how it is a critical part to successful submission, registration, and post-marketing. 

On this week’s Tech Nation, Dr. Dan Gold, CEO of MEI Pharma, joins Moira to talk about the eight out of nine drugs which fail FDA clinical trials. MEI Pharma sees this as opportunity.

On this week’s Tech Nation, Forbes.com columnist Carmine Gallo returns with “Five Stars … The Communication Secrets to Get from Good to Great”. Then on Tech Nation Health, Dr. Dan Gold, CEO of MEI Pharma, joins Moira to talk about the eight out of nine drugs which fail FDA clinical trials. MEI Pharma sees this as opportunity.

On this week’s Tech Nation, Forbes.com columnist Carmine Gallo returns with “Five Stars … The Communication Secrets to Get from Good to Great”. Then on Tech Nation Health, Dr. Dan Gold, CEO of MEI Pharma, joins Moira to talk about the eight out of nine drugs which fail FDA clinical trials. MEI Pharma sees this as opportunity.

Today in FirstWord:

Today in FirstWord: