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Future of Genetic Testing and Treatment in Prostate Cancer

Panelists: Raoul S. Concepcion, MD, FACS, The Comprehensive Prostate Center; Jorge A. Garcia, MD, FACP, Taussig Cancer Institute; Alicia K. Morgans, MD, MPH, Vanderbilt University Medical Center; Ashley E. Ross, MD, PhD, Johns Hopkins Medical Institution; Daniel R. Saltzstein, MD, Urology San Antonio
Published: Wednesday, Mar 01, 2017


Transcript:

Raoul S. Concepcion, MD:
Dan, how do you think this is going to play out in the community urology world? They’re already having difficulty with genetic testing, who has better risk stratification on tissue. Now, you’re getting into this arena of genetic testing.

Daniel R. Saltzstein, MD: Right. It’s going to be very complicated in the urologic world, simply because you go back to the Pritchard data—4% local, 11% in metastatic. And then, the heavily pretreated guys in Mateo, most of those guys are already outside of our bailiwick. They’ve moved on to oncology. Now, again, we’re unique; we are going to do a PARP inhibitor trial. I’ve got an alliance with an oncologist in town, but they’re able to manage that patient’s side effect profile much better than a urologist is. But I’m not sure. We were also part of, and I’m going to bring up another trial, the Tokai trial for galeterone, and I have a feeling they’re going to have the same stumbling blocks. It’s going to take 100 patients to find 3 that actually qualify, and it depends on what stage they are in the progression of their prostate cancer. I think in San Antonio, we screened 15 for Tokai and found 0 that actually had the AR-V7 mutation. I have a feeling that PARP inhibitors are going to struggle in that same regard.

Jorge A. Garcia, MD: If I may, I think your point is well taken. The difference with the Tokai trial, the galeterone trial, is that we were looking for a splice variant, looking at CTCs. And, unfortunately, not every patient with metastatic CRPC has circulating tumor cells, whereas this is going to be a germline change, for the most part, or a somatic change that you may be able to capture in the tumor. But it’s still very restrictive, I agree with you.

Ashley E. Ross, MD, PhD: I think where it’s really going is two-fold. One, more than doing germline analysis, we have to start getting more and more used to biopsying the tumors at this stage, because beyond just looking at, like, DNA breaker permutations, there are some interesting data on mutational load and possible sensitization to PD-1 for mismatch things. And I think that the second point along those lines is that for the PARP inhibitors and maybe for some other drugs, too, it may be exactly what you guys are saying. Because it’s a salvage pathway, you may really need to have seen all the other therapies so that the regulation of repair in the cells is so dependent on the PARP action, that now you’re going to see that therapeutic index.

Raoul S. Concepcion, MD: As always, this is always a pleasure to have you guys and moderate these sessions. I think this has been extremely informative. Before we end the discussion, I’d like to get final thoughts from all of you upon our discussions today. Jorge, I’m going to start with you.

Jorge A. Garcia, MD: Thanks for the opportunity to be with you guys. It has been a great time. So, I think patient selection, understanding the appropriate sequence of therapy, and trying to understand mechanisms of resistance are, for me, the 3 peak clinical issues that we’re facing at this time. I’m not sure that tumor genomics are going to pan out to be as hot as people feel that they’re going to be, and I certainly don’t believe the immuno-oncology (I-O) agents are going to stick with us for a long time. The vast majority of patients on these I-Os do not respond to I-Os, and it’s no different than many other solid tumors. Developing a better biomarker that we can utilize to predict response and perhaps even outcome is key and fundamental in what we’re doing in prostate cancer. But I think that understanding mechanisms of resistance and how people evolve through therapies is probably one of the challenges that we’re facing right now because not every patient can get a biopsy. And getting biopsies in prostate cancer patients is very, very challenging, not speaking about even intratumoral heterogeneity.

I think that in the next 3 to 5 years to come, I predict that we’re going to continue to see an AR-driven therapy. I think we’re going to be able to understand mechanisms of resistance better, how we move patients and intertwine those treatments that we have. And I would argue, stay tuned for genomics because they are to stay but, still, there’s a lot of work that we have to do to be able to overcome those challenges that we’re faced with in regards to infrastructure and understand what is actionable and what is not.

Raoul S. Concepcion, MD: Great. Dan?

Daniel R. Saltzstein, MD: Thanks, Raoul, for inviting me also today. I’m going to echo a lot of what Jorge said in that I think we’re in an exciting time, that we’re hopefully going to be able to do this personalized medicine and compendium diagnostics, and that we’re going to have some new information. Whether it’s with some of the biomarkers, AR-V7 or BRCA2, we’re going to be able to treat patients more appropriately versus what we’ve done in the past, which is more of a shotgun method of how to take care of these folks. So, it’s a very exciting time to be in the urologic oncology world.

Raoul S. Concepcion, MD: Great. Alicia?

Alicia K. Morgans, MD, MPH: Thank you again, too. I would say that there are a couple of things I would want to emphasize. So, similarly to the precision medicine approach, I say that we should really emphasize a precision survivorship approach, too; understand who is going to be at risk for what complication and use that as we’re choosing our therapies wisely. We have a lot of choices. We are very lucky, but understanding treatment effects is not just effects on overall survival, it’s also what that patient is going to experience. And I would agree that genomics is here to stay, and rationally counseling our patients and their families on how to use that information is going to be critical as we move forward.

Raoul S. Concepcion, MD: Ash?

Ashley E. Ross, MD, PhD: Dr. Concepcion, thank you for having me, and thank you to the whole panel. I really had a great time discussing this. I think, again, genomics and genetics are going to get us there in the future. I’ve looked at it evolve in my young career, and I think the progression is going to be even faster. We’re going to move from having to do tumor biopsies to actually being able to get that data from the CTCs or something in the next 5, maybe 10 years. I also have some hope for immunotherapies in prostate cancer, but just like the other therapies that we’ve talked about that are here and we’re using now, combination therapeutic approaches are going to be key. And then, finally, where we talk about states where we want to limit toxicity are the M0 states and being very judicious about who you start on therapy. We also brought up, as a panel, that this is an ideal population where we may take patients that are possibly incurable, and with these new therapies, with combination approaches, possibly looking at them on trials, shifting them toward curability. If the providers are out there and really want to treat these patients with something, they should be looking at what trials are open and what can they open, if possible.

Raoul S. Concepcion, MD: So, again, thanks to everyone for your contributions to this discussion. On behalf of our panel, we thank you for joining us. We hope you found this Peer Exchange® discussion to be useful and informative.

Transcript Edited for Clarity
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Transcript:

Raoul S. Concepcion, MD:
Dan, how do you think this is going to play out in the community urology world? They’re already having difficulty with genetic testing, who has better risk stratification on tissue. Now, you’re getting into this arena of genetic testing.

Daniel R. Saltzstein, MD: Right. It’s going to be very complicated in the urologic world, simply because you go back to the Pritchard data—4% local, 11% in metastatic. And then, the heavily pretreated guys in Mateo, most of those guys are already outside of our bailiwick. They’ve moved on to oncology. Now, again, we’re unique; we are going to do a PARP inhibitor trial. I’ve got an alliance with an oncologist in town, but they’re able to manage that patient’s side effect profile much better than a urologist is. But I’m not sure. We were also part of, and I’m going to bring up another trial, the Tokai trial for galeterone, and I have a feeling they’re going to have the same stumbling blocks. It’s going to take 100 patients to find 3 that actually qualify, and it depends on what stage they are in the progression of their prostate cancer. I think in San Antonio, we screened 15 for Tokai and found 0 that actually had the AR-V7 mutation. I have a feeling that PARP inhibitors are going to struggle in that same regard.

Jorge A. Garcia, MD: If I may, I think your point is well taken. The difference with the Tokai trial, the galeterone trial, is that we were looking for a splice variant, looking at CTCs. And, unfortunately, not every patient with metastatic CRPC has circulating tumor cells, whereas this is going to be a germline change, for the most part, or a somatic change that you may be able to capture in the tumor. But it’s still very restrictive, I agree with you.

Ashley E. Ross, MD, PhD: I think where it’s really going is two-fold. One, more than doing germline analysis, we have to start getting more and more used to biopsying the tumors at this stage, because beyond just looking at, like, DNA breaker permutations, there are some interesting data on mutational load and possible sensitization to PD-1 for mismatch things. And I think that the second point along those lines is that for the PARP inhibitors and maybe for some other drugs, too, it may be exactly what you guys are saying. Because it’s a salvage pathway, you may really need to have seen all the other therapies so that the regulation of repair in the cells is so dependent on the PARP action, that now you’re going to see that therapeutic index.

Raoul S. Concepcion, MD: As always, this is always a pleasure to have you guys and moderate these sessions. I think this has been extremely informative. Before we end the discussion, I’d like to get final thoughts from all of you upon our discussions today. Jorge, I’m going to start with you.

Jorge A. Garcia, MD: Thanks for the opportunity to be with you guys. It has been a great time. So, I think patient selection, understanding the appropriate sequence of therapy, and trying to understand mechanisms of resistance are, for me, the 3 peak clinical issues that we’re facing at this time. I’m not sure that tumor genomics are going to pan out to be as hot as people feel that they’re going to be, and I certainly don’t believe the immuno-oncology (I-O) agents are going to stick with us for a long time. The vast majority of patients on these I-Os do not respond to I-Os, and it’s no different than many other solid tumors. Developing a better biomarker that we can utilize to predict response and perhaps even outcome is key and fundamental in what we’re doing in prostate cancer. But I think that understanding mechanisms of resistance and how people evolve through therapies is probably one of the challenges that we’re facing right now because not every patient can get a biopsy. And getting biopsies in prostate cancer patients is very, very challenging, not speaking about even intratumoral heterogeneity.

I think that in the next 3 to 5 years to come, I predict that we’re going to continue to see an AR-driven therapy. I think we’re going to be able to understand mechanisms of resistance better, how we move patients and intertwine those treatments that we have. And I would argue, stay tuned for genomics because they are to stay but, still, there’s a lot of work that we have to do to be able to overcome those challenges that we’re faced with in regards to infrastructure and understand what is actionable and what is not.

Raoul S. Concepcion, MD: Great. Dan?

Daniel R. Saltzstein, MD: Thanks, Raoul, for inviting me also today. I’m going to echo a lot of what Jorge said in that I think we’re in an exciting time, that we’re hopefully going to be able to do this personalized medicine and compendium diagnostics, and that we’re going to have some new information. Whether it’s with some of the biomarkers, AR-V7 or BRCA2, we’re going to be able to treat patients more appropriately versus what we’ve done in the past, which is more of a shotgun method of how to take care of these folks. So, it’s a very exciting time to be in the urologic oncology world.

Raoul S. Concepcion, MD: Great. Alicia?

Alicia K. Morgans, MD, MPH: Thank you again, too. I would say that there are a couple of things I would want to emphasize. So, similarly to the precision medicine approach, I say that we should really emphasize a precision survivorship approach, too; understand who is going to be at risk for what complication and use that as we’re choosing our therapies wisely. We have a lot of choices. We are very lucky, but understanding treatment effects is not just effects on overall survival, it’s also what that patient is going to experience. And I would agree that genomics is here to stay, and rationally counseling our patients and their families on how to use that information is going to be critical as we move forward.

Raoul S. Concepcion, MD: Ash?

Ashley E. Ross, MD, PhD: Dr. Concepcion, thank you for having me, and thank you to the whole panel. I really had a great time discussing this. I think, again, genomics and genetics are going to get us there in the future. I’ve looked at it evolve in my young career, and I think the progression is going to be even faster. We’re going to move from having to do tumor biopsies to actually being able to get that data from the CTCs or something in the next 5, maybe 10 years. I also have some hope for immunotherapies in prostate cancer, but just like the other therapies that we’ve talked about that are here and we’re using now, combination therapeutic approaches are going to be key. And then, finally, where we talk about states where we want to limit toxicity are the M0 states and being very judicious about who you start on therapy. We also brought up, as a panel, that this is an ideal population where we may take patients that are possibly incurable, and with these new therapies, with combination approaches, possibly looking at them on trials, shifting them toward curability. If the providers are out there and really want to treat these patients with something, they should be looking at what trials are open and what can they open, if possible.

Raoul S. Concepcion, MD: So, again, thanks to everyone for your contributions to this discussion. On behalf of our panel, we thank you for joining us. We hope you found this Peer Exchange® discussion to be useful and informative.

Transcript Edited for Clarity
View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Community Practice Connections™: Personalized Sequencing in Castration-Resistant Prostate Cancer: Bridging the Latest Evidence to the Bedside in Clinical ManagementAug 25, 20181.5
Community Practice Connections™: Precision Medicine for Community Oncologists: Assessing the Role of Tumor-Testing Technologies in Cancer CareNov 30, 20181.0
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