Oliver Sartor: Hi, I'm Dr. Oliver Sartor. I'm with the UroToday and it's truly a pleasure to have Neeraj Agarwal who needs no introduction, but I'm going to introduce him anyway. Neeraj is professor in the Huntsman Cancer Center at the University of Utah, has a variety of leadership positions. I won't give all of his titles, but Neeraj, welcome to UroToday for the maybe 120th time.

Neeraj Agarwal: Thank you, Oliver. It's such a pleasure to be here with you.

Oliver Sartor: I really wanted to focus today on the TALAPRO-2 trial and the overall survival. I thought it was interesting, and I think our readers should understand that and who better to explain than you. So I wonder if you can tell us a little bit about the trial, a little bit about the overall survival, and maybe some gene-by-gene analysis. And first, I'll ask any questions that might arise in the meantime.

Neeraj Agarwal: Very happy to do that. Thank you, Oliver. Very happy to talk about the overall survival results from the talazoparib plus enzalutamide combination trial in patients with metastatic castration-resistant prostate cancer. As we know, this was a phase 3 TALAPRO-2 trial, which led to approval of the combination of talazoparib plus enzalutamide for our patients in 2023. Before we delve into the results, I'd like to bring our audience's attention to this design of the trial.

So first of all, who are these patients? Patients have metastatic castration-resistant prostate cancer who were newly diagnosed mCRPC, who had to have an ECOG performance status of zero to one. They had to be on continuous androgen deprivation therapy. They could have received prior abiraterone or docetaxel, and the stratification factors, including prior treatment with intensification therapy in metastatic hormone-sensitive prostate cancer and the HRR gene alteration status by deficient versus non-deficient or unknown.

So this is the schema in front of us. Patients were randomized to talazoparib plus enzalutamide versus an active control of enzalutamide. There were two cohorts. Cohort one was recruited first; these were all-comer patients. They didn't get recruited based on whether they had HRR positivity or negativity. So all-comer patient population. After this enrollment was completed, HRR-deficient cohort was recruited, so there were 800 patients in all-comer patient population, and then 400 patients in the HRR-deficient cohort. Radiographic progression-free survival by blinded independent review was the primary endpoint, and overall survival was a key alpha-protected endpoint.

And here we can see the genes HRR gene alterations, which were eligible to be included under the HRR-deficient cohort. And these included the common ones as we know, BRCA1, BRCA2, ATM, CDK12, and many more. So I'll get to that later. So now coming to the radiographic progression-free survival results, we did update these results in all-comer patient population.

And as we can see here, there was a 14-month improvement in radiographic progression-free survival in this all-comer patient population from 19 months, which we expect based on the data from the PREVAIL trial with enzalutamide alone versus 33 months with the combination.

Now let's look at the overall survival. If you look at the overall survival data in all-comer patient population, there was about nine-month improvement in overall survival, which went from 37 months with enzalutamide alone to 46 months, 45.8 months to be more precise, with a hazard ratio of 0.79. So about 20% reduction in risk of that, this is significant statistically speaking.

Now, let's look at the overall survival by HRR alteration status. So I would like to bring your attention to those patients first. And this is exploratory analysis because ctDNA and tumor tissue both were used to determine HRR negative status. So if you just look at those patients who did not have HRR gene alterations by both ctDNA and tumor tissue, the median survival went up from 37.4 months to 46.6 months, about 22% reduction in risk of death.

Now, let's look at the patients who are HRR-deficient and what is the overall survival status in those patients. So just quite remarkable to see that patients who were HRR-deficient, the median overall survival was improved by 14 months. So the median was 31 months in patients who got enzalutamide alone, and it was 45 months in patients who received enzalutamide plus talazoparib with a 40% reduction in risk of death by adding talazoparib to enzalutamide. And briefly, quality of life was maintained in both cohorts. There was no compromise in quality of life. And I do like to talk about the side effect profile, which was dominated by anemia in these patients, about 45% of these patients, so 49% in all-comer patient population, and 43% of patients who were in HRR-deficient cohort had grade three, four anemia.

Now, I like to bring your attention to the fact that only a small number of patients had to discontinue because of anemia. So based on my personal experience and the data from the clinical trial, the anemia, the grade three anemia happens three to four months after starting treatment, which led to dose modifications, mostly decreasing the dose by one level. And once we do that, these patients are able to tolerate the combination for a long time as evident by a lower discontinuation rate of these patients because of anemia.

And again, this is a side effect profile snapshot of the side effect profile in both cohorts. I would also like to bring your attention to the more common side effects which are associated with detriment of quality of life. If you look at nausea, vomiting, falls, fatigue, grade 3 were quite low in single digits. So based on that, what we saw... Again, reflecting the same side effect profile, we saw that quality of life as depicted here in both arms, cohort 1 and cohort 2, there was no compromise in the quality of life which was maintained while these patients were experiencing benefit in survival outcomes.

So to conclude, talazoparib plus enzalutamide improves overall survival compared to enzalutamide alone in both all-comer patient population and in patients with HRR-deficient patient population. Now you brought up this interesting point of gene-by-gene analysis. So I will take a moment to talk about gene-by-gene analysis. So Dr. Stefanie Zschäbitz from Germany presented these data in the oral presentation in ASCO 2025. So I'll come straight to the gene-by-gene analysis. So if you look at the more common genes, such as BRCA1, BRCA2, ATM, CDK12, PALB2, CHEK2, again, the trial is not covered for individual genes, but we just look at ATM, for example. There was a 12-month improvement in radiographic progression-free survival in the ATM category. Like patients who had ATM mutations.

BRCA2 obviously, is the most powerful player here, a 75% reduction in risk of progression. BRCA1, again, you can see 60% reduction in risk of progression. What was striking was the CDK12-positive patients. Again, quite remarkable improvement with the hazard ratio of 0.35. So about 65% reduction risk of progression. And PALB2 is another one we know is associated with response to PARP inhibitors. And again, quite striking improvement. Of course, not powered, but hazard ratio gives us an indication of the direction of RPFS benefit. Overall survival benefit. Again, not powered for individual subgroups, but we do see a consistent trend in the hazard ratio. The direction of OS benefit favors talazoparib plus enzalutamide versus enzalutamide.

And again, these are the objective responses by individual gene subsets. Time to PSA progression by individual gene subsets. We know that time to PSA progression is quite meaningful to our patients because we often do not do scans every three months in regular practice for many of these patients. So if you look at the time to PSA progression in, say, ATM mutation-positive patients, it was about 20 months delay in time to PSA progression in these patients.

BRCA1, 21-month delay, BRCA2, the time to PSA progression is not even reached. So again, very similar, consistent with what we have seen with radiographic progression-free survival and overall survival data. We see consistent results in time to PSA progression and time to PSA responses. With that, I'd like to conclude that enzalutamide plus talazoparib is an effective treatment option for patients who have metastatic castration-resistant prostate cancer. And who in the US have HRR gene mutations because this is how FDA has approved the combination is for HRR mutation-positive metastatic CRPC patient population.

But because the combination is also approved in many countries, regardless of HRR mutations, I do like to mention that we did see benefit in those patients who did not have HRR mutations and the benefit expands beyond BRCA1 and BRCA2 cohorts.

Oliver Sartor: Thank you very much, Neeraj. Beautiful overview of the TALAPRO-2. Let me ask you a couple of questions. One of the things is that the abiraterone was allowed within the context of the hormone-sensitive. How many of the patients actually had abiraterone prior to initiating treatment on the trial?

Neeraj Agarwal: About 6%. And the trial started enrolling in 2000... It was late 2000 about... I would say 2019, 2018. And as we know, the ARPIs, which were approved in around that time for metastatic hormone-sensitive prostate cancer, we just did not have sufficient number of ARPI-treated patients. But as we know, there are many trials which have already started, which are going to be treating patients with limited duration ARPI. And these patients have not typically progressed on ARPI. We do have a lot of patients who start ARPI but discontinue for non-progression. For example, intermittent therapy trials are coming up. So I do think there are going to be a lot of patients who have not progressed on ARPI and simply speaking, where we are contemplating using enzalutamide. This is an effective strategy for these patients.

Oliver Sartor: Interesting. So one of the things that was a bit of a surprise to me was not the BRCA2, where we have beautiful data to indicate that the PARP inhibitor is extremely active, but the CDK12 was the one that really caught my attention because typically CDK12 we know is a bad actor. It's a fairly common mutation, yet we didn't have the other PARP inhibitors seemingly show much in the way of activity here. And I wonder if you might comment on the CDK12 subset, which I found particularly interesting.

Neeraj Agarwal: Yeah, I agree with you. I don't know what else to add, what else to say beyond what you have already said. The combination seemed to be efficacious in some of the gene subsets, going beyond BRCA1, BRCA2. And we saw the example of CDK12. We saw the example with PALB2, and there are other subsets like RAD51, RAD54, which we didn't even present because of the lower number of patients. But definitely, there is an activity of the combination.

And I like to use this opportunity to mention that based on my experience with these patients over time, such as patients who do not have any HRR mutations by both ctDNA or tumor tissue testing. And we saw an absolute nine-month improvement in overall survival benefit even in those patients. This combination seemed to exploit the synergy between the AR pathway and PARP pathway inhibition. And we know the data started coming up in 2012, Dr. Karen Knudsen and our colleagues, I think the first author, they presented the first data of the combination, the efficacy or synergy, if you will, of these two pathways and both are targeting together. And then we saw BRCAAway trial. If I may use this opportunity to talk briefly about BRCAAway. Again, not a large trial, it was an IIT study started by us.

Dr. Maha Hussain was the PI, and we saw that if you looked at abiraterone followed by olaparib, olaparib followed by abiraterone, or upfront combination of abiraterone plus olaparib in patients who had BRCA1, BRCA2 or ATM mutations. We saw the combined PFS with abiraterone followed by olaparib or olaparib followed by abiraterone, was 16 months. But if you look at the PFS of abiraterone plus olaparib, it was 39 months. Based on that, I think it's a synergy between these two pathways, which is creating this signal of efficacy in patients who do not have BRCA1, BRCA2 mutations who have these other mutations, and even in those patients who do not have any of these mutations.

Oliver Sartor: Interesting, Neeraj. We're going to need to finish it up here in just a moment. You've given a comprehensive overview talking about the eligibility, the individual genes involved, overall survival, gene-by-gene analysis, toxicity, adverse events. Thank you for that presentation. Any final comment you'd like to make for our audience?

Neeraj Agarwal: I think the most important thing is the testing. I personally think the NGS testing is not being done in the community out there. We presented from the flat iron database, which is the patient-level database directly extracted from the electronic medical record of large cancer hospitals. We are not talking about clinics who do not have electronic medical records, solo oncology practices, or small urology practices. These are large cancer centers. 27% of patients with metastatic castration-resistant prostate cancer underwent NGS testing. And we know that NGS testing results are not only to select patients for PARP inhibitors.

We see 5% of these patients with MSI-high TMB-high patients who achieve beautiful responses. You have published the paper on ctDNA-based MSI status and response to pembrolizumab. And now we also know that several other targeted therapies which are being tested and will be approved in the near future. And more importantly, about one-third of these patients who have tumor NGS testing-based HRR mutations have germline mutations, which can have implications, devastating implications, if you will, on family members, on their daughters, sisters, sons, and brothers. And I think it's so more important to do perform NGS testing in our patients and to see only 27% of patients getting NGS testing in 2022 and '23. I think we should do better on that.

Oliver Sartor: Thank you, Neeraj. A pleasure to listen to an expert in the field, somebody with vast clinical trial experience, vast genetic experience, and a real expert in prostate cancer. Thank you, Neeraj.

Neeraj Agarwal: Thank you for having me today.