Differential Treatment Responses Across HRR Gene Alterations in Prostate Cancer - Stefanie Zschäbitz
July 14, 2025
Neeraj Agarwal discusses the TALAPRO-2 gene-by-gene analysis with Stefanie Zschäbitz. The phase 3 trial demonstrated significant radiographic progression-free survival and overall survival benefits with talazoparib plus enzalutamide versus enzalutamide alone in first-line metastatic castration-resistant prostate cancer patients. Dr. Zschäbitz's analysis focused on 92% of HRR-mutant patients harboring alterations in six key genes: BRCA1, BRCA2, ATM, CHEK2, CDK12, and PALB2. All six gene subgroups showed RPFS benefit from combination therapy, with five of six demonstrating overall survival improvement. Unexpectedly, CDK12-mutated patients performed exceptionally well, contrasting with historical PARP monotherapy data, suggesting dual androgen receptor and PARP targeting enhances efficacy. PSA response rates exceeded 80% across all gene groups with combination therapy versus 51-71% with placebo. The 14-month absolute overall survival benefit in HRR-positive patients extends beyond BRCA1/2 to most common HRR mutations, emphasizing the critical importance of comprehensive genomic testing.
Biographies:
Stefanie Zschäbitz, PD, MD, Senior Physician, Department of Medical Oncology, National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany
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
Biographies:
Stefanie Zschäbitz, PD, MD, Senior Physician, Department of Medical Oncology, National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany
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
Related Content:
ASCO 2025: Exploratory Analyses of Homologous Recombination Repair Alterations by Gene Subgroup and Potential Associations with Efficacy in the HRR-Deficient Population from TALAPRO-2
Talazoparib Improves Survival in HRR-Mutated mCRPC Patients in TALAPRO-2 Trial - Karim Fizazi
TALAPRO-2 Analysis: Talazoparib Enzalutamide Combo in Pretreated mCRPC - Neeraj Agarwal
ASCO 2025: Exploratory Analyses of Homologous Recombination Repair Alterations by Gene Subgroup and Potential Associations with Efficacy in the HRR-Deficient Population from TALAPRO-2
Talazoparib Improves Survival in HRR-Mutated mCRPC Patients in TALAPRO-2 Trial - Karim Fizazi
TALAPRO-2 Analysis: Talazoparib Enzalutamide Combo in Pretreated mCRPC - Neeraj Agarwal
Read the Full Video Transcript
Neeraj Agarwal: Hi. My name is Dr. Neeraj Agarwal. I'm a professor of medicine and director of genitourinary oncology program at the University of Utah Huntsman Cancer Hospital. I'd like to welcome Dr. Stefanie Zschäbitz, medical oncologist at the Heidelberg University Hospital in Germany. Welcome, Stefanie
Stefanie Zschäbitz: Welcome. Thanks for having me.
Neeraj Agarwal: So first of all, I'd like to congratulate you on your oral presentation on the gene by gene analysis from the TALAPRO-2 phase 3 trial. So please tell us about the trial first, the overall results just for our audience. And then we can talk about the data being presented at the ASCO 2025 meeting.
Stefanie Zschäbitz: So TALAPRO-2 is a phase 3 study that recruited patients with first line mCRPC who were mildly or asymptomatic. And patients were first recruited in an all-comer fashion but prospectively tested for HRR alterations, and later on, only patients whose tumors harbored HRR alterations could participate.
Patients from cohort 1 are all-comers, and patients from cohort 2 are patients who have HRR altered tumors.
Patients were randomized 1 to 1 and received either enzalutamide plus talazoparib or enzalutamide plus placebo. The primary endpoint of this study was RPFS, and the key secondary endpoint was overall survival. And both showed that there was a statistically significant improvement for both endpoints and for both cohorts actually.
Neeraj Agarwal: Wonderful. So addition of talazoparib to enzalutamide led to a significantly improved radiographic progression free survival and overall survival in all-comer patient population with metastatic CRPC newly diagnosed mCRPC as well as patients who were harboring homologous recombination repair mutations in the tumors. So tell us about the data you are presenting in the ASCO 2025 meeting.
Stefanie Zschäbitz: So in this presentation, I showed exploratory biomarker analysis gene by gene analysis for patients with HRR mutant tumors, patients from cohort 2. And we were looking at markers of efficacy, RPFS, OS, overall response rate, time to PSA progression, and PSA response.
Neeraj Agarwal: So please tell us about what did you find. We expect patients with BRCA1 and BRCA2 mutations to be doing the best, but please tell us about other genes as well in addition to the BRCA1 and BRCA2.
Stefanie Zschäbitz: So 92% of the study population from cohort 2 had a gene mutation in one of six genes, that was BRCA1, BRCA2, ATM, CHEK2, CDK12, and PALB2. We focused on these six biogene subgroups to have reasonable numbers of patients to look into.
And we prospectively tested and we used all data that we had at screening or prescreening for those patients ctDNA and tumor tissue. And we were looking at those endpoints that I just said, exploratory endpoints. And we found that especially in BRCA1 and BRCA2, those patients had a huge benefit in favor for the combination.
But also if those patients had other mutations, they had a benefit when they used combination of tala plus enza versus placebo plus enza. So for RPFS, all 6 biogene subgroups showed that the combination was in favor. For OS, five of the six subgroups showed a benefit for one subgroup, the hazard ratio was close to 1.
And one interesting finding was that especially patients with CDK12 mutations did exceptionally well, which is a little bit in contrast to what we have seen prior with monotherapy of PARP inhibition. And we hence assume that potentially due to the dual effect of targeting the androgen receptor and PARP, this effect might have been visible.
Neeraj Agarwal: So this is quite striking that results are favoring the talazoparib plus enzalutamide not only in BRCA1 and BRCA2 2, but most of the other common HRR gene mutations, including CDK12, which is historically considered not so responsive to PARP inhibitor therapy in the past. And we saw the radiographic progression free survival data from the RPF for the CDK12 cohort.
But this time you are also showing the favorable trends or favorable overall survival with the combination in all these genes, in addition to CDK12 and BRCA1 and BRCA2.
Stefanie Zschäbitz: When we look at PSA response, for example, we see that the PSA response is above 80% for all of the six biogene groups, whereas when patients only received enza and placebo, the PSA response is between 51 and 71%. So again, we see that also for this exploratory endpoint the combination is beneficial.
Neeraj Agarwal: So just for our audience today, the overall survival benefit, if you look at the patients with homologous recombination repair mutations, the overall survival benefit was 14 months absolute survival benefit in HRR mutation positive patients. And we saw BRCA1 and BRCA2 positive patients to be benefiting the most. But now you are showing that the benefit is extending to pretty much all other common HRR mutations.
Stefanie Zschäbitz: Yes, That's true.
Neeraj Agarwal: And it is consistently seen across the response endpoints. So radiographic progression free survival, overall survival, and PSA responses.
Stefanie Zschäbitz: Yes, that's true.
Neeraj Agarwal: Any other comment before we conclude today from the perspective of testing specifically?
Stefanie Zschäbitz: I think testing is still very important. We need to know what the prognosis of our patients is and also counsel the families if it is relevant for them. So I still would think that testing is very important, but we see that it's not only the BRCA1, BRCA2 altered patient population that has some benefit of the combination of talazoparib plus enzalutamide.
Neeraj Agarwal: We need to work on genomic testing of these patients and germline testing. And it is surprising to me personally that almost all guidelines, whether it is ASCO guidelines or NCCN guidelines or AUA guidelines, and I'm sure guidelines in Europe, in Germany, all of the guidelines endorse testing for tumor genomic mutations and germline pathogenic variants.
But unfortunately, a substantial number of patients are not being tested despite having such major implications from the therapeutic perspective and from the perspective of effect on their families. So well, thank you very much for joining us today, and congratulations again for your oral presentation.
Stefanie Zschäbitz: Thank you.
Neeraj Agarwal: Hi. My name is Dr. Neeraj Agarwal. I'm a professor of medicine and director of genitourinary oncology program at the University of Utah Huntsman Cancer Hospital. I'd like to welcome Dr. Stefanie Zschäbitz, medical oncologist at the Heidelberg University Hospital in Germany. Welcome, Stefanie
Stefanie Zschäbitz: Welcome. Thanks for having me.
Neeraj Agarwal: So first of all, I'd like to congratulate you on your oral presentation on the gene by gene analysis from the TALAPRO-2 phase 3 trial. So please tell us about the trial first, the overall results just for our audience. And then we can talk about the data being presented at the ASCO 2025 meeting.
Stefanie Zschäbitz: So TALAPRO-2 is a phase 3 study that recruited patients with first line mCRPC who were mildly or asymptomatic. And patients were first recruited in an all-comer fashion but prospectively tested for HRR alterations, and later on, only patients whose tumors harbored HRR alterations could participate.
Patients from cohort 1 are all-comers, and patients from cohort 2 are patients who have HRR altered tumors.
Patients were randomized 1 to 1 and received either enzalutamide plus talazoparib or enzalutamide plus placebo. The primary endpoint of this study was RPFS, and the key secondary endpoint was overall survival. And both showed that there was a statistically significant improvement for both endpoints and for both cohorts actually.
Neeraj Agarwal: Wonderful. So addition of talazoparib to enzalutamide led to a significantly improved radiographic progression free survival and overall survival in all-comer patient population with metastatic CRPC newly diagnosed mCRPC as well as patients who were harboring homologous recombination repair mutations in the tumors. So tell us about the data you are presenting in the ASCO 2025 meeting.
Stefanie Zschäbitz: So in this presentation, I showed exploratory biomarker analysis gene by gene analysis for patients with HRR mutant tumors, patients from cohort 2. And we were looking at markers of efficacy, RPFS, OS, overall response rate, time to PSA progression, and PSA response.
Neeraj Agarwal: So please tell us about what did you find. We expect patients with BRCA1 and BRCA2 mutations to be doing the best, but please tell us about other genes as well in addition to the BRCA1 and BRCA2.
Stefanie Zschäbitz: So 92% of the study population from cohort 2 had a gene mutation in one of six genes, that was BRCA1, BRCA2, ATM, CHEK2, CDK12, and PALB2. We focused on these six biogene subgroups to have reasonable numbers of patients to look into.
And we prospectively tested and we used all data that we had at screening or prescreening for those patients ctDNA and tumor tissue. And we were looking at those endpoints that I just said, exploratory endpoints. And we found that especially in BRCA1 and BRCA2, those patients had a huge benefit in favor for the combination.
But also if those patients had other mutations, they had a benefit when they used combination of tala plus enza versus placebo plus enza. So for RPFS, all 6 biogene subgroups showed that the combination was in favor. For OS, five of the six subgroups showed a benefit for one subgroup, the hazard ratio was close to 1.
And one interesting finding was that especially patients with CDK12 mutations did exceptionally well, which is a little bit in contrast to what we have seen prior with monotherapy of PARP inhibition. And we hence assume that potentially due to the dual effect of targeting the androgen receptor and PARP, this effect might have been visible.
Neeraj Agarwal: So this is quite striking that results are favoring the talazoparib plus enzalutamide not only in BRCA1 and BRCA2 2, but most of the other common HRR gene mutations, including CDK12, which is historically considered not so responsive to PARP inhibitor therapy in the past. And we saw the radiographic progression free survival data from the RPF for the CDK12 cohort.
But this time you are also showing the favorable trends or favorable overall survival with the combination in all these genes, in addition to CDK12 and BRCA1 and BRCA2.
Stefanie Zschäbitz: When we look at PSA response, for example, we see that the PSA response is above 80% for all of the six biogene groups, whereas when patients only received enza and placebo, the PSA response is between 51 and 71%. So again, we see that also for this exploratory endpoint the combination is beneficial.
Neeraj Agarwal: So just for our audience today, the overall survival benefit, if you look at the patients with homologous recombination repair mutations, the overall survival benefit was 14 months absolute survival benefit in HRR mutation positive patients. And we saw BRCA1 and BRCA2 positive patients to be benefiting the most. But now you are showing that the benefit is extending to pretty much all other common HRR mutations.
Stefanie Zschäbitz: Yes, That's true.
Neeraj Agarwal: And it is consistently seen across the response endpoints. So radiographic progression free survival, overall survival, and PSA responses.
Stefanie Zschäbitz: Yes, that's true.
Neeraj Agarwal: Any other comment before we conclude today from the perspective of testing specifically?
Stefanie Zschäbitz: I think testing is still very important. We need to know what the prognosis of our patients is and also counsel the families if it is relevant for them. So I still would think that testing is very important, but we see that it's not only the BRCA1, BRCA2 altered patient population that has some benefit of the combination of talazoparib plus enzalutamide.
Neeraj Agarwal: We need to work on genomic testing of these patients and germline testing. And it is surprising to me personally that almost all guidelines, whether it is ASCO guidelines or NCCN guidelines or AUA guidelines, and I'm sure guidelines in Europe, in Germany, all of the guidelines endorse testing for tumor genomic mutations and germline pathogenic variants.
But unfortunately, a substantial number of patients are not being tested despite having such major implications from the therapeutic perspective and from the perspective of effect on their families. So well, thank you very much for joining us today, and congratulations again for your oral presentation.
Stefanie Zschäbitz: Thank you.