Podcasts about solid tumor oncology

Welcome back to The Genetics Podcast! Today, we're joined by Dr. Luis Diaz, Head of the Division of Solid Tumor Oncology at Memorial Sloan Kettering and a White House Appointee to the National Cancer Advisory Board. Dr. Diaz's career has been defined by his commitment to translating cutting-edge cancer genomics into clinical practice. In this episode, he and Patrick dive into his groundbreaking trial on mismatch repair (MMR)-deficient rectal cancer, along with his pioneering work on liquid biopsies, immunotherapies targeting tumors with microsatellite instability, and advancements in precision oncology. To learn more about Dr. Diaz and his work, visit his research page here: https://www.mskcc.org/research-areas/labs/luis-diaz.

JCO PO author Dr. Mohamed Salem shares insights into his JCO PO article, “Landscape of KRASG12C, Associated Genomic Alterations, and Interrelation With Immuno-Oncology Biomarkers in KRAS-Mutated Cancers” and the article's findings of a large-scale, pan-cancer genomic characterization of KRASG12C. Host Dr. Rafeh Naqash and Dr. Salem discuss KRASG12C mutation, KRASG12C -mutated tumors and comutation with STK11 and KEAP1. Click here to read the article!   TRANSCRIPT Dr. Abdul 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. Abdul Rafeh Naqash, Social Media Editor for JCO Precision Oncology and assistant professor of Medical Oncology at the OU Stephenson Cancer Center.  Today I'm thrilled to be joined by Dr. Mohamed Salem, Gastrointestinal Medical Oncologist, and Research Director at the Levine Cancer Institute in Charlotte, North Carolina. Dr. Salem is the lead author of the JCO Precision Oncology article ‘Landscape of KRASG12C, Associated Genomic Alterations, and Interrelation With Immuno-Oncology Biomarkers in KRAS-Mutated Cancers'.  Our guest's disclosures will be linked in the transcript.  Dr. Salem, welcome to our podcast, and thank you for joining us today. Dr. Mohamed Salem: Thank you for having me. A pleasure and honor. Dr. Abdul Rafeh Naqash: For the sake of this podcast, we'll be referring to each other using our first names. So thank you for coming on to our podcast and discussing this very interesting paper. And one of the reasons why we decided to incorporate this is because, as you very well know, KRAS is one of the most common altered genes in cancer, and I'm pretty confident and sure that oncologists, whether it's academic oncologists or community oncologists, have treated patients in different settings having tumors that harbor KRAS alterations. So give us a little bit of a background on where KRAS alterations stand currently and where is drug development in the space of KRAS to give our listeners some idea of why we're interested in this gene. Dr. Mohamed Salem: Sure, thanks again for having me. And as you mentioned, KRAS mutation happens to be, I think, by far the most common oncogenic mutation we see in oncology and solid tumors. The problem with KRAS is that, for a long, long time, there was very much nothing we could do about it; it was, in fact, called an undruggable target. Until recently, we started to realize this might not be true, and, in fact, we start to see successful efforts trying to target KRAS mutation. Currently, there are several KRAS inhibitors. I think it started with G12C. I personally don't think there was anything specific about G12C, but it just happened to be one of the first targets that we were able to approach. And the initial result from using anti-G12C therapy that was published in the New England Journal of Medicine, I think, a year ago now, showed this is feasible and perhaps effective. Dr. Abdul Rafeh Naqash: Thank you so much, Dr. Salem, for that explanation. And being a Phase I trialist, I personally have seen a lot of exciting combination-based approaches in the setting of KRAS-altered tumors, especially KRASG12C.  Now, specifically delving into your paper, given the extensive length and breadth of data that you've covered here, could you tell us a little bit about why you decided to use KRAS as an interesting topic for your study and the kind of data set that you chose to explore this question?  Dr. Mohamed Salem: What happened once we started to realize how important it is to figure out which KRAS mutation we're dealing with because, at least in colorectal cancer, it's a very common mutation, almost like 40-50% of patients with colorectal cancer tumors carry KRAS mutation. Until very recently, we really didn't pay close attention to which variant it is. Is it KRAS G12D, 13, or G12C? And so on and so forth. And the reason we didn't really pay much attention to that is because there was nothing to do about it; whether the patient has this or that variant was really nothing therapeutically wise it really didn't have an impact. But once we started to realize now there is a therapeutic option and, in fact, now there is a change in the way we think about KRAS mutation, there is a proof of concept that we actually can target KRAS mutation, we started to pay closer attention to this.  And I think this was a paradigm shift in our thinking. So for patients who have KRAS mutation, now we have data showing that KRASG12C is something we can target, whether with single agent or with combination therapy. But it was a new era for us because most of us realized it's not going to stop there. It's not going to be just G12C; I think G12C is the tip of the iceberg, and likely the science is going to go forward, try to target the other variants. So one of the obvious questions was what are the other variants and how commonly those exist, and which tumor types also carry those variants. Because as we were talking before the recording for Phase I, now it is not like one approach fits all; it started to kind of like focus on either molecularly driven or disease-type approaches. And it was very important for us to try to figure out, okay, which tumor type carries the most KRAS variants and, within that tumor, which variants are the most common. And this is what we're trying to answer in this paper.  Dr. Abdul Rafeh Naqash: Thank you so much, Mohamed. I looked at your data set that you had access to, very large data set of around 79,000 tumor samples and close to 14,000 KRAS mutated tumors. Could you tell us a little more about this data set and how you started with looking at the distribution of KRAS across different tumors, and what were the kind of interesting results that you came across as far as KRAS distribution is concerned? Dr. Mohamed Salem: It's very obvious to all of us now that the field is moving from one size fits all to a targeted approach or treatment target approach. And this is very important and very interesting because usually, when we do that, we achieve better outcomes and lesser toxicity. But the problem that comes with this is that none of us, as a single, even two centers, will have enough data to ask and answer questions. And when you are talking about something like MSI-high or BRAF or KRAS, usually it becomes very challenging for one single institution, doesn't matter how big they are, to try to answer either prevalent or therapeutic approaches. Because of that, most of us now start to understand that cooperation is very important across centers and also across nations.  So, like as you see here in this paper, there was a global cooperation between investigators in the U.S. and in Europe and Austria, and other countries. And what we did as a group we worked with one of the third-party profiling companies. Our group tried to answer what is the prevalence, just a very simple question, what is the prevalence of KRAS mutation, and what is the prevalence of each variant type in each tumor? And none of us could have answered that question on their own. Because of that, we actually collaborated with one of the third-party companies that do next-generation sequencing for tumors, and we were able to collaborate with them to have access to that database and answer some of those questions.  Dr. Abdul Rafeh Naqash: Excellent. As everybody knows, NGS is a standard of care testing that oncologists do, especially for advanced settings, to identify driver alterations or therapeutic interventions that may be relevant for patients. So in this data set, it seems you had access to NGS data, tumor mutational burden, and PD-L1 data for these tumor types. Could you tell us about the differences in the distribution for KRAS and the KRAS subtypes that you identified in this data set? Dr. Mohamed Salem: Sure. So, as you mentioned, we looked actually at almost 79,000 tumor samples that underwent next-generation sequencing by our collaborator. And it appears that about 17% of the tumors or so had some kind of KRAS mutation. And then, after that, we start to see G12C when we start looking at each variant. G12C were about 11%, 12%, and about 88% of the remaining KRAS mutant tumors harbored some different kind of KRAS mutation.  The next question was, in general, in all tumors, what was the most common KRAS variant seen? I think it mimicked what was already out there. It appears that G12D happened to be perhaps the most frequent mutation seen in KRAS mutation tumors, followed by G12V, followed by G12C, and then G12/13, and then others. What was very interesting, actually, an observation we saw, is that we were able to realize the distribution of KRAS variants varies according to the tumor subtype. So, for example, in pancreatic cancer, we could see patients who had G12R KRAS mutation variants. This was not seen commonly in other tumors. And the reason that's important is because maybe that will be something in pancreatic cancer tumors that will be worth looking at and do therapeutic approach there. But also, I'm sure you're already dealing with this in your clinic quite often. It was interesting, obviously, that non-small cell lung cancer was the most common organ that actually carries G12C, followed by colorectal cancer; followed by a very interesting actual observation that was very interesting for us to see was in appendiceal cancer. As you know, appendiceal cancer is not a common disease; it's a relatively rare disease. And we were surprised to see some of them actually have G12C mutation. And again, the reason that's important is that it just opens the door for possible therapeutic options and in context of clinical trials. Dr. Abdul Rafeh Naqash: Excellent. Definitely, the advantage of having such a rich data set like you did enabled you to look into some of these unique distributions across rare tumors, which makes it very interesting.  Now, one thing that I realized in the paper is that these tumors of unknown origin, where you identified or your group identified that they had a certain percentage of KRAS alterations, suggesting maybe their tumor of origin is perhaps lung or upper diaphragm, which could have therapeutic implications. Could you tell us a little more about this? Dr. Mohamed Salem: Yeah, this was another very interesting observation we saw because it is not uncommon for us in the clinic, we get like a cancer biopsy, but we cannot tell where it's coming from. And there are multiple ongoing efforts to try to identify that for the obvious reasons. But it was very interesting when we looked at those groups that when you had cancer adenocarcinoma but of no identified origin, it was the fourth common tumor that we see G12C. I think if you can just make the assumption - I don't think we have proved that - but since lung cancer was the most common tumor that exhibited G12C mutation, and now we have tumors of unknown origin also, many of them exhibit G12C mutation, we thought this could be a lung primary. As you know, there are also now a few platforms trying to identify the tumor origin based on the agent sequencing, but we didn't try to associate it with that. Dr. Abdul Rafeh Naqash: Thank you for that explanation. Now, one of the other things I observed is you tried to delve into smoking status, very interestingly, and how that correlated with KRAS alterations. And as we know, lung cancer, obviously there is a strong predilection in patients who are smokers, but irrespective of smoking, there can be other alterations that drive lung cancer. But interestingly, in your paper, you identified a unique correlation between smoking and G12C and also found out something on those lines in colorectal cancer, which, to my understanding, has not been described before. What is your understanding of why that happens? What could be the mutational events that lead to something like that, and how could that be potentially therapeutically exploited? Dr. Mohamed Salem: I think this was one of the very interesting findings we observed. And you are right; just because the nature of lung cancer, we know many of patients are either active smokers or former smokers. So it was not a surprise for us to see that there is some kind of association with smoking status and lung cancer. But to your point, what was really surprising and, in a way, interesting for us to see, actually, that association for patients with colorectal cancer. Smoking actually happens to be one of the risk factors, like in colon cancer, but obviously not as high as lung cancer. But when we looked at the data, demographic, and clinical features, it was obvious actually that current smoking status, whether a current smoker or prior smoker, had an association with G12C. And also, with gender as well, females tend to have more G12C, or G12C mutation was more likely to be seen in females than males. So the fact that we were able to identify the smoking status and gender as more likely to harbor G12C mutation was interesting.  I have to tell you, the reviewer, when we submitted the paper for review, the reviewer came back and asked us, did this happen just because you had too many lung cancer, and most lung cancer patients smoke, that's why you're seeing that association? And we went back and looked at the data again and spoke with our biostat team in the study, and we were able to actually run the analysis and show that, no, it is not just because of the enrichment; it's actually a real association between the smoking status and G12C. It's very interesting to see, at least in colorectal cancer, it's following the same trend in lung cancer. Dr. Abdul Rafeh Naqash: Right. And one of the other things I remember when I was reading through your paper and smoking status, I remembered this paper that was published in Science Magazine 2016, looking at how mutational burden changes in patients that have a history of smoking. But when you connect the dots here, interestingly, it seems like, especially in lung cancer, from what you guys have described here, is that the smoking status impacts what kind of KRAS alteration is present. But at the same time, you didn't see a tumor mutational burden that was significantly higher in G12C, mutated non-small cell lung cancer, where you would expect a lot of these G12Cs to be related to smoking. But on the other hand, the tumor mutational burden was not necessarily increased. And I understand you may not have an explanation for that through the data that you've published on, but that was kind of an interesting observation that I had. I don't know if you have any specific comments on that. Dr. Mohamed Salem: No, it's absolutely correct. What we thought is that we should see that because the obvious rationale is just cited, but it wasn't. And until today, we're actually trying to figure out why the disconnect because you have people who smoke usually you expect like PD-L1 is positive, you expect higher tumor burden, but it didn't show at least a statistically significant correlation.  Dr. Abdul Rafeh Naqash: Thank you. And I guess it's notable to mention that you did have some interesting correlations for tumor mutational burden overall, and with PD-L1. Could you tell us about that for different KRAS genetic alterations?  Dr. Mohamed Salem: There were few papers published before by our colleagues trying also to understand the correlation between G12C mutation and immunostatus or immune microenvironment and some biomarkers. And I think, at least to my understanding, there was not one consensus. I think it was different findings to some degree. So, in general, when we actually looked at the entire cohort, regardless of the tumor type, it appears that tumors that carry G12C mutation also happened to have higher PD-L1 expression. What was very interesting was that once we started to look at different tumor types, this was not seen across all tumors. So some tumors did actually carry that, and some other tumor types didn't show that correlation. And to be honest with you, I'm still, until today, I'm not sure why. Is this just a function of number, or actually there is more tumor biology that reflects that? I have to say my own feeling, and that's something we need to study further, is that I think it is tumor biology. One thing was also very interesting to us from the clinical side. You have G12C mutation in lung, and you have G12C mutation in colorectal, and in the New England Phase I study, you could see very clearly that targeted G12C is more effective in the lung compared to colorectal. It's the same target, the same drug, yet the response is different once you start to have two different tumor types. So that just got me to think there must be something with the tumor type and microenvironment of the tumor and also associated co-mutations and other factors that impact that.  Dr. Abdul Rafeh Naqash: I couldn't agree with you more, and I totally have seen that in some of the work that has been published or data that I've been part of where different tumor biology, the tumor microenvironments, even sites of metastasis make a difference in how a certain mutation behaves. So definitely something that needs further validation with perhaps proteomic and transcriptomic data to understand functional characterization of the downstream consequences for some of these mutations. And you pointed out co-mutation status. That's an ever-emerging question for some of the potentially druggable alterations, whether combination approaches targeting some other co-occurring common co-mutation would have more benefit. Could you tell us about some of the unique, interesting commutations that you identified in your cohort that were more common in certain KRAS subtypes? Dr. Mohamed Salem: Sure. I think that's also something we try to look at for the reason I just mentioned. We know that tumor origin and tumor type influence response and sensitivity to therapy. I think the best example we have, at least in colorectal cancer, is the BRAF mutation. When we saw the BRAF inhibitor having very nice response rate and control of BRAF mutant melanoma in colorectal cancer, we saw that it's going to be the same thing, the same drug, the same target, same thing's going to happen. And obviously, it was not the case. And this was a lesson for all of us to understand. Even if it is the same target, even if it's the same drug, tumor origin matters, and that's likely because of the associated co-mutations that will influence the pathway of the tumor and perhaps either the sensitivity to the drug or maybe resistance to the drug.  So it was very important for us to look also at the associated co-mutations. And I think one of the KEAP1, and perhaps you will comment on this more than me, but the KEAP1 gene was likely to be mutated in those tumors who have G12C mutation than others. Another one was STK11. And there were a few other ones, it depends on which tumor type, but KEAP1 was a very interesting finding for us too. Because as you're aware, it's important, at least in lung cancer, and maybe will impact therapeutic approach too. Dr. Abdul Rafeh Naqash: You're definitely right. It is important in lung cancer, and there's data that has shown both the STK11 and KEAP1 tumors have inferior outcomes to checkpoint inhibitors and are partly involved in metabolic reprogramming of the tumors. So there's definitely emerging targets that are trying to see if combination approaches in STK11 mutant lung cancer will demonstrate some level of benefit. But I think the co-mutation status would potentially have some sort of impact. But again, functional studies that help us understand what are the downstream consequences of one mutation versus another need to be further performed to get a better understanding of this space.   But I think this is definitely interesting work and very interesting results. Hopefully, our listeners will feel the same and maybe even try to go through the paper to understand some of the other additional results that you have published as part of this extensive paper.  We thank you on behalf of JCO Precision Oncology for submitting your work to JCO Precision Oncology, and hopefully, you'll consider us for further subsequent work in this space. Thank you so much for being with us today. Dr. Mohamed Salem:  No, thank you for having me, and actually, on behalf of my co-authors, I also wanted to thank JCO Precision Oncology for their interest in our paper. And, of course, for the reviewers, because there was no doubt they actually made our paper a much better one. So thank you for having me today, thank you for the entire team. Dr. Abdul Rafeh Naqash:  Reviewers definitely remain the people hidden behind the scenes who help in getting work refined and eventually published. So thank you again. And thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating or a 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, 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. Guest Bio Mohamed E. Salem, MD, is Research Director, Associate Professor of Medicine, and Gastrointestinal Medical Oncologist in the Department of Solid Tumor Oncology at the Levine Cancer Institute.  Guest Disclosures (See also: Landscape of KRASG12C, Associated Genomic Alterations, and Interrelation With Immuno-Oncology Biomarkers in KRAS-Mutated Cancers) Mohamed Salem: Consulting or Advisory Role: Taiho Pharmaceutical, Exelixis, Bristol-Myers Squibb, QED Therapeutics, Novartis, Pfizer, Daiichi Sankyo/Astra Zeneca, Merck  Speakers' Bureau: Taiho Pharmaceutical, Daiichi Sankyo/Astra Zeneca, BMS, Merck, Pfizer 

Luis Diaz, MD, is the Head of the Division of Solid Tumor Oncology and holds the Grayer Family Chair at Memorial Sloan Kettering Cancer Center. Dr. Diaz is an internationally recognized physician-scientist, accomplished physician, researcher, and leader in the field of clinical oncology. He has pioneered several diagnostic and therapeutic genomic approaches to cancer and has developed the basis for a molecular pap smear, a promising way to detect early-stage ovarian and endometrial cancers based on genetic markers. He is one of the seven distinguished members of the National Cancer Advisory Board at The White House and was recently inducted into the prestigious Giants of Cancer Care. “Trust amongst a team enables ideas to emerge that can change a project from one that is mundane or incremental, into one that can deliver a world class result. Try to assimilate yourself in teams which not only have passion, resources, and talent, but that also give you the opportunity to speak freely; so that when moments come, ideas can flow that make a world class difference.” Pearls of Wisdom:   1. Trust is the key component of successful teams, and it is what will create an environment where creative ideas are unleashed and take incremental success to world-class success. 2. Leadership is about being nervous that sets the stage for equanimity and having comfort and clarity that allows you to navigate the situation. 3. We have to be better every day and the mindset of continuous development is the key to making the difference between great and master clinicians.

PharmaDrug Inc (CSE:BUZZ) (OTCMKTS:LMLLF) CEO Daniel Cohen tells Proactive its subsidiary Sairiyo Therapeutics Inc, a biotechnology company developing Cepharanthine, a repurposed naturally-derived compound for the potential treatment of cancer and other diseases, has tapped two experts to join its newly-formed scientific and clinical advisory board. Cohen says that drug-repurposing expert Moshe Rogosnitzky has joined as an advisor, with more than 15 years of experience in the use of Cepharanthine for treating advanced cancers, as well as androgenic alopecia, or male-pattern baldness. Along with him is gastric cancer expert Yelena Janjigian, who has joined as an advisor. She is the chief of the Gastrointestinal Medical Oncology Service in the Division of Solid Tumor Oncology within the Department of Medicine at Memorial Sloan Kettering Cancer Center (MSK) in New York.

In this episode, Edward S. Kim, MD, FACP, and Leora Horn, MD, MSc, FRCPC, answer questions focused on biomarker testing and selecting targeted therapy for patients with advanced non-small-cell lung cancer with topics including:How to approach discordant results with liquid vs tissue biopsiesRepeating NGS testing at progressionSelecting urgent treatment when molecular results are not yet availablePoint mutations in NTRK fusion–positive diseaseSelecting second-line therapy for EGFR-positive disease with high PD-L1 expression after first-line TKISelecting first-line and second-line therapy for ROS1-positive diseaseStandard of care for MET-altered diseaseSelecting second-line therapy for RET fusion–positive disease after first-line TKIPresenters:Edward S. Kim, MD, FACPChair, Solid Tumor Oncology and Investigational TherapeuticsDonald S. Kim Distinguished Chair for Cancer ResearchLevine Cancer InstituteAtrium HealthCharlotte, North CarolinaLeora Horn, MD, MSc, FRCPCIngram Associate Professor of Cancer ResearchDirector, Thoracic Oncology Research ProgramAssistant Vice Chairman for Faculty DevelopmentVanderbilt Ingram Cancer CenterNashville, TennesseeContent based on an online CME program supported by an educational grant from Lilly.Link to full program, including associated downloadable slidesets: https://bit.ly/3a3e1Xs

In this episode, Edward S. Kim, MD, FACP, and Leora Horn, MD, MSc, FRCPC, answer questions focused on current and evolving biomarkers for immune checkpoint inhibitor–based therapies in advanced non-small-cell lung cancer with topics including:Selecting therapy for advanced NSCLC without actionable mutations and with different levels of PD-L1 expressionChoosing therapy for advanced NSCLC with an actionable mutation on NGS and high PD-L1 expressionLeveraging key data from CheckMate 9LA to identify patients who may benefit from chemotherapy plus nivolumab/ipilimumabSTK11/KEAP1 as potential predictors for a lack of response to immune checkpoint inhibitor–based therapyTreatment for NSCLC after progression on chemotherapy plus an immune checkpoint inhibitorRechallenging after stopping immune checkpoint inhibitor due to immune-related adverse eventsPresenters:Edward S. Kim, MD, FACPChair, Solid Tumor Oncology and Investigational TherapeuticsDonald S. Kim Distinguished Chair for Cancer ResearchLevine Cancer InstituteAtrium HealthCharlotte, North CarolinaLeora Horn, MD, MSc, FRCPCIngram Associate Professor of Cancer ResearchDirector, Thoracic Oncology Research ProgramAssistant Vice Chairman for Faculty DevelopmentVanderbilt Ingram Cancer CenterNashville, TennesseeContent based on an online CME program supported by an educational grant from Lilly.Link to full program, including associated downloadable slidesets: https://bit.ly/3a3e1Xs

Host: Paul P. Doghramji, MD, FAAFP Guest: Edward S. Kim, MD Thanks to recent research, we can now use a non-small cell cancer patient’s cancer type and genomic makeup to create targeted treatment plans. Joining Dr. Paul Doghramji to share what that approach looks like in practice is Dr. Edward Kim, the Chair of Solid Tumor Oncology and Investigational Therapeutics at the Levine Cancer Institute Atrium Health in Charlotte, North Carolina.

Host: Paul P. Doghramji, MD, FAAFP Guest: Edward S. Kim, MD Thanks to recent research, we can now use a non-small cell cancer patient’s cancer type and genomic makeup to create targeted treatment plans. Joining Dr. Paul Doghramji to share what that approach looks like in practice is Dr. Edward Kim, the Chair of Solid Tumor Oncology and Investigational Therapeutics at the Levine Cancer Institute Atrium Health in Charlotte, North Carolina.

Go online to PeerView.com/RKN860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. The recent validation of poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors in ovarian and breast cancer management and the emergence of early clinical data in prostate and pancreatic cancers promises a new era in targeted therapy, particularly in the subset of cancer patients harboring DNA-damage response (DDR) pathway mutations. In this 3-part activity, Robert Coleman, MD, Maha H.A. Hussain, MD, FACP, FASCO, and Mark E. Robson, MD discuss the rationale for targeting DDR pathways in cancer therapy and review recent safety and efficacy evidence with PARP inhibitors in patients with a range of solid tumor types. They also highlight companion diagnostics that can be used to identify patients across different cancers who might benefit from PARP inhibitor therapy and outline how these new regimens can be integrated into existing treatment paradigms. Upon completion of this activity, participants will be able to: Discuss DNA damage repair (DDR) pathways and the rationale for targeting DDR mutations with PARP inhibitors in cancer therapy, Assess the evidence on the safety and efficacy of PARP inhibitors across tumor types such as ovarian, breast, prostate, and pancreatic cancers, Describe the role of validated and emerging companion diagnostic assays to identify patient populations with different molecular subtypes across a range of cancers that might benefit with PARP inhibitor therapy, Integrate PARP inhibitors or novel therapeutic agents targeting DDR mutations into treatment plans for patients with cancer based on approved indications or in the context of clinical trials

Go online to PeerView.com/RKN860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. The recent validation of poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors in ovarian and breast cancer management and the emergence of early clinical data in prostate and pancreatic cancers promises a new era in targeted therapy, particularly in the subset of cancer patients harboring DNA-damage response (DDR) pathway mutations. In this 3-part activity, Robert Coleman, MD, Maha H.A. Hussain, MD, FACP, FASCO, and Mark E. Robson, MD discuss the rationale for targeting DDR pathways in cancer therapy and review recent safety and efficacy evidence with PARP inhibitors in patients with a range of solid tumor types. They also highlight companion diagnostics that can be used to identify patients across different cancers who might benefit from PARP inhibitor therapy and outline how these new regimens can be integrated into existing treatment paradigms. Upon completion of this activity, participants will be able to: Discuss DNA damage repair (DDR) pathways and the rationale for targeting DDR mutations with PARP inhibitors in cancer therapy, Assess the evidence on the safety and efficacy of PARP inhibitors across tumor types such as ovarian, breast, prostate, and pancreatic cancers, Describe the role of validated and emerging companion diagnostic assays to identify patient populations with different molecular subtypes across a range of cancers that might benefit with PARP inhibitor therapy, Integrate PARP inhibitors or novel therapeutic agents targeting DDR mutations into treatment plans for patients with cancer based on approved indications or in the context of clinical trials

Go online to PeerView.com/RKN860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. The recent validation of poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors in ovarian and breast cancer management and the emergence of early clinical data in prostate and pancreatic cancers promises a new era in targeted therapy, particularly in the subset of cancer patients harboring DNA-damage response (DDR) pathway mutations. In this 3-part activity, Robert Coleman, MD, Maha H.A. Hussain, MD, FACP, FASCO, and Mark E. Robson, MD discuss the rationale for targeting DDR pathways in cancer therapy and review recent safety and efficacy evidence with PARP inhibitors in patients with a range of solid tumor types. They also highlight companion diagnostics that can be used to identify patients across different cancers who might benefit from PARP inhibitor therapy and outline how these new regimens can be integrated into existing treatment paradigms. Upon completion of this activity, participants will be able to: Discuss DNA damage repair (DDR) pathways and the rationale for targeting DDR mutations with PARP inhibitors in cancer therapy, Assess the evidence on the safety and efficacy of PARP inhibitors across tumor types such as ovarian, breast, prostate, and pancreatic cancers, Describe the role of validated and emerging companion diagnostic assays to identify patient populations with different molecular subtypes across a range of cancers that might benefit with PARP inhibitor therapy, Integrate PARP inhibitors or novel therapeutic agents targeting DDR mutations into treatment plans for patients with cancer based on approved indications or in the context of clinical trials

Go online to PeerView.com/RKN860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. The recent validation of poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors in ovarian and breast cancer management and the emergence of early clinical data in prostate and pancreatic cancers promises a new era in targeted therapy, particularly in the subset of cancer patients harboring DNA-damage response (DDR) pathway mutations. In this 3-part activity, Robert Coleman, MD, Maha H.A. Hussain, MD, FACP, FASCO, and Mark E. Robson, MD discuss the rationale for targeting DDR pathways in cancer therapy and review recent safety and efficacy evidence with PARP inhibitors in patients with a range of solid tumor types. They also highlight companion diagnostics that can be used to identify patients across different cancers who might benefit from PARP inhibitor therapy and outline how these new regimens can be integrated into existing treatment paradigms. Upon completion of this activity, participants will be able to: Discuss DNA damage repair (DDR) pathways and the rationale for targeting DDR mutations with PARP inhibitors in cancer therapy, Assess the evidence on the safety and efficacy of PARP inhibitors across tumor types such as ovarian, breast, prostate, and pancreatic cancers, Describe the role of validated and emerging companion diagnostic assays to identify patient populations with different molecular subtypes across a range of cancers that might benefit with PARP inhibitor therapy, Integrate PARP inhibitors or novel therapeutic agents targeting DDR mutations into treatment plans for patients with cancer based on approved indications or in the context of clinical trials

Go online to PeerView.com/RKN860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. The recent validation of poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors in ovarian and breast cancer management and the emergence of early clinical data in prostate and pancreatic cancers promises a new era in targeted therapy, particularly in the subset of cancer patients harboring DNA-damage response (DDR) pathway mutations. In this 3-part activity, Robert Coleman, MD, Maha H.A. Hussain, MD, FACP, FASCO, and Mark E. Robson, MD discuss the rationale for targeting DDR pathways in cancer therapy and review recent safety and efficacy evidence with PARP inhibitors in patients with a range of solid tumor types. They also highlight companion diagnostics that can be used to identify patients across different cancers who might benefit from PARP inhibitor therapy and outline how these new regimens can be integrated into existing treatment paradigms. Upon completion of this activity, participants will be able to: Discuss DNA damage repair (DDR) pathways and the rationale for targeting DDR mutations with PARP inhibitors in cancer therapy, Assess the evidence on the safety and efficacy of PARP inhibitors across tumor types such as ovarian, breast, prostate, and pancreatic cancers, Describe the role of validated and emerging companion diagnostic assays to identify patient populations with different molecular subtypes across a range of cancers that might benefit with PARP inhibitor therapy, Integrate PARP inhibitors or novel therapeutic agents targeting DDR mutations into treatment plans for patients with cancer based on approved indications or in the context of clinical trials

Go online to PeerView.com/RKN860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. The recent validation of poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors in ovarian and breast cancer management and the emergence of early clinical data in prostate and pancreatic cancers promises a new era in targeted therapy, particularly in the subset of cancer patients harboring DNA-damage response (DDR) pathway mutations. In this 3-part activity, Robert Coleman, MD, Maha H.A. Hussain, MD, FACP, FASCO, and Mark E. Robson, MD discuss the rationale for targeting DDR pathways in cancer therapy and review recent safety and efficacy evidence with PARP inhibitors in patients with a range of solid tumor types. They also highlight companion diagnostics that can be used to identify patients across different cancers who might benefit from PARP inhibitor therapy and outline how these new regimens can be integrated into existing treatment paradigms. Upon completion of this activity, participants will be able to: Discuss DNA damage repair (DDR) pathways and the rationale for targeting DDR mutations with PARP inhibitors in cancer therapy, Assess the evidence on the safety and efficacy of PARP inhibitors across tumor types such as ovarian, breast, prostate, and pancreatic cancers, Describe the role of validated and emerging companion diagnostic assays to identify patient populations with different molecular subtypes across a range of cancers that might benefit with PARP inhibitor therapy, Integrate PARP inhibitors or novel therapeutic agents targeting DDR mutations into treatment plans for patients with cancer based on approved indications or in the context of clinical trials

Go online to PeerView.com/RKN860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. The recent validation of poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors in ovarian and breast cancer management and the emergence of early clinical data in prostate and pancreatic cancers promises a new era in targeted therapy, particularly in the subset of cancer patients harboring DNA-damage response (DDR) pathway mutations. In this 3-part activity, Robert Coleman, MD, Maha H.A. Hussain, MD, FACP, FASCO, and Mark E. Robson, MD discuss the rationale for targeting DDR pathways in cancer therapy and review recent safety and efficacy evidence with PARP inhibitors in patients with a range of solid tumor types. They also highlight companion diagnostics that can be used to identify patients across different cancers who might benefit from PARP inhibitor therapy and outline how these new regimens can be integrated into existing treatment paradigms. Upon completion of this activity, participants will be able to: Discuss DNA damage repair (DDR) pathways and the rationale for targeting DDR mutations with PARP inhibitors in cancer therapy, Assess the evidence on the safety and efficacy of PARP inhibitors across tumor types such as ovarian, breast, prostate, and pancreatic cancers, Describe the role of validated and emerging companion diagnostic assays to identify patient populations with different molecular subtypes across a range of cancers that might benefit with PARP inhibitor therapy, Integrate PARP inhibitors or novel therapeutic agents targeting DDR mutations into treatment plans for patients with cancer based on approved indications or in the context of clinical trials

Go online to PeerView.com/RKN860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. The recent validation of poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors in ovarian and breast cancer management and the emergence of early clinical data in prostate and pancreatic cancers promises a new era in targeted therapy, particularly in the subset of cancer patients harboring DNA-damage response (DDR) pathway mutations. In this 3-part activity, Robert Coleman, MD, Maha H.A. Hussain, MD, FACP, FASCO, and Mark E. Robson, MD discuss the rationale for targeting DDR pathways in cancer therapy and review recent safety and efficacy evidence with PARP inhibitors in patients with a range of solid tumor types. They also highlight companion diagnostics that can be used to identify patients across different cancers who might benefit from PARP inhibitor therapy and outline how these new regimens can be integrated into existing treatment paradigms. Upon completion of this activity, participants will be able to: Discuss DNA damage repair (DDR) pathways and the rationale for targeting DDR mutations with PARP inhibitors in cancer therapy, Assess the evidence on the safety and efficacy of PARP inhibitors across tumor types such as ovarian, breast, prostate, and pancreatic cancers, Describe the role of validated and emerging companion diagnostic assays to identify patient populations with different molecular subtypes across a range of cancers that might benefit with PARP inhibitor therapy, Integrate PARP inhibitors or novel therapeutic agents targeting DDR mutations into treatment plans for patients with cancer based on approved indications or in the context of clinical trials

Meet Dr. Kim, a Midwesterner, who's found himself in Charlotte with Levine Cancer Institute.  This Chair of Solid Tumor Oncology is not only creating Clinical Pathways but also Dancing with the Stars.  

Episode 43 features perspectives from Atrium Health teammates who attended the 10th anniversary Health Datapalooza conference on March 27-28 in Washington, DC. Hosted by AcademyHealth, Health Datapalooza brings together a diverse group of healthcare leaders, policymakers, entrepreneurs, and data analysts to discuss collaboration opportunities at the intersection of policy, data, and innovation. A sponsor at this year's event, Atrium Health also sponsored the attendance of several Charlotte-area patients who were able to contribute their insights to the national conversation on how to harness the power of data to improve the health of our country. Our very own Dr. Rasu Shrestha, EVP and Chief Strategy Officer, kicks off our interviews. You'll also hear some new voices, including Dr. Ed Kim, Chair of the Department of Solid Tumor Oncology at Levine Cancer Institute; Jason Schneider, Senior Director of Corporate Communications; and Allyson Cochran, Senior Clinical Data Manager for the Carolinas Center for Surgical Outcomes Science. Tune in and . . . #pinksocks! @hdpalooza @AcademyHealth @RasuShrestha @AtriumHealth @LevineCancer @EdKimMDLCI ‏ @theNCI @CancerResrch @ASCO@JSchneide12 Atrium Health Datapalooza site. Learn about the Pink Socks movement.  - A Sherpa's Guide to Innovation is a proud member of the Health Podcast Network @HealthPodNet -Support the show

ASCO: You’re listening to a podcast from Cancer.Net. This cancer information website is produced by the American Society of Clinical Oncology, known as ASCO, the world’s leading professional organization for doctors who care for people with cancer. 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. Cancer research discussed in this podcast is ongoing, so the data described here may change as research progresses. In this podcast, Cancer.Net Editorial Board members Dr. Brian Rini and Dr. Jorge Garcia discuss new research in kidney and prostate cancer presented at the European Society for Medical Oncology 2018 Congress, held October nineteenth through twenty-third in Munich, Germany. Dr. Rini is a Professor of Medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University. Dr. Garcia is an Assistant Professor of Medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University. They are both also staff members of the Department of Solid Tumor Oncology at Cleveland Clinic Taussig Cancer Institute. ASCO would like to thank Dr. Rini and Dr. Garcia for discussing this research. Dr. Rini: Hello. This is Brian Rini from the Cleveland Clinic Taussig Cancer Center. I'm a professor of medicine and lead the GU program here at Cleveland Clinic, and I'm joined by my friend and colleague Dr. Jorge Garcia. Dr. Garcia: Thank you, Brian. I'm Jorge Garcia. I'm a GU medical oncologist at the Cleveland Clinic as well. Dr. Rini: And we're going to talk to you today about highlights in genitourinary or GU cancers from the European Society of Medical Oncology Meeting, which took place a couple of months ago in Munich, Germany. It's one of the major cancer meetings, with a lot of big data starting to be presented at that meeting in addition to the main ASCO meeting and other meetings. And I'm going to start off by talking about a couple of the highlights in renal cancer, and then Dr. Garcia will describe a couple of the highlights in prostate cancer. In kidney cancer, generally speaking, it's been a pretty exciting time. So about 10 or 15 years ago we went through a wave where VEGF-targeted therapy or therapy targeted against blood vessel sort of became the standard of care. And this was exciting because, frankly, at the time there wasn't much else that was available for patients with metastatic kidney cancer. And that's really been the foundation of how we've treated this disease over the last decade or so. More recently, we've started to use immune stimulating agents, commonly called immunotherapy or IO therapy, as is being used across many, many malignancies, but especially in kidney cancer. And so now we have 2 ways that we treat metastatic kidney cancer. We still use therapy targeted against blood vessels, also called VEGF-targeted therapy, and now we're increasingly using immune therapies. And the most recent efforts at this have actually combined these different modalities. And so probably the largest data that was presented was something called the JAVELIN 101 trial. So this was a randomized phase III trial that compared patients with metastatic kidney cancer who had not gotten any prior treatment to receive either sunitinib, which is a VEGF-targeted agent that's been our standard of care, again, for the last 10 or 15 years, or a combination of axitinib, which is another VEGF-targeted therapy, plus avelumab. And avelumab is 1 of a class of drugs that I mentioned that are immunotherapeutics. We also call them checkpoint inhibitors because of the mechanism by which they work. And there are many of these combination studies that are starting to be reported. A couple have been reported, this is the third, and there will be more to come over the next 6 to 12 months. It's really transforming the way that kidney cancer patients are treated when they walk in the door. So as mentioned, this was a large phase III trial. And the rationale is really that it's 2 different ways to attack the cancer, both attacking blood vessels and trying to stimulate the immune system. About 900 patients were treated on this trial, so about 450 patients treated with either sunitinib or this combination therapy. And what was shown was that, the—what we call—progression-free survival, which I usually describe to patients as how long we can control tumors, was significantly greater with the combination therapy. It was almost 14 months, which is, I believe one of the highest ever reported in this disease, compared to only 7 months with sunitinib. So there was a significant advantage in terms of disease control, which was the primary end point of this trial. What was also looked at is response rate. So when we talk about response, it's really patients who have a significant amount of tumor shrinking on a scan. And what was seen in the overall population who received the combination therapy was that just over half the patients, 51%, had an objective response. And most people had some degree of tumors getting smaller. If tumors get just a little bit smaller we don't necessarily call that a response. If they get at least 30% smaller, that's our threshold for a response. So over half the patients reached that threshold, which is again a very high number compared to usually about 30 or 40 percent with the single-agent anti-blood vessel drugs. And importantly, 3% of patients had a complete response. One of the great things that immunotherapy has done in kidney cancer is change our mindset a little bit from really just trying to control disease to now recognizing that there's a subset of patients who can be cured with this disease. And that really hasn't been true on any large scale ever really, certainly in the time that I've been doing it. And so these new regimens are not only controlling disease longer, but leading to more potential cures of disease. The cure part, obviously, we need more time to pass. We need to follow patients, etc., but I think certainly the possibility is there. They reported on overall survival results, although, the data was what we call relatively immature, meaning—which is a good thing—that most patients were still alive who had received either regimen. So we can't quite yet say for this regimen that it makes patients live longer, on average, but certainly has benefits in terms of tumor shrinkage and disease control. And with more time, other data will come. Interestingly, there was also a very similar study involving a combination with axitinib and pembrolizumab. That data was not presented at the meeting, but there was a press release that happened to come out on the first day of the meeting showing that it also had effects in terms of tumor shrinkage and disease control, and interestingly, also showed a survival benefit. So one of the things we'll sort out over the next year or so is the relative merits of each of these regimens. They're certainly not identical. They'll have different side effect profiles, different ways that they help patients, different patients in whom they might help, etc. So the good news is that there are a number of these regimens that are likely to get approved over the next 6 to 12 months, and then comes the next wave of work of trying to figure out how best to apply them to patients, but this is certainly very exciting data. It was the first combination regimen that included a drug like axitinib, that included a pill that inhibits blood vessels. The other main piece of data that I wanted to go over, I had the privilege of presenting there, which was from a different trial than I just presented, but a similar one. So it was a trial called IMmotion151. And what that trial did was take patients with kidney cancer that had not yet been treated. It randomized them to either sunitinib, as I mentioned, a standard therapy, or to another combination of an immune agent in an anti-blood vessel agent. The names of these drugs were atezolizumab and bevacizumab. It's a regimen that's shown effects in lung cancer and some other cancers. And the clinical data from this study had been presented at the GU Symposium early in 2018. And what we presented at ESMO was some of the correlates from the study. Some of the secondary scientific analyses that often happen in these large clinical trials. And the details of how these analyses are done are a bit complicated but suffice it to say that if we look at patient's tumors, we can look at the expression of genes from these tumors. And different tumors have different biology. They express different genes. And one of the stories that's emerged from analysis of the samples from this trial and also a small prior trial was that some patients have tumors that are very rich in blood vessels and that are very reliant on angiogenesis, and other patients have tumors that are very reliant on T cells and on the immune system effects, and obviously some patients have both of those types of tumor cells in an individual tumor. And so the data are really starting to show this trend that there's different biologic subtypes of kidney cancer. And anybody who treats patients knows this. We give a group of patients the same drug, and some people respond wonderfully, and unfortunately, others don't, and everywhere in between. And it just means the underlying tumors are different. And these large data sets and large analyses are now starting to sort that out and say, "We now have a genetic basis for those clinical differences that we observe in patients." I think it's important because it's a first step, hopefully, towards individualizing therapy and not just treating everybody with the same combination. Treating certain patients with one drug, certain patients with another drug, other patients with a combination. And as I mentioned before, there are many of these combinations coming out, so it would be nice to have a test that would allow us to choose the best combination for the best patient. We're not there yet. We're, I would say unfortunately, a little ways from that point. But these data were presented at ESMO, I think, started to take that step by characterizing tumors. And then the last thing I'll mention is something called sarcomatoid tumors. So the word sarcomatoid is applied in kidney cancer to a subset of about 10 or 15, maybe 20% of tumors that are generally more aggressive. The cells under the microscope are spindle shape. That's what the word sarcomatoid means. And they've always been very difficult to treat. It looks like, however, with these immune therapies that that patient population is particularly susceptible, so they actually do better with immune therapies. And when these genetic signatures were applied to specifically those tumors, not surprisingly, they had a very—what we'd say—an immune rich environment. They were characterized by expression of genes that are relevant to the immune system. So again, it provides a biologic basis for some of the clinical observations that we've made for years, and hopefully, makes us smarter. And I think the immune therapies are certainly going to be of benefit to patients with sarcomatoid kidney cancer, I think that much is clear, and some of the clinical data has pointed towards that. And the ESMO data really provides, again, a biologic basis. Just to summarize kidney cancer from ESMO 2018, one phase III trial presented the JAVELIN 101 with axitinib plus avelumab showing advantages over sunitinib, and then some interesting biologic data. And certainly, more to come with these combos moving forward. I'll ask Dr. Garcia now if he has any comments on the kidney cancer data that I mentioned and then I'll have him describe the prostate update. Dr. Garcia: Thank you, Brian. I think that's an excellent overview of that exciting data. Perhaps my only comment is that the lack of biomarkers can indeed put a lot of pressure on how we select patients and select therapy for those patients with metastatic renal cell carcinoma. And I think that with the JAVELIN trial and 2 or 3 trials also coming very soon into the space, I think that we clinicians are going to be faced with the challenge of deciding between dual immune-oncology approaches or doing it in a sequential manner. And, for that matter, also perhaps looking at the combination of vascular disrupting agents plus immunotherapy. Clearly, we need to actually look at clinical features of patient disease to make those treatment decisions because we haven't been able to pin down biomarkers that can help us guide which is the best approach for those patients up front. Dr. Rini: Yeah, I agree. It's a good problem to have that we have so many active drugs, and we're trying to decide which ones to give which patients, but it's going to be a big challenge moving forward. Dr. Garcia: Great. So let me move now and briefly review what I think is probably the 2 or 3 most exciting reports out of ESMO, in Munich, in prostate cancer. So similar to what Brian mentioned, obviously, there has been a lot of movement into how we manage patients with advanced prostate cancer. I think that the last 3 years have changed how we practice and how we manage patients who are walking in the office with metastatic prostate cancer. That is, patients who either have had their primary tumor resected or have had radiation therapy for primary definitive treatment and over time they will go on and progress and develop systemic disease, or patients who never had their chance to have their prostate treated with either surgery or radiation therapy. The latter group is uncommon because of PSA screening, at least in North America. And we see about 20, perhaps, 30 percent of patients walking in the office with metastatic disease. So just as a way of background, the standard of care for men with advanced disease for the last 3 or 4 decades has been suppression of testosterone, so-called castration, which is removal of testosterone either medically and/or by surgical orchiectomy. Most of us in the United States just do medical suppression with what we call hormonal therapy, which is basically injections received at various intervals to suppress the function between the pituitary access and the testicles so patients are suppressed with their testosterone. Therefore, the disease gets controlled. Traditionally, all patients, the longer they live suppressed from testosterone, the more likely for them to develop resistance to that approach. And traditionally what we have done when that happens is you talk about chemotherapy. You talk about some of the novel oral agents that are able to inhibit signals within prostate cancer cells that allow growth or signals or hormones in our body that we make specifically in the renal glands. With agents such as abiraterone acetate, there are agents capable of suppressing testosterone and production of hormones, then can also activate the signaling within prostate cancer growth. So we now divide patients into 2 main groups when they walk in the office with metastatic disease, what we'll call high volume and low volume. And that definition has been actually processed through the American data called charter data. Patients with high volume disease, specifically speaking, visceral metastases, which is uncommon in prostate cancer—that means lung disease or liver disease—or men with more than 4 metastases in bone, one of which has to be outside the spine and/or the pelvic region, receive hormones and chemotherapy. And clearly, adding docetaxel-based chemotherapy to these men drastically improves their outcome. The French last year in 2017 presented the data of a trial called LATITUDE, which is a trial that looked at the utilization of oral therapy up front in combination with testosterone suppression. In this case, they used abiraterone acetate. And that trial also specifically was aimed for patients with metastatic disease with high volume features. Although, their definition for high volume disease was a bit different than the American definition, that didn't include visceral disease and the presence of bone metastases, but they did include a Gleason score of 8, 9, and 10, which reflects the biology of the tumors of these patients. And in that trial also it was demonstrated that patients who received the combination of abiraterone acetate and suppression of testosterone have a drastic improvement in outcome. We often times tell our patients that with ADT or hormonal suppression and abiraterone we can decrease their risk of dying from prostate cancer by almost 40%. With the LATITUDE and the charter data from America, we now have a standard of care of either using chemotherapy and/or abiraterone for this patient population, but we didn't have a good sense as to what to do for patients with low volume disease. Throughout this time, the British also helped us a little bit with supporting the role of chemotherapy in our patients. The British did a trial called STAMPEDE. It's a very complex trial statistically speaking, but it's a trial that basically takes a significant number of patients with metastatic disease, and basically, you have a backbone of a treatment, in this case, suppression of testosterone or androgen deprivation therapy, and you add newer treatments over time. And it allows you the flexibility of removing treatments that are not performing or adding new treatments that are becoming part of what we use for our patients. This trial actually demonstrated a couple of years ago that the addition of docetaxel-based chemotherapy for patients with metastatic disease made people live longer—specifically, reducing the risk of mortality from their disease—and therefore, solidified the role of docetaxel similar to what we did in the American data. They also included an arm that included abiraterone, and that data also presented last year demonstrated significant survival improvement for those patients with metastatic disease. So now the biggest question was, what do you offer patients with low volume metastases? So their data didn't actually stratify patients by volume of disease, and this is what actually was presented at ESMO this year. And I think the nutshell of this is quite simple. Patients with low-volume disease and/or high volume disease—whether you use the French definition or the American definition—regardless of volume the addition of abiraterone to patients with metastatic disease drastically improves outcome and reduces the relative risk of mortality when you do all therapy. So the standard of care for low volume patients now is suppressing testosterone and adding abiraterone acetate. Perhaps, what is more interesting of this data is they also had an arm within their trial looking at the addition of radiation therapy to a primary tumor for those men with metastatic disease who did not have a primary tumor treated—meaning, with radiation upfront or with surgery—and they walk in the office with metastatic disease. And they randomized those patients to the standard of care at the time, ADT, suppression of testosterone, and docetaxel, or the combination plus radiation therapy to the prostate tumor. And what we saw in that data, there was not a survival improvement when you take all comers. Meaning, the high and low volume patients. However, when you stratify by volume of disease—the low volume disease against high volume disease—it was clear then there is a significant survival improvement for those men with metastatic disease, with low volume disease, who went on to receive ADP, meaning suppression of testosterone, the addition of docetaxel-based chemotherapy, and radiation therapy to the prostate gland. There was almost a 20% difference at 3 years in survival with the hazard ratio, which is the risk reduction of mortality, of what we call 0.68, which is what we tell patients around almost a 30%, 32% risk reduction mortality when we get radiation therapy to a primary tumor. So what that does for our practice is that now if we see someone with low volume metastatic prostate cancer with their primary in place, the standard of care has become suppression of testosterone, the addition of abiraterone acetate, and primary radiation to the prostate tumor. Period. For high volume patients, I would argue the standard of care remains either suppression of testosterone, plus docetaxel-based chemotherapy or suppression of testosterone plus abiraterone. And I think most of us in practice are simply using the combination of oral therapy plus suppression of testosterone. Lastly, I know a very interesting and provocative trial is the trial that is called ERA 233 that looks at the combination of this particular agent, abiraterone acetate, and a radiopharmaceutical agent, also approved in men with advanced castration-resistant prostate cancer. Meaning, men who become resistant to a lack of testosterone and go on to develop progressive disease in the bones. So the rationale behind this combination was that both agents are life-prolonging agents. And since abiraterone can be used in the pre-chemotherapy space in that setting and Radium-223 as a radionuclide can also be used in that particular patient population, we thought that maybe combining a novel oral hormonal approach against a radionuclide-based approach could actually lead to a better improvement in outcome for our castration-resistant prostate cancer patients. So this trial looked at over 800 patients with castration-resistant disease who have never seen chemotherapy and randomized them to receive either the combination of abiraterone plus Radium-223 against abiraterone and a matching placebo. And the primary end point of this trial was, again, looking at survival along with a reduction in skeletal symptomatic events, which is how likely it is for you as a patient to develop symptoms from bony metastases, which is the most common site of metastases in men with prostate cancer. It specifically relates to the need for radiation therapy for pain control. Developing a fracture then requires orthopedic surgery, or developing a tumor in the spine that is pushing the spinal canal, possibly leading to neurologic symptoms. That was the primary end point of the trial. What we learned from this trial is that there was not really a drastic difference in outcome. Meaning, in the ability to delay the progression of disease. There was no difference in the survival between the 2 groups. Meaning, adding Radium-223 didn't improve outcome. What we did learn is that the combination of abiraterone and Radium-223, unfortunately, does increase the risk of this patient population for developing fractures. Specifically, either pathologic, which are fractures in sites where you have bony metastases or complications from areas of bony disease leading to a bone fracture. So that was a big issue because some clinicians are using the combination of abi and Radium-223, and since this trial I think most of now refrain from using this combination. I think it's important for our physicians to understand that this trial did not test the timing of using Radium-223 in castration-resistant disease. It only was aimed to test the combination of both agents. So I think Radium-223 remains a life-prolonging agent that should be offered to our patients with castration-resistant disease, to specifically the patient population for which this agent has been labeled for, but the combination with an oral agent such as abiraterone should actually not be used at this point. This trial and the results of this study changed the label of Radium-223 in the United States and also in the European region, and I think that it’s fair to say that most of us now refrain from using the combination with this oral agent. Whether or not this means that you can now combine Radium-223 with another oral agent, such as an AR inhibitor, remains to be seen. But clearly, with the significant increase in pathological fractures, almost a 16% difference for all patients in the combination arm, I think most of us would be concerned as to seeing patients developing complications from the combination. I don't think we really know the biology behind why this happened, but I think it's fair to say that the data is confident enough for us not to use in clinical practice. So just to summarize, I think the standard of care for prostate cancer now for low volume and high volume disease is using suppression of testosterone and the oral agent abiraterone acetate. For those patients with low volume disease who have their primary tumor in place, radiation therapy to the primary tumor is now the standard of care. The timing remains debatable. So I think most of us will treat patients with systemic therapy, and down the road at some given time we probably will include radiation oncologist to offer radiation therapy. And secondly, the use of the combination of Radium-223 and abiraterone acetate is not now something that one can support with the data from this new trial looking at the combination of those 2 agents. Brian, I don't know if you have any comments or thoughts? Dr. Rini: Sure. Yeah, I mean, as you can tell there's a lot going in prostate cancer as well. I think maybe just to broaden it, 1 of the areas that we're all thinking about is control of the primary tumor in patients whose disease has already spread. And so Dr. Garcia mentioned the data with radiating the primary tumor in a subset of patients, especially in patients with low volume, sometimes called oligometastatic disease. There are studies that are ongoing that are looking at that. Can we treat those patients more aggressively by either radiating or surgically removing their primary, surgically removing lymph nodes, even radiating metastatic site? Hopefully, the window for cure for some prostate cancer patients has expanded to include some of those low volume patients. But I think there's a lot of work to be done because I think there are patients who may not benefit from that, and I think some of these ongoing trials will help to define that. But that's a totally different concept than we had thought about for advanced prostate cancer really. Certainly, in our time that we've been doing this. So I'd like to thank Dr. Garcia for that excellent summary. Thank you for tuning into this podcast. As you can tell, in GU cancers—and we've really just given you a small slice of what went on at one meeting—but there's a lot of important studies going on. A lot of important data that's coming out of large phase III trials that are changing the standard of care and changing it for the better as we continue to move forward in clinical research. Thank you again for your attention. Dr. Garcia: Thank you, Brian. Thanks for the opportunity. ASCO: Thank you, Dr. Rini and Dr. Garcia. Learn more about genitourinary cancers at www.cancer.net. And if this podcast was useful, please take a minute to subscribe, rate, and review the show on Apple Podcasts or Google Play. Cancer.Net is supported by ASCO’s Conquer Cancer Foundation, which funds breakthrough research for every type of cancer, helping patients everywhere. To help fund Cancer.Net and programs like it, donate at conquer.org/support.

In the latest ASCO in Action Podcast, Dr. Edward Kim, Chair of the Department of Solid Tumor Oncology at the Levine Cancer Institute, joined ASCO CEO Dr. Clifford A. Hudis to discuss eligibility criteria for cancer clinical trials.

Pediatric Grand Rounds with Reto Baertsciger, MD, PhD

This podcast is part of a series for patients who have just been diagnosed with a specific genitourinary, or GU cancer. In this series, Dr. Charles Ryan, a medical oncologist and associate professor who specializes in the genitourinary tract at the UCSF Helen Diller Family Comprehensive Cancer Center, speaks with experts on specific GU cancers to shed light on what happens after an initial diagnosis.  Today’s guest is Dr. Brian Rini, an associate professor of medicine and a staff member in the Department of Solid Tumor Oncology at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University. Dr. Ryan and Dr. Rini discuss the decisions that doctors make when a patient is diagnosed with kidney cancer, including some of the factors that go into recommending certain treatment options. Cancer Basics