Podcasts about PFS

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Sep 11, 2025 – Are we on the brink of a second Cold War turning hot? Geopolitical strategist Christian Takushi reveals the hidden forces reshaping global power—and why the West may be more vulnerable than we think. In this riveting discussion, Takushi delves...

Sep 9, 2025 – Is the US dollar nearing a historic turning point? Join Cris Sheridan and market strategist Marc Chandler for an unfiltered, must-hear discussion—where currencies, commodities, and global power collide...

September 8, 2025 – Think you know who really benefits from today's tax laws? In this eye-opening episode, Jim Puplava and renowned tax expert Dan Pilla pull back the curtain on the truth behind the headlines. Together, they break down the latest...

JCO fellow Dr. Ece Cali speaks with JCO Associate Editor Dr. Thomas E. Stinchcombe to discuss the JCO article "Phase 2 Dose-Randomized Study of Sunvozertinib in Platinum-Pretreated Non-Small-Cell Lung Cancer with Epidermal Growth Factor Receptor Exon 20 Insertion Mutations (WU-KONG1B)", that was simultaneously released at the IASLC 2025 World Conference on Lung Cancer. TRANSCRIPT Dr. Ece Cali: Hello, and welcome to our series where we cover some of the top JCO papers published simultaneously with their abstract presentation at this year's most important oncology meetings. I am your host, Dr. Ece Cali, JCO editorial fellow, and I am joined by Dr. Tom Stinchcombe, JCO associate editor, to discuss the Journal of Clinical Oncology article and 2025 World Conference on Lung Cancer abstract presentation, “Phase II Dose-Randomized Study of Sunvozertinib in Platinum-Pretreated Non–Small Cell Lung Cancer With EGFR Exon 20 Insertion Mutations.” The WU-KONG1B trial is a multinational, phase II study that investigated the efficacy and safety of different doses of sunvozertinib in patients with metastatic non-small cell lung cancer and EGFR exon 20 insertion mutations after progression on platinum based chemotherapy. Tom, before we dive into the results, could you walk us through the rationale for this study, and how does it fit into the current treatment options for patients with EGFR exon 20 insertion? Dr. Tom Stinchcombe: Thank you, Dr. Cali. I think the clinical context is always important. We have known that EGFR exon 20 insertions exist and that they are resistant to our currently available EGFR tyrosine kinase inhibitors, and I think there have been attempts in the past to develop a tyrosine kinase inhibitor, but there is a very narrow therapeutic window between the dose you need to inhibit the EGFR mutation in the cancer and the EGFR receptor on normal tissues, most notably the mucosa, the gut, and the skin. And so, our previous attempts have failed largely because the dose required was not tolerable for patients and they could not really stay on the drug for a long time or they were not very active. And so, I think there was a real desire to develop an EGFR tyrosine kinase inhibitor, and then, historically, the standard had been a platinum based doublet as the standard of care. And more recently, platinum based doublet with amivantamab has proven to be superior to platinum based chemotherapy alone. I think the context is also important that amivantamab is not necessarily available in all the countries, and so, there are patients who do not have access to amivantamab. Going to the rationale, I think that this drug had shown preliminary promise of having activity but without that being encumbered by those EGFR wild type toxicities, and, therefore, it was really explored in this larger study. Dr. Ece Cali: And what are some key findings from this trial? Dr. Tom Stinchcombe: So, I think that we should look at the study design. It is a little quirky, for lack of a better term, in that there is a randomization to 200 versus 300 mg, and then, there was a nonrandomized cohort of 300 mg. So, when you look at the study, if you are a purist, you will just look at the randomized patients. If you are sort of an aggregator, you look at all patients. So, it shows reporting on three cohorts, but I think the key findings are that the 200 mg and the 300 mg treatments had similar toxicities in terms of response rate, duration of response, and progression free survival. And as you know going through the review, there was a lot of queries from the reviewers as to which would be the preferred dose, and to me, I think this really illustrates a dose finding component to a trial design because there is a lot of debate about what the minimal effective dose is or the optimal dose. And in this case, having the two dose cohorts did provide us some valuable efficacy and toxicity information. And then, when I look at the study, I want to make sure it reflects my patient population, and about a quarter of patients had brain metastases, and about 15% had previous amivantamab, and about 5% to 10% had another EGFR tyrosine kinase inhibitor. Dr. Ece Cali: And what is the objective response rate and the duration of response? These are pretty good numbers for this patient population. Dr. Tom Stinchcombe: In the 200 mg cohort, it was about 46%. The duration of response was around 11 months, and the PFS was around 8 months. The 300 mg cohort was 46%, duration of response 9.8, and the median PFS is 6.9 months, and I think that this is greater activity than we have seen with our previous attempts at EGFR tyrosine kinase inhibitors. Dr. Ece Cali: And based on these data, FDA granted accelerated approval for sunvozertinib very recently at 200 mg once daily dosing in this setting. So, that is a major step forward for our patients. Dr. Stinchcombe, how does this impact your clinical practice, and what side effects should oncologists be watching for if they prescribe this medication? Dr. Tom Stinchcombe: So, I think it was very interesting that they chose the 200 mg dose, which I think was more tolerable, and when we kind of look at this, there still was a rate of diarrhea, all grade, rash, paronychia, which are the EGFR related toxicities. There can be some decreased appetite, stomatitis, and then, it can lead to some lab abnormalities, like increased CPK and creatinine that physicians have to be aware of. You know, how it will affect my practice is that all these patients had received a platinum based chemotherapy as the first line therapy. I think that this would become my preferred second line therapy for patients outside the context of a trial because of the activity and the tolerability. Dr. Ece Cali: And lastly, several other tyrosine kinase inhibitors are being evaluated for EGFR exon 20 insertion, including in the frontline setting. So, what are some of the outstanding questions in this space, and what data should our listeners keep an eye on moving forward? Dr. Tom Stinchcombe: I think you are right that now, there is going to be another EGFR tyrosine kinase that may become available in the next year, and there is another drug, furmonertinib, that is being investigated. I think, for the clinical question, is, well, can we move these into the first line setting? And actually, the development path has two ways of doing this. There is EGFR tyrosine kinase compared to platinum based chemotherapy, and then, platinum based chemotherapy with an EGFR tyrosine kinase versus platinum based chemotherapy, and both have their merits and strengths. And so, I think it is going to be very interesting as we see if those first line trials, one, can they be demonstrated to be superior to platinum based chemotherapy, and then by what magnitude and what the side effects are. But I think we are hoping that in the next couple of years, we will have an additional first line option for our patients. Dr. Ece Cali: Yeah, it is always great to have more options for our patients. Thank you, Dr. Stinchcombe, for speaking about the JCO article, “Phase II Dose-Randomized Study of Sunvozertinib in Platinum-Pretreated Non-Small Cell Lung Cancer With EGFR Exon 20 Insertion Mutations.” Join us again for the latest JCO simultaneous publications. Please take a moment to rate, review, and subscribe to all ASCO podcast shows at asco.org/podcasts. Until then, enjoy the rest of World Lung Conference. 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. Pedro Barata and Dr. Rana McKay discuss the integration of innovative advances in molecular imaging and therapeutics to personalize treatment for patients with renal cell and urothelial carcinomas. TRANSCRIPT Dr. Pedro Barata: Hello, I'm Dr. Pedro Barata, your guest host of By the Book, a podcast series featuring insightful conversations between authors and editors of the ASCO Educational Book. I'm a medical oncologist at University Hospitals Seidman Cancer Center and an associate professor of medicine at Case Western Reserve University in Cleveland, Ohio. I'm also an associate editor of the ASCO Educational Book. Now, we all know the field of genitourinary cancers (GU) is evolving quite rapidly, and we have new innovations in molecular imaging as well as targeted therapeutics. Today's episode will be exploring novel approaches that are transforming the management of renal cell and urothelial carcinomas and also their potential to offer a more personalized treatment to patients. For that, joining for today's discussion is Dr. Rana McKay, a GU medical oncologist and professor at University of California San Diego. Dr. McKay will discuss her recently published article titled, “Emerging Paradigms in Genitourinary Cancers: Integrating Molecular Imaging, Hypoxia-Inducible Factor-Targeted Therapies, and Antibody-Drug Conjugates in Renal Cell and Urothelial Carcinomas.”  Our full disclosures are available in the transcript of this episode.  And with that, Rana McKay, great to have you on the podcast today. Dr. Rana McKay: Oh, thank you so much, Dr. Barata. It's really wonderful to be here with you. So, thanks for hosting. Dr. Pedro Barata: No, thanks for taking the time, and I'm looking forward to this conversation. And by the way, let me start by saying congrats on a great article in the Educational Book. Really super helpful paper. I'm recommending it to a lot of the residents and fellows at my own institution. I would like to first ask you to kind of give our listeners some context of how novel approaches in the molecular imaging as well as targeted therapeutics are actually changing the way we're managing patients with GU, but specifically with renal cell carcinoma and urothelial carcinoma. So, what are the areas you would call out as like being big areas for innovation in this context, and why are they important? Dr. Rana McKay: Very good question. And I think this is really what this article highlights. It highlights where are we going from an imaging diagnostics standpoint? Where are we going from a therapeutic standpoint? And I think if we have to step back, from the standpoint of diagnostics, we've seen PET imaging really transform diagnostics in prostate cancer with the advent of PSMA PET imaging, and now PSMA PET imaging is used as a biomarker for selection for theranostics therapy. And so, we're starting to see that enter into the RCC landscape, enter into the urothelial cancer landscape to a lesser extent. And I think it's going to potentially be transformative as these tools get more refined. I think when we think about therapeutics, what's been transformative most recently in the renal cell carcinoma landscape has been the advent of HIF2α inhibition to improve outcomes for patients. And we have seen the approval of belzutifan most recently that has reshaped the landscape. And now there's other HIF2α inhibitors that are being developed that are going to be further important as they get refined. And lastly, I think when we think about urothelial carcinoma, the greatest transformation to treatment in that context has been the displacement of cisplatin and platinum-based chemotherapy as a frontline standard with the combination of enfortumab vedotin plus pembrolizumab. And we've seen antibody-drug conjugates really reshape treatment and tremendously improve outcomes for patients. So, I think those are the three key areas of interest. Dr. Pedro Barata: So with that, let's focus first on the imaging and then we'll get to the therapeutic area. So, we know there's been a paradigm shift, really, when prostate-specific targets emerged as tracers for PET scanning. And so, we now commonly use prostate-specific membrane antigen, or PSMA-based PET scanning, and really transform how we manage prostate cancer. Now, it appears that we're kind of seeing a similar wave in renal cell carcinoma with the new radiotracer against the target carbonic anhydrase IX. What can you tell us about this? And is this going to be available to us anytime soon? And how do you think that might potentially change the way we're managing patients with RCC today? Dr. Rana McKay: First, I'll step back and say that in the context of PSMA PET imaging, we have actually been able to better understand RCC as well. So, we know that PSMA is expressed in the neovasculature of tumors, and it can actually be used to detect renal cell carcinoma tumors. It has a detection rate of about 84% when used for detection. And so, you know, I don't think it's just restricted to carbonic anhydrase IX, but we will talk about that. So, PSMA expressed in the neovasculature has a detection rate of around 84%, particularly if we're looking at clear cell RCC. CAlX is overexpressed in clear cell RCC, and it's actually used in diagnosing renal cell carcinoma when we think of CAlX IHC for diagnosing clear cell RCC. And now there are CAlX PET tracers. The first foray was with the ZIRCON study that was actually an interestingly designed study because it was designed to detect the likelihood of PET imaging to identify clear cell RCC. So, it was actually used in the early diagnostics setting when somebody presents with a renal mass to discriminate that renal mass from a clear cell versus a non-clear cell, and it was a positive study. But when I think about the potential application for these agents, you know, I think about the entire landscape of renal cell carcinoma. This is a disease that we do treat with metastasis-directed therapy. We have certainly seen patients who've undergone metastasectomy have long, durable remissions from such an approach. And I think if we can detect very early onset oligometastatic disease where a metastasis-directed therapy or SABR could be introduced - obviously tested in a trial to demonstrate its efficacy - I think it could potentially be transformative. Dr. Pedro Barata: Wonderful. It's a great summary, and I should highlight you are involved in some of those ongoing studies testing the performance of this specific PET scanning for RCC against conventional imaging, right? And to remind the listeners, thus far, for the most part, we don't really do FDG-PET for RCC. There are some specific cases we do, but in general, they're not a standard scanning. But maybe that will change in the future. Maybe RCC will have their own PSMA-PET. And to your point, there's also emerging data about the role of PSMA-PET scanning in RCC as well, as you very elegantly summarized. Wonderful. So, let me shift gears a little bit because you did, in your introduction, you did highlight a novel MOA that we have in renal cell carcinoma, approved for use, initially for VHL disease, and after that for sporadic clear cell renal cell carcinoma. We're talking about hypoxia-inducible factor 2-alpha inhibitors, or HIF2α inhibitors, such as belzutifan. But there's also others coming up. So, as a way to kind of summarize that, what can you tell us about this breakthrough in terms of therapeutic class, this MOA that got to our toolbox of options for patients with advanced RCC? Tell us a little bit what is being utilized currently in the management of advanced RCC. And where do you see the future going, as far as, is it moving early on? Is it getting monotherapy versus combinations? Maybe other therapies? What are your thoughts about that? What can you tell us about it? Dr. Rana McKay: Belzutifan is a first-in-class HIF2α inhibitor that really established clinical validation for HIF2α as a therapeutic target. When we think about the activity of this agent, the pivotal LITESPARK-005 trial really led to the approval of belzutifan in patients who were really heavily pretreated. It was patients who had received prior IO therapy, patients who had received prior VEGF-targeted therapy. And in the context of this study, we saw a median PFS of 5.6 months, and there did seem to be a tail on the curve when you looked at the 12-month PFS rate with belzutifan. It was 33.7% compared to 17.6% with everolimus. And then when we look at the response rate, it was higher with belzutifan on the order of 22-23%, and very low with everolimus, as we've previously seen. I think one of the Achilles heels of this regimen is the primary PD rate, which was 34% when used in later line. There are multiple studies that are testing belzutifan in combination across the treatment landscape. So, we have LITESPARK-011, which is looking at the combination of belzutifan plus lenvatinib in the second-line setting. We've got the MK-012 [LITESPARK-012] study, which is looking at belzutifan in various combinations in the frontline setting. So there is a combination with IO plus belzutifan. And so this is also being looked at in that context. And then we also have the LITESPARK-022 study, which is looking at pembrolizumab with belzutifan in the adjuvant setting. So there's a series of studies that will be exploring belzutifan really across the treatment landscape. Many of these studies in combination. Additionally, there are other HIF2α inhibitors that are being developed. We have casdatifan, which is another very potent HIF2α inhibitor. You know, I think pharmacologically, these are different agents. There's a different half-life, different dosing. What is going to be the recommended phase 3 dose for both agents, the EPO suppression levels, the degree of EPO suppression, and sustainability of EPO suppression is very different. So, I think we've seen data from casdatifan from the ARC-20 trial from monotherapy with a respectable response rate, over 30%, primary PD rate hovering just around 10%.  And then we've also seen data of the combination of casdatifan with cabozantinib as well that were recently presented this year. And that agent is also being tested across the spectrum of RCC. It's being looked at in combination with cabozantinib in the PEAK-1 study, and actually just at the KCRS (Kidney Cancer Research Summit), we saw the unveiling of the eVOLVE-RCC trial, which is going to be looking at a volrustomig, which is a PD-1/CTLA-4 inhibitor plus casdatifan compared to nivo-ipi in the frontline setting.  So, we're going to see some competition in this space of the HIF2α inhibitors. I think when we think of mechanism of action in that these are very potent, not a lot of off-target activity, and they target a driver mutation in the disease. And that driver mutation happens very early in the pathogenesis. These are going to be positioned much earlier in the treatment landscape. Dr. Pedro Barata: All these studies, as you're saying, look really promising. And when we talk about them, you mentioned a lot of combinations. And to me, when I think of these agents, it makes a lot of sense to combine because there's not a lot of overlapping toxicities, if you will. But perhaps for some of our listeners, who have not used HIF2α inhibitors in practice yet, and they might be thinking about that, what can you tell us about the safety profile? How do you present it to your patients, and how do you handle things like hypoxia or anemia? How do you walk through the safety profile and tolerability profile of those agents like belzutifan? Dr. Rana McKay: I think these drugs are very different than your traditional TKIs, and they don't cause the classic symptoms that are associated with traditional TKIs that many of us are very familiar with like the rash, hand-foot syndrome, hypertension, diarrhea. And honestly, these are very nuanced symptoms that patients really struggle with the chronicity of being on a chronic daily TKI. The three key side effects that I warn patients about with HIF2α inhibitors are: (1) fatigue; (2) anemia; and (3) hypoxia and dysregulation in the ability to sense oxygen levels. And so, many of these side effects - actually, all of them - are very dose-dependent. They can be very well-managed. So, we can start off with the anemia. I think it's critically important before you even start somebody on belzutifan that you are optimizing their hemoglobin and bone marrow function. Make sure they don't have an underlying iron deficiency anemia. Make sure they don't have B12 or folate deficiency. Check for these parameters. Many patients who have kidney cancer may have some hematuria, other things where there could be some low-level blood loss. So, make sure that those are resolved or you're at least addressing them and supplementing people appropriately. I monitor anemia very closely every 3 to 4 weeks, at least, when people start on these medications. And I do initiate EPO, erythropoietin, should the anemia start to worsen. And I typically use a threshold of around 10g/dL  for implementing utilization of an EPO agent, and that's been done very safely in the context of the early studies and phase 3 studies as well. Now, with regards to the hypoxia, I think it's also important to make sure that you're selecting the appropriate individual for this treatment. People who have underlying COPD, or even those individuals who have just a very high burden of disease in their lung, lymphangitic spread, pleural effusions, maybe they're already on oxygen - that's not an ideal candidate for belzutifan. Something that very easily can be done in the clinic before you think about initiating somebody on this treatment, and has certainly been integrated into some of the trials, is just a 6-minute walk test. You know, have the patient walk around the clinic with one of the MAs, one of the nurses, put the O2 sat on [measuring oxygen saturation], make sure they're doing okay. But these side effects, like I said, are very dose-dependent. Typically, if a patient requires, if the symptoms are severe, the therapy can be discontinued and dose reduced. The standing dose is 120 mg daily, and there's two dose reductions to 80 mg and 40 mg should somebody warrant that dose modification. Dr. Pedro Barata: This is relatively new, right? Like, it was not that we're used to checking oxygen levels, right? In general, we're treating these patients, so I certainly think there's a learning curve there, and some of the points that you highlight are truly critical. And I do share many of those as well in our practice. Since I have you, I want to make sure we touch base on antibody-drug conjugates as well. It's also been a hot area, a lot of developments there. When I think of urothelial carcinoma and renal cell carcinoma, I see it a little bit different. I think perhaps in urothelial carcinoma, antibody-drug conjugates, or ADCs, are somewhat established already. You already mentioned enfortumab vedotin. I might ask you to expand a little bit on that. And then in renal cell carcinoma, we have some ADCs as well that you include in your chapter, and that I would like you to tell us what's coming from that perspective. So, tell us a little bit about how do you see ADCs in general for GU tumors, particularly UC and RCC? Tell us a little bit about the complexity or perhaps the challenges you still see. At the same time, tell us about the successes. Dr. Rana McKay: Stepping back, let's just talk about like the principles and design of ADCs. So, most ADCs have three components. There's a monoclonal antibody that typically targets a cell surface antigen, which is conjugated by a linker, which is the second component, to a payload drug. And typically, that payload drug has been chemotherapy, whether it be topoisomerase or whether it be MMAE or other chemotherapeutic. We can start in the RCC space. There's been multiple antibody-drug conjugates that have been tested. There's antibody-drug conjugates to CD70, which is expressed on clear cell RCC. There's been antibody-drug conjugates to ENPP3, which is also expressed on RCC. There's antibody-drug conjugates to CDH6. And they have different payloads, like I said, whether it be topoisomerase I or other microtubule inhibitors. Now, when we think about kidney cancer, we don't treat this disease with chemotherapy. This disease is treated with immunotherapy. It is treated with treatments that target the VEGF pathway and historically has not been sensitive to chemo. So, I think even though the targets have been very exciting, we've seen very underwhelming data regarding activity, and in some context, seen increased toxicity with the ADCs. So, I think we need to tread lightly in the context of the integration and the testing of ADCs in RCC. We just came back from the KCRS meeting, and there was some very intriguing data about a c-Kit ADC that's being developed for chromophobe RCC, which is, you know, a huge unmet need, these variant tumors that really lack appropriate therapeutics. But I just caution us to tread lightly around how can we optimize the payload to make sure that the tumor that we're treating is actually sensitive to the agent that's targeting the cell kill. So, that's a little bit on the ADCs in RCC. I still think we have a long way to go and still in early testing. Now, ADCs for UC are now the standard of care. I think the prototypical agent, enfortumab vedotin, is a nectin-4-directed ADC that's conjugated to an MMAE payload and was the first ADC approved for advanced urothelial, received accelerated approval following the EV-201 trial, which was basically a multicenter, single-arm study that was investigating EV in cisplatin-ineligible patients with advanced urothelial carcinoma, and then ultimately confirmed in the EV-301 study as well. And so, that study ended up demonstrating the support superiority of EV from an overall survival standpoint, even PFS standpoint. Building on that backbone is the EV-302 study, which tested EV in combination with pembrolizumab versus platinum-based chemotherapy in the frontline setting. And that was a pivotal, landmark study that, like I said, has displaced platinum therapy as a frontline treatment for people with advanced urothelial carcinoma. And when we think about that study and the median overall survival and just how far we've come in urothelial cancer, the median OS with EV-pembro from that trial was 31 and a half months. I mean, that's just incredible. The control arm survival was 16 and a half months. The hazard ratio for OS, 0.47. I mean this is why when this data was presented, it was literally a standing ovation that lasted for several minutes because we just haven't seen data that have looked that good. And there are other antibody-drug conjugates that are being tested. We've all been involved in the saga with sacituzumab govitecan, which is a trophoblast cell surface antigen 2 (Trop-2) targeted ADC with a topoisomerase I payload. It was the second ADC to receive approval, but then that approval was subsequently withdrawn when the confirmatory phase 3 was negative, the TROPiCS-04 trial. So, approval was granted based off of the TROPHY-U-01, single-arm, phase 2 study, demonstrating a response rate of around 28% and a PFS of, you know, about 5 and a half months. But then failure to show any benefit from an OS standpoint. And I think there's a lot of controversy in the field around whether this agent still has a role in advanced urothelial carcinoma. And I think particularly for individuals who do not have molecular targets, like they're not HER2-amplified or have HER2-positivity or FGFR or other things like that. Dr. Pedro Barata: Fantastic summary, Rana. You were talking about the EV, and it came to mind that it might not be over, right, for the number of ADCs we use in clinical practice in the near future. I mean, we've seen very promising data for ADC against the HER2, right, and over-expression. It also can create some challenges, right, in the clinics because we're asking to test for HER2 expression. It's almost like, it's not exactly the same to do it in breast cancer, but it looks one more time that we're a little bit behind the breast cancer field in a lot of angles. And also has vedotin as a payload. Of course, I'm referring to disitamab vedotin, and there's very elegant data described by you in your review chapter as well. And it's going to be very interesting to see how we sequence the different ADCs, to your point as well. So, before we wrap it up, I just want to give you the opportunity to tell us if there's any area that we have not touched, any take-home points you'd like to bring up for our listeners before we call it a day. Dr. Rana McKay: Thank you so much. I have to say, you know, I was so excited at ASCO this year looking at the GU program. It was fantastic to see the progress being made, novel therapeutics that really there's a tremendous excitement about, not just in RCC and in UC, but also in prostate cancer, thinking about the integration of therapies, not just for people with refractory disease that, even though our goal is to improve survival, our likelihood of cure is low, but also thinking about how do we integrate these therapies early in the treatment landscape to enhance cure rates for patients, which is just really spectacular. We're seeing many of these agents move into the perioperative setting or in combination with radiation for localized disease. And then the special symposium on biomarkers, I mean, we've really come a long, long way. And I think that we're going to continue to evolve over the next several years. I'm super excited about where the field is going in the treatment of genitourinary malignancies. Dr. Pedro Barata: Oh, absolutely true. And I would say within the Annual Meeting, we have outstanding Educational Sessions. And just a reminder to the listeners that actually that's where the different teams or topics for the Educational Book chapters come from, from actually the educational sessions from ASCO. And your fantastic chapter is an example of that, right, focusing on advanced GU tumors. So, thank you so much, Rana, for taking the time, sharing your insights with us today on the podcast. It was a fantastic conversation as always. Dr. Rana McKay: My pleasure. Thanks so much for having me, Dr. Barata. Dr. Pedro Barata: Of course.  And thank you to our listeners for your time today. You will find the link to the article discussed today in the transcript of this episode. I also encourage you to check out the 2025 ASCO Educational Book. You'll find an incredible wealth of information there. It's free, available online, and you'll find, hopefully, super, super important information on the key science and issues that are shaping modern oncology, as we've heard from Dr. McKay and many other outstanding authors. So, thank you, everyone, and I hope to see you soon. 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. Pedro Barata @PBarataMD Dr. Rana McKay @DrRanaMcKay Follow ASCO on social media:        @ASCO on X (formerly Twitter)        ASCO on Bluesky       ASCO on Facebook        ASCO on LinkedIn        Disclosures:     Dr. Pedro Barata: Stock and Other Ownership Interests: Luminate Medical Honoraria: UroToday Consulting or Advisory Role: Bayer, BMS, Pfizer, EMD Serono, Eisai, Caris Life Sciences, AstraZeneca, Exelixis, AVEO, Merck, Ipson, Astellas Medivation, Novartis, Dendreon Speakers' Bureau: AstraZeneca, Merck, Caris Life Sciences, Bayer, Pfizer/Astellas Research Funding (Inst.): Exelixis, Blue Earth, AVEO, Pfizer, Merck  Dr. Rana McKay: Consulting or Advisory Role: Janssen, Novartis, Tempus, Pfizer, Astellas Medivation, Dendreon, Bayer, Sanofi, Vividion, Calithera, Caris Life Sciences, Sorrento Therapeutics, AVEO, Seattle Genetics, Telix, Eli Lilly, Blue Earth Diagnostics, Ambrx, Sumitomo Pharma Oncology, Esiai, NeoMorph, Arcus Biosciences, Daiichi Sankyo, Exelixis, Bristol Myers Squibb, Merck, Astrazeneca, Myovant Research Funding (Inst.): Bayer, Tempus, AstraZeneca, Exelixis, Bristol Myers Squibb, Oncternal Therapeutics, Artera    

We're joined by Luke Alexander, President & CEO of Newcore Gold (TSX.V:NCAU - OTCQX:NCAUF), to discuss the latest results from the company's ongoing 35,000m drill program at the Enchi Gold Project in Ghana. With recent highlights including 184 g/t gold over 1m and 3.1 g/t over 13m at the Kojina Hill target, the company is balancing resource expansion drilling with advancing toward a PFS. Key Topics Covered: Drill results at Kojina Hill, including one of the highest-grade intercepts to date and the potential for future resource inclusion. The importance of deeper drilling to test high-grade feeder zones at the Sewum and Boin deposits. Funding position and upcoming warrant exercises that could add ~$13M to the treasury. Strategy for converting resources from Inferred to Indicated while growing beyond the current 1.71Moz resource base. Outlook for an updated resource estimate and upcoming PFS as catalysts. If you have any follow up questions for Luke please email me at Fleck@kereport.com. Click here to visit the Newcore Gold website.    For more market commentary & interview summaries, subscribe to our Substacks: The KE Report: https://kereport.substack.com/ Shad's resource market commentary: https://excelsiorprosperity.substack.com/   Investment disclaimer: This content is for informational and educational purposes only and does not constitute investment advice, an offer, or a solicitation to buy or sell any security. Investing in equities and commodities involves risk, including the possible loss of principal. Do your own research and consult a licensed financial advisor before making any investment decisions. Guests may own shares in companies mentioned.

Sep 25, 2025 – What's really driving gold and silver to record levels, and why are mining stocks suddenly outshining tech giants? In this episode, Jim Puplava sits down with Greg Weldon at Weldon Live to unpack the forces shaking up markets...

Sep 5, 2025 – Gold hit a new record high this week, while silver surged above $40 for the first time in 14 years. Financial Sense's Jim Puplava interviews Mish Schneider, Chief Strategist at MarketGauge, covering the big move in metals and mining stocks, sector...

When business owners skip exit planning, the fallout can be brutal; value lost, families divided, legacies diminished. But with the right strategy, an exit isn't chaos, it's a launchpad: valuations climb, transitions smooth out, and owners step confidently into their next chapter. In this episode of the AICPA Personal Financial Planning Podcast, host Cary Sinnett welcomes Daniel D. Meiklejohn, JD, CPA, PFS. With his rare combination of legal, tax, and financial planning expertise, Daniel helps business owners turn exits from reactive scrambles into deliberate successes, covering everything from succession and valuation to wealth transfer and legacy planning. Listeners will learn: · The #1 risks owners overlook before selling · Why building the right advisory team changes the outcome · How early planning boosts valuations (and reduces stress) · Where CPA financial planners fit into the exit conversation · Practical ways to help clients start planning today This episode is a must-listen for CPA financial planners who work with business owners—or anyone who wants to sharpen their edge in succession and legacy planning. AICPA Resources: https://www.aicpa-cima.com/cpe-learning/webcast/business-exit-planning https://pfplanning.libsyn.com/business-exit-transitions-for-cpa-financial-planners https://www.aicpa-cima.com/professional-insights/article/pcps-succession-planning-survey

Interview with Rafael Moreno, Managing Director & CEO of Viridis Mining & MineralsRecording date: 2nd Sept 2025Viridis Mining & Minerals (ASX:VMM) is advancing the Colossus ionic clay rare earth project in Brazil's Minas Gerais state, focused on producing high-value rare earth elements neodymium, praseodymium, dysprosium, and terbium (NdPr-DyTb) with very low radioactive content. The project benefits from simple free-dig mining of shallow deposits and straightforward atmospheric-pressure processing, enabled by a unique ionic clay geological formation. These factors contribute to superior economics, with a pre-feasibility study (PFS) estimating a net present value (NPV) of US$1.41 billion and annual operating cash flow around US$200 million at current rare earth prices.Colossus's grades are 4 to 6 times higher than comparable Chinese projects, supporting competitive costs even at lower commodity prices. Regulatory advantages include a radiological exemption from Brazil's nuclear regulator, which keeps environmental approvals at the state level rather than federal, accelerating permitting timelines from years to weeks. The project also features strong environmental credentials, with 100% renewable power, 75% water recycling, and immediate site rehabilitation.Financing momentum is strong, with up to US$30 million committed from leading Brazilian asset managers and ongoing discussions with Brazil's development bank BNDES. Offtake talks span Brazil, Europe, and North America, positioning Colossus as a globally relevant supply source. Near-term milestones include imminent environmental approval, a demonstration plant operational by Q1 2026, mineral resource updates by mid-2026, and a definitive feasibility study (DFS) by June 2026.Led by CEO Rafael Moreno, with deep project execution experience, Viridis is developing Colossus to meet growing global demand driven by electric vehicles, renewable energy, and supply chain diversification concerns. The project's combination of high-grade ore, regulatory fast-tracking, operational simplicity, and sustainable practices create a compelling investment thesis for establishing a non-Chinese rare earth supply focused on permanent magnets, with a potential 60-year mine life ensuring long-term value and market resilience.View Viridis Mining & Minerals' company profile: https://www.cruxinvestor.com/companies/viridis-metals-miningSign up for Crux Investor: https://cruxinvestor.com

Sep 4, 2025 – What happens when politics, technology, and global alliances collide? In this wide-ranging interview, renowned strategist David Woo joins FS Insider's Cris Sheridan to discuss the high-stakes battle for control at the Federal Reserve...

In this episode, guests Jonathan Blattmachr and Martin Shenkman share their thoughts on key OBBBA provisions and the Act's impact on estate and tax planning with host Kristin Yokomoto. Planning considerations include use of non-grantor trusts for charitable planning, basis-focused income tax planning, and more. They will also discuss the benefits of reviewing existing SLATs and other irrevocable trusts, as well as the importance of preparing customized estate plans that address family dynamics to minimize the chances of litigation. Host: Kristin YokomotoGuests: Jonathan G. Blattmachr and Martin M. ShenkmanJonathan G. Blattmachr is the Editor-in-Chief and Co-Founder of Interactive Legal, and Co-Author of Wealth Transfer Planning™. He is a principal in ILS Management, LLC and a retired member of Milbank Tweed Hadley & McCloy LLP in New York, NY and of the Alaska, California and New York Bars. He has written and lectured extensively on estate and trust taxation and charitable giving. Jonathan graduated from Columbia University School of Law cum laude, where he was recognized as a Harlan Fiske Stone Scholar, and received his A.B. degree from Bucknell University, majoring in mathematics. He has served as a lecturer-in-law of the Columbia University School of Law and is an Adjunct Professor of Law at New York University Law School in its Masters in Tax Program (LLM). He is a former chairperson of the Trusts & Estates Law Section of the New York State Bar Association and of several committees of the American Bar Association. Jonathan is a Fellow and a former Regent of the American College of Trust and Estate Counsel and past chair of its Estate and Gift Tax Committee. He is author or co-author of eight books and more than 500 articles on estate planning and tax topics. Martin M. Shenkman, CPA, MBA, PFS, AEP (distinguished), JD, is an attorney in private practice in Fort Lee, New Jersey and New York City. He is the founder of Shenkman Law, a boutique firm focused on the legal needs of high-net-worth individuals, professionals, close business owners, and real estate owners and developers. Martin's practice includes estate and tax planning, planning for closely held businesses, and estate administration. He is the author of 42 books and more than 1,000 articles. Martin is an Editorial Board Member of Trusts & Estates Magazine, CCH (Wolter's Kluwer), and the Matrimonial Strategist. He has previously served on the editorial board of many other tax, estate and real estate publications. Martin earned his Bachelor of Science degree from Wharton School with concentrations in accounting and economics, MBA from the University of Michigan with concentrations in tax and finance, and law degree from Fordham University School of Law. He is admitted to the bar in New York, New Jersey, and Washington, D.C. and is a licensed CPA in New Jersey, Michigan, and New York. Click here to listen to Interactive Legal's 4-Part webinar series on OBBBA - https://interactivelegal.com/big-beautiful-bill/Thank you for listening to Trust Me!Trust Me is Produced by Foley Marra StudiosEdited by Cat Hammons and Todd Gajdusek

What does it take to scale a business without losing your core values? In Episode 163, Vince Virga of PFS shares how conviction, belief, and systems helped him move from chaos to clarity. Joey Brannon and Cameron Earhart unpack the leadership principles behind his journey — from letting go of control to empowering a culture of accountability and growth.This candid conversation offers entrepreneurs practical tools and timeless wisdom for scaling with intention.

Sep 1, 2025 – Discover how retiring business owners can unlock powerful, little-known tax advantages while preserving their legacy in this insightful interview with Lawrence Kaplan of CSG Partners. Financial Sense host Jim Puplava explores how employee...

Aug 22, 2025 – What if China has already secretly surpassed the US as the world's largest holder of gold? In this compelling interview, Jim Puplava is joined by author Dominic Frisby to unravel the forces driving gold's explosive bull market...

Aug 29, 2025 – The Hunt Brothers tried to corner the silver market, driving it up to $50/ounce in the late 70s and early 80s. Now, it's the world's two largest economies trying to corner an increasing list of critical commodities. In this important update...

Aug 28, 2025 – What if the next decade on Wall Street eclipses even the Roaring 1920s? Dr. Ed Yardeni, President and Chief Investment Strategist at Yardeni Research, speaks with FS Insider to give an update on his bullish case for the S&P 500 soaring to...

Aug 27, 2025 – Step inside a world where AI builds worlds, rewrites language, and merges minds—today, not decades from now. In this fascinating conversation, Dr. Alan D. Thompson, renowned AI analyst, breaks down the race toward...

Aug 22, 2025 – This morning in Jackson Hole, Wyoming, Fed Chair Jay Powell stated that monetary policy remains restrictive and that adjustments are likely needed. While a rate cut was already widely anticipated for next month's Fed meeting...

Aug 22, 2025 – Speaking with Financial Sense, Substack powerhouse Doomberg explores how energy has become the decisive factor in the new global power struggle. The conversation highlights China's rapid ascent as the largest producer...

Leif Nilsson, CEO & Director of Surge Copper (TSX.V:SURG – OTCQX:SRGXF), joins me for a comprehensive update covering ongoing field activities, 3 types of drilling, and various derisking work initiatives and development work streams all building towards their updated Resource Estimate and Pre-Feasibility Study (PFS), at their flagship copper-molybdenum-silver-gold Berg Project in British Columbia.   We start off reviewing the resource size and different metals contributions as well as the key economic metrics from the Preliminary Economic Assessment (PEA) that was released in June 2023. The updated Mineral Resource Estimate includes combined Measured & Indicated resource of 1.0 billion tonnes grading 0.23% copper, 0.03% molybdenum, 4.6 g/t silver, and 0.02 g/t gold, containing 5.1 billion pounds of copper, 633 million pounds of molybdenum, 150 million ounces of silver, and 744 thousand ounces of gold, plus an additional 0.5 billion tonnes of material in the Inferred category.  Leif reviewed some of the results from their substantial metallurgical testing program, where a bulk concentrate has been successfully separated into a copper concentrate containing the precious metals and a high-value molybdenum concentrate.   Next we shifted over to the 3 different types of drilling that have been ongoing or are still underway at the Berg Project. Leif highlights that there has a been a fair bit of infill drilling completed over the last 2 years, including the recent 1,500 meter 5-hole program from this summer's program, where more ounces will be moving from the inferred category into the measured and indicated category when it gets updated along with the coming PFS. In addition to this infill and definition drilling, there has been a fair bit of geo-technical drilling to characterize ground conditions at proposed infrastructure areas of the project footprint, including the first-ever uphill-angle drilling at Berg. Lastly there in ongoing ARD drilling using an underground drill, testing the outer margins of Berg mineralization to evaluate acid rock drainage potential within the conceptual pit's waste rock zone.   Additional workstreams remain active across the site, including geophysical surveys, environmental baseline studies, and logistical field preparations such as pad construction and line cutting. The Berg camp is currently a hub of coordinated technical activity, with drill contractors, field geologists, environmental and geotechnical engineers, helicopter crew, line cutters, pad builders, geophysical crews, and camp support staff all contributing to the program. Collectively, these efforts are generating the critical datasets required to support robust design parameters and reduce risk ahead of the upcoming pre-feasibility study.   Wrapping up we discussed a number of factors from what the permitting process will look like for EA readiness, the value in the strategic partner they have in African Rainbow Minerals Limited (“ARM”) assisting the Project both financially and technically, and an overall sense of how the size and scale of the Berg stacks up to other large copper development assets in Canada.     If you have any follow-up questions for Leif regarding Surge Copper, then please email them to me at Shad@kereport.com.   In full disclosure, Shad is a shareholder of Surge Copper at the time of this recording, and may choose to buy or sell shares at any time.   Click here to follow the latest news from Surge Copper

Aug 19, 2025 – Are you prepared for the next move in markets? Find out how global liquidity, tariffs, and fiscal policy are shaping the investment landscape in our exclusive conversation with macro strategist Jonathan Petersen at Variant Perception...

Aug 20, 2025 – Explore the decisive factors in the US-China race for AI supremacy with Woody Preucil of 13D Research and Strategy. While the US leads in chip design and AI models, China's focus on digital infrastructure, 5G, and electricity production...

JCO PO author Dr. Alison M. Schram at Memorial Sloan Kettering Cancer Center shares insights into her JCO PO article, “Retrospective Analysis of BRCA-Altered Uterine Sarcoma Treated With Poly(ADP-ribose) Polymerase Inhibitors.” Host Dr. Rafeh Naqash and Dr. Schram discuss relevant genomic and clinical features of patients with BRCA-altered uterine sarcoma and the efficacy of PARPis in this population. TRANSCRIPT Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCO PO articles. I'm your host, Dr. Rafeh Naqash, podcast editor for JCO Precision Oncology and associate professor at the OU Health Stephenson Cancer Center. Today, we are excited to be joined by Dr. Alison Schram, Associate Attending Physician and Section Head of Oral Therapeutics with Early Drug Development and Gynecologic Medical Oncology Services at the Memorial Sloan Kettering Cancer Center, and the senior author of the JCO Precision Oncology article titled, "Retrospective Analysis of BRCA-Altered Uterine Sarcoma Treated With Poly(ADP-ribose) Polymerase Inhibitors." At the time of this recording, our guest's disclosures will be linked in the transcript. Dr. Schram, thank you for joining us today. I am excited to be discussing this very interesting, unique topic based on what you published in JCO PO. Dr. Alison Schram: Thank you for having me. Dr. Rafeh Naqash: What we like to do for these podcasts is try to make them scientifically interesting but at the same time, keep them at a level where our trainees and other community oncology professionals understand the implications of what you've published. So I'd like to start by asking you, what is leiomyosarcoma for those of us who don't necessarily know a lot about leiomyosarcoma, and what are some of the treatment options for these uterine sarcomas? Dr. Alison Schram: Uterine leiomyosarcoma is a rare subtype of uterine cancer, and it represents about 1% of all female cancers in the reproductive tract. This is a rare malignancy that arises from the myometrial lining of the uterus, and it is generally pretty aggressive. In terms of the standard therapy, the standard therapy for uterine leiomyosarcoma includes chemotherapy, generally combination chemotherapy, but despite a few regimens that tend to be effective, the duration of effectiveness is relatively short-lived, and patients with advanced uterine leiomyosarcoma eventually progress and require additional therapy. I will say that localized uterine leiomyosarcoma can be treated with surgery as well. Dr. Rafeh Naqash: Thank you for that description. Now, there are two aspects to what you published. One is the sarcoma aspect, the leiomyosarcoma, and the second is the BRCA mutation. Since we are a precision medicine journal, although we've discussed BRCA a couple of times before, but again, for the sake of our listeners, could you highlight some of the aspects of BRCA and PARP sensitivity for us? Dr. Alison Schram: Yes. So BRCA is a gene that's important for DNA repair, and BRCA mutations can be either inherited as a germline mutation, so one of your parents likely had a BRCA mutation and you inherited one copy. In patients who have an inherited BRCA mutation, the normal cells tend to have one abnormal copy of BRCA, but if a second copy in the cell becomes altered, then that develops into cancer. And so these patients are at increased risk of developing cancers. Specifically, they are at an increased risk of developing ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, and a few others. These cancers are considered BRCA-associated tumors. Alternatively, some patients, more rarely, can develop BRCA-altered cancers completely sporadically. So it's a mutation that happens in the tumor itself, and that can lead to impaired DNA repair and promote cancer progression. And those patients are not, they don't have any inherited risk, but just a random event caused a BRCA mutation in the tumor. The reason this is important is because, in addition to it being potentially important for family members, there are certain treatments that are more effective in BRCA-altered cancers. And the main example is PARP inhibitors, which are small molecule inhibitors that inhibit the PARP enzyme, and there is what we call synthetic lethality. So PARP is important for DNA repair, for single-stranded DNA repair, BRCA is important for double-stranded DNA repair, and in a patient that has a cancer that has a BRCA mutation, that cancer becomes more reliant on single-stranded DNA repair. And if you inhibit it with a PARP inhibitor, the cancer cells are unable to repair DNA, and the cells die. So we call that synthetic lethality. PARP inhibitors are FDA approved in several diseases, predominantly the BRCA-associated diseases I mentioned: breast cancer, ovarian cancer, pancreatic cancer, and prostate cancer. Dr. Rafeh Naqash: That was very beautifully explained. Honestly, I've heard many people explain BRCA before, but you kind of put it in a very simple, easy to understand format. You mentioned this earlier describing germline or hereditary BRCA and somatic BRCA. And from what I gather, you had a predominant population of somatic BRCA, but a couple of germline BRCA as well in your patient population, which we'll go into details as we understand the study. You mentioned the second hit on the germline BRCA that is required for the other copy of the gene to be altered. In your clinical experience, have you seen outside of the study that you published, a difference in the sensitivity of PARP for germline BRCA versus a somatic BRCA that has loss of both alleles? Dr. Alison Schram: So we will get into what's unique about uterine sarcomas in just a minute. In uterine sarcomas, what we have found is that the BRCA mutations tend to be somatic and not germline, as you mentioned. That is in contrast to the other diseases we mentioned, where the vast majority of these tumors are in patients that have germline BRCA alterations. So one thing that's really unique about the uterine sarcoma population and our paper, I believe, is that it is demonstrating an indication for PARP inhibitors in a population that is not characterized by germline BRCA alterations, but truly these by somatic BRCA alterations. If you look at the diseases that PARP inhibitors are validated to be effective in, including the, you know, the ones I mentioned, the BRCA-associated tumors, there's some data in specific context that suggests that perhaps germline alterations are more sensitive to PARP inhibitors, but that's not universal, and it's really tricky to do because the genetic testing that we have doesn't always tell you if you have two hits or just one hit. So you need more complex genetic analysis to truly understand if there is what we call a biallelic loss. And sometimes it's not a second mutation in BRCA. Sometimes it's silencing of the gene by hypermethylation or epigenetics. Some of our clinical trials are now incorporating this data collection to really understand if biallelic loss that we can identify on more complex genetic testing predicts for better outcomes. And we think it's probably true that the patients that have biallelic loss, whether it be germline or somatic biallelic loss, are more likely to benefit from these treatments. That still needs to be tested in a larger cohort of patients prospectively. Dr. Rafeh Naqash: In your clinical experience, I know you predominantly use MSK-IMPACT, but maybe you've perhaps used some other NGS platforms, next-generation sequencing platforms. Have you noticed that these reports for BRCA alterations the report mentioning biallelic loss in certain cases? I personally don't- I do lung cancer, I do early-phase lung cancer as well, but I personally don't actually remember if I've seen a report that actually says biallelic loss. So after this podcast, I'm going to check some of those NGS reports and make sure I look at it. But have you seen it, or what would be a learning point for the listeners there? Dr. Alison Schram: Exactly. And they usually do not. They usually do not explicitly say, “This looks like biallelic loss,” on the reports. The exception would be if there's a deep deletion, then that implies both copies of the gene have been deleted, and so then you can assume that it's a biallelic loss. But oftentimes, when you see a frameshift alteration or a mutation, you don't know whether or not it's a biallelic loss. And you may be able to get some clues based on the variant allele frequencies, but due to things like whole genome duplication or more complex tumor genomics, it's not clear from these reports, and you really do need a more in-depth bioinformatic analysis to understand whether these are biallelic or not. So that is why I suggest that this really needs to be done in the context of a clinical trial, but there is definitely a theoretical rationale for reporting and treating patients with biallelic losses perhaps more so than someone who has a variant of unknown significance that seems to be monoallelic. The other tricky part, as I mentioned, is the fact that there could be epigenetic changes that silence the second copy, so that wouldn't be necessarily evident on a DNA report, and you would need more complex molecular testing to understand that as well. Dr. Rafeh Naqash: Sure. Now, going to your study, could you tell us what prompted the study, what was the patient population that you collected, and how did you go about this research study design? Dr. Alison Schram: It's actually a great story. I was the principal investigator for a clinical trial enrolling patients regardless of their tumor type to a combination of a PARP inhibitor and immunotherapy. And this was a large clinical trial that was being done as a basket study, as I mentioned, for patients that have either germline or somatic alterations with advanced solid tumors that had progressed on standard therapy. And the hypothesis was that the combination of a PARP inhibitor and immunotherapy would be synergistic and that there would be increased efficacy compared to either agent alone and that patients who had BRCA alterations were a sensitive population to test because of their inherent sensitivity to PARP inhibitors and perhaps their increased neoantigen burden from having loss of DNA repair. So this large study, it's been published, really did show that there was efficacy across several tumor types, but it didn't seem to clearly demonstrate synergy between the immunotherapy and the PARP inhibitor as compared to what you might expect from a PARP inhibitor alone, and in addition to a couple of cases, perhaps attributable to the immunotherapy. So maybe additive rather than synergistic efficacy. However, what really struck me looking at the data was that there were three patients with uterine leiomyosarcoma with BRCA deletions who had the best responses of anyone on the study. So incredible, durable responses. One of my patients with a complete response that continues to not have any evidence of cancer eight years after the initiation of this regimen. And for those of us that treat uterine leiomyosarcoma, this is unheard of. These patients generally, as I mentioned, respond, if they do respond to chemotherapy, it's generally short-lived and the cancer progresses. And so a complete response nearly a decade later turns heads in this field. The other interesting thing was that these uterine leiomyosarcoma patients had somatic alterations rather than a germline alteration with a second hit, and the diseases that are best validated for being responsive to PARP inhibitors include the BRCA-associated diseases, the ones that you're at increased risk for if you have a germline BRCA mutation, including breast, pancreas, prostate, and ovarian. And so it was very interesting that this disease type that seemed to be uniquely sensitive to PARP inhibitors with immunotherapy was also different in that patients with uterine leiomyosarcoma don't tend to have a high frequency of BRCA alterations, and in patients that are born with a BRCA alteration, there doesn't seem to be a clearly increased risk of uterine sarcomas. So this population really jumped out as a uniquely sensitive population that differed from the prior indications for PARP inhibitors. Given this patient and these couple of patients that we observed on the combination, in addition to some other case reports and case series that had started to come out in small numbers, we wanted to look back at our large cohort of patients at Memorial Sloan Kettering to see if we could really get a better sense of the numbers. How many patients at Sloan Kettering with uterine sarcomas have BRCA alterations? Are they generally somatic or germline? Are there unique features about these patients in terms of their clinical characteristics? How many of them have received PARP inhibitors, and if so, is this just luck that these three patients did so well, or is this really a good treatment option for patients with BRCA-altered uterine sarcomas? And so we did this retrospective analysis identifying the patients at Sloan Kettering who met these criteria. So in total, we found 35 patients with uterine sarcomas harboring BRCA alterations, and the majority were leiomyosarcoma, about 86% of them had leiomyosarcoma, which is interesting because there are other uterine sarcomas, but it does seem like BRCA alterations tend to be more often in the leiomyosarcomas. And 13 of these patients with uterine leiomyosarcoma were treated with PARP inhibitors in the recurrent or metastatic setting with about half of those patients having an overall response, so that's a significant tumor shrinkage that sustained, and a clinical benefit rate of 62%. And if we look at the patients that had these BRCA2 deep deletions, which was the patient I had that had this amazing response, the overall response rate jumped to 60% and the clinical benefit rate to 80%. And we defined clinical benefit rate as having maintained on the PARP inhibitor without evidence of progression at six months. So this is really impressive for patients with a difficult to treat disease. And we couldn't do a randomized controlled trial comparing it to chemotherapy, but looking retrospectively at outcomes on chemotherapy studies, this was very favorable, particularly because many of these patients were heavily pretreated. So to get a sense of, you know, how this might compare to chemotherapy, we tried to use patients as their own internal controls, and we looked at how long patients were maintained on the PARP inhibitor as compared to how long they were on the treatment just prior. And we used a ratio of 1.3 to say if they were on the PARP inhibitor for 1.3 times what their previous treatment was or longer, that is pretty clearly better, more of a benefit from that regimen. And the majority of patients did meet that bar. So 58% had a PFS ratio greater than 1.3, and the average PFS ratio was 1.9, suggesting, you know, you would expect the the later lines of therapy to actually not work as well, but this suggests that it's actually working better than the immediately prior line of therapy, to me, suggesting that this is truly a good treatment option for these patients. Dr. Rafeh Naqash: Very interesting. And you mentioned that individuals with tumors having deep deletions were probably more responsive. How did you figure out that there was biallelic loss or deep deletions? Was that part of an extended analysis that was done subsequently? Dr. Alison Schram: So the deletions reported on our report, if it's a biallelic deletion, that is the one biallelic molecular alteration that would be reported. So those are, by definition, biallelic, and I think that that may be one of the reasons that's a good biomarker. But also, what's interesting is that if you have both copies deleted of BRCA, you can't develop reversion mutations. So one of the the known mechanisms of resistance to PARP inhibitors in patients who have BRCA alterations are something called a reversion mutation where, if you have a frameshift alteration, for example, in BRCA that makes BRCA protein nonfunctional, you can develop a second mutation that actually puts the DNA back in frame, and a functional protein is now made. And so a mechanism of resistance to PARP inhibitors is actually reverting BRCA to a wild-type protein, and then BRCA's synthetic lethality no longer makes sense and is no longer effective. But if you've deleted both copies of BRCA, you don't have the ability to restore the function, and you can't develop reversion mutations. And that's perhaps why, you know, my patient and others have had these prolonged responses to PARP inhibitors because you don't have the same ability to develop that mechanism of resistance. Dr. Rafeh Naqash: I remember thinking a year and a half back, I had an individual with prostate cancer and with BRCA2, and using liquid biopsy, I had a reversion mutation that we caught. In your practice, have you seen the utility of doing the serial liquid biopsies in these individuals to catch these reversion mutations? Dr. Alison Schram: Yes, absolutely. And in patients that have the ability to develop a reversion mutation, serial cell-free DNA can catch it, but the caveat is that it doesn't always. So if you see an acquired reversion mutation in cell-free DNA, that can be helpful, particularly if you're planning on putting the patient on another line of therapy that might require a dysfunctional BRCA. So if you're putting them on a clinical trial with a PARP combination and the rationale is that they're sensitive because they don't have a functional BRCA, you would want to know if they developed a reversion mutation, and serial cell-free DNA can definitely identify these reversion mutations. Some of the major clinical trials in ovarian cancer have done serial cell-free DNA and have demonstrated the utility of that approach. The caveat is that some of these reversion mutations are not readily caught on cell-free DNA because they're more complex reversion mutations, or they're not, the part of the gene that develops the reversion mutation is not tiled on the panel. And so it doesn't always catch the reversion mutations. Also, depends on the cell-free DNA shedding, depends on the tumor volume and other factors. And we published a related paper of a patient, it was a really interesting case of a patient with prostate cancer who was on a PARP inhibitor and developed what appeared to be a single reversion mutation on one sample, had negative cell-free DNA, single reversion mutation in a tissue biopsy, and then developed disease progression. And we did an autopsy, and the patient kindly consented to an autopsy, and at the time of autopsy, there were 10 unique reversion mutations identified across 11 metastases. So almost each metastasis had a unique reversion mutation, and only one of them had been seen premortem on a tissue biopsy and not on a cell-free DNA. But that autopsy really drove home to me how much we're missing by doing clinical testing in real time and we really don't know the entire genomic complexity of our patients by doing single samples. And theoretically, cell-free DNA can catch DNA from all the metastases, so you might think that that would be a solution, and it definitely can catch reversion mutations that are not seen in a single biopsy, but you really need to do it all. I mean, you need to do the tissue biopsy sampling, you need to do cell-free DNA, and probably one cell-free DNA test is not enough. Dr. Rafeh Naqash: Thank you, again, for that very nice explanation. Now, one quick provocative question. I remember when I was training, the lab that I used to work in, they used to do a lot of phosphorylation markers for DNA damage response, like phospho NBS, RAD51. Have you seen anything of that sort on these biallelic BRCA mutations where tumors are responding, but they also have a very high signature on the phosphorylation side, and it may or may not necessarily correspond to HRD signatures, but have you noticed or done any of that analysis? Dr. Alison Schram: I think that it would be great to do that analysis. And some of the work we're doing now is actually trying to dig a little bit deeper in our cohort of patients to understand are these HRD-positive tumors? Does HRD positivity correlate with response to BRCA alterations? In terms of the functional assays, I would love to be able to do a functional assay in these samples. One of the challenges is that this was a retrospective study and many of the patients were previously treated as standard of care or off-label with these agents, and so we didn't have prospective tissue collection, and so we're really limited by the tissue that was collected as part of standard of care and the consent forms that the patient signed that allow us to do genomic and molecular testing on their samples. So, I think that is hopefully future work that we will do and others will do. Dr. Rafeh Naqash: Sure. Shifting gears to your career trajectory, I'd like to spend a couple of minutes there before we end the podcast. So Dr. Schram, you've obviously been a trailblazer in this space of drug development, early-phase trials. Can you give us a brief synopsis of your journey and how you've successfully done what you're doing and what are some of the things that drive you? Dr. Alison Schram: Well, thank you for saying that. I don't know if that's true, but I'll take the bait. I've been interested in oncology since college and was always very interested in not only the science of oncology but of course, treating patients. And in medical school, I did basic science research in a laboratory and it was very inspiring and made me want to do research in oncology in addition to clinical care. When I became an oncology fellow, I was presented with a very difficult question, which is, “Do you want to be a lab PI and be in the lab, or do you want to do clinical care and clinical research?” And I couldn't choose. I found a mentor who thankfully really had this amazing vision of combining the two and doing very early drug development, taking the data that was being generated by labs and translating it into patients at the earliest stage. So, you know, phase one drug development in molecularly targeted therapies. And so I became very interested as a fellow in early drug development and this ability to translate brand new molecular insights into novel drugs. And I joined the- at Sloan Kettering, there was the Early Drug Development, it was actually a clinic, it was called something different, and it was very fortuitous. My last year of fellowship, the clinic became its own service with the ability to hire staff at Sloan Kettering, and I was the first ever hire to our Early Drug Development Service. And that really inspired me to try and bring these drugs to patients and to really translate the amazing molecular insights that my colleagues here at Sloan Kettering are discovering, and you know, of course, at other institutions and in pharma. And you know, there 's been an amazing revolution in in drug development over the last several years, and I feel very grateful that I've been here for it. You know, I've been able to take the brilliant insights from my colleagues and put these drugs in patients, and I have the amazing privilege of watching patients in many cases that benefit from these treatments. And so I do mostly phase one drug development and molecularly targeted therapies, and truthfully, I am just very fortunate to be around such brilliant people and to have both patients and labs trust me to be able to deliver these new drugs to patients and hopefully develop better drugs that move forward through FDA approval and reach patients across the country. Dr. Rafeh Naqash: Thank you so much. That was very nicely put. And hopefully our trainees and junior faculty find that useful based on their own career trajectories. Thank you, Dr. Schram, for joining us today. Hopefully, we'll see more of your subsequent work in JCO PO. Thank you for giving us all these insights today. Dr. Alison Schram: Thank you for having me. Dr. Rafeh Naqash: Thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcasts. 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. Alison Schram Disclosures Consulting or Advisory Role Company: Mersana, Merus NV, Relay Therapeutics, Schrodinger, PMV Pharma ,Blueprint Medicines, Flagship Pioneering, Redona Therapeutics, Repare Therapeutics, Endeavor BioMedicines Research Funding Company: Recipient: Your Institution  Merus, Kura, Surface Oncology, AstraZeneca, Lilly, Pfizer , Black Diamond Therapeutics, BeiGene, Relay Therapeutics, Revolution Medicines,  Repare Therapeutics, PMV Pharma, Elevation Oncology, Boehringer Ingelheim Travel, Accommodations, Expenses Company: PMV Pharma 

Aug 18, 2025 – Losing a spouse or loved one is a difficult and overwhelming experience, often leaving many unsure of what to do next. In this insightful interview, Jim Puplava walks listeners through a comprehensive survivor checklist...

Gwen Preston, VP of Communication at West Red Lake Gold Mines (TSX.V:WRLG – OTCQB:WRLGF), joins us for a wide-ranging discussion on various operational and exploration updates around their 100% owned Madsen Mine located in the Red Lake Gold District of Northwestern Ontario, Canada.   We also review the key metrics and takeaways from the Rowan Project Preliminary Economic Assessment (PEA).   In July 2025, three gold pours were made at Madsen, producing a total of 3,800 ounces of gold. Of that, 3,595 ounces were sold at an average price of US$3,320 per oz, which generated CND $16.4 million in revenue.  In July the Madsen mine operations team completed sill development and mining in eight (8) areas spread across McVeigh, South Austin, and Austin. Mined material carried an average grade of 8.9 grams per tonne gold.   Gwen outlines that the Company currently has a dual focus during the Madsen Mine ramp-up for the balance of 2025.   Achieving targeted ramp-up gold ounce production. Instituting new operational efficiencies.   These objectives will be reached by continuing to adding new equipment and haul trucks, developing more underground access to high-priority mining areas and stopes, and getting the first phase of Madsen Shaft rehabilitation operational.  Additionally, their operations team is working to get the Cemented Rock Fill (CRF) Project in place to convert waste rock into cement to be filled into historic underground voids, which are ideal repositories for this waste rock.    Once those objects have been achieved, then the Company will feel confident in declaring commercial production; with an internal target to reach this by year-end.   Next, we discussed the exploration strategy moving forward for expanding high-confidence ounces in the South Austin Zone of Madsen, which have seen some bonanza-grade intercepts from drilling throughout this year:   SOUTH AUSTIN ZONE EXPLORATION HIGHLIGHTS:   Hole MM24D-08-4447-069 - Intersected 6 meters (m) @ 114.26 g/t gold (Au), from 122.0m to 132.6m, Including 0.7m @ 1,609.26 g/t Au, from 130.5m to 131.2m, within a broader high-grade interval of 4.25m @ 282.00 g/t Au Hole MM25D-12-4669-011 - Intersected 5m @ 52.86 g/t Au, from 25.0m to 29.5m, Including 1m @ 213.62 g/t Au, from 26.5m to 27.5m Hole MM25D-12-4669-024 - Intersected 7m @ 48.97 g/t Au, from 5.3m to 24.0m, Including 2m @ 428.83 g/t Au, from 20.5m to 22.5m Hole MM25D-08-4380-011 -Intersected 1m @ 61.51 g/t Au, from 11.0m to 23.1m, Including 1m @ 725.00 g/t Au, from 12m to 13m, Hole MM25D-11-4420-024 Intersected 6.9m @ 36.85 g/t Au, from 79.1m to 86.0m   In addition to growing the known areas, there will also be a renewed focus on making new discoveries and following up on the promising earlier-stage drill targets tested in last year's program like the high-grade shoot at Upper 8, the MJ/Wedge area, North Venus, and North Shore.  Gwen also highlights how the Fork Deposit will get some more drilling to further define the higher-grade zone and move it up the matrix of areas to potentially come into the mine sequencing in the medium-term.   Wrapping up we reviewed NI 43-101 PEA prepared on June 30th, 2025, for a toll milling mine operation at its 100%-owned Rowan project in the Red Lake Gold District of northwestern Ontario, Canada.   Rowan PEA Highlights:   High-Grade Efficient Mine: Underground mine via long hole retreat method, delivering an average diluted head grade of 8.0 grams per tonne (“g/t”) gold (“Au”), accentuated by 10.4 g/t Au average grade in Year 1. Notable Production: 35,230 oz. average annual Au production over the 5-year mine life from an average mining rate of 385 tonnes per day (“tpd”). Strong Value: $125.3M post-tax Net Present Value (“NPV”) at US$2,500 per oz Au. Post-tax NPV rises to $239M at US$3,250 per oz Au. Low Costs and Strong Returns: US$1,408/oz all-in sustaining cost (“AISC”) and 41.9% post-tax internal rate of return (“IRR”), underscoring the viability of the Company's second potential mine in the region. IRR increases to 81.7% at a US$3,250/oz gold price. Modest Initial Capital: Multiple mills in the area with excess capacity create the opportunity to develop Rowan as a toll milling operation with initial capital of just over $70 million. High Confidence Inventory: PEA mine design includes 63% of mined tonnes and 72% of mined ounces from the Indicated category – provides solid base for transition into prefeasibility study (“PFS”) level assessment.     If you have any follow up questions for Gwen or the team over at West Red Lake Gold, then please email us at either Fleck@kereport.com or Shad@kereport.com.   In full disclosure, Shad is shareholder of West Red Lake Gold Mines at the time of this recording, and may choose to buy or sell shares at any time.   Click here to follow the latest news from West Red Lake Gold Mines

Join Dave and Bethlie as they continue a study on a few select chapters of the book Ten Pillars of an Awesome Marriage by Charles Shoemaker.    PART 2 5. Chapter 5 Conflict Resolution Goal - not to avoid but to handle wisely Illustration of Lady Astor to Winston Churchill - If you were my husband, I would give you poison; if you were my wife, I would take it! P. 85 Swindoll Quote Frequently, marital warfare is in the trenches of belligerence or moodiness. Some battles are night attacks or surprise assaults. Others are cold wars of stoic silence.  Cruel methods of torture are also employed—public criticism, fearful threats, intimidation, ugly sarcasm, and hateful remarks designed to put down one's mate. Such tactics are popular . . . but wrong because they are unfair and they never lead to domestic peace.” P. 87 PFS - personal filtering system Age Gender Education Life experiences Culture Temperament  Skills Personality Spirituality How do you resolve conflicts Be right with God Be swift to hear and slow to speak Own it when you are wrong Stay focused on issue at hand Face conflicts with a team mindset We not me A marriage struggles when it has two “I”s

Aug 15, 2025 – Could net negative immigration, not just economic cycles, be reshaping the US job market? Jim Bianco at Bianco Research brings a fresh lens to the latest employment data, inflation, and what investors should really watch...

Aug 15, 2025 – The Fed's next move could hinge on flawed data—with serious market and economic consequences. Join Jim Puplava and Macro Tides' Jim Welsh as they dissect inflation reports, reveal weaknesses in government stats, and unpack...

Aug 14, 2025 – Beneath steady US growth, historic tariffs and simmering inflation hint at turbulence on the horizon. Today, we speak with Lauren Saidel-Baker of ITR Economics discussing the US economic outlook. She explains why ITR...

Aug 13, 2025 – FS Insider's Cris Sheridan speaks with Bruce Mehlman of Mehlman Consulting about the growing role of artificial intelligence in politics. They discuss AI's potential to reshape elections through hyper-optimized redistricting...

In our conversation, Dr Akhave discussed the addition of toripalimab (Loqtorzi), a PD-1 inhibitor, to the NCCN Guidelines following its launch in the United States. Supported by data from the phase 3 JUPITER-02 trial (NCT03581786), toripalimab is now incorporated into frontline therapy for patients with recurrent metastatic or de novo metastatic Epstein–Barr virus (EBV)–positive NPC, in combination with gemcitabine and cisplatin. He explained how this regimen has produced substantial improvements in progression-free survival (PFS), nearly tripling median PFS compared with chemotherapy alone, while maintaining a manageable safety profile.

Aug 12, 2025 – As uncertainty over trade and policy continues, discover why one of the world's top metals analysts believes the bull market in gold and silver is far from over. FS Insider interviews Jeff Christian for an in-depth discussion on gold...

Aug 11, 2025 – Discover the cutting edge of personalized health technology on this episode of the Lifetime Planning Show! Financial Sense founder Jim Puplava dives deep into how wearables are transforming early detection, prevention, and...

Aug 8, 2025 – In this wide-ranging conversation, Jim Puplava and Mark Mills, Executive Director of the National Center for Energy Analytics, challenge the prevailing narrative of an “inevitable energy transition.” Mills explains why the world's...

Aug 8, 2025 – John Kosar of Asbury Research speaks with Financial Sense Newshour's Jim Puplava to provide an update on his technical outlook for the US stock market, leading sectors, precious metals, energy, and the dollar. While the S&P 500...

Aug 7, 2025 – Today we explore the evolving landscape of U.S. industrial policy, featuring insights from two policy experts on the bipartisan shift away from neoliberal free trade, the increasing use of tariffs, the strategic importance of...

Aug 5, 2025 – As Wall Street's optimism collides with mounting signs of economic fragility, investors are left to wonder: is today's market rally a testament to genuine strength—or simply the calm before a storm? In today's deep-dive, FS Insider taps Tom Essaye...

Aug 4, 2025 – Wondering how the sweeping tax changes in the One Big Beautiful Bill could impact your retirement? In this edition of Lifetime Planning on the Financial Sense Newshour, Jim Puplava and Crystal Colbert break down the latest rules...

Aug 1, 2025 – Financial Sense Newshour's Jim Puplava interviews Gail Tverberg at Our Finite World about the World Energy Institute's 2025 Statistical Review of World Energy, focusing on looming shortages in critical resources like diesel...

Aug 1, 2025 – Financial Sense Newshour speaks with well-known market technician Tom McClellan about four bearish factors coming together for stocks this quarter: a liquidity crunch, an overly tight Fed, weakening breadth numbers, and bearish seasonality...

Jul 30, 2025 – FS Insider interviews Adriano Bosoni, RANE's Director of Geopolitical Analysis, to discuss the major forces shaping today's global landscape. The conversation explores recent shifts in US trade policy, rising tariffs, rare earth supply...

Jul 29, 2025 – With markets at a crossroads and policymakers under unprecedented pressure, few voices cut through the noise like Peter Boockvar's. In this in-depth interview, Peter Boockvar offers candid insights into Federal Reserve policy, the impact...

Jul 28, 2025 – What if a simple, drug-free therapy could slash your risk of heart attack by 50%, stroke by 61%, and dementia by 66%? In this eye-opening discussion, Jim Puplava sits down with Vic Riffel of Sunlighten Saunas to explore the science...

Jul 25, 2025 – In this timely roundtable, Financial Sense Newshour's Jim Puplava interviews Dave Morgan (The Morgan Report) and Bob Coleman (Idaho Armored Bulls) for a deep dive into silver's extraordinary rally and future outlook in light of...

Jul 25, 2025 – Amid a backdrop of historic market highs, rising geopolitical tensions, and evolving investment paradigms, where should discerning professionals look for opportunity—and risk? Mish Schneider at Market Gauge and...

Jul 23, 2025 – Are stablecoins quietly reshaping the future of global finance? In this insightful conversation, Izabella Kaminska, founder of The Blind Spot and former FT Alphaville editor, joins FS Insider's Cris Sheridan to explore why stablecoins...