Rucaparib for Patients with Metastatic Castration-Resistant Prostate Cancer in the TRITON3 Trial – Oliver Sartor

January 23, 2023

Oliver Sartor and Alicia Morgans discuss the TRITON 3 clinical trial. TRITON 3 is a phase three clinical trial observing how patients with metastatic castration-resistant prostate cancer with a homologous recombination gene deficiency respond to treatment with rucaparib versus treatment with a physician’s choice of abiraterone, enzalutamide, or docetaxel. Results found that rucaparib improved radiographic progression-free survival rates for metastatic castration-resistant prostate cancer patients with a germline or somatic BRCA1, BRCA2 or ATM mutation.


A. Oliver Sartor, MD, Professor of Medicine, Urology, and Radiology, Director Radiopharmaceutical Trials, Mayo Clinic, Rochester, MN

Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts

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Alicia Morgans: Hi, I'm so excited to be here at the Prostate Cancer Foundation Annual Retreat with Dr. Oliver Sartor of Tulane. Thank you so much for joining me today.

Oliver Sartor: Thank you, Alicia. Good to be here.

Alicia Morgans: Well it is great to be here, wonderful to be back in person. I wanted to talk to you a little bit about what you're most excited about at this year's retreat. Lots of stuff going on, lots of just general buzz, but what are you most excited about?

Oliver Sartor: Well, I think we have something a little bit unusual that we actually got to see a phase III trial presented here for the first time. And that's the TRITON3. Now, people may not be familiar with it. It was biomarker-selected patients with BRCA1, BRCA2, and ATM. And these are in the post-abi, enza type setting, and they could be choosing to go onto a novel hormone or a taxane as a control group. And that taxane control group, I think, is very important, because nobody's been able to beat a taxane, and I think everybody knows that.

Alicia Morgans: And quite an active control, right?

Oliver Sartor: A very active control. This is not just abi, enza in the second line setting. The significant number of people had taxanes, and it was investigator choice so they could do whatever they wanted to do. Turns out that the rucaparib performed quite well in the BRCA population. And the initial analysis was looking at BRCA, which is BRCA1, BRCA2, as you well know, very heavily weighted toward the BRCA2 because that's more prevalent in patients with prostate cancer. And they used a variety of testing by the way. They used germline testing, ctDNA testing. They used tissue. So whatever type of testing that you did, just document the BRCA2. It did not have to be [inaudible 00:01:44], just had to be pathologic. So against that active comparator, rucaparib did very, very well on the rPFS, and essentially doubled the rPFS. And that, I think, is clinically significant, a hazard ratio of about 0.5-ish. And there was no OS presented. Crossover was allowed for those who progressed, so the OS may be diluted. But nevertheless, unusual to see at PCF an initial presentation of a phase III.

And I think this will elevate the rucaparib story. It had an accelerated approval, as you likely know. But at the same time, we didn't have that active comparator against a taxane treatment for many of the patients, not all the treatments, in the control arm. Another thing I think that was potentially important, there were dose reductions. There were doses that needed to be held. So if you're using a PARP inhibitor, you do have to be careful. You can't just give it and run away from it. You got to give it and watch the patient, particularly anemia and GI effects. But nevertheless, I think it was exciting to be able to see that result presented here. And I think it's going to be impactful because it follows up in the accelerated approval of rucaparib. And I think this will lead to a full approval. Oh, one more thing. They also look at ATM. So it was BRCA1, BRCA2 combined, and then ATM. ATM of the PARP inhibitor and the control group were essentially the same. No difference in the ATM population. So it's really BRCA positive, not ATM positive.

Alicia Morgans: So a couple things I want to dig into here. First, it's nice that they broke that out so explicitly. I assume it wasn't powered, but that was probably a pre-planned subgroup analysis to look at things, which is so important because I don't think we've had that kind of clarity from some of our other data. Although there are clearly these forest plots that we think we see something, it's not necessarily as clear. So that's really exciting. And the other piece I wanted to ask about is rucaparib is currently approved in the metastatic CRPC setting, but it is post-AR targeted agent and post-taxane. So this was looking at a pre-taxane population.

Oliver Sartor: Yes, there were a number of patients pre-taxane. There was taxane allowed in the hormone sensitive setting, but only minority the patients had that. So it was predominantly a pre-taxane CRPC setting. And so that moves it up a little bit in the treatment paradigm.

Alicia Morgans: Yeah, so very, very interesting. From your perspective, is this something that you expect is going to change that label, potentially?

Oliver Sartor: I do. I think it's label changing. And it'll move the accelerated approval into a full approval. And the PARP inhibitor space is a little bit interesting. We have PROpel, which we probably don't need to get into a whole lot. We also have a new data set announced in a press release. And this is coming from a talazoparib-enzalutamide combination as compared to enzalutamide alone. And it's in that first line metastatic CRPC, so it's like PROpel in that these are chemotherapy naive, predominantly, and naive to prior novel hormones. And that's called the TALAPRO-2 trial. TALAPRO-3 is in the hormone sensitive space, but TALAPRO-2 has now been reported topline positive. Now, we don't know what it looks like.

And just like PROpel, there's a lot of interest in the subsets. We don't really know other than it's quote, positive in biomarker selected, biomarker non-selected patients. But I think we'll probably hear about that at ASCO GU, and that'll cause a lot of scrutiny. And this idea of combining a novel hormone with a PARP inhibitor is going to get some more data. We had niraparib of course, as you remember from the MAGNITUDE trial, but now we're going to have a pretty full data set to evaluate, and I think that'll be good for the field.

Alicia Morgans: I think that'll be great for the field. And it also extends to a different AR targeting agent with a different PARP, and really may help us understand whether that question of whether these biomarker negative patients may have at least some benefit in a PFS type of a setting or endpoint, which will be very, very, very interesting given the sort of juxtaposition of those two studies that we've already seen.

Oliver Sartor: Absolutely. So niraparib, talazoparib, olaparib. So now when we take the totality of data, we'll have three PARP inhibitors, and we'll have abiraterone and enzalutamide. And again, I think that'll sort of round out the picture. We'll have some ideas. All the trial designs are not identical, particularly MAGNITUDE was different than PROpel. But nevertheless, I think we'll have a look at the data in a way that'll allow the skeptics to either declare their skepticism is validated, or those who are currently on the believer side to say, "Oh, I told you so." We'll wait and see.

Alicia Morgans: We will definitely wait and see. So any final thoughts as you think about this PCF retreat? We are only halfway through, so we're not giving you the full opportunity to say what you're most excited about. But anything else you wanted to mention before we sign out?

Oliver Sartor: Maybe one more little thing. There was a CXCR2 antagonist, and this seems to be looking at some of these myeloid cells. And I think we all realize that things like the neutrophil to lymphocyte ratio is important. Probably some of this inflammatory cells, the neutrophils that we find within the tumor, probably do promote tumor growth. And we have a little bit of a hint with the CXCR2 antagonists. I think that it's going to take a lot more to bring it into kind of clinical fruition, but it showed that there was some activity, and that was interesting. So that was an AZ drug, a CXCR2 antagonist that seemed to show some activity in the enzalutamide-resistant patient population.

Alicia Morgans: Very interesting, especially, when we have these novel approaches, these new innovations, and we get to see them at a PCF meeting. It's always exciting.

Oliver Sartor: It's really nice because you get a chance to talk to the authors, ask your questions, see all your colleagues, ask them what they thought. And part of the fun of this meeting is the interaction that occurs and the one-on-ones that occur, whether it be dinner, breakfast, lunch, or during the meetings or coffee. So it's a great meeting.

Alicia Morgans: It is a great meeting, and we are late for dinner, to that point. So we will take the opportunity now for me to say thank you to you for your expertise and for relaying some of the most important aspects of this meeting so far, at least for this year. I always appreciate your honesty, your collaboration, and your thoughts on the field. So thank you for your time and expertise.

Oliver Sartor: Thank you, Alicia.