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Oliver Sartor: I'm here at ASCO GU 2025 and have a very well-known guest, Neeraj Agarwal, professor of oncology at University of Utah, a long-time friend and colleague. Welcome, Neeraj.

Neeraj Agarwal: Thank you for having me. Such a pleasure and an honor.

Oliver Sartor: You are the one that we need to honor because you've just presented a really big trial with talazoparib and enzalutamide. But before we get into the trial, I just want to back up just a little bit because not everybody might know talazoparib. So let's start off with the experimental compound that is actually FDA approved already. But make sure people know what we're dealing with here.

Neeraj Agarwal: So talazoparib is an inhibitor of poly ADP ribose polymerase. We also call it PARP. And it is already approved for treatment of patients with breast cancer and ovarian cancer. Its entry in the prostate cancer field, more specifically in the metastatic castration resistant prostate cancer field, is quite recent, and it only happened last year after the primary results of the TALAPRO-2 trial, which was a phase III trial we'll be talking about in a moment, showed positive radiographic progression free survival results.

And then talazoparib was approved for patients with metastatic CRPC in 2023, in combination with enzalutamide, which is a way more commonly known drug as an androgen receptor pathway inhibitor. So we will be talking about mostly combination because talazoparib does not have monotherapy approval for patients with metastatic castration resistant prostate cancer.

Oliver Sartor: Going back to the approval just for a minute. It's not approved in everyone. It's approved in some folks. And I wonder if you could clarify that for our listeners.

Neeraj Agarwal: Yes, so talazoparib plus enzalutamide is currently approved for patients with metastatic castration resistant prostate cancer in the US, only for those patients who have these DNA repair gene defects, as evident by the presence of homologous recombination repair mutations, and these are about 20% to 25% of total patients with mCRPC.

Oliver Sartor: Got it. So the background is FDA-approved drug with an HRR-mutated metastatic CRPC in combination with enzalutamide. Now, before we get to the trial design, let's talk a little bit about the dose of talazoparib, which is different when given with enzalutamide as compared to, say, monotherapy in ovarian. So I just want to set that stage a little bit to help people prepare who might be listening.

Neeraj Agarwal: That's such a great point. I'm so glad you brought this up. So when we combined talazoparib with enzalutamide in the phase I trial, which happened about seven years ago, the talazoparib level went up in plasma by twofold. So obviously, that level is not acceptable because it was causing anemia in pretty much all those patients.

So based on the PK data or pharmacokinetic data, we decreased the dose of talazoparib from 1 milligram orally daily to 0.5 milligrams. And then when we did that in combination with enzalutamide, the blood level of talazoparib went down to those levels which we would expect from talazoparib 1 milligram monotherapy doses.

Oliver Sartor: Got it. Thank you for that clarification. And I'm just trying to set the stage. Now, we get to the really important part. You had an oral presentation. Congratulations. Only reserved for the very top of the abstracts accepted here at ASCO GU. Tell us a little bit about your oral presentation with TALAPRO-2.

Neeraj Agarwal: So phase III trial, which randomized patients with newly diagnosed metastatic castration resistant prostate cancer, meaning they could not have received any treatment for castration resistant disease. They were randomized 1 to 1 to talazoparib plus enzalutamide versus placebo plus enzalutamide. There were a total of 800 patients, and randomization was stratified by prior receipt of abiraterone or docetaxel chemotherapy, which was just picking up when we started the trial, or presence of HRR-deficient status, meaning presence of HRR mutations, versus absence or unknown status of HRR gene mutations.

And the trial had a primary endpoint of radiographic progression free survival. But overall survival, which I presented in this 2025 GU ASCO, was a key secondary alpha-protected endpoint. So statistically, the trial was designed to independently answer the results on the overall survival.

Oliver Sartor: Now, let's talk a little bit more about the patient presentation in the beginning. So these were no prior metastatic CRPC treatment. How many patients had had an ARPI prior to reaching the metastatic CRPC state, and how many had docetaxel? Just so we can understand, was this ADT monotherapy? Was ADT docetaxel precursor? Tell us a little more about the actual patients who enrolled.

Neeraj Agarwal: Great question, again. So about 21% of patients had either docetaxel or ARPI. As we know, these therapies were used separately in those days. We did not have triplet therapy data. And about 15% to 16% of these patients received docetaxel in the hormone sensitive setting. And about 6% of patients received abiraterone, so a small number of patients.

Oliver Sartor: So predominant ADT monotherapy going into metastatic CRPC. First exposure to an ARPI, given in combination here with the talazoparib, an all-comers cohort with various segmentations according to stratification. That's--

Neeraj Agarwal: Right.

Oliver Sartor: OK, good.

Neeraj Agarwal: And I'd just like to add, 20% of these patients had HRR mutations out of a total 805 patients, which pretty much reflects what we would expect in an all-comers mCRPC patient population.

Oliver Sartor: And maybe to drill down just a tiny bit further, we know that it will probably be BRCA2 as a predominant. And then things like ATM, CDK12, CHEK2—just run through the top mutations that qualified for the trial.

Neeraj Agarwal: Yes. So BRCA2, BRCA1 were 7% of these patients. And then CDK12, ATM, PALB2, all those mutations which we know.

Oliver Sartor: A little bit more.

Neeraj Agarwal: Yeah, in that order. And they were evenly balanced between the two arms, as you would expect from a randomized trial.

Oliver Sartor: Yeah. I've been giving you a tough time on all the preliminary information, because I think you have to get your mind set around different things, like how many HR, how much precursor treatment there might have been, et cetera. So I hope I've not been interfering with your flow of thought, but let's get down to the meat of the story and the punchlines that are the takeaways from your presentation.

Neeraj Agarwal: Yeah. So first of all, radiographic progression free survival update, which was also one of the reasons for this presentation—we finally got the medians, which really helps with our patients when we are talking to them. So the median radiographic progression free survival is 33 months in the combination arm with enzalutamide plus talazoparib. It's 19.5 months—this is what we would expect from enzalutamide monotherapy—in the control arm. Very similar to the PREVAIL trial.

Oliver Sartor: Very similar.

Neeraj Agarwal: Thirty-three percent reduction in risk of progression or death with RPFS. So this is the median for our patients. And then if you look at overall survival, there was about 20% decrease in the risk of death. Hazard ratio 0.79. And if you look at absolute medians, which our patients like to hear, about nine months' improvement in survival—median overall survival with the addition of talazoparib to enzalutamide.

Oliver Sartor: So you ended up with a hazard ratio. Two questions. Is that statistically significant, number one? And number two is, what are the actual medians in the two groups?

Neeraj Agarwal: Yeah, and which really helps our patients to put things in perspective. So yes, hazard ratio is statistically significant and did not reach confidence interval of 1. It was less than 1. And the median values are 45.4 months in the experimental arm and about 37 months in the control arm. So 8.8 months, close to nine months, of improvement in overall survival.

Oliver Sartor: Nice. That's nice work. So first of all, congratulations. And obviously, oral presentation here at ASCO GU 2025 and an overall survival that is reporting positive in the intent-to-treat analysis. So that's really important.

Now, let's talk about some of the adverse events, and then we'll drill down on some of the stratification factors.

Neeraj Agarwal: Adverse events were mostly anemia and neutropenia. Before I get there, I would like to mention that the adverse events of special interest—we all worry about AML, MDS. So we had previously reported that when we reported the radiographic progression free survival two years ago, one case of AML and one case of MDS had happened. And after two more years of follow-up at the data cutoff, we didn't see any more patients with MDS or AML, which was quite comforting.

And if you talk about the most common adverse events which were treatment emergent, anemia and neutropenia were the most common. And anemia, I would like to highlight anemia because it was quite common. Forty-nine percent of these patients developed grade 3, 4 anemia.

And while I'm talking about this, I'd like to give some background on anemia. Forty-nine percent of these patients had baseline grade 1 to 2 anemia, and 49% of these patients developed grade 3, 4 anemia after a median of 3.3 months. So it happened pretty early. And then after that, patients underwent protocol-mandated dose reduction.

So before that, the protocol didn't require dose reduction to optimize dosing. And once the dose was reduced, the patients were able to tolerate talazoparib pretty well, in my view, as evidenced by a relatively long median duration of treatment with talazoparib. It was 19.7 months, about 20 months, and only 8.5% of patients ultimately discontinued talazoparib because of anemia.

So just for our viewers, anemia is something we need to watch for because nausea, vomiting, anorexia, which are maybe associated with other PARP inhibitors more commonly, are quite rare with talazoparib. So for anemia, I like to see my patients—or at least follow the CBC every month. And patients who are drifting down quickly—because only half of these patients will develop grade 3, 4 anemia, so half will not—so I will not preemptively reduce the dose. I will see who is drifting down quickly and then reduce the dose before they reach maybe grade 3 or 4.

Oliver Sartor: And leukopenia is relatively rare, thrombocytopenia is relatively rare?

Neeraj Agarwal: Correct.

Oliver Sartor: OK.

Neeraj Agarwal: Yeah, and we never use growth factors for neutropenia or low platelets.

Oliver Sartor: Good. Stratification factors. A lot of people have their eyes on this trial, because we already have the HRR-mutated indication approved by the FDA, but we don't have the all-comers. And so go through the stratification factors for pre-specified and talk about those subsets a little bit. I think there'll be a lot of eyes on that data, and I want to give you the chance to go through it.

Neeraj Agarwal: Prior abiraterone or docetaxel use was a stratification factor. And as I said, about 20% of patients got these agents. So again, from the practical perspective, do these data apply to those patients? Answer is, the trial did not answer that. But obviously, the trial was started when these therapies were not used as commonly in metastatic hormone sensitive prostate cancer.

But if you look at a hazard ratio of patients—again, small number of patients—if you just look at docetaxel chemotherapy, it was 0.56, so favoring the combination. And so patients in general who received abiraterone plus docetaxel or docetaxel, they seem to have benefit with the combination. Again, with the grain of salt. This is not powered for this small subgroup.

Oliver Sartor: Sure.

Neeraj Agarwal: It's not the ITT patient population. But just to inform practice, if I am switching someone from abiraterone to enzalutamide—if I'm doing that, and ARPI to ARPI switch is commonly practiced in the community. So if there is one of the patients slowly rising PSA level and I decide to switch, I think it is good to know the hazard ratio.

And if you look at the HRR mutation positive patients versus those who did not have HRR mutations or who had unknown status, the hazard ratio was 0.87, so lesser magnitude of benefit. So to address that unknown status—because at the time of initial negotiation with the regulatory bodies, unknown patients were allowed to enroll on the trial so that we don't exclude those patients.

So now things have changed. Now we have ctDNA testing more commonly utilized, much more advanced in the last eight years. So we were able to do a post hoc analysis of those patients who had ctDNA collected, but it was not used for prospective testing. Only tissue was used for prospective testing. So we stringently performed the analysis, looking at both ctDNA and tissue to inform HRR positivity or negativity.

So there were about 314 patients who had HRR-negative status by both ctDNA and tissue testing. So if you look at those patients, the hazard ratio was 0.78, favoring the combination.

Oliver Sartor: This is the OS?

Neeraj Agarwal: The OS? Yeah, overall-- About nine month difference in overall survival, median overall survival.

Oliver Sartor: So, Neeraj, there will be a lot of eyes on the regulatory bodies with regard to this particular trial. And we know from the past that in the United States, the FDA has not embraced the all-comers approach with another PARP inhibitor called olaparib. And that trial is called the PROpel trial, and it created a lot of eyes. Having said that, this will also be evaluated in Europe, and I'm a little bit curious about how you perceive both the US FDA and the European regulators with regard to this trial.

Neeraj Agarwal: Yeah, great question. So first of all, EMA, as we know, has already approved the combination in all-comer patient population, but with the caveat that they could not be—they were not proceeding with chemotherapy. They were not pursuing chemotherapy. US FDA has approved the combination based on the RPFS data for those patients who had HRR mutation positivity.

Just for the context, we are talking about the PROpel trial. PROpel trial led to approval of the combination of abiraterone plus olaparib for patients with BRCA1 and BRCA2 mutations. And again, there are differences in the design. This was a prospective tissue testing; in PROpel, it was retrospective.

So without getting into the details of comparing these two trials, we do have approval of talazoparib plus enzalutamide by the US FDA for patients with HRR mutation positivity. And I think the OS data was required for potential expansion of the label.

Oliver Sartor: I think there'll be a lot of eyes on the FDA regulatory action, and it would be a tremendous increase in the utilization of talazoparib if, in fact, this is the case. Now, we're not addressing the fact that prior ARPI use is much more common today. And so the use of hormone sensitive patients receiving the ARPIs is much more common today than it was then. That's a separate issue--

Neeraj Agarwal: And I'd like to comment on that one.

Oliver Sartor: Please.

Neeraj Agarwal: Yeah. So we just looked—presented at AUA—the number of new mCRPC patients from the Flatiron database, again, hundreds of patients. And Flatiron is mostly a medical oncology dataset. We know that in urology practices, the use of ARPIs is even lower than in medical oncology practices. And what we found was quite surprising. Thirty-five percent of these patients with new mCRPC had any exposure to ARPI in the past.

So that's number one. But number two, we will be seeing a lot of trials in the localized setting, high-risk setting. We already have abiraterone approved for locally advanced prostate cancer—two years of abiraterone and three years of ADT. Many patients progress to mCRPC without recovering their testosterone even after discontinuation of localized or definitive therapy abiraterone.

We are going to see many of the trials here involved in DASL-HiCaP, ENZAMET trial, ATLAS trial with darolutamide, enzalutamide, and apalutamide, respectively, which are using ARPI for limited duration of two years. We have ARASTEP trial and PRIMORDIUM trial with darolutamide and apalutamide, respectively, which are using two years of these ARPIs in the presence of PSMA PET-positive metastatic disease but conventional-negative disease.

And then we are starting de-escalation trials in the metastatic hormone sensitive setting. And then there are patients who continue to not get ARPI in the metastatic hormone sensitive setting. So if we combine all of this population, I think we will see a new type of patient who has not really progressed on an ARPI but has been exposed to the ARPI.

And the question for those patients will be, should they get ARPI or not? So, really, without going into the details of that, my practice will be moving forward. If somebody has really progressed on an ARPI, then I will probably not use another ARPI. But if somebody has been exposed to an ARPI but not really progressed on ARPI, I will not be hesitant to use ARPI for those patients.

Oliver Sartor: Very important distinction. Neeraj, we're going to need to wrap up, but I wanted to thank you for being on UroToday, and thank you for your contributions to the field and in particular your session, oral session here at ASCO GU.

Neeraj Agarwal: Thank you very much for having me. It's always great to talk to you.