TALAPRO-2 Analysis: Talazoparib Enzalutamide Combo in Pretreated mCRPC - Neeraj Agarwal
September 30, 2024
Neeraj Agarwal discusses a post-hoc analysis of the TALAPRO-2 Phase III study, which evaluates the efficacy of talazoparib and enzalutamide in metastatic castrate-resistant prostate cancer patients with prior ARPI or docetaxel treatment. The analysis shows promising results for the combination therapy, particularly in patients with HRR-deficient tumors. Dr. Agarwal emphasizes the potential benefits of combining talazoparib and enzalutamide, even for patients previously treated with ARPI or docetaxel in the hormone-sensitive setting. They discuss the implications of these findings, including the potential extension of PARP inhibitor activity beyond BRCA1 and BRCA2 mutations. The conversation highlights the importance of implementing clinical evidence in practice and the need for further research to address remaining questions about the efficacy of this combination therapy in various patient subgroups.
Biographies:
Neeraj Agarwal, MD, FASCO, Professor, Presidential Endowed Chair of Cancer Research, Director GU Program, and the Center of Investigational Therapeutics (CIT), Huntsman Cancer Institute, University of Utah, Salt Lake City, UT
Oliver Sartor, MD, Medical Oncologist, Professor of Medicine, Urology and Radiology, Director, Radiopharmaceutical Trials, Mayo Clinic, Rochester, MN
Biographies:
Neeraj Agarwal, MD, FASCO, Professor, Presidential Endowed Chair of Cancer Research, Director GU Program, and the Center of Investigational Therapeutics (CIT), Huntsman Cancer Institute, University of Utah, Salt Lake City, UT
Oliver Sartor, MD, Medical Oncologist, Professor of Medicine, Urology and Radiology, Director, Radiopharmaceutical Trials, Mayo Clinic, Rochester, MN
Related Content:
ESMO 2024: Efficacy of Talazoparib and Enzalutamide in mCRPC Patients Previously Treated with Androgen Receptor Pathway Inhibitors or Docetaxel – Post Hoc Analysis from Both Cohorts in TALAPRO-2 Study
Beyond BRCA-1 and 2: The Impact of the TALAPRO-2 Study on Prostate Cancer Care - Cora Sternberg
ESMO 2024: Efficacy of Talazoparib and Enzalutamide in mCRPC Patients Previously Treated with Androgen Receptor Pathway Inhibitors or Docetaxel – Post Hoc Analysis from Both Cohorts in TALAPRO-2 Study
Beyond BRCA-1 and 2: The Impact of the TALAPRO-2 Study on Prostate Cancer Care - Cora Sternberg
Read the Full Video Transcript
Oliver Sartor: Hi, I am Dr. Oliver Sartor with UroToday. We have special updates from ESMO 2024. And with us is Neeraj Agarwal, Professor of Oncology at the Huntsman Cancer Center at University of Utah and head of their GU Cancer Group. So welcome, Neeraj.
Neeraj Agarwal: Thank you for having me.
Oliver Sartor: So let's hear a little bit about TALAPRO-2 updates.
Neeraj Agarwal: During the ESMO 2024 meeting, we presented the efficacy of talazoparib and enzalutamide in patients with mCRPC who had prior treatment with an ARPI or docetaxel. So this was a post-hoc analysis from both cohorts of the Phase III TALAPRO-2 study. So just for our audience's recollection, TALAPRO-2 trial tested the combination of enzalutamide plus talazoparib, a PARP inhibitor, versus enzalutamide plus placebo in patients with metastatic castrate-resistant prostate cancer. And they could not have received any treatment for mCRPC in the mCRPC setting, but they were allowed to receive docetaxel chemotherapy or an ARPI prior to onset of mCRPC. And this trial started accruing in about 2017–18, and we didn't have ARPI widely used in the mHSPC setting. So we decided to go back and look at the efficacy of the combination of talazoparib plus enzalutamide compared to enzalutamide in those patients who had received therapy intensification or combination therapy in the metastatic hormone-sensitive prostate cancer setting.
So again, I want to bring your attention to the fact that this is a post-hoc analysis and the number of patients is quite small in terms of who had received ARPI or docetaxel prior to onset of mCRPC. So this is the overall schema of the all-comer patient population, 805 patients total. And of these patients, 402 patients were randomized to talazoparib plus enzalutamide, and 403 patients were randomized to enzalutamide plus placebo. If you look at the number of patients who had received prior ARPI, 23 patients in the tala-enza arm and 86 patients had received docetaxel in the tala-enza arm. In the placebo enzalutamide arm, 27 patients had received ARPI, and 93 patients had received prior docetaxel chemotherapy. If you look at cohort two, which only focused on HRR-deficient patient population, again, patients with prior ARPI were 17, and patients with prior docetaxel were 57 in the tala-enza arm, and patients who had received ARPI were 17, and patients who had received prior docetaxel chemotherapy were 60 in the placebo enzalutamide arm.
So let's look at the efficacy data in these groups, in this all-comer patient population first. So again, all-comer patient population in the TALAPRO-2 trial, patients who had received prior ARPI. Here is the Kaplan-Meier curve with talazoparib plus enzalutamide versus enzalutamide. The hazard ratio is 0.57. It favors the combination. If you look at the patients who had received prior docetaxel chemotherapy prior to coming on the TALAPRO-2 study, again, we see that talazoparib plus enzalutamide seemed to provide a higher magnitude of benefit compared to placebo plus enzalutamide with a hazard ratio of 0.51.
Now let's move to the HRR-deficient patient population. So again, small numbers. So with that in mind, talazoparib plus enzalutamide seemed to provide a greater magnitude of benefit to these patients who had received prior ARPI and who had HRR-deficient prostate cancer with a hazard ratio of 0.53. Now, if you look at patients who had HRR deficiency and who had received prior docetaxel chemotherapy, again, talazoparib plus enzalutamide seemed to provide a higher magnitude of benefit compared to placebo plus enzalutamide with a hazard ratio of 0.39.
So we concluded that, again, I want to repeat, limited number of patients, post-hoc analysis. We concluded that talazoparib plus enzalutamide seemed to provide benefit regardless of whether patients have received ARPI or docetaxel in the hormone-sensitive setting compared to enzalutamide alone. And this benefit seemed to be present in the all-comer cohort in the TALAPRO-2 trial and in the HRR-deficient patient population.
Oliver Sartor: Thank you, Neeraj. There's some really interesting data here, and we're looking at some pretty significant hazard ratios, and in fact, 0.39 is, to me, quite outstanding. Now that's in the HRR-deficient population. But just to make clear that I understand it properly, when you're looking at all comers, that includes the HRR-deficient, correct?
Neeraj Agarwal: Yes.
Oliver Sartor: So when you come out to be 0.51 and you've got a rough number of patients, has there been an analysis of that non-HRR-deficient population in these various subsets? I mean, truly where we look at it in and of itself in non-HRR-deficient, because I think that's where a lot of the questions are. We're pretty convinced on the HRR side, but I think there's a lot of skepticism on the non-HRR side. And I wonder if you might elaborate just a little bit on that point.
Neeraj Agarwal: Absolutely. So first of all, again, these are small number of patients, post-hoc analysis. So with that in mind, if I look at the all-comers population, the hazard ratio was 0.57 favoring tala-enza in patients who had received prior ARPI in the hormone-sensitive setting, and it was exactly similar or 0.51 in patients who had received prior docetaxel in the all-comers patient population. There is no doubt that much of this benefit is driven by patients who have BRCA1, BRCA2 positivity. But if you look at the all-comers patient population, vast majority of patients did not have HRR deficiency. I would say out of 805 patients in the all-comers patient population, about 160 had HRR deficiency, and BRCA1 and BRCA2 patients were 5 to 6%, then they were not dominating the landscape of HRR deficiency.
So I would say again, hypothesis generating data, if I have a patient who had been exposed to abiraterone, and I'd like to remind our audience that only ARPIs which were allowed prior to enrollment into the TALAPRO-2 study were abiraterone. And because at that time orteronel was being tested in a SWOG trial, we also allowed orteronel, which is very similar to abiraterone without steroids. So patients were not allowed to have apalutamide or darolutamide, one of those potent AR inhibitors.
So with that point being addressed, if I have a patient who is slowly progressing on abiraterone and is on, if I'm contemplating enzalutamide for this patient and patient doesn't, say, patient is not willing to undergo chemotherapy in one of my clinical settings or is not eligible for chemotherapy, and if patient has HRR deficiency, because we only have approval for enza-tala right now in the US for HRR-deficient patient population. So if I have a patient with HRR deficiency and they have slowly progressing PSA level, PSA rise on abiraterone, and if I'm contemplating, if I'm considering enzalutamide, I'll definitely consider combining enzalutamide with talazoparib in this patient. So that would be my take from these data.
Oliver Sartor: Yeah, no, I was extremely impressed with some of the hazard ratios, particularly in the HRR mutated, admittedly dominated by the BRCA mutations. However, there were some other interesting alterations. It also seemed to show a pretty strong move towards significance, I mean, CDK12 which is quite frankly a pretty bad actor, and that came out well. This is not exactly on point here, but it's a big issue, I think, for the use of PARP inhibitors. If you look at talazoparib, do you believe that it's appropriate to extend the activity, at least from a conceptual perspective, beyond the BRCA1 and BRCA2, where I believe that's where the perception is most of the benefit may lie?
Neeraj Agarwal: Yes. So if you look at the TALAPRO-2 publication in the HRR-deficient cohort, it was published in Nature Medicine last year, Dr. Fizazi was the first author, we provided the efficacy data by individual subgroups and CDK12 was something which seemed to be benefiting with the hazard ratio of almost 0.5. PALB2 was another group, which definitely showed benefit with the combination. And again, I would like to bring this to our audience's attention that the trial was not powered to look for efficacy in individual subgroups. And you have done those trials, Oliver.
Oliver Sartor: Yeah.
Neeraj Agarwal: By the time we finish accruing, we are looking at, some of them have single-digit numbers. So definitely it's hard to glean, hard to have enough power for individual subgroups. But I definitely see some benefit of combining tala plus enza versus sequencing, which was further, there was a suggestion of benefit from the BRCAAway trial, for example, Maha presented the trial in GU-ASCO, and then we just published that in Clinical Cancer Research, abiraterone followed by olaparib versus olaparib followed by abiraterone in BRCA1, BRCA2, ATM-positive patients in mCRPC. The combined PFS was 16 months.
And if you look at abiraterone plus olaparib upfront combination, the PFS was 39 months. Again, it's a small group of patients, 20 patients in each arm. So again, hypothesis generating data, but it is impossible in my view, to do another trial sequencing these therapies in a timely fashion. So I would say based on BRCAAway trial data, based on the fact that 50%, and you have been part of those publications, the seminal publications when you showed in the real world, patients don't receive—half of the patients don't receive subsequent lines of therapies. So if I have a chance to combine drugs, especially with HRR-deficient patient population, I would like to do that.
Oliver Sartor: No, it certainly makes sense. Before we wrap up, any additional thoughts you'd like to share with our audience regarding these results presented at ESMO?
Neeraj Agarwal: Yes. I think implementation of medicine, implementation of clinical level one evidence from all trials is very important. We consistently see even ARPI is not being used in hormone-sensitive setting. So I think education is one of the most important tools we have to get these data to the community out there to many of our colleagues who may not have the luxury, simply speaking, to attend these big meetings or read those journal articles. Regarding this study in particular, this was a post-hoc analysis, sample sizes were small, but we did see some hint of benefit with the combination of enza plus tala despite prior use of ARPI or docetaxel. I don't think we'll be able to do a randomized trial asking this question in the near future, but these kinds of analysis do help me in making decision in my clinic.
Oliver Sartor: Thank you so much, Neeraj, Professor of Oncology at the Huntsman Cancer Center, University of Utah. Pleasure to have you on today.
Neeraj Agarwal: Thank you very much for having me.
Oliver Sartor: Hi, I am Dr. Oliver Sartor with UroToday. We have special updates from ESMO 2024. And with us is Neeraj Agarwal, Professor of Oncology at the Huntsman Cancer Center at University of Utah and head of their GU Cancer Group. So welcome, Neeraj.
Neeraj Agarwal: Thank you for having me.
Oliver Sartor: So let's hear a little bit about TALAPRO-2 updates.
Neeraj Agarwal: During the ESMO 2024 meeting, we presented the efficacy of talazoparib and enzalutamide in patients with mCRPC who had prior treatment with an ARPI or docetaxel. So this was a post-hoc analysis from both cohorts of the Phase III TALAPRO-2 study. So just for our audience's recollection, TALAPRO-2 trial tested the combination of enzalutamide plus talazoparib, a PARP inhibitor, versus enzalutamide plus placebo in patients with metastatic castrate-resistant prostate cancer. And they could not have received any treatment for mCRPC in the mCRPC setting, but they were allowed to receive docetaxel chemotherapy or an ARPI prior to onset of mCRPC. And this trial started accruing in about 2017–18, and we didn't have ARPI widely used in the mHSPC setting. So we decided to go back and look at the efficacy of the combination of talazoparib plus enzalutamide compared to enzalutamide in those patients who had received therapy intensification or combination therapy in the metastatic hormone-sensitive prostate cancer setting.
So again, I want to bring your attention to the fact that this is a post-hoc analysis and the number of patients is quite small in terms of who had received ARPI or docetaxel prior to onset of mCRPC. So this is the overall schema of the all-comer patient population, 805 patients total. And of these patients, 402 patients were randomized to talazoparib plus enzalutamide, and 403 patients were randomized to enzalutamide plus placebo. If you look at the number of patients who had received prior ARPI, 23 patients in the tala-enza arm and 86 patients had received docetaxel in the tala-enza arm. In the placebo enzalutamide arm, 27 patients had received ARPI, and 93 patients had received prior docetaxel chemotherapy. If you look at cohort two, which only focused on HRR-deficient patient population, again, patients with prior ARPI were 17, and patients with prior docetaxel were 57 in the tala-enza arm, and patients who had received ARPI were 17, and patients who had received prior docetaxel chemotherapy were 60 in the placebo enzalutamide arm.
So let's look at the efficacy data in these groups, in this all-comer patient population first. So again, all-comer patient population in the TALAPRO-2 trial, patients who had received prior ARPI. Here is the Kaplan-Meier curve with talazoparib plus enzalutamide versus enzalutamide. The hazard ratio is 0.57. It favors the combination. If you look at the patients who had received prior docetaxel chemotherapy prior to coming on the TALAPRO-2 study, again, we see that talazoparib plus enzalutamide seemed to provide a higher magnitude of benefit compared to placebo plus enzalutamide with a hazard ratio of 0.51.
Now let's move to the HRR-deficient patient population. So again, small numbers. So with that in mind, talazoparib plus enzalutamide seemed to provide a greater magnitude of benefit to these patients who had received prior ARPI and who had HRR-deficient prostate cancer with a hazard ratio of 0.53. Now, if you look at patients who had HRR deficiency and who had received prior docetaxel chemotherapy, again, talazoparib plus enzalutamide seemed to provide a higher magnitude of benefit compared to placebo plus enzalutamide with a hazard ratio of 0.39.
So we concluded that, again, I want to repeat, limited number of patients, post-hoc analysis. We concluded that talazoparib plus enzalutamide seemed to provide benefit regardless of whether patients have received ARPI or docetaxel in the hormone-sensitive setting compared to enzalutamide alone. And this benefit seemed to be present in the all-comer cohort in the TALAPRO-2 trial and in the HRR-deficient patient population.
Oliver Sartor: Thank you, Neeraj. There's some really interesting data here, and we're looking at some pretty significant hazard ratios, and in fact, 0.39 is, to me, quite outstanding. Now that's in the HRR-deficient population. But just to make clear that I understand it properly, when you're looking at all comers, that includes the HRR-deficient, correct?
Neeraj Agarwal: Yes.
Oliver Sartor: So when you come out to be 0.51 and you've got a rough number of patients, has there been an analysis of that non-HRR-deficient population in these various subsets? I mean, truly where we look at it in and of itself in non-HRR-deficient, because I think that's where a lot of the questions are. We're pretty convinced on the HRR side, but I think there's a lot of skepticism on the non-HRR side. And I wonder if you might elaborate just a little bit on that point.
Neeraj Agarwal: Absolutely. So first of all, again, these are small number of patients, post-hoc analysis. So with that in mind, if I look at the all-comers population, the hazard ratio was 0.57 favoring tala-enza in patients who had received prior ARPI in the hormone-sensitive setting, and it was exactly similar or 0.51 in patients who had received prior docetaxel in the all-comers patient population. There is no doubt that much of this benefit is driven by patients who have BRCA1, BRCA2 positivity. But if you look at the all-comers patient population, vast majority of patients did not have HRR deficiency. I would say out of 805 patients in the all-comers patient population, about 160 had HRR deficiency, and BRCA1 and BRCA2 patients were 5 to 6%, then they were not dominating the landscape of HRR deficiency.
So I would say again, hypothesis generating data, if I have a patient who had been exposed to abiraterone, and I'd like to remind our audience that only ARPIs which were allowed prior to enrollment into the TALAPRO-2 study were abiraterone. And because at that time orteronel was being tested in a SWOG trial, we also allowed orteronel, which is very similar to abiraterone without steroids. So patients were not allowed to have apalutamide or darolutamide, one of those potent AR inhibitors.
So with that point being addressed, if I have a patient who is slowly progressing on abiraterone and is on, if I'm contemplating enzalutamide for this patient and patient doesn't, say, patient is not willing to undergo chemotherapy in one of my clinical settings or is not eligible for chemotherapy, and if patient has HRR deficiency, because we only have approval for enza-tala right now in the US for HRR-deficient patient population. So if I have a patient with HRR deficiency and they have slowly progressing PSA level, PSA rise on abiraterone, and if I'm contemplating, if I'm considering enzalutamide, I'll definitely consider combining enzalutamide with talazoparib in this patient. So that would be my take from these data.
Oliver Sartor: Yeah, no, I was extremely impressed with some of the hazard ratios, particularly in the HRR mutated, admittedly dominated by the BRCA mutations. However, there were some other interesting alterations. It also seemed to show a pretty strong move towards significance, I mean, CDK12 which is quite frankly a pretty bad actor, and that came out well. This is not exactly on point here, but it's a big issue, I think, for the use of PARP inhibitors. If you look at talazoparib, do you believe that it's appropriate to extend the activity, at least from a conceptual perspective, beyond the BRCA1 and BRCA2, where I believe that's where the perception is most of the benefit may lie?
Neeraj Agarwal: Yes. So if you look at the TALAPRO-2 publication in the HRR-deficient cohort, it was published in Nature Medicine last year, Dr. Fizazi was the first author, we provided the efficacy data by individual subgroups and CDK12 was something which seemed to be benefiting with the hazard ratio of almost 0.5. PALB2 was another group, which definitely showed benefit with the combination. And again, I would like to bring this to our audience's attention that the trial was not powered to look for efficacy in individual subgroups. And you have done those trials, Oliver.
Oliver Sartor: Yeah.
Neeraj Agarwal: By the time we finish accruing, we are looking at, some of them have single-digit numbers. So definitely it's hard to glean, hard to have enough power for individual subgroups. But I definitely see some benefit of combining tala plus enza versus sequencing, which was further, there was a suggestion of benefit from the BRCAAway trial, for example, Maha presented the trial in GU-ASCO, and then we just published that in Clinical Cancer Research, abiraterone followed by olaparib versus olaparib followed by abiraterone in BRCA1, BRCA2, ATM-positive patients in mCRPC. The combined PFS was 16 months.
And if you look at abiraterone plus olaparib upfront combination, the PFS was 39 months. Again, it's a small group of patients, 20 patients in each arm. So again, hypothesis generating data, but it is impossible in my view, to do another trial sequencing these therapies in a timely fashion. So I would say based on BRCAAway trial data, based on the fact that 50%, and you have been part of those publications, the seminal publications when you showed in the real world, patients don't receive—half of the patients don't receive subsequent lines of therapies. So if I have a chance to combine drugs, especially with HRR-deficient patient population, I would like to do that.
Oliver Sartor: No, it certainly makes sense. Before we wrap up, any additional thoughts you'd like to share with our audience regarding these results presented at ESMO?
Neeraj Agarwal: Yes. I think implementation of medicine, implementation of clinical level one evidence from all trials is very important. We consistently see even ARPI is not being used in hormone-sensitive setting. So I think education is one of the most important tools we have to get these data to the community out there to many of our colleagues who may not have the luxury, simply speaking, to attend these big meetings or read those journal articles. Regarding this study in particular, this was a post-hoc analysis, sample sizes were small, but we did see some hint of benefit with the combination of enza plus tala despite prior use of ARPI or docetaxel. I don't think we'll be able to do a randomized trial asking this question in the near future, but these kinds of analysis do help me in making decision in my clinic.
Oliver Sartor: Thank you so much, Neeraj, Professor of Oncology at the Huntsman Cancer Center, University of Utah. Pleasure to have you on today.
Neeraj Agarwal: Thank you very much for having me.