STAMPEDE2 Trial Explores Combination Niraparib and Abiraterone in mHSPC - Sarah Howlett & Mahaz Kayani
October 15, 2024
Zachary Klaassen hosts Sarah Howlett and Mahaz Kayani about the STAMPEDE2 platform trial, focusing on Arm N, which tests niraparib-abiraterone in metastatic hormone-sensitive prostate cancer patients with specific homologous recombination repair gene alterations. They discuss the trial's design, which randomizes patients to receive either a dual-action tablet of niraparib-abiraterone or standard ARPI treatment. The study targets patients with BRCA1, BRCA2, or CDK12 mutations, aiming to improve overall survival compared to ADT and ARPI alone. The researchers explain the rationale behind the drug combination and patient selection criteria, emphasizing the importance of biomarker-driven treatment intensification. They highlight the trial's unique features, including its primary endpoint of overall survival and the option for patients to co-enroll in other STAMPEDE2 comparisons. The discussion concludes with updates on the trial's status and its potential to provide robust data on early PARP inhibition in advanced prostate cancer.
Biographies:
Sarah Howlett, MD, Clinical Research Fellow, University College London, London, UK
Mahaz Kayani, MD, Clinical Research Fellow, University College London, London, UK
Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Wellstar MCG, Georgia Cancer Center, Augusta, GA
Biographies:
Sarah Howlett, MD, Clinical Research Fellow, University College London, London, UK
Mahaz Kayani, MD, Clinical Research Fellow, University College London, London, UK
Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Wellstar MCG, Georgia Cancer Center, Augusta, GA
Read the Full Video Transcript
Zachary Klaassen: Hi, my name is Zach Klaassen. I'm a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. I'm delighted to be joined today on UroToday for an ESMO discussion with Dr. Sarah Howlett and Dr. Mahaz Kayani from University College London. We're going to be talking about STAMPEDE2 Arm N from this trial. Thank you both for joining us today.
Sarah Howlett: Thank you, and thank you for your invitation to have us.
Mahaz Kayani: Yeah, thanks for having us.
Zachary Klaassen: No, we're excited to learn about STAMPEDE2. If you guys want to roll through your slides, that would be fabulous.
Sarah Howlett: Thanks again for inviting us today to speak about the STAMPEDE2 Phase III trial of niraparib-abiraterone in patients with metastatic hormone-sensitive prostate cancer who harbor a deleterious alteration in a homologous recombination repair gene. Firstly, we would like to introduce the STAMPEDE2 platform. As you know, STAMPEDE1 led to the implementation of practice-changing treatments in advanced prostate cancer. STAMPEDE2 is a Phase III multicenter platform trial of three randomized controlled trials testing the addition of treatments to standard of care in metastatic hormone-sensitive prostate cancer. Our colleagues will be speaking to you separately about the other Phase III trials within the STAMPEDE2 platform, but today we'd like to share with you information about the niraparib-abiraterone trial.
We know that patients with homologous recombination repair altered tumors have worse outcomes and may benefit most from escalation of their treatment. Currently, single-agent PARP inhibitors are licensed for use in the castration-resistant setting for biomarker-selected patients following the results of previous Phase III studies such as PROfound. However, unfortunately, responses are often short-lived and resistance rapidly arises. We also know that when PARP inhibitors are combined with ARPIs such as abiraterone, they can have a synergistic effect. Recent data from the Phase II BRCAAway study showed that the median PFS on a combination of olaparib and abiraterone far exceeded that on either agent by itself. Our hypothesis is that the use of upfront abiraterone with niraparib in patients with HRR alterations will improve overall survival when compared to ADT and ARPI alone.
Mahaz Kayani: Patients will be eligible for this study if they have a known deleterious mutation in either BRCA1, BRCA2, or CDK12. Patients can have already started ADT or ARPI for up to six months, provided that there isn't any evidence of progression on either agent. In the trial, patients are randomized in a 1:1 fashion. In the investigational arm, they receive a single dual-action tablet, which contains both niraparib and abiraterone together. Patients in the control arm will receive an ARPI as decided by their physician. In addition to the trial treatments, the patients can also receive either docetaxel or local radiotherapy to the prostate, again, as decided by their own clinician. Finally, patients can also be co-enrolled into one of the other two comparisons of STAMPEDE2. So some patients will also receive either lutetium PSMA or SABR in addition to the investigational agents. The primary endpoint of this trial, unlike some of the other trials that you might have seen in this area, is overall survival.
So in conclusion, STAMPEDE2 niraparib and abiraterone will provide robust overall survival data for the benefit of using upfront PARP inhibition in combination with an ARPI agent for patients who harbor a BRCA1, BRCA2, or CDK12 mutation. Patients also have the option in this trial to co-enroll into one of the other comparisons of STAMPEDE2, so some of them will also receive lutetium or SABR. Thank you for listening.
Zachary Klaassen: Thank you both for that presentation. I think you mentioned STAMPEDE1 really has been transformational for advanced prostate cancer, and we're excited to see these new three arms from STAMPEDE2, specifically the one looking at niraparib and abiraterone. Just out of curiosity, there's been several combinations of PARP inhibitors and ARPIs. How did you guys decide on niraparib and abiraterone for this arm of the STAMPEDE2?
Mahaz Kayani: Our colleagues who treat ovarian cancers have much greater experience using PARP inhibitors than we do, and their feeling was that, certainly when it came to ovarian cancers, there was reasonable equivalence between the different agents. Therefore, we were quite agnostic when choosing the combination of PARP inhibitor and ARPI. There are also several other trials in this area, so AMPLITUDE and TALAPRO-3. Having said that, one of the advantages of the STAMPEDE2 platform is that in the future, if data emerges which suggests that another combination of PARP inhibitor and ARPI is superior to the one that we're testing, we could consider adding another comparison in to test that.
Zachary Klaassen: Yeah, that's great. And that's the beauty of the platform, right? You can just add additional arms, and if it's Enza plus something, we can always adapt to it, which is great. In terms of your selecting very stringently for BRCA1/2 or CDK12, were there discussions about having all comers enrolled in this trial or was it very specific in the design for these three mutations?
Mahaz Kayani: Again, we learned from STAMPEDE1 here where we saw that in the abiraterone arm, after seven years, about 20-25% of patients were still in disease remission. So actually, for lots of patients, we know that further treatment and intensification isn't necessarily needed, and we know that PARP inhibitors come with toxicity. So we thought it was really important to run a biomarker-selected trial, firstly to identify those poor prognosis patients that really need treatment intensification, but also to prevent other patients who won't benefit from getting needless toxicity.
Zachary Klaassen: Absolutely. Sarah, maybe I'll ask you about an update on the trial itself. How is enrollment going? Has it been about 15% are having these mutations? Maybe you can update us on the trial status.
Sarah Howlett: Excitingly, the other two comparisons within the platform—so P, which is testing lutetium, and S, which is testing SABR—are already open and actively recruiting. Unfortunately, we've still got a few things that we need to finalize amendment-wise with our regulators before we can open this comparison, but we're hoping to have that all finalized by the beginning of next year.
Zachary Klaassen: Wonderful. That's great. Great discussion. Again, this STAMPEDE2 platform is going to be so fun to watch over the next several years, and thank you both for joining us. Maybe a couple of take-home messages for our listeners today.
Sarah Howlett: I think what's really going to be useful from this trial is patients with these alterations, at this point, I don't think we have enough robust data to say that giving PARP inhibitors or platinum, different agents like that, is definitely the right strategy for them. And I think that this trial is going to provide patients with the right overall survival data to know that using these agents, particularly in the early versus late setting, is the right thing. And it's a really exciting opportunity for them to potentially, within the platform, receive a novel combination of treatments.
Zachary Klaassen: Yeah, absolutely. Thank you both for joining us. We'll look forward to this trial starting enrollment and certainly for the other two arms as well of STAMPEDE2.
Sarah Howlett: Great. Thanks for meeting with us.
Mahaz Kayani: Thank you for having us.
Zachary Klaassen: Hi, my name is Zach Klaassen. I'm a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. I'm delighted to be joined today on UroToday for an ESMO discussion with Dr. Sarah Howlett and Dr. Mahaz Kayani from University College London. We're going to be talking about STAMPEDE2 Arm N from this trial. Thank you both for joining us today.
Sarah Howlett: Thank you, and thank you for your invitation to have us.
Mahaz Kayani: Yeah, thanks for having us.
Zachary Klaassen: No, we're excited to learn about STAMPEDE2. If you guys want to roll through your slides, that would be fabulous.
Sarah Howlett: Thanks again for inviting us today to speak about the STAMPEDE2 Phase III trial of niraparib-abiraterone in patients with metastatic hormone-sensitive prostate cancer who harbor a deleterious alteration in a homologous recombination repair gene. Firstly, we would like to introduce the STAMPEDE2 platform. As you know, STAMPEDE1 led to the implementation of practice-changing treatments in advanced prostate cancer. STAMPEDE2 is a Phase III multicenter platform trial of three randomized controlled trials testing the addition of treatments to standard of care in metastatic hormone-sensitive prostate cancer. Our colleagues will be speaking to you separately about the other Phase III trials within the STAMPEDE2 platform, but today we'd like to share with you information about the niraparib-abiraterone trial.
We know that patients with homologous recombination repair altered tumors have worse outcomes and may benefit most from escalation of their treatment. Currently, single-agent PARP inhibitors are licensed for use in the castration-resistant setting for biomarker-selected patients following the results of previous Phase III studies such as PROfound. However, unfortunately, responses are often short-lived and resistance rapidly arises. We also know that when PARP inhibitors are combined with ARPIs such as abiraterone, they can have a synergistic effect. Recent data from the Phase II BRCAAway study showed that the median PFS on a combination of olaparib and abiraterone far exceeded that on either agent by itself. Our hypothesis is that the use of upfront abiraterone with niraparib in patients with HRR alterations will improve overall survival when compared to ADT and ARPI alone.
Mahaz Kayani: Patients will be eligible for this study if they have a known deleterious mutation in either BRCA1, BRCA2, or CDK12. Patients can have already started ADT or ARPI for up to six months, provided that there isn't any evidence of progression on either agent. In the trial, patients are randomized in a 1:1 fashion. In the investigational arm, they receive a single dual-action tablet, which contains both niraparib and abiraterone together. Patients in the control arm will receive an ARPI as decided by their physician. In addition to the trial treatments, the patients can also receive either docetaxel or local radiotherapy to the prostate, again, as decided by their own clinician. Finally, patients can also be co-enrolled into one of the other two comparisons of STAMPEDE2. So some patients will also receive either lutetium PSMA or SABR in addition to the investigational agents. The primary endpoint of this trial, unlike some of the other trials that you might have seen in this area, is overall survival.
So in conclusion, STAMPEDE2 niraparib and abiraterone will provide robust overall survival data for the benefit of using upfront PARP inhibition in combination with an ARPI agent for patients who harbor a BRCA1, BRCA2, or CDK12 mutation. Patients also have the option in this trial to co-enroll into one of the other comparisons of STAMPEDE2, so some of them will also receive lutetium or SABR. Thank you for listening.
Zachary Klaassen: Thank you both for that presentation. I think you mentioned STAMPEDE1 really has been transformational for advanced prostate cancer, and we're excited to see these new three arms from STAMPEDE2, specifically the one looking at niraparib and abiraterone. Just out of curiosity, there's been several combinations of PARP inhibitors and ARPIs. How did you guys decide on niraparib and abiraterone for this arm of the STAMPEDE2?
Mahaz Kayani: Our colleagues who treat ovarian cancers have much greater experience using PARP inhibitors than we do, and their feeling was that, certainly when it came to ovarian cancers, there was reasonable equivalence between the different agents. Therefore, we were quite agnostic when choosing the combination of PARP inhibitor and ARPI. There are also several other trials in this area, so AMPLITUDE and TALAPRO-3. Having said that, one of the advantages of the STAMPEDE2 platform is that in the future, if data emerges which suggests that another combination of PARP inhibitor and ARPI is superior to the one that we're testing, we could consider adding another comparison in to test that.
Zachary Klaassen: Yeah, that's great. And that's the beauty of the platform, right? You can just add additional arms, and if it's Enza plus something, we can always adapt to it, which is great. In terms of your selecting very stringently for BRCA1/2 or CDK12, were there discussions about having all comers enrolled in this trial or was it very specific in the design for these three mutations?
Mahaz Kayani: Again, we learned from STAMPEDE1 here where we saw that in the abiraterone arm, after seven years, about 20-25% of patients were still in disease remission. So actually, for lots of patients, we know that further treatment and intensification isn't necessarily needed, and we know that PARP inhibitors come with toxicity. So we thought it was really important to run a biomarker-selected trial, firstly to identify those poor prognosis patients that really need treatment intensification, but also to prevent other patients who won't benefit from getting needless toxicity.
Zachary Klaassen: Absolutely. Sarah, maybe I'll ask you about an update on the trial itself. How is enrollment going? Has it been about 15% are having these mutations? Maybe you can update us on the trial status.
Sarah Howlett: Excitingly, the other two comparisons within the platform—so P, which is testing lutetium, and S, which is testing SABR—are already open and actively recruiting. Unfortunately, we've still got a few things that we need to finalize amendment-wise with our regulators before we can open this comparison, but we're hoping to have that all finalized by the beginning of next year.
Zachary Klaassen: Wonderful. That's great. Great discussion. Again, this STAMPEDE2 platform is going to be so fun to watch over the next several years, and thank you both for joining us. Maybe a couple of take-home messages for our listeners today.
Sarah Howlett: I think what's really going to be useful from this trial is patients with these alterations, at this point, I don't think we have enough robust data to say that giving PARP inhibitors or platinum, different agents like that, is definitely the right strategy for them. And I think that this trial is going to provide patients with the right overall survival data to know that using these agents, particularly in the early versus late setting, is the right thing. And it's a really exciting opportunity for them to potentially, within the platform, receive a novel combination of treatments.
Zachary Klaassen: Yeah, absolutely. Thank you both for joining us. We'll look forward to this trial starting enrollment and certainly for the other two arms as well of STAMPEDE2.
Sarah Howlett: Great. Thanks for meeting with us.
Mahaz Kayani: Thank you for having us.