COncurrent adMinistration of Bipolar Androgen Therapy and nivolumab in men with mCRPC, The COMBAT Study - Mark Markowski
July 29, 2021
In this UroToday discussion between Charles Ryan and Mark Markowski, they focus on Dr Markowski’s recent study, entitled COMAT-CRPC. The COMBAT-CRPC study is a study with bipolar androgen therapy and nivolumab, which was conducted through the Prostate Cancer Clinical Trials Consortium. Dr. Markowski begins by discussing the criteria for patient eligibility, which was quite broad, which was to be a castrate-resistant prostate cancer (CRPC) patient who had previously been treated with novel AR targeted therapy. He then touches on the difficulty of teasing apart the data, specifically on how much the immunotherapy added to the bipolar androgen treatment. Dr. Markowski discusses the need for a deeper genomic analysis on these patients, which could demonstrate why certain patients respond to the immunotherapy, and some do not. As the conversation wraps up, Dr. Ryan and Dr. Markowski discuss the exciting future of bipolar androgen therapy in men with CRPC.
Biographies:
Mark Markowski, MD, Ph.D., Medical Oncologist, Kimmel Cancer Center, Sibley Memorial Hospital
Charles J. Ryan, MD, the President and Chief Executive Officer of The Prostate Cancer Foundation (PCF), the world’s leading philanthropic organization dedicated to funding life-saving prostate cancer research. Charles J. Ryan is an internationally recognized genitourinary (GU) oncologist with expertise in the biology and treatment of advanced prostate cancer. Dr. Ryan joined the PCF from the University of Minnesota, Minneapolis, where he served as Director of the Hematology, Oncology, and Transplantation Division in the Department of Medicine. He also served as Associate Director for Clinical Research in the Masonic Cancer Center and held the B.J. Kennedy Chair in Clinical Medical Oncology.
Biographies:
Mark Markowski, MD, Ph.D., Medical Oncologist, Kimmel Cancer Center, Sibley Memorial Hospital
Charles J. Ryan, MD, the President and Chief Executive Officer of The Prostate Cancer Foundation (PCF), the world’s leading philanthropic organization dedicated to funding life-saving prostate cancer research. Charles J. Ryan is an internationally recognized genitourinary (GU) oncologist with expertise in the biology and treatment of advanced prostate cancer. Dr. Ryan joined the PCF from the University of Minnesota, Minneapolis, where he served as Director of the Hematology, Oncology, and Transplantation Division in the Department of Medicine. He also served as Associate Director for Clinical Research in the Masonic Cancer Center and held the B.J. Kennedy Chair in Clinical Medical Oncology.
Read the Full Video Transcript
Charles Ryan: Hello from ASCO 2021. Chuck Ryan here from the University of Minnesota. I'm with Mark Markowski, MD Ph.D., who is an Assistant Professor at Johns Hopkins University in the Department of Oncology. Dr. Markowski recently presented at ASCO in a poster discussion session, a really interesting study that moves the idea of bipolar androgen therapy a step forward. This is a study with bipolar androgen therapy plus nivolumab, a study that was conducted and completed through the Prostate Cancer Clinical Trials Consortium. Mark, welcome to the program.
Mark Markowski: Pleasure to be here. Thanks for having me.
Charles Ryan: So this is a study called COMBAT-CRPC, and tell us a little bit about how you came about designing a study with testosterone and nivolumab.
Mark Markowski: So we've done a lot of work over the years with bipolar androgen therapy, mostly as a single agent, and so as we thought about how to move bipolar androgen forward, we were thinking about logical partners, and obviously immunotherapy always comes to mind. We did some data mining on patients that had previously been treated with bipolar androgen, and we found several patients that subsequently had very large clinical responses to immunotherapy that we couldn't explain entirely by genomics or next-generation sequencing.
And so the more we looked at these patients that were responding, it seemed that bipolar androgen was part of their treatment portfolio before they received immunotherapy. And I think that got the juices flowing here to think about that, about putting it together at least clinically, and there's also preclinical data showing that bipolar androgen can induce genomic rearrangements and DNA damage. And so the idea of creating these neoantigens, certainly it was low-hanging fruit, and then put together with the clinical data, it made sense to combine it with an immune checkpoint inhibitor.
Charles Ryan: So these were men with CRPC, and to what extent are these pretreated, heavily pretreated patients? What prior therapies have they had?
Mark Markowski: So we had a pretty wide open eligibility criterion, so all patients on the study had to have one prior treatment with a novel AR targeted therapy, and that was basically the only requirement. We didn't have a limit on prior treatments. You could have had chemotherapy for the castration-resistant disease, and so the vast majority of our patients were very heavily pretreated. Even a third of them had more than two novel AR targeted therapies with taxane chemotherapy, and so they were fairly far along in their clinical course. So the vast majority of people were heavily pretreated.
Charles Ryan: And what's the regimen? How are they treated?
Mark Markowski: So we had an interesting design. So we did a single-arm phase II study, and every patient got the same treatment. What we wanted to try to tease out in our design is how much is being driven by bipolar androgen and how much is being driven by immunotherapy. So we didn't want to put them both together at the same time. We wanted to do a priming technique with bipolar androgen, and so what we did is each patient got three cycles of bipolar androgen therapy by itself, and then subsequently we would add the nivolumab.
So what we were able to see, and if we go back and look at prior bipolar androgen studies, the overwhelming majority, if they're going to respond to bipolar androgen, do so within the first three months. So we felt that we would capture those bipolar androgen responders early on, and then when we added nivolumab, we would see if we can rescue some of those non-responders and possibly extend the duration of bipolar androgen therapy if they were benefiting upfront.
Charles Ryan: So what did you see with regards to the benefiting upfront versus the addition of nivolumab?
Mark Markowski: Well, so if you look at the poster, the vast majority of responses occurred during bipolar androgen. Actually, when we look at the group of patients we had, we had 45 patients. We had a PSA response rate of 40%, which is higher than what we would see previously with a bipolar androgen study. So it did seem like we were onto something, but the vast majority of them happened on bipolar androgen.
However, there were a handful of patients that either had deeper responses on nivolumab or if they progressed on bipolar androgen, certainly we saw some PSA reduction with the nivolumab. So, you know, I think it's tough to tease out. We did the best we could here. I would say that the vast majority responded to bipolar androgen and there were a handful of responders to immunotherapy.
Charles Ryan: Okay, and I don't think you've presented it yet, but I assume that there's some work going on in the background looking at other factors that may be associated with those responses to the immunotherapy, genomic findings, those kinds of things.
Mark Markowski: Yeah, absolutely, and I think we're just getting started on that. When we designed the study, we wanted to have it very heavily enriched with biomarker work, so we were collecting, you know, blood specimens. We have two mandatory biopsies on the study, so one before you start the study and one's after you've completed the priming with bipolar androgen. So we really have... Rectal swabs, I mean, you name it, we're collecting it, and so we're just starting to scratch the surface now about how are we going to predict for immune responses, and hopefully we'll have that in the coming months.
Charles Ryan: Right. I mean, this has long been a real challenge in prostate cancer, is trying to understand why there are such low responses to PD-L1 therapy in this disease, and whether it's microenvironment-related or genomic-related, or perhaps the key that you're turning here, which is androgen-related or androgen deprivation-related. We will see. So congratulations on this work, and where are you going next with it?
Mark Markowski: Good question. So I think what we wanted to do when we saw this result is done the deep dive genomic analysis and say, yeah, we have a handful of responders to the nivolumab. Who are those people and why are they responding, and can we identify a biomarker of response? Then you develop a randomized phase II study where we're going to do this in a biomarker selected population. So ideally, it'd be nice to complete the study and roll right into the next steps. Here, I think we need to be a little bit more prudent, analyze what we have, and then make a smart plan moving forward.
Charles Ryan: Finally, any safety concerns that we should be aware of? I mean, it's always a concern about whether we should be giving testosterone to patients with CRPC. Certainly off study, I don't recommend it, but there are safety concerns with the nivo and safety concerns with the androgens. What did you find?
Mark Markowski: So, great question. So it turns out that that patients had a very low grade, grade 1, or 2 toxicity across the board, whether attributable to bipolar androgen or nivolumab. So the vast majority of toxicities we saw were edema, nausea, vomiting, and back pain, and those were all grade 1 or 2. I believe we had one or two grade 3 edema and back pain, and we see that very commonly with bipolar androgen from our previous studies.
In terms of immune-related toxicities, those were also grade 1 or 2, and, you know, very common, diarrhea, thyroiditis, some low-grade rash, and pruritis. But for the most part, there were no alarming safety signals and patients did quite well.
Charles Ryan: So, you know, we've now seen a few presentations of BAT therapy coming from your center. It's really intriguing data. It's really provocative. To the clinicians out there watching this, is this something they should be doing in their clinic at this time with their patients?
Mark Markowski: That's a great question. I think the answer to that is probably not, just until we fully discover how best to use bipolar androgen. I think we're starting to understand it a bit more and where it may benefit. I mean, if you look at Sam Denmeade's TRANSFORMER study, sure, we see clinical responses to bipolar androgen by itself, but perhaps the biggest benefit is when you re-challenge those patients with AR targeted therapies that they were previously resistant to. Now it gets a second life, and we're able to use those again. So how are we going to use that information and use bipolar androgen in a smart way to get the biggest benefit? So I think we are working on it. I think we are close, but I think doing it off-label, I wouldn't recommend it at this time.
Charles Ryan: Yeah, I would agree. I mean, I've been following this area pretty closely and I'm a big fan of it and I love the biology behind it, but I just think until we know exactly who the patients are who can take this safely and how to do that, which I look forward to more data from you and your colleagues at Hopkins on this point because you're really leading the world in this really innovative, thoughtful treatment of men with CRPC.
So thank you, Mark Markowski, from Johns Hopkins for joining us, and congratulations again on your presentation.
Mark Markowski: I appreciate it. Thanks.
Charles Ryan: Hello from ASCO 2021. Chuck Ryan here from the University of Minnesota. I'm with Mark Markowski, MD Ph.D., who is an Assistant Professor at Johns Hopkins University in the Department of Oncology. Dr. Markowski recently presented at ASCO in a poster discussion session, a really interesting study that moves the idea of bipolar androgen therapy a step forward. This is a study with bipolar androgen therapy plus nivolumab, a study that was conducted and completed through the Prostate Cancer Clinical Trials Consortium. Mark, welcome to the program.
Mark Markowski: Pleasure to be here. Thanks for having me.
Charles Ryan: So this is a study called COMBAT-CRPC, and tell us a little bit about how you came about designing a study with testosterone and nivolumab.
Mark Markowski: So we've done a lot of work over the years with bipolar androgen therapy, mostly as a single agent, and so as we thought about how to move bipolar androgen forward, we were thinking about logical partners, and obviously immunotherapy always comes to mind. We did some data mining on patients that had previously been treated with bipolar androgen, and we found several patients that subsequently had very large clinical responses to immunotherapy that we couldn't explain entirely by genomics or next-generation sequencing.
And so the more we looked at these patients that were responding, it seemed that bipolar androgen was part of their treatment portfolio before they received immunotherapy. And I think that got the juices flowing here to think about that, about putting it together at least clinically, and there's also preclinical data showing that bipolar androgen can induce genomic rearrangements and DNA damage. And so the idea of creating these neoantigens, certainly it was low-hanging fruit, and then put together with the clinical data, it made sense to combine it with an immune checkpoint inhibitor.
Charles Ryan: So these were men with CRPC, and to what extent are these pretreated, heavily pretreated patients? What prior therapies have they had?
Mark Markowski: So we had a pretty wide open eligibility criterion, so all patients on the study had to have one prior treatment with a novel AR targeted therapy, and that was basically the only requirement. We didn't have a limit on prior treatments. You could have had chemotherapy for the castration-resistant disease, and so the vast majority of our patients were very heavily pretreated. Even a third of them had more than two novel AR targeted therapies with taxane chemotherapy, and so they were fairly far along in their clinical course. So the vast majority of people were heavily pretreated.
Charles Ryan: And what's the regimen? How are they treated?
Mark Markowski: So we had an interesting design. So we did a single-arm phase II study, and every patient got the same treatment. What we wanted to try to tease out in our design is how much is being driven by bipolar androgen and how much is being driven by immunotherapy. So we didn't want to put them both together at the same time. We wanted to do a priming technique with bipolar androgen, and so what we did is each patient got three cycles of bipolar androgen therapy by itself, and then subsequently we would add the nivolumab.
So what we were able to see, and if we go back and look at prior bipolar androgen studies, the overwhelming majority, if they're going to respond to bipolar androgen, do so within the first three months. So we felt that we would capture those bipolar androgen responders early on, and then when we added nivolumab, we would see if we can rescue some of those non-responders and possibly extend the duration of bipolar androgen therapy if they were benefiting upfront.
Charles Ryan: So what did you see with regards to the benefiting upfront versus the addition of nivolumab?
Mark Markowski: Well, so if you look at the poster, the vast majority of responses occurred during bipolar androgen. Actually, when we look at the group of patients we had, we had 45 patients. We had a PSA response rate of 40%, which is higher than what we would see previously with a bipolar androgen study. So it did seem like we were onto something, but the vast majority of them happened on bipolar androgen.
However, there were a handful of patients that either had deeper responses on nivolumab or if they progressed on bipolar androgen, certainly we saw some PSA reduction with the nivolumab. So, you know, I think it's tough to tease out. We did the best we could here. I would say that the vast majority responded to bipolar androgen and there were a handful of responders to immunotherapy.
Charles Ryan: Okay, and I don't think you've presented it yet, but I assume that there's some work going on in the background looking at other factors that may be associated with those responses to the immunotherapy, genomic findings, those kinds of things.
Mark Markowski: Yeah, absolutely, and I think we're just getting started on that. When we designed the study, we wanted to have it very heavily enriched with biomarker work, so we were collecting, you know, blood specimens. We have two mandatory biopsies on the study, so one before you start the study and one's after you've completed the priming with bipolar androgen. So we really have... Rectal swabs, I mean, you name it, we're collecting it, and so we're just starting to scratch the surface now about how are we going to predict for immune responses, and hopefully we'll have that in the coming months.
Charles Ryan: Right. I mean, this has long been a real challenge in prostate cancer, is trying to understand why there are such low responses to PD-L1 therapy in this disease, and whether it's microenvironment-related or genomic-related, or perhaps the key that you're turning here, which is androgen-related or androgen deprivation-related. We will see. So congratulations on this work, and where are you going next with it?
Mark Markowski: Good question. So I think what we wanted to do when we saw this result is done the deep dive genomic analysis and say, yeah, we have a handful of responders to the nivolumab. Who are those people and why are they responding, and can we identify a biomarker of response? Then you develop a randomized phase II study where we're going to do this in a biomarker selected population. So ideally, it'd be nice to complete the study and roll right into the next steps. Here, I think we need to be a little bit more prudent, analyze what we have, and then make a smart plan moving forward.
Charles Ryan: Finally, any safety concerns that we should be aware of? I mean, it's always a concern about whether we should be giving testosterone to patients with CRPC. Certainly off study, I don't recommend it, but there are safety concerns with the nivo and safety concerns with the androgens. What did you find?
Mark Markowski: So, great question. So it turns out that that patients had a very low grade, grade 1, or 2 toxicity across the board, whether attributable to bipolar androgen or nivolumab. So the vast majority of toxicities we saw were edema, nausea, vomiting, and back pain, and those were all grade 1 or 2. I believe we had one or two grade 3 edema and back pain, and we see that very commonly with bipolar androgen from our previous studies.
In terms of immune-related toxicities, those were also grade 1 or 2, and, you know, very common, diarrhea, thyroiditis, some low-grade rash, and pruritis. But for the most part, there were no alarming safety signals and patients did quite well.
Charles Ryan: So, you know, we've now seen a few presentations of BAT therapy coming from your center. It's really intriguing data. It's really provocative. To the clinicians out there watching this, is this something they should be doing in their clinic at this time with their patients?
Mark Markowski: That's a great question. I think the answer to that is probably not, just until we fully discover how best to use bipolar androgen. I think we're starting to understand it a bit more and where it may benefit. I mean, if you look at Sam Denmeade's TRANSFORMER study, sure, we see clinical responses to bipolar androgen by itself, but perhaps the biggest benefit is when you re-challenge those patients with AR targeted therapies that they were previously resistant to. Now it gets a second life, and we're able to use those again. So how are we going to use that information and use bipolar androgen in a smart way to get the biggest benefit? So I think we are working on it. I think we are close, but I think doing it off-label, I wouldn't recommend it at this time.
Charles Ryan: Yeah, I would agree. I mean, I've been following this area pretty closely and I'm a big fan of it and I love the biology behind it, but I just think until we know exactly who the patients are who can take this safely and how to do that, which I look forward to more data from you and your colleagues at Hopkins on this point because you're really leading the world in this really innovative, thoughtful treatment of men with CRPC.
So thank you, Mark Markowski, from Johns Hopkins for joining us, and congratulations again on your presentation.
Mark Markowski: I appreciate it. Thanks.