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PARP Inhibitors in Prostate Cancer: A Decade of Development and the Combination vs Monotherapy Debate for HRR-Mutated Disease - Neeraj Agarwal

November 5, 2025

Pedro Barata interviews Neeraj Agarwal about PARP inhibitors in prostate cancer following an educational session. Dr. Agarwal traces the decade-long journey beginning with TOPARP-A in 2015, progressing through PROfound and TRITON3 trials demonstrating monotherapy efficacy, and evolving into first-line metastatic castration-resistant prostate cancer combinations with TALAPRO-2, PROpel, and MAGNITUDE. The discussion explores preclinical rationale showing androgen receptor pathway inhibitors upregulate PARP while PARP inhibition downregulates androgen receptor, supporting combination strategies. Dr. Agarwal highlights the BRCAAway trial demonstrating progression-free survival with combination therapy versus sequential approaches. TALAPRO-2 data showed unprecedented 14-month absolute overall survival benefit in HRR mutation-positive patients, extending median survival from 31 to 45 months with enzalutamide plus talazoparib. The conversation addresses complexities around specific gene alterations, noting strongest monotherapy signals occur with BRCA1/2 mutations while combination benefits extend across broader HRR alterations, potentially negating the poor prognosis associated with these mutations.

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

Pedro C. Barata, MD, MSc, FACP, Miggo Family Chair in Cancer Research, Co-Leader Genitourinary (GU) Disease Team, Director of GU Medical Oncology Research Program, University Hospitals Seidman Cancer Center, Associate Professor of Medicine, Case Western Reserve University, Case Comprehensive Cancer Center, Cleveland, OH

Related Content:

ESMO 2025: Exploiting Homologous Recombination Alteration Across the Spectrum Disease Stages
Read the Full Video Transcript

Pedro Barata: Hello everyone and welcome to another video from UroToday, this time covering ESMO 2025, the European Society of Medical Oncology annual meeting that just took place in Berlin. I'm so excited to be joined today by Dr. Neeraj Agarwal. Neeraj, you don't really need an introduction, but you are indeed a big leader in the field of GU malignancies, particularly prostate cancer. You lead the group at Huntsman Cancer Institute in Salt Lake City. Not only that, you have an important role, a leadership role, at the cancer center there. You really put the institution on the map from that perspective. We go to you for guidance, advice, leadership, and so on. So thank you so much for taking the time to talk to us today.

Neeraj Agarwal: It's such a pleasure. Thank you for having me.

Pedro Barata: Absolutely. And I'm a GU oncologist. I'm Pedro Barata, a GU oncologist out of Cleveland, Case Western Reserve University. So Neeraj, the reason why we felt it was important to have a conversation is in the context of your fabulous educational session on homologous recombination repair gene defects in prostate cancer. We've come such a long way. I think the first data we saw were probably around 2015. So it's been about a decade, right? It's 10 years of data, not even including the preclinical data that I expect you will be alluding to, that got us to where we are today where we have different PARP inhibitors available, both as monotherapies and in combination strategies for patients with prostate cancer. But I want to pick your brain on that. You did a great job walking us through where we came from, where we are and perhaps what the future might bring for targeted therapy. So let me ask you first: Can you give us a summary of the storyline around PARP inhibitors in prostate cancer like you did in the educational session?

Neeraj Agarwal: Yeah. So first of all, thank you again for the opportunity to talk about these special sessions we put together during the ESMO meeting. It was focused on biomarkers in prostate cancer and my task was to go through the journey of homologous recombination repair pathway alterations and therapeutics, as well as other aspects on prognosis and testing and so on. So I'll first start with the PARP inhibitors because those are the drugs which are so much more mature than other drugs which are being developed to target these pathways.

Pedro Barata: Right.

Neeraj Agarwal: And if you look at the PARP inhibitor journey, it started with the TOPARP-A trial in 2015. It's hard to believe it has been 10 years, and that led to the PROfound trial with olaparib as a monotherapy and the TRITON3 trial with rucaparib presented by Alan Bryce and Chuck Ryan and Dr. Karim Fizazi's team, the PROfound trial by Dr. Maha Hussain and Dr. de Bono. Both drugs showed improved survival outcomes. Both were approved. And in fact, olaparib was the first biomarker-based therapy approved in prostate cancer. And then we saw these agents moving upstream to the metastatic CRPC first-line setting. So the TALAPRO-2 trial, PROpel trial, MAGNITUDE trial—basically in all these trials, PARP inhibitors were combined with an ARPI.

Pedro Barata: So on that note, let me just ask you because we go from monotherapy to combination strategies. Perhaps can you give us a little summary of the preclinical data and then the phase I, phase II data that translated into why would we combine it with an ARPI? What is the science behind it? What is the synergistic activity, if any, that justifies exploring combination strategies? Why not just stay with PARP monotherapy?

Neeraj Agarwal: Very good point. So the way I explain to my patients, when we target prostate cancer cells with androgen receptor pathway inhibitors, that leads to upregulation of PARP and PARP comes to the rescue of cancer cells.

Pedro Barata: Right.

Neeraj Agarwal: When we target PARP, it leads to downregulation of the androgen receptor. So there are a lot of preclinical data based on which all these trials came up, but I'd also like to bring your attention to the BRCAAway trial, which was a simple investigator-initiated trial we did under the leadership of Dr. Maha Hussain. And in this trial, a small trial, patients were randomized to abiraterone or olaparib or abiraterone plus olaparib. These patients had BRCA1, BRCA2 or ATM alterations, first-line mCRPC setting, and the monotherapy patients were allowed to switch over to the other arm. So if you look at the combined PFS of abiraterone followed by olaparib or olaparib followed by abiraterone, it was 16 months. But the PFS of abiraterone plus olaparib was 39 months. So I think despite being a small trial, my learning lesson from this trial was that if we have the opportunity, we ought to be combining these drugs rather than sequencing. Because first of all, we don't get the value for the money, but more importantly we lose half of the patients.

Pedro Barata: Right.

Neeraj Agarwal: Your data, Pedro, you have shown that we lose half of our patients with prostate cancer to disease progression once they experience disease progression.

Pedro Barata: Right.

Neeraj Agarwal: So I think all of these reasons put together, especially with the overall survival results from the TALAPRO-2 trial, 14-month absolute overall survival benefit in HRR mutation-positive patients going from 31 months to 45 months when you combine enzalutamide plus talazoparib compared to enzalutamide, I think we have solid rationale now for combining these two drugs if we have the opportunity.

Pedro Barata: Absolutely. And you also described very elegantly, Neeraj, the importance of the type of biomarker, right? So you mentioned the BRCAAway trial with BRCA1, BRCA2, ATM. But then we look at the approvals and that depends on the type of therapy. Where are they approved? What genes? What type of HRR family genes are we talking about? I still remember from the trial from 2015, looking at the breakdown between germline and somatic. That's one. And then the other one is, "Okay, let's talk about BRCA1, BRCA2, ATM," but then you get the non-BRCA alterations beyond ATM like CHEK2, PALB2, FANCA, CDK12, et cetera. So it is easy to get confused by all this. And on top of that, you look at data with monotherapy and where we see differential activity from the PARP inhibitors by themselves. But then when you bring in the combination strategies that you alluded to, at least in my mind the signal seems to be more evident or stronger, particularly in the non-BRCA genomic alterations.

Neeraj Agarwal: Absolutely.

Pedro Barata: How do you see that? How do you explain it for a provider to make sense of all this?

Neeraj Agarwal: Yeah, I think there is no doubt that if you look at monotherapy data, the signal of benefit is maximum in BRCA1- and BRCA2-positive patients. But then this benefit seems to extend beyond BRCA1 and BRCA2 to many other mutations like CDK12, PALB2, RAD51. And I would like to just emphasize this fact that I think it is impossible to design a trial which is powered to look for survival benefit in individual gene subsets. I don't think we will have that kind of trial in the near future.

So based on what we have, I keep it very simple. I talk about the data, survival outcomes, radiographic PFS, overall survival data, for example, in the context of enzalutamide plus talazoparib, which has the label in this setting in the US. We have these two drugs. You have one of these mutations for which the drug is approved. Let's try that. If it doesn't work, we'll know very quickly. These are oral pills. And if they are tolerating the drug well and they're responding, I'm happy. And we will show you the overall survival data from the BRCAAway trial in the very near future and I think there won't be any doubt. Especially if you look at the PFS data and OS data from this TALAPRO-2 trial and other trials, these patients, despite having these deleterious mutations, are exceeding overall survival of four years. Some of them are getting into their fifth year and sixth year. I don't think we had ever seen this kind of survival in the mCRPC setting.

Pedro Barata: It's really unprecedented.

Neeraj Agarwal: Unprecedented, yeah.

Pedro Barata: Over and over before the combinations came into place, certainly the median overall survival in trials was shy of three years, right?

Neeraj Agarwal: Forty-five months in the experimental arm.

Pedro Barata: In the experimental arm.

Neeraj Agarwal: Yeah.

Pedro Barata: So we're really talking a year or more for patients who are destined not to do well, because it alludes to your point earlier about how HRR alteration is a poor prognostic marker. In other words, patients destined not to do well, when you bring a therapy, whether monotherapy or combined with ARPI, you change that and you're actually able to control the disease, as defined by rPFS, and also get them to live longer with these therapies.

Neeraj Agarwal: I'm glad you brought this up because if you look at the radiographic PFS for enzalutamide monotherapy in the TALAPRO-2 trial, that was 13 months. So in the PREVAIL trial with enzalutamide, same setting, it was 20 months.

Pedro Barata: Exactly.

Neeraj Agarwal: So there is no doubt that if you have these alterations, it is also associated with poor prognosis. And they actually respond so well to PARP inhibitor combinations that these PARP inhibitors seem to negate the bad prognosis associated with HRR alterations.

Pedro Barata: Absolutely. Neeraj, this has been fantastic. I mean, it was a highly regarded session within ESMO and this is why you were able to actually bring all the data throughout a decade really in the session and the Q&A was super interesting. I invite everybody to get the chance to access that recording of the session, and also the slides were really well done. So congratulations, Neeraj. Thanks for taking the time to be with me today and I hope this has been helpful for you. Thank you.

Neeraj Agarwal: Always a pleasure. Thank you.