PARP Inhibitor + AR Signaling Inhibitor Combos Improve mCRPC Outcomes in Meta-Analysis - Rashid Sayyid
April 9, 2024
Rashid Sayyid discusses a systematic review and meta-analysis on combining PARP inhibitors with AR signaling inhibitors in mCRPC treatment, published in BJU International. The study, which synthesized data from three significant trials, sought to improve survival across all patients, focusing on those without specific biomarkers. Results showed a 35% reduction in radiographic progression-free survival across the board, with a notable 68% reduction in BRCA1/2 mutated patients. While overall survival data remains immature, preliminary findings indicate a potential 16% improvement. The research, highlighting both the promise and complexities of this therapeutic approach, underscores the importance of genetic testing in advanced prostate cancer stages and signals a shift towards more personalized and effective treatment strategies.
Biographies:
Rashid Sayyid, MD, MSc, Urologic Oncology Fellow, Division of Urology, University of Toronto, Toronto, ON
Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, MA
Biographies:
Rashid Sayyid, MD, MSc, Urologic Oncology Fellow, Division of Urology, University of Toronto, Toronto, ON
Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, MA
Read the Full Video Transcript
Alicia Morgans: Hi, I am so excited to be here today with Dr. Rashid Sayyid, who is joining me from the Princess Margaret Cancer Centre in Toronto, to talk about a recently published paper looking at the combination of PARP inhibitors and AR signaling inhibitors published in BJU International. Thank you so much for being here with me today.
Rashid Sayyid: Yeah, thanks for having me, Dr. Morgans. I'm very excited to do this recording with you and the UroToday team.
Alicia Morgans: Well, we are so excited to have you and really to bring your thoughts to bear on what has been a complex situation, a complex story being told in prostate cancer. So tell me a little bit about what you did. This was a systematic review, meta-analysis; tell me about how you got the data and what you did to answer this question.
Rashid Sayyid: Yeah, thank you for that. We've seen a lot of advances in the first-line mCRPC treatment space over the last couple of years, and we know that we need to do better for our patients. We know that from the randomized trials, the COUGAR data, that their survival is about two to three years, and that's even shorter when we look at real-world data. So there's been a lot of effort made into this disease space, and we know that there have been three major trials that looked at PARP inhibitors as well as the ARSIs, meaning like ABI and ENZA, etc. And so the goal of this endeavor is to improve survival across all patients, and not only patients who have specific biomarkers, meaning they have the homologous recombination repair mutations. And so that was kind of the hypothesis in combining these two drugs working for all patients.
And we saw these results with these trials being presented, and we saw some disparities in the results. Some of them were great in all patients, others were kind of more specific to those that had the mutations. So there was a lack of clarity at that time. And at that time, we didn't really have the regulatory approval for these agents, and we thought it was very important from an evidence synthesis standpoint to bring the results from these trials together in order to inform the public and get a global picture of how these drugs work.
And so what we did was we used the data that's publicly available from these three trials, meaning PROpel, which looked at Olaparib with ABI versus just ABI alone. We had MAGNITUDE that looked at Niraparib plus ABI versus ABI alone. Then we had TALAPRO-2 that looked at Talazoparib plus ENZA versus ENZA alone.
So three different PARP inhibitors with two different areas. So there are some differences there. But overall, mechanistically, they all work similarly enough where we felt that it was reasonable to look at all three trials together and inform the outcomes. Mainly overall survival, of course, which remains the holy grail, but also radiographic progression-free survival, which is the primary endpoint in these trials. Obviously, importantly, when you add drugs together, there's the aspect of toxicity. And so we also looked at that as well. And so that was kind of the impetus for looking at this systematic review meta-analysis.
Alicia Morgans: Fantastic. And as you said, your primary endpoint was radiographic progression-free survival. That's really the mature endpoint that we have. And I would love to hear what you found on that and overall survival, and certainly tell us about adverse events, which are part of what we're talking about, certainly as we take care of these patients.
Rashid Sayyid: Absolutely. So there's been some good data that radiographic progression-free survival may correlate with overall survival in these patients, but the data from ICECaP hasn't been that robust. Nonetheless, it is what it is in terms of that's the primary outcome of these studies, and they were designed and powered to answer that question. So to answer the radiographic progression-free survival question, we focused on the blinded central review because that's a bit more robust and less prone to biases compared to the investigator-assessed radiographic progression-free survival.
We noticed that when we combine the PARP inhibitors with these ARSIs compared to ARSIs alone, there's about a 35% reduction in the rate of radiographic progression-free survival in the overall cohort. So any patient who comes in with mCRPC without any genetic testing, although obviously, these patients should undergo such testing, there's a 35% reduction in the rate of radiographic progression if we combine a PARP inhibitor with an ARSI.
And then we ask the question, well, does it differ if patients had specific mutations? The hot one obviously is the BRCA1/2 mutation where we know these patients are the most likely to benefit from a PARP inhibitor. And so there was about a 68% reduction, so almost double the reduction in the overall cohort in the BRCA1/2 mutated patients. Next, the obvious question was what about the HRR mutated or the homologous recombination repair? And that includes the BRCA1/2 mutated plus those with, let's say, an ATM, check two, etc. And so these patients had a 45% reduction in radiographic progression-free survival. And then when we looked at patients as well who were non-HRR mutated. So these are patients who come through the door, we test them, they don't have the mutation, is there any benefit in adding a PARP inhibitor to these patients? And we saw the reduction is still significant at 26%.
So obviously, the magnitude of benefit in these patients is lower, but it's still there. Now, in terms of overall survival, which obviously remains the holy grail, the data maturity for this outcome from these trials was not very mature, so when we look at overall survival maturity, we're asking what are the number of events that have happened out of the overall target? So we have 31 to 48% data maturity, which is not that mature at this point, but what we saw was that the overall survival improved by about 16% in the overall cohort. And it's important to note that overall survival data was at the time of the analysis not yet available from MAGNITUDE. And so we only used data from PROpel and TALAPRO-2, so about a 16% reduction in overall survival in the overall cohort.
This was obviously better than those who are HRR-mutated, with a benefit of 24%, and then the BRCA1/2 even better, with a reduction of about almost 50%, so 47%. So clearly, we see a stepwise improvement in these responses as patients go from overall to HRR-mutated to BRCA1/2. And this is very important when we're obviously counseling our patients about what the expected benefit is. And then, one of the most important components is the adverse events, especially we focus on the grade three or worse. And the one that comes up a lot with these agents, as you know well, Dr. Morgans, is the anemia. And when we look at the anemia, about 32% of patients experience grade three or worse anemia when they took the PARP inhibitors compared to about only 5%. There's about a sixfold increase in the rate of grade three or worse anemia when we add the PARP inhibitors to the ARSIs in the first-line mCRPC setting.
Alicia Morgans: Wow. It's so important, and I so appreciate that you pulled out the grade three and specifically the anemia, which can be challenging and may require transfusions. It's been sort of the talk of a lot of our conversations around balancing the risks and benefits with these agents. So really nice to have that put into context for us in your study. With any study like this, there are limitations, and I wonder if you could share some of the limitations that you faced and thought about and what you may have done to try to minimize those limitations.
Rashid Sayyid: Yeah, that's a great question. With these meta-analyses, the limitations of the meta-analysis are pretty much related to those of the underlying trials. There's not really much that you can overcome. You can overcome the power aspect when you combine all these trials together data, but obviously, there are some limitations. First, this was not an IPD or an individual patient data meta-analysis. So this is essentially crude data being pulled together, so that comes with certain limitations.
The other thing is that drugs are different. Their mechanisms work differently, their efficacy is different, and their adverse event profile is very different. If we look at the grade three anemia, we know that the rates are lower with olaparib versus niraparib, talazoparib. And so that's one of the arguments that the investigators of the PROpel trial argued was that, well, you can't really pool our results with the results from the other trials, and that's understandable.
The other thing is we see a lot of heterogeneity in the study designs. So we know pretty well from MAGNITUDE that the patients were essentially based on biomarker preselection, meaning before they were enrolled in the trial, or excuse me, randomized to one arm versus the other, they underwent genetic testing, and then they were separated into cohort one, which was HR negative versus the other cohort, which was the HR positive or vice versa.
And so this was different, let's say, as opposed to PROpel and TALAPRO-2 where the patients were essentially enrolled, randomized, and then underwent the testing. That didn't really change how the study design was. So there are some nuances which make these different. And I think from a clinical aspect, one of the major limitations of these trials, and not just this analysis, is that many of our patients have seen these agents in the mHSPC setting as they go potentially from de novo, or they transition from clinically localized by chemical regression, etc., to mHSPC to mCRPC. They have seen a lot of these drugs earlier on. And so when we call this a first-line mCRPC setting, this may apply to historical mCRPC patients who have not seen these agents before. So it's going to be hard to translate these results to the more contemporary mCRPC patients, but it's still important data to inform future practice and future clinical trial design.
Alicia Morgans: Absolutely. Well, it's a lot of work that you've done, and I so appreciate you walking through your findings and certainly the limitations as well. I wonder if you can sum it all up and give the listeners a message from your work from this paper that they should take back to the clinic.
Rashid Sayyid: Yeah, absolutely. So I think there are two important messages from these results. First, the importance of genetic testing in the advanced stages, specifically mCRPC, is very, very important. We're seeing more and more data whereby we have biomarker-driven treatment options for our patients. So it's important for our patients to advocate for themselves to undergo genetic testing in this setting.
The second thing is we're seeing a lot of improvement in the survival outcomes of these patients. The two to three years that we saw earlier on is changing a lot, and this is because of the first-line treatment options that we are seeing, but also importantly, the second, third-line rescue treatment options that are emerging. So I think these results pretty much confirm the regulatory approvals that we have seen for these drugs. We've seen these drugs, these combinations be approved in either the BRCA1/2 positive or the HRR positive cohorts as well. So it's important for them to be optimistic that the studies are being reflected in these regulatory approvals and are increasing the options they have in place.
Alicia Morgans: Wonderful. Well, thank you so much for taking the time today to share these findings and for doing the work in the first place. We sincerely appreciate your time and your expertise.
Rashid Sayyid: Yeah, thank you, Dr. Morgans. It's my pleasure. And before I leave, I want to acknowledge all my co-authors, Dr. Zach Klaassen, Julian Chavarriaga, and Dr. Neil Fleshner, and the rest of the team who were instrumental in making this team effort happen.
Alicia Morgans: Wonderful. Thank you to all of them and to you.
Alicia Morgans: Hi, I am so excited to be here today with Dr. Rashid Sayyid, who is joining me from the Princess Margaret Cancer Centre in Toronto, to talk about a recently published paper looking at the combination of PARP inhibitors and AR signaling inhibitors published in BJU International. Thank you so much for being here with me today.
Rashid Sayyid: Yeah, thanks for having me, Dr. Morgans. I'm very excited to do this recording with you and the UroToday team.
Alicia Morgans: Well, we are so excited to have you and really to bring your thoughts to bear on what has been a complex situation, a complex story being told in prostate cancer. So tell me a little bit about what you did. This was a systematic review, meta-analysis; tell me about how you got the data and what you did to answer this question.
Rashid Sayyid: Yeah, thank you for that. We've seen a lot of advances in the first-line mCRPC treatment space over the last couple of years, and we know that we need to do better for our patients. We know that from the randomized trials, the COUGAR data, that their survival is about two to three years, and that's even shorter when we look at real-world data. So there's been a lot of effort made into this disease space, and we know that there have been three major trials that looked at PARP inhibitors as well as the ARSIs, meaning like ABI and ENZA, etc. And so the goal of this endeavor is to improve survival across all patients, and not only patients who have specific biomarkers, meaning they have the homologous recombination repair mutations. And so that was kind of the hypothesis in combining these two drugs working for all patients.
And we saw these results with these trials being presented, and we saw some disparities in the results. Some of them were great in all patients, others were kind of more specific to those that had the mutations. So there was a lack of clarity at that time. And at that time, we didn't really have the regulatory approval for these agents, and we thought it was very important from an evidence synthesis standpoint to bring the results from these trials together in order to inform the public and get a global picture of how these drugs work.
And so what we did was we used the data that's publicly available from these three trials, meaning PROpel, which looked at Olaparib with ABI versus just ABI alone. We had MAGNITUDE that looked at Niraparib plus ABI versus ABI alone. Then we had TALAPRO-2 that looked at Talazoparib plus ENZA versus ENZA alone.
So three different PARP inhibitors with two different areas. So there are some differences there. But overall, mechanistically, they all work similarly enough where we felt that it was reasonable to look at all three trials together and inform the outcomes. Mainly overall survival, of course, which remains the holy grail, but also radiographic progression-free survival, which is the primary endpoint in these trials. Obviously, importantly, when you add drugs together, there's the aspect of toxicity. And so we also looked at that as well. And so that was kind of the impetus for looking at this systematic review meta-analysis.
Alicia Morgans: Fantastic. And as you said, your primary endpoint was radiographic progression-free survival. That's really the mature endpoint that we have. And I would love to hear what you found on that and overall survival, and certainly tell us about adverse events, which are part of what we're talking about, certainly as we take care of these patients.
Rashid Sayyid: Absolutely. So there's been some good data that radiographic progression-free survival may correlate with overall survival in these patients, but the data from ICECaP hasn't been that robust. Nonetheless, it is what it is in terms of that's the primary outcome of these studies, and they were designed and powered to answer that question. So to answer the radiographic progression-free survival question, we focused on the blinded central review because that's a bit more robust and less prone to biases compared to the investigator-assessed radiographic progression-free survival.
We noticed that when we combine the PARP inhibitors with these ARSIs compared to ARSIs alone, there's about a 35% reduction in the rate of radiographic progression-free survival in the overall cohort. So any patient who comes in with mCRPC without any genetic testing, although obviously, these patients should undergo such testing, there's a 35% reduction in the rate of radiographic progression if we combine a PARP inhibitor with an ARSI.
And then we ask the question, well, does it differ if patients had specific mutations? The hot one obviously is the BRCA1/2 mutation where we know these patients are the most likely to benefit from a PARP inhibitor. And so there was about a 68% reduction, so almost double the reduction in the overall cohort in the BRCA1/2 mutated patients. Next, the obvious question was what about the HRR mutated or the homologous recombination repair? And that includes the BRCA1/2 mutated plus those with, let's say, an ATM, check two, etc. And so these patients had a 45% reduction in radiographic progression-free survival. And then when we looked at patients as well who were non-HRR mutated. So these are patients who come through the door, we test them, they don't have the mutation, is there any benefit in adding a PARP inhibitor to these patients? And we saw the reduction is still significant at 26%.
So obviously, the magnitude of benefit in these patients is lower, but it's still there. Now, in terms of overall survival, which obviously remains the holy grail, the data maturity for this outcome from these trials was not very mature, so when we look at overall survival maturity, we're asking what are the number of events that have happened out of the overall target? So we have 31 to 48% data maturity, which is not that mature at this point, but what we saw was that the overall survival improved by about 16% in the overall cohort. And it's important to note that overall survival data was at the time of the analysis not yet available from MAGNITUDE. And so we only used data from PROpel and TALAPRO-2, so about a 16% reduction in overall survival in the overall cohort.
This was obviously better than those who are HRR-mutated, with a benefit of 24%, and then the BRCA1/2 even better, with a reduction of about almost 50%, so 47%. So clearly, we see a stepwise improvement in these responses as patients go from overall to HRR-mutated to BRCA1/2. And this is very important when we're obviously counseling our patients about what the expected benefit is. And then, one of the most important components is the adverse events, especially we focus on the grade three or worse. And the one that comes up a lot with these agents, as you know well, Dr. Morgans, is the anemia. And when we look at the anemia, about 32% of patients experience grade three or worse anemia when they took the PARP inhibitors compared to about only 5%. There's about a sixfold increase in the rate of grade three or worse anemia when we add the PARP inhibitors to the ARSIs in the first-line mCRPC setting.
Alicia Morgans: Wow. It's so important, and I so appreciate that you pulled out the grade three and specifically the anemia, which can be challenging and may require transfusions. It's been sort of the talk of a lot of our conversations around balancing the risks and benefits with these agents. So really nice to have that put into context for us in your study. With any study like this, there are limitations, and I wonder if you could share some of the limitations that you faced and thought about and what you may have done to try to minimize those limitations.
Rashid Sayyid: Yeah, that's a great question. With these meta-analyses, the limitations of the meta-analysis are pretty much related to those of the underlying trials. There's not really much that you can overcome. You can overcome the power aspect when you combine all these trials together data, but obviously, there are some limitations. First, this was not an IPD or an individual patient data meta-analysis. So this is essentially crude data being pulled together, so that comes with certain limitations.
The other thing is that drugs are different. Their mechanisms work differently, their efficacy is different, and their adverse event profile is very different. If we look at the grade three anemia, we know that the rates are lower with olaparib versus niraparib, talazoparib. And so that's one of the arguments that the investigators of the PROpel trial argued was that, well, you can't really pool our results with the results from the other trials, and that's understandable.
The other thing is we see a lot of heterogeneity in the study designs. So we know pretty well from MAGNITUDE that the patients were essentially based on biomarker preselection, meaning before they were enrolled in the trial, or excuse me, randomized to one arm versus the other, they underwent genetic testing, and then they were separated into cohort one, which was HR negative versus the other cohort, which was the HR positive or vice versa.
And so this was different, let's say, as opposed to PROpel and TALAPRO-2 where the patients were essentially enrolled, randomized, and then underwent the testing. That didn't really change how the study design was. So there are some nuances which make these different. And I think from a clinical aspect, one of the major limitations of these trials, and not just this analysis, is that many of our patients have seen these agents in the mHSPC setting as they go potentially from de novo, or they transition from clinically localized by chemical regression, etc., to mHSPC to mCRPC. They have seen a lot of these drugs earlier on. And so when we call this a first-line mCRPC setting, this may apply to historical mCRPC patients who have not seen these agents before. So it's going to be hard to translate these results to the more contemporary mCRPC patients, but it's still important data to inform future practice and future clinical trial design.
Alicia Morgans: Absolutely. Well, it's a lot of work that you've done, and I so appreciate you walking through your findings and certainly the limitations as well. I wonder if you can sum it all up and give the listeners a message from your work from this paper that they should take back to the clinic.
Rashid Sayyid: Yeah, absolutely. So I think there are two important messages from these results. First, the importance of genetic testing in the advanced stages, specifically mCRPC, is very, very important. We're seeing more and more data whereby we have biomarker-driven treatment options for our patients. So it's important for our patients to advocate for themselves to undergo genetic testing in this setting.
The second thing is we're seeing a lot of improvement in the survival outcomes of these patients. The two to three years that we saw earlier on is changing a lot, and this is because of the first-line treatment options that we are seeing, but also importantly, the second, third-line rescue treatment options that are emerging. So I think these results pretty much confirm the regulatory approvals that we have seen for these drugs. We've seen these drugs, these combinations be approved in either the BRCA1/2 positive or the HRR positive cohorts as well. So it's important for them to be optimistic that the studies are being reflected in these regulatory approvals and are increasing the options they have in place.
Alicia Morgans: Wonderful. Well, thank you so much for taking the time today to share these findings and for doing the work in the first place. We sincerely appreciate your time and your expertise.
Rashid Sayyid: Yeah, thank you, Dr. Morgans. It's my pleasure. And before I leave, I want to acknowledge all my co-authors, Dr. Zach Klaassen, Julian Chavarriaga, and Dr. Neil Fleshner, and the rest of the team who were instrumental in making this team effort happen.
Alicia Morgans: Wonderful. Thank you to all of them and to you.