Oliver Sartor: Hi, I'm Oliver Sartor. I'm here with UroToday. We're at the U.S. Prostate Cancer Consensus Conference, third annual here in Colorado Springs. Very warm welcome to Pedro Barata, whom I know extremely well. Pedro is Associate Professor at Case Western and heads the GU Group there in Cleveland. So welcome, Pedro.

Pedro Barata: Thank you so much, Oliver, for having me. It's a fantastic meeting. I agree with you.

Oliver Sartor: We're going to talk a little bit about PARP.

Pedro Barata: Okay.

Oliver Sartor: And we're going to look at the genes beyond thinking simply about HR mutated.

Pedro Barata: Right.

Oliver Sartor: We talk sort of glibly about HR mutated, but we don't really drill down that much and there are a lot of distinctions in the genes. And so I'm going to pick your brain a little bit and share your knowledge about BRCA2, BRCA1, maybe ATM, maybe CHEK2, maybe PALB2, some of the major ones and any other ones you want to mention. But let's just kind of run through it gene by gene and let me get your assessment. So you take it whatever order you want.

Pedro Barata: Right.

Oliver Sartor: And we're just going to talk about PARP individual genes and then we'll come back and talk about how it might fit into different paradigms.

Pedro Barata: Right. Thank you so much for your question, Oliver, and the gene by gene evaluation is a very complicated and not easy answer, but let's get a step back because we all understand exactly what you just start by saying, right? We identify biomarker, which actually a gene, a family genes if you will, whereas BRCA, as you said, BRCA, ATM, FANCA, RAD51, RAD54, CHEK2, CDK12, et cetera. They're all part of that. But that was the first step. We start offering PARP inhibitor, either monotherapy or combination strategies, and we can talk a little bit about the synergistic effect that we've seen in the lab and we're trying to translate that to clinical practice, but we use that and apply it to the different genes. And so one thing that was obvious even from the studies with PARP monotherapy that you were part of with the Olaparib, going back to TOPARP and then PROfound, but you also can look at that from the Rucaparib studies. Right.

With TRITON2 and TRITON3 with Alan Bryce is actually, you can see that the differential activity of the PARP inhibition in monotherapy depending on the genes. And so we start, the conversation evolved from we have a marker, biomarker we can detect in the tissue, in the circulating free DNA, and then you move beyond that and you say, wait a minute, it matters what type of genomic alteration we have. But it's not just that. If I change it or make it slightly more complicated, it also matters what's the type of alteration that you have? Is that a monoallelic alteration? Is that a biallelic? Is the patient born with that alteration or did it pick it up at the tumor level? Although we know most of these alterations tend to be truncal, right?

So a lot of times when we do more than one test, sometimes we don't see in the first, we see it later, that's not necessarily the case the tumor picked it up. It might have to do with the methodology of the testing that would justify tests get better over time. So just to make it more complicated, but I think we learn, even if we go back to the data from TOPARP, remember we had little stars for the germ line and we saw the signal was the strongest for the biallelic alterations compared to the monoallelic, for example, even going through the gene by gene. So when we look at the PARP inhibitors by itself, the conversation starts coming up. It was obvious, I think to everybody, that the signal seems to be the strongest in the BRCA2 group.

The other problem is we start understanding those differential signals. So for example, we were not quite sure if what ATM represented in terms of activity. We were also disappointed by what happened with PARP inhibitors in CDK12, for example. Fairly disappointed if you will. And at the same time, there was this data coming out that perhaps it opens the door to immunotherapy.

Oliver Sartor: Let's come back to that one very specifically with Talazoparib versus the other PARP inhibitors. So CDK12 to me is very complicated. So right now we're talking about the kind of rest of the genes in a gene by gene way. So anyway, the CDK12 is very interesting.

Pedro Barata: I agree. And to your point, and the other thing that also gets too complicated is when you exactly, are we talking about the PARP by itself and the activity of PARP, the synthetic lethality, if you will, or you talking that in the context of the androgen inhibition? Because to me, I happen to be on the side that I do think that the data that's available preclinical and what we've seen in PROpel and TALAPRO-2 do seem to suggest that whether or not we test it well, but it does seem to suggest that the activity is enhanced beyond what we call it, the biomarker that's a predictor of activity.

Oliver Sartor: You want to briefly mention the BRCAAway study?

Pedro Barata: Absolutely.

Oliver Sartor: And yeah, because I think that gets to one of those interesting points.

Pedro Barata: So when the several studies were designed that leveraged prior data that if you inhibit androgen pathway with an ARPI, whether it's Abiraterone or anti-androgen like Enzalutamide, you are able to, number one, you see significant activity and that leverage, the phase three trials PROpel, MAGNITUDE, TALAPRO-2. And they were all done, for the most part they were all done in the ARPI naive population. In other words, those patients have not progressed on a prior ARPI. And so that's one part of the story. But once we saw that data, and we did see survival advantage from that approach, for example, in TALAPRO-2, to your point, we did see a survival advantage not just in the HR specific group, but also in the overall unselected group of patients. So everybody who came in the door and enrolled in that study with 800 patients or so.

Oliver Sartor: Yeah. But that was driven by a subset.

Pedro Barata: Oh. Oh.

Oliver Sartor: Let's not go there yet.

Pedro Barata: Not discussing the design details. Because essentially for those who are listening, the study was not designed to answer the question specifically for HR negative. What we have is two cohorts, the large cohort, 800 patients, and then another cohort, which was like 400 patients, was in reach for HR to answer the question about the combination of Enza with Talazoparib in the HR one cohort and the all unselected group of patients. So, but moving on from that, if you see an activity of the combination of a PARP inhibitor Talazoparib with an ARPI Enzalutamide, and you know that PARP inhibitors after progressing a prior ARPI such as Olaparib is able to make people live longer and control the diseases in the form of RPFS, then what should you do? Should you do combination or should you do sequencing? And so that's why trials like BRCAAway are super smart because they really, and you can tell this investigator-initiated study academic studies that many were involved.

I believe you were involved in many others, Neeraj, Maha, many others really asking that question. And what's interesting is a proof of concept study. Not a very large study, but in my opinion, enough to drive some conclusions. By the way, we're talking about BRCA ATM now, which is an important aspect to our conversation. And basically you offer Olaparib followed by Abi, who progress on Olaparib. You followed by Abi, followed by Olaparib for those who progress on Abiraterone or you actually offer the combination up front. And what that study shows you is two or three different things. Number one, the tumor control that you gain from offering the combination of the PARP with Abiraterone, it's more than adding the Olaparib and the Abiraterone by itself. So the second aspect that to me is probably as relevant if not more, is the amount of people that you lose in the pathway.

And that always brings us back to what the real world shows us. We are not able to treat a lot of patients beyond first line. Right. And what that means is things happen to patients. They have cardiovascular events. Unfortunately they progress and go to comfort care or hospice. Unfortunately, they die from other reasons. So when we are having the thought process around, it's now or later, now or later, sequencing, sequencing, sequencing, which is a very hot topic, we always assume that now or later, we're testing that thought versus a combination. Now, that's not real life. In real life we lose a lot of patients, I would say at least half that never make it to it later. So I think what BRCAAway is perhaps challenging is the concept that maybe even if there's no synergistic activity, which as I said preclinical, that it does seem to suggest the case, but there's something about offering the two different mechanisms of action for BRCA ATM in the case of BRCAAway that improves the outcomes of these patients.

Oliver Sartor: Let's get back, and I want to be succinct because we actually don't have that much more time. If you look at BRCA2, you have beautiful activity. What about ATM,

Pedro Barata: Right. So-

Oliver Sartor: Short.

Pedro Barata: Short.

Oliver Sartor: Not long. Short.

Pedro Barata: The best, so just to give a reference because when people hear the video and go out there, the best reference that I still use to me is actually the FDA pooled analysis gene by gene. And they do that for the monotherapy, but also for the combo. So I do practice a little bit different depending on the gene that you're asking. In some cases, I'm very confident with the PARP by itself. In some cases I'm not. So BRCA2 as Dr. Saad says, and I'm going to steal his line, "You only need to smell a PARP." So I do a PARP in monotherapy, but you ask me for ATM. In fact, for ATM, and as you know, we look at gene by gene, that's not much excitement there. Actually as the ratios, when you look at the-

Oliver Sartor: The Rucaparib study negative.

Pedro Barata: Correct.

Oliver Sartor: Cold, cold, negative.

Pedro Barata: And it's one. We don't see a signal there. So if folks are conceding for whatever reason, you're preventing chemo, you really want to do a PARP in my hands, you would give them a combination.

Oliver Sartor: Okay, succinct. Very succinct. We're going to wrap it up. Let's talk about CHEK2.

Pedro Barata: Same.

Oliver Sartor: Let's talk about BRCA1.

Pedro Barata: Right. BRCA1, the signal is stronger than what, appears to be stronger. I have to be careful because we are never powered for this gene by gene. But I do see BRCA1 in a better position, closer to the BRCA2, a little bit further away from ATM or even CHEK2.

Oliver Sartor: CDK12.

Pedro Barata: That's tough, but I do a combination in those patients.

Oliver Sartor: Yeah.

Pedro Barata: PARP ARPI.

Oliver Sartor: Good deal. We're going to wrap up and I'm going to thank Pedro Barata for going over interesting things like BRCAAway, gene by gene analysis. And lots of, I'm going to say things still to learn particularly about the spacing and timing and whether or not we can bring it earlier and earlier and earlier.

Pedro Barata: That's right.

Oliver Sartor: But right now we're still in the learning phase except BRCA2 is the real deal. Smell the PARP. It works.

Pedro Barata: Perfect. Thank you, Oliver, for having me.

Oliver Sartor: Thank you.