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Alicia Morgans: Hi, I'm so excited to be here with Dr. Alan Bryce talking about the TRITON3 study that was presented at GU ASCO 2023. Really exciting data. Thank you so much for talking.

Alan Bryce: Thanks for having me. It's a pleasure.

Alicia Morgans: Wonderful. Can you tell me a little bit about the study design and what you presented?

Alan Bryce: TRITON3 is the phase III randomized controlled trial registration study for rucaparib in patients with BRCA or ATM mutant mCRPC. This is the follow on to the TRITON2 study. As you recall, that was a phase II study that led to the accelerated approval for rucaparib in the post-docetaxel setting. Importantly, this is in the pre-docetaxel setting for patients who have had at least one androgen receptor pathway inhibitor, right, Abi, Enza, apalutamide as it were in this study, and they were chemotherapy-naive in the castration-resistance setting. About 20% of patients did receive docetaxel for hormone-sensitive disease because that was allowed, but nothing for CRPC. So this is a study where rucaparib was randomized versus either docetaxel, abiraterone, or enzalutamide, and really meant to be the definitive study to say, is rucaparib a good option for these patients?

Alicia Morgans: Wonderful. I think, importantly, just to emphasize that you did include docetaxel in that lineup for physicians to choose as a comparator, which is novel and different than other studies in this space.

Alan Bryce: Yeah. That's something where I think it is important. It's an important detail. We're quite proud of the fact that the study allowed for that, because I think we've learned that over the last several years that after you treat with one androgen receptor pathway inhibitor, really, the second one doesn't give you much mileage. The active comparative here is docetaxel.

It was a big debate, certainly. A lot of people say you can't randomize an oral drug versus an IV, but I think we've shown we can. And importantly, here at GU ASCO, we presented the final analysis of the primary endpoint of radiographic progression-free survival, and this is a positive study. What it means is, rucaparib is clearly better than standard of care therapy, physician's choice standard of care, for this patient population. And in the subset analysis that we presented, it's clearly better than docetaxel as well. As you know, 30 years of docetaxel, this is the first time any drug has beaten docetaxel in mCRPC. So, I think that, to me, is one of the critical questions that we have in practice in the clinic. What's better for this patient, a PARP inhibitor or Doce? And for the first time, we have the data.

Alicia Morgans: Which is so important, as you said. Some of the other important subgroup analyses that you reported out were really assessments by gene mutation, and I'd love you to share some of that.

Alan Bryce: Yeah. In this study, only three genes. We included BRCA1, BRCA2, and ATM. The study design was powered around the BRCA subgroup, that's 75% of the total patients, and then the intention to treat population included BRCA1, BRCA2, and ATM. In the primary analysis of the BRCA subgroup, strongly positive study. In the intention to treat, again, a strongly positive study for rPFS, but we absolutely, and intentionally, designed the subset analysis to look at by gene response. And in the ATM-mutant patients, we really didn't see a meaningful benefit. Rucaparib was comparable, almost identical, to standard of care therapy, hazard ratio 0.95. As you know, this is consistent with what we've seen in the other randomized controlled trials of PARP inhibitors. With ATM-altered disease, the hazard ratio is always right around 1. So this is not a surprising finding, but it was important to report it out independently. That graph is available in the slide presentation and in the paper as well.

Alicia Morgans: And really to emphasize too, this is a New England Journal of Medicine.

Alan Bryce: Yes. Published on Thursday morning, so the manuscript is available for everyone. Again, obviously that's a pleasure to be able to present a study and say that it's published at the same time.

Alicia Morgans: What a treat for us in the audience, and of course for everyone, to be able to read it. One thing that I think is important to understand too is that you did have some interesting assessments just in terms of other endpoints. Can you tell us anything about safety and other things that you were investigating?

Alan Bryce: Yep. Absolutely. Safety, critically important. With the PARP inhibitors and with rucaparib specifically, we know that myelosuppression is an issue, and of course patients can be on treatment for a long time. So compared to the standard of care therapy, 29% of patients required at least one blood transfusion, only 2% with standard of care. Of course, with chemotherapy, with docetaxel, you see a lot of neuropathy. We basically don't see that with rucaparib.

With rucaparib, however, the proportion of patients that required treatment discontinuation is very low. It's only a few percent. Much higher with chemotherapy. And the message there is that despite the myelosuppression, the need for transfusions, with rucaparib as an oral PARP inhibitor, treatment interruption followed by dose reduction really makes the drug very manageable. And of course, in a clinical trial setting, we have to do those dose reductions in a very disciplined organized fashion. But I think in clinical practice, the clinician is going to have the option of making those adjustments before blood transfusion is necessary or mandated. We're all accustomed to doing this, and in my experience, it's very easy to titrate oral PARP inhibitors to a dose that's sustainable for a patient.

Alicia Morgans: Very, very true. One other thing that I just wanted to dig into, genetic testing is something that we as a prostate cancer community have started to do, I think, much more frequently, though it's not ubiquitous, though, hopefully someday.

Alan Bryce: Yeah.

Alicia Morgans: Can you share any of the information about whether you included germline or somatic mutations and what the breakdown was there?

Alan Bryce: Yeah. No, this is a critically important point. We know what the guidelines are. At this point, the guidelines are clear. ASCO, AUA, NCCN, they all agree, all men with high-risk, very high-risk for metastatic prostate cancer should have germline testing. So, in a medical oncology practice, that means essentially everyone. From the first appointment, we talk about germline testing. And if you do that, then about half of the patients with DNA damage response gene mutations will be caught just by the germline testing.

Now, of course, the flip side of that statement is the other half have aberrations only in the tumor, so somatic testing is critically important. We've talked about this so many times in our practices, in academic practices, somatic testing also happens right at the beginning. And if we have tissue, we do tissue. If it's bone-only disease, we'll do cell-free DNA if necessary. But one way or the other, we profile everybody. And then, of course, most of us reprofile at each progression event because disease evolves over time. Of course the first priority, just because of prevalence, is to look for the DNA damage response gene mutations. 20-25% of patients ultimately will qualify. But of course, the second population we're looking for is those patients who might be eligible for checkpoint inhibitor therapy, the TMB-high, the MSI-high, and that can evolve over time.

So, we know from the real world data that genetic testing in metastatic prostate cancer is very low. It's far below what we'd like it to be. What this suggests is that there's a significant population of patients, maybe 10% of all prostate cancer patients, who are eligible for targeted therapy but never get the option because the sequencing isn't being done, the genetic testing. I think that is an educational point for our community, to really educate all providers about the importance of doing this testing. We want to give every patient the maximum number of options for treatment and for best outcomes. We can't do that in this era without doing genetic testing.

Alicia Morgans: That's very, very important. To your point, patients who do have these alterations, the BRCA alterations, at least, can do better on rucaparib than they can on docetaxel, which has been demonstrated in this study, which is really important. If you have to sum up the findings from your study and share it with listeners, what would that be?

Alan Bryce: Clearly rucaparib is a viable option for patients with BRCA1 or BRCA2 aberrant mCRPC. It can now be moved up according to the data before docetaxel. Now, that's pending a label expansion from the FDA. But this is a positive study. Clearly shows that rucaparib is effective earlier in the disease course and is a good option for your patients.

Alicia Morgans: Wonderful. Well, thank you so much for your time, your expertise. Congratulations on the New England Journal manuscript, and thank you again for taking the time today.

Alan Bryce: Oh, thank you. It's a pleasure to be here.