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Potential Predictive Markers in Prostate Cancer

Panelists:Raoul S. Concepcion, MD, FACS, Urology Associates; Michael S. Cookson, MD, MMHC, University of Oklahoma Health Sciences Center; Daniel P. Petrylak, MD, Yale School of Medicine; Daniel I. Quinn, MBBS, PhD, FRACP, FACP, University of Southern California; Neal D. Shore, MD, FACS, Carolina Urologic Research Center; Charles J. Ryan, MD, UCSF Helen Diller Family Comprehensive Cancer Center
Published: Monday, Jul 11, 2016


Transcript:

Raoul S. Concepcion, MD:
Mike, as part of your managing of these patients, should we be pushing more for biopsying of the metastatic site even if it is bone, which is obviously quite difficult, and/or soft tissue?

Michael S. Cookson, MD, MMHC: Well, until we have those tools available and they’re proven, it’s kind of hard to recommend a biopsy anywhere in the USA. If you do have a tool and it’s proven to be effective, it makes complete sense. I think one of the things that I’m really impressed with though, if you remember in 2004 where Dan’s SWOG study led to Taxotere approval, and the TAX-327 study. There was a 3-month survival advantage that started the whole ball rolling. And altered the history of all that we knew about ways to control advanced prostate cancer. That was the first chemotherapeutic agent that actually moved the needle to 3 months. Then, look at the CHAARTED, STAMPEDE, and even the French study. There is a 1-year survival advantage and in high-risk people there is 16, 18 months survival advantage, moving the chemotherapy back to an earlier stage in their disease process. We don’t know the results of the non-metastatic, high-risk local disease. But it seems like when we move these therapies back, you get a better response. In the absence of a perfect way to the Holy Grail, personalize their therapy, know whether it’s androgen access, and whether it’s systemic therapy and which systemic therapy. I think treating them aggressively early on is probably going to be in our best interest in somebody like this. I don’t know that we need to wait very long for the metastases to become apparent.

Raoul S. Concepcion, MD: Clearly, the other thing that we completely lack is any availability of reproducible predictive markers to try to determine therapy. We have so many new drugs, but they’re mechanistically different. David, you looked at this. Where do we stand with some of the development of such liquid markers?

David I. Quinn, MBBS, PhD: I think the thing that’s come to the forefront is the circulating tumor cell assay of androgen receptor variant 7 (AR-V7). This has been led predominantly out of Johns Hopkins but also we have some good data from MD Anderson. If you manifest AR-V7 in the circulating tumor cells—which is a mutational change of the ligand-binding domain of the androgen receptor where dihydrotestosterone and other androgens plug in, and where the androgen receptor blockers plug in—then you’re going to be very likely resistant to androgen receptor blockers like enzalutamide and also interestingly to the androgen biosynthesis inhibitors like abiraterone. It’s not a universal marker of resistance, because we’re measuring it in the blood. When patients are on enzalutamide and abiraterone and they’re becoming resistant, the number of circulating tumor cells that have the AR-V7 copy in them—and also within an individual cell—the number that are aberrant in this way increases. When you stop the therapy—and perhaps you treat them with something else or nothing, we don’t know—certainly in a proportion of patients, the phenotype tends to be reduced and even go away. Not that it’s quite reversible, we’re selecting out clones that are sensitive or not. And this is now being tested as a predictor in a prospective study. So, after patients become initially castration resistant without further therapy, we’re screening patients for a study looking at a drug that binds to the other end, to the N-terminal of the androgen receptor called galeterone—which is not dependent on this receptor mutation. We have some data in some patients to suggest that it will be effective, and certainly we get PSA responses in the AR-V7 predominant patients. That’s being compared to enzalutamide, but in that study, called ARMOR3, we expect to see only 12% of the patients have AR-V7. So, we’ve got to screen a lot of patients, in fact several thousand, to do a study of somewhere between 120 and 150 patients, a small phase III. But they’re expecting the difference to be very significant.

When we go later in the disease course, after patients have had enzalutamide, abiraterone, or both, the numbers of patients that manifest AR-V7 are very much increased. More than two-thirds will have it. And particularly in patients that at that time have progressive visceral disease, their prognosis is actually extremely poor. But they may respond importantly to taxane chemotherapy and to platinums. And some of those patients do well with the drugs that Dan was mentioning—the PARP (poly ADP ribose polymerase) and ATM (ataxia telangiectasia mutated) inhibitors that we have in clinical trial. And hopefully, in the case of PARP inhibitors, may be available on the market soon.

Raoul S. Concepcion, MD: So, Dan, everybody is coming to this recognition about this AR-V7 just being one of the variants. Obviously, there’s a ton of AR variants looking at CTCs (circulating tumor cells). Any other technology that people are investigating in terms of potential predictive markers that are not CTC based?

Daniel P. Petrylak, MD: Axonal mRNA is being looked at, as are DNA specimens from blood circulating DNA. A variety of different other DNA markers are being evaluated, so not only the CTCs. Remember that if you go back to the original CTC data, only about half of patients make CTCs. So, there is room for this technology, and there’s a need for it. I think that also one of the points that Dave makes about AR-V7 is very interesting, about the taxanes. The AR-V7 mutants are sensitive to taxane-based therapy. And you may say, well, that’s sort of a bit of a contradiction because we know that there may be a mechanism of androgen binding or actually androgen receptor localization from taxanes. And it’s a different portion of the receptor, so it makes total sense that you can treat one of these VR-7 mutant patients with taxanes, and potentially clear it. And there are studies now being done to look at enzalutamide or other agents after taxane treatment to see if they do become re-sensitized to it.

Raoul S. Concepcion, MD: Neal, didn’t Howard Scher present some data looking at CTCs, and LDH (lactate dehydrogenase), and a number of things?

Neal D. Shore, MD: Yes. Howard and his entire team over at Sloan Kettering have done some phenomenal work looking at this issue of liquid biopsying and biomarkers. But I just want to comment. I think it’s really interesting what Dan said at the end about how making sure that chemotherapy is given more appropriately when the V7 is there could potentially change the biology/phenotype of the disease. And then you could later on rechallenge with a novel hormonal line of therapy. That’s actually very intriguing. We’re participating in a trial like that, but it’s hard given all the other therapeutic options that are there. But to your point, yes, there was a nice paper that was written about looking at CTC status, vis-a-vis LDH and that response as a marker to see when novel hormonal lines of therapy were most effective.

Transcript Edited for Clarity
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Transcript:

Raoul S. Concepcion, MD:
Mike, as part of your managing of these patients, should we be pushing more for biopsying of the metastatic site even if it is bone, which is obviously quite difficult, and/or soft tissue?

Michael S. Cookson, MD, MMHC: Well, until we have those tools available and they’re proven, it’s kind of hard to recommend a biopsy anywhere in the USA. If you do have a tool and it’s proven to be effective, it makes complete sense. I think one of the things that I’m really impressed with though, if you remember in 2004 where Dan’s SWOG study led to Taxotere approval, and the TAX-327 study. There was a 3-month survival advantage that started the whole ball rolling. And altered the history of all that we knew about ways to control advanced prostate cancer. That was the first chemotherapeutic agent that actually moved the needle to 3 months. Then, look at the CHAARTED, STAMPEDE, and even the French study. There is a 1-year survival advantage and in high-risk people there is 16, 18 months survival advantage, moving the chemotherapy back to an earlier stage in their disease process. We don’t know the results of the non-metastatic, high-risk local disease. But it seems like when we move these therapies back, you get a better response. In the absence of a perfect way to the Holy Grail, personalize their therapy, know whether it’s androgen access, and whether it’s systemic therapy and which systemic therapy. I think treating them aggressively early on is probably going to be in our best interest in somebody like this. I don’t know that we need to wait very long for the metastases to become apparent.

Raoul S. Concepcion, MD: Clearly, the other thing that we completely lack is any availability of reproducible predictive markers to try to determine therapy. We have so many new drugs, but they’re mechanistically different. David, you looked at this. Where do we stand with some of the development of such liquid markers?

David I. Quinn, MBBS, PhD: I think the thing that’s come to the forefront is the circulating tumor cell assay of androgen receptor variant 7 (AR-V7). This has been led predominantly out of Johns Hopkins but also we have some good data from MD Anderson. If you manifest AR-V7 in the circulating tumor cells—which is a mutational change of the ligand-binding domain of the androgen receptor where dihydrotestosterone and other androgens plug in, and where the androgen receptor blockers plug in—then you’re going to be very likely resistant to androgen receptor blockers like enzalutamide and also interestingly to the androgen biosynthesis inhibitors like abiraterone. It’s not a universal marker of resistance, because we’re measuring it in the blood. When patients are on enzalutamide and abiraterone and they’re becoming resistant, the number of circulating tumor cells that have the AR-V7 copy in them—and also within an individual cell—the number that are aberrant in this way increases. When you stop the therapy—and perhaps you treat them with something else or nothing, we don’t know—certainly in a proportion of patients, the phenotype tends to be reduced and even go away. Not that it’s quite reversible, we’re selecting out clones that are sensitive or not. And this is now being tested as a predictor in a prospective study. So, after patients become initially castration resistant without further therapy, we’re screening patients for a study looking at a drug that binds to the other end, to the N-terminal of the androgen receptor called galeterone—which is not dependent on this receptor mutation. We have some data in some patients to suggest that it will be effective, and certainly we get PSA responses in the AR-V7 predominant patients. That’s being compared to enzalutamide, but in that study, called ARMOR3, we expect to see only 12% of the patients have AR-V7. So, we’ve got to screen a lot of patients, in fact several thousand, to do a study of somewhere between 120 and 150 patients, a small phase III. But they’re expecting the difference to be very significant.

When we go later in the disease course, after patients have had enzalutamide, abiraterone, or both, the numbers of patients that manifest AR-V7 are very much increased. More than two-thirds will have it. And particularly in patients that at that time have progressive visceral disease, their prognosis is actually extremely poor. But they may respond importantly to taxane chemotherapy and to platinums. And some of those patients do well with the drugs that Dan was mentioning—the PARP (poly ADP ribose polymerase) and ATM (ataxia telangiectasia mutated) inhibitors that we have in clinical trial. And hopefully, in the case of PARP inhibitors, may be available on the market soon.

Raoul S. Concepcion, MD: So, Dan, everybody is coming to this recognition about this AR-V7 just being one of the variants. Obviously, there’s a ton of AR variants looking at CTCs (circulating tumor cells). Any other technology that people are investigating in terms of potential predictive markers that are not CTC based?

Daniel P. Petrylak, MD: Axonal mRNA is being looked at, as are DNA specimens from blood circulating DNA. A variety of different other DNA markers are being evaluated, so not only the CTCs. Remember that if you go back to the original CTC data, only about half of patients make CTCs. So, there is room for this technology, and there’s a need for it. I think that also one of the points that Dave makes about AR-V7 is very interesting, about the taxanes. The AR-V7 mutants are sensitive to taxane-based therapy. And you may say, well, that’s sort of a bit of a contradiction because we know that there may be a mechanism of androgen binding or actually androgen receptor localization from taxanes. And it’s a different portion of the receptor, so it makes total sense that you can treat one of these VR-7 mutant patients with taxanes, and potentially clear it. And there are studies now being done to look at enzalutamide or other agents after taxane treatment to see if they do become re-sensitized to it.

Raoul S. Concepcion, MD: Neal, didn’t Howard Scher present some data looking at CTCs, and LDH (lactate dehydrogenase), and a number of things?

Neal D. Shore, MD: Yes. Howard and his entire team over at Sloan Kettering have done some phenomenal work looking at this issue of liquid biopsying and biomarkers. But I just want to comment. I think it’s really interesting what Dan said at the end about how making sure that chemotherapy is given more appropriately when the V7 is there could potentially change the biology/phenotype of the disease. And then you could later on rechallenge with a novel hormonal line of therapy. That’s actually very intriguing. We’re participating in a trial like that, but it’s hard given all the other therapeutic options that are there. But to your point, yes, there was a nice paper that was written about looking at CTC status, vis-a-vis LDH and that response as a marker to see when novel hormonal lines of therapy were most effective.

Transcript Edited for Clarity
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TitleExpiration DateCME Credits
Clinical Vignette Series: 34th Annual Chemotherapy Foundation Symposium: Innovative Cancer Therapy for Tomorrow®Feb 28, 20182.0
Community Practice Connections™: Personalized Sequencing in Castration-Resistant Prostate Cancer: Bridging the Latest Evidence to the Bedside in Clinical ManagementAug 25, 20181.5
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