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Zach Klaassen: Hi, my name is Dr. Zach Klaassen, and I'm a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. I'm delighted to be joined today by a great friend of UroToday, Dr. Neeraj Agarwal, who is a Professor of Medicine, Director of GU-Oncology at the Huntsman Cancer Institute.

Neeraj, thanks so much for joining us today.

Neeraj Agarwal: It's a pleasure.

Zach Klaassen: Neeraj, you presented some really interesting trial-in-progress data at the AUA 2024 in San Antonio, Texas. This was the EvoPAR-Prostate 01 trial, and it involved a combination of a new PARP inhibitor, which we'll talk about, in combination with ARPI in both the biomarker-negative and biomarker-positive HHR mutation population. So why don't you give us some background on that rationale.

Neeraj Agarwal: This is in the metastatic hormone-sensitive prostate cancer setting. And the rationale, we have a lot of preclinical rationale, we've discussed that, but I think the most recent data came from large phase III trials in metastatic castration-resistant prostate cancer. We saw the data from the PROpel trial and the TALAPRO-2 trial, combining ARPI, abiraterone, or enzalutamide with olaparib and talazoparib, respectively. Interestingly, in both the PROpel and the TALAPRO-2 trials, we saw striking efficacy of the combination versus ARPI alone in patients with homologous recombination repair mutations. But interestingly, there was a clear signal that patients who did not have homologous recombination repair mutations, especially if you look at the TALAPRO-2 data, they were all tested by tissue testing or they all had prospective tumor tissue testing. Specifically, looking at patients who did not have HRR mutation, by tumor tissue testing the hazard ratio for rPFS was 0.66 favoring enzalutamide plus talazoparib versus enzalutamide alone.

So I think there is definitely something out there, and we just do not know what is driving the benefit. If we don't know, it doesn't mean it doesn't exist. Obviously, we do not have the approval for HRR mutation-negative patients for these combinations. We only have approval for HRR mutation-positive patients, but I think we have clinical data to support the combination. Now taking a step back, just for the completeness for the audience, preclinical data have suggested that when we target prostate cancer cells with androgen receptor pathway inhibitors, that leads to up-regulation of PARP. So the way I explain to my patients, PARP seems like it is coming to the rescue of the prostate cancer cells when we are targeting them with the ARPIs. And there is more crosstalk, more interaction; they interact quite a bit based on the preclinical data.

But then this was sort of confirmed in these large phase III trials. Zach, if I may just spend 30 seconds talking about the BRCAAway trial presented by Dr. Maha Hussain, a small trial, 20 patients in each arm, but this was the only trial which compared the combination of a PARP inhibitor with ARPI versus ARPI versus PARP inhibitor monotherapy in patients who had metastatic CRPC with BRCA1, BRCA2, and ATM mutations. The main message from the BRCAAway trial was if you just look at the olaparib and abiraterone-only arm and then patients were allowed to cross over, if you include olaparib followed by abiraterone, abiraterone followed by olaparib, the radiographic progression-free survival of combined therapy in sequence was 16 months. But if you look at the third arm, abi with olaparib, the radiographic PFS was 39 months. So there is no doubt in my mind that there is synergy, there is cooperativity between the ARPIs and PARP inhibitor, at least based on the metastatic castration-resistant prostate cancer trials.

Zach Klaassen: Yes. And so I'm going to pull up the slide design for the EvoPAR-Prostate 01 because I want you to walk our listeners through that trial. And as we pull this up, maybe you can explain the rationale for testing this in metastatic castration-sensitive prostate cancer first.

Neeraj Agarwal: Absolutely. So based on the CRPC trials, there are two trials which are happening with ARPI and PARP inhibitors in metastatic hormone-sensitive prostate cancer for a few years now. These two trials are the TALAPRO-3 trial combining enzalutamide with talazoparib and the AMPLITUDE trial combining abiraterone with niraparib. The main patient population eligible for this is newly diagnosed patients with MHSPC who have homologous recombination repair mutations.

The EvoPAR-Prostate 01 trial is different from these trials in that it is not only recruiting patients with homologous recombination repair mutations but also includes a separate cohort of patients who do not have homologous recombination repair mutations based on prospective tumor tissue testing. All of these patients must have prospective tumor tissue testing done to establish the status of the homologous recombination repair genes. In this trial, there are essentially two trials in one: 550 patients with HRR mutations and about 1,200 patients who do not have HRR mutations.

But before I talk more about this trial, I'll take a step back and talk briefly about saruparib because many of our colleagues may not be aware of this novel PARP inhibitor. Based on the preclinical data, treatment with saruparib demonstrated selectivity for PARP1 versus PARP2, and as mentioned, I would like to emphasize that saruparib has not been compared head-to-head with any other PARP inhibitor, clinically speaking. We should not be drawing any comparisons here, and I clearly mentioned that in our AUA presentation. Just for our audience, in the phase 1a/2 PETRA study, saruparib was tested as monotherapy from 10 mg daily to 140 mg daily in various patient populations including breast cancer, ovarian cancer, pancreatic cancer, and prostate cancer patients.

The most recent data were presented at the 2024 ASCR Meeting, and overall saruparib demonstrated a favorable safety profile among a heavily pre-treated patient population. The main message is that in various doses, the maximum tolerated dose was not reached, and overall saruparib was associated with a pretty good safety profile in these heavily pre-treated patients. The dose of 60 mg daily was chosen as the phase 2 dose based on various observations. Even though no MTD was reached, the investigators didn't see any more responses with 90 mg and 140 mg. So, I think the conclusion was that 60 mg daily was the right dose for phase 2.

There was another study presented by Dr. Arun Azad at the 2024 ASCO GU meeting, the phase 1/2 PETRANHA study, so P-E-T-R-A-N-H-A in case people want to look it up. In this study, saruparib was combined with three ARPIs: abiraterone, enzalutamide, and darolutamide in separate cohorts. They did not find any dose-limiting toxicities or clinically significant drug-drug interactions of saruparib with any of these ARPIs. So this is the background on saruparib, Zach.

Zach Klaassen: Excellent. And just from a trial design standpoint, were there statistical considerations why the biomarker negative cohort had so many more patients than the biomarker positive?

Neeraj Agarwal: If you look at the PARP inhibitor ARPI trials which have already been reported, you will see the magnitude of benefit is definitely higher in patients who have, say, BRCA1 or BRCA2 mutations or homologous recombination repair mutations. The magnitude of benefit is lower, although it is present. There is a clear benefit present in HRR mutation-negative patients, at least in the prospectively tested tissue-confirmed HRR mutation-negative patients in the TALAPRO-2 trial, but the magnitude is definitely lower with a hazard ratio of, say, 0.66 versus a hazard ratio of 0.45 in patients who have HRR mutations. So if you're expecting a lesser magnitude of efficacy, I think we need an overall larger sample size.

Zach Klaassen: Makes sense.

Neeraj Agarwal: I think that's the reason why, in my view, we have 1,250 patients in the HRR mutation-negative cohort in the EvoPAR-Prostate 01 and 550 patients in the HRR mutation-positive cohort.

Zach Klaassen: Excellent. How about the endpoints, Neeraj? So very similar to the previous trials, radiographic progression-free survival, overall survival. Can you speak to whether these are primary, secondary, or if they are co-primary endpoints?

Neeraj Agarwal: At this time, I would like to just mention we'll be presenting these data, this trial in progress again in future meetings and we'll be getting the manuscript out on the outline of the design of the trial. I think at this point in time we would like to focus on two main endpoints, radiographic progression-free survival and overall survival. And these are going to be the selected endpoints, but there are going to be a lot of other endpoints, clinically meaningful endpoints such as time to chemotherapy, time to pain progression, and quality of life. And we are going to be elaborating on those endpoints in future meetings. But I think we all agree that these are the most meaningful endpoints, not only for the patients but also from the regulatory perspective.

Zach Klaassen: Absolutely. Excellent. So where are we at with this trial, Neeraj? What's the recruiting plan? What's the enrollment plan? I'm assuming this is a multinational trial.

Neeraj Agarwal: So the trial has already started accrual in November 2023, and this is open in 370 study sites-

Zach Klaassen: Excellent.

Neeraj Agarwal: In 26 countries, so we are talking about North America, South America, Europe, Asia, and Australia. So this is a large trial, but like any large trial, we look at accruing patients over many, many months to years and then it will be a while before we present the data. But I think the focus right now is to complete accrual on this trial and that's why we really appreciate all these opportunities to talk about this trial.

Zach Klaassen: Absolutely. So I just want to take a step back from my last question, Neeraj. We've seen obviously the progression with multiple different treatment lines, start with mCRPC, move to metastatic castrate-sensitive. How do you see with this trial and some of the other ones you mentioned, TALAPRO-3, we're seeing the PARP inhibitors tested earlier. What's your forecast over the next 5 to 10 years with the PARP inhibitors?

Neeraj Agarwal: We all like these trials to be positive. So much of our patients' time and resources go into these trials, so we are hoping that these trials are positive. Summarizing the landscape of ongoing phase III trials in metastatic hormone-sensitive prostate cancer, there are many. CAPItello trial looking at patients with PTEN-deficient tumors. We are talking about TALAPRO-3, AMPLITUDE trial, and now EvoPAR-Prostate 01 trial looking at patients with DNA repair mutations or homologous recombination repair mutations, although EvoPAR-Prostate 01 trial also has patients who do not have these mutations. And then we have the PSMAddition trial going on where lutetium-177 PSMA-617 is being used in patients who have PSMA-expressing tumors.

Zach Klaassen: Right.

Neeraj Agarwal: So I think we are going to see a revolution in how we treat patients with metastatic hormone-sensitive prostate cancer in the next few years. And I think we'll be seeing increasing survival of our patients that are going to be living longer and hopefully, with better quality of life.

Zach Klaassen: Yeah. Great summary. Before we go, Neeraj, any last-minute things we haven't hit on, any take-home points for our listeners? I know it's been a great discussion of the EvoPAR-Prostate 01 trial. Any last remarks?

Neeraj Agarwal: I think this is an exciting time for our patients, a great time to be a GU medical oncologist or a doctor focusing on prostate cancer. And I think at this time, the focus is on improving our patients' participation in these clinical trials so that we can expedite accrual, report these results in a timely fashion, and ultimately improve outcomes for all patients across the planet.

Zach Klaassen: Wonderfully said. Neeraj, always great chatting with you. Thanks so much for your time and expertise.

Neeraj Agarwal: Thank you, Zach, for having me.