DDR and PARP Inhibition: What's the Damage? - David VanderWeele

July 10, 2023

David VanderWeele elucidates findings from the TALAPRO-2 study, emphasizing the substantial hazard ratio benefits observed in metastatic CRPC patients with HRR mutations, especially those with BRCA1 and 2 mutations, treated with enzalutamide combined with talazoparib. However, he raises questions regarding the true representation of the trial's population and a lack of subsequent PARP inhibitor treatment, stressing the need for further clarity on the interaction between PARP and AR pathway inhibitors. The discussion moves to the ongoing BRCAAway and CASPAR trials, potentially shedding light on this issue. The conversation rounds off with the Phase I LuPARP study, which explores the combination of olaparib and radioligand lutetium PSMA therapy, and the promising early safety results. Dr. VanderWeele underscores the importance of diligent molecular testing, highlighting its role in informing treatment decisions.


David J. VanderWeele, MD, PhD, Associate Professor of Medicine (Hematology and Oncology), Northwestern University Feinberg School of Medicine, Chicago, IL

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

Read the Full Video Transcript

Alicia Morgans: Hi, I'm so excited to be here today with Dr. David VanderWeele, who's an Associate Professor of Medicine at Northwestern University, and a good friend. Thank you so much for being here today, David.

David VanderWeele: Oh, thanks for having me.

Alicia Morgans: Wonderful. So David, you gave a fantastic discussion of some of the oral presentations at ASCO 2023, and I would really love to just have you share some of those insights with us today.

David VanderWeele: Sure. So one of the studies that I discussed was TALAPRO-2, which was an update on a study that had previously been presented in February, but this was with an updated population, now focused on patients who carry HRR mutations. And so, it's first-line metastatic CRPC setting, enzalutamide with either talazoparib or placebo. And the takeaway is that, the hazard ratios look great, especially in BRCA1 and 2. So for all HRR mutated patients, the hazard ratio of benefit for radiographic progression-free survival was, I think it was 0.45. And then they looked specifically at patients with BRCA1 and 2 mutations, and that hazard ratio was 0.20, which kind of falls in line with what we saw with PROpel trial and with MAGNITUDE, which, of course, are different trials, different designs, but also with an AR pathway inhibitor, also with a PARP inhibitor, and also, in the first-line metastatic CRPC setting. For all of them, we saw pretty good hazard ratios of benefit in HRR mutated patients, and even better hazard ratios, patients with BRCA1 and 2 mutations.

However, what I pointed out in the discussion is that, the trial population doesn't really represent our current patient populations. So for example, what had been pointed out previously with PROpel, MAGNITUDE, is that for the most part, patients have presented on ADT alone and not with therapy intensification. That was mostly true with this trial too, although there were quite a few patients, I think it was around 30% or so, who did receive docetaxel, but only 8% had received a prior AR pathway inhibitor.

But I think, even more importantly, there were very few patients on the placebo arm who went on to receive a PARP inhibitor after the trial, after they had progressed. And so, all of these patients are HRR mutated, or have HRR mutations in their cancer, and yet, only 17%, so out of 104 progression events with radiographic progression-free survival, there are only 18 patients. So it breaks down to 17% who went on to receive a PARP inhibitor after they had progressed on the trial.

And so, the study isn't really asking a question, is there a benefit, or is there synergy between an AR pathway inhibitor and a PARP inhibitor? It was really looking at the benefit of a PARP inhibitor in a time and in a place where many of these patients didn't have access to a PARP inhibitor outside the trial.

And so, my takeaway was that, BRCA1 and 2, which was the population that had the best hazard ratio, seemed to have the most benefit. Those genes are great predictors of benefit from PARP inhibition, but whether or not the PARP inhibitor needs to be given with an AR pathway inhibitor is still not answered.

I think, what do we do with this data? And well, of course this is in the background of abiraterone and olaparib just recently being approved by the FDA in this setting. But specifically, for patients with BRCA1 and 2 mutations, I guess I think that approval is reasonable, but those same caveats apply to that combination as to what was seen in the TALAPRO-2 study.

And so, I think this kind of strategy, or this combination, is probably best reserved for patients who have very aggressive disease, or symptomatic disease, or there's some concern that they would not be able to make it to receiving a PARP inhibitor in a later line of therapy.

They did look at quality of life, and by their measurements, it was preserved in the interventional arm and the talazoparib arm, but there still was a lot more toxicity in the arm with talazoparib, and they're not reporting on financial toxicity. So I think, for patients that have the most symptoms from their disease, then it makes sense to tolerate more symptoms, or more toxicity from the therapy, to try to relieve those symptoms of the disease. But I do think we have to continue to be thoughtful about who we would be recommending this kind of a combination for.

Alicia Morgans: Yeah. I think, and thank you so much for that. I think there is so much to think about when we're considering these combinations. I know there's a trial that your team is leading the BRCAAway trial, with Maha Hussain, and certainly, you and the PCCTC who are participating. That may give us a better understanding of the combination versus the sequence of these agents, right?

David VanderWeele: Yeah, that's right. That's a three arm trial, two monotherapy arms, abiraterone and prednisone, and then olaparib. And actually, those monotherapy arms have crossover built in. And then also, a combination arm with both of those together. And so hopefully, well, that is designed specifically to look at the combination versus sequencing, and hopefully, that gives us a signal. Although it is a relatively smaller trial, so if we see that signal, it probably means it's a pretty big signal, and there really is quite a bit of synergy by giving the agents at the same time, and with a combination therapy approach.

Alicia Morgans: So David, are there any other relevant studies that really could help answer some of the questions in this setting?

David VanderWeele: Well, the CASPAR study is a Cooperative Group study that's also in the same space, first-line metastatic CRPC. It also is looking at an AR pathway inhibitor and a PARP inhibitor. The agents being looked at in that study are with enzalutamide and rucaparib. So it's sort of a late comer after PROpel, MAGNITUDE, TALAPRO-2, it's the fourth on the scene. But I think it could be helpful in answering some of these questions about, is there really a benefit to giving both agents together? Versus, is it okay to do one and then the other sequentially? First of all, it has more open eligibility criteria, and so, the patients in the metastatic hormone-sensitive setting, they could have received anything except enzalutamide or a PARP inhibitor. And presumably, a lot of those patients will have received abiraterone and prednisone, or another AR pathway inhibitor in that setting.

And in addition, because it's a late comer, there's much more access to a PARP inhibitor, for patients after they progressed if they weren't on the rucaparib arm. And so, I think it probably will give us a better answer about, if there really is a true benefit to giving both an AR pathway inhibitor and a PARP inhibitor together, instead of just doing it sequentially.

Unfortunately, that study is on hold right now, because of issues around rucaparib and availability. Hopeful that that will open up again and pick up, and it really could be a very helpful study, I think, in really answering these key questions.

Alicia Morgans: Yeah. Well, and one of the other presentations that we heard at ASCO, and I think this is a general theme, BRCA1, BRCA2, these are poor prognostic markers, and certainly in the CRPC setting, they portend to poor prognosis. It's not common, probably in your practice or in my practice, that we see a patient who enters mCRPC has only had ADT in the past and also has a BRCA2 mutation. I mean, this would be a relatively uncommon situation for us. But if you did happen to see that patient young and fit, would you consider, I think we often consider about using a PARP as soon as possible. Would you consider the combination? And if you say you're not sure, or it's a shared decision, it's also okay to say that.

David VanderWeele: Yeah. I think, in most scenarios, it's a shared decision. As you pointed out, it would be unusual, I think, for a patient to come, or to have a metastatic CRPC and having progressed just on ADT, because I do think of those patients as having more aggressive disease. The patients who are the ones who progress on just ADT alone often have a more indolent disease. And if there were other features outside of the BRCA1 or 2 mutation that made it seem like it was very indolent disease, I probably would not be pushing or recommending this kind of a strategy. But of course, we try to have shared decision making as much as possible.

Alicia Morgans: Always, and of course. All right. Well, let's move on to the other abstract, or one of the other abstracts that you discussed. Can you share your thoughts?

David VanderWeele: Sure. So another one is the LuPARP study, which is a Phase I study looking at intermittent olaparib with standard of care radioligand lutetium PSMA therapy, as a way to try to, converts the single strand DNA breaks that we are expecting to get from the radioligand therapy into double strand breaks, and therefore, make the radioligand therapy a more effective therapy.

I commented that this is a very exciting trial. That radioligand therapy, there's a lot of enthusiasm for it on the side of physicians, but very much also on the side of the patients. It tends to have relatively low toxicity. And certainly, some patients seem to have a huge benefit from it, but not everybody has a huge benefit. And even those patients that do, seem to have a significant clinical benefit, that benefit just doesn't seem to last as long as we want it to. So for multiple reasons, we're very interested in this combination therapy trial. And there are also actually a lot of other combination trials in the works as well, that we'll keep an eye out for in the near future.

But for this one, of course, the first thing that you're interested in with a Phase I study is safety and toxicity. And from that aspect, it looked very good, at least for short term toxicity. I think it's still early to say anything about efficacy. From PSA response rate, it seems pretty similar to TheraP study, although they're just getting into the later cohorts with a little bit more intensive dosing, so maybe that'll change.

And then of course, the two things that we're very interested in are, taking longer for us to learn those answers about long-term toxicity, and also about the duration of response, or duration of benefit. So far, it looks encouraging in terms of safety. There's some signals that it may be more effective than monotherapy, but still stay tuned, and hope to hear more in the near future.

Alicia Morgans: It is really interesting. And just to remind everyone, this is a mCRPC population; they weren't a population with HRR alterations, right?

David VanderWeele: That's correct, yeah. It is not biomarker selected. It's using the PARP inhibitor as a sensitizing agent to the radioligand therapy.

Alicia Morgans: And how was it given? It wasn't given concurrently. It was an interesting schedule, right?

David VanderWeele: Yeah, that's right. Well, it also changed in depending on what cohort it was in, but basically, it was given initially for two weeks, and then for three weeks, around the time that the radioligand was infused. Initially, starting a day or two afterwards, and then later on, starting before the infusion, and then continuing for the next two to three weeks. Yeah. So for the idea that it would sensitize to the toxicity, or to enhance the efficacy of the radioligand therapy, but with this intermittent approach, then you would miss some of the toxicity, or not accumulate some of the toxicity that you might otherwise with continuous dosing of the PARP inhibitor.

Alicia Morgans: Which is so interesting. I really think that was such a thoughtful approach to, really, as you said, use it as a radio sensitizer, just in the context of that exposure. And then, it's not an HRR positive population, so stop that treatment, and give that patient some time to recover. Maybe this will be associated, hopefully, with enhanced efficacy, but I assume, it's probably going to be at least associated with reduced toxicity than continuous PARP.

David VanderWeele: Yeah, I think so. Certainly, the toxicity and safety data look pretty promising, at least in the short term, as I said. But both these agents have the tendency to have, or at least the capacity, to have significant toxicity, in terms of the bone marrow. So yeah, I'd be very interested to see what that looks like once they've had patients on therapy for a bit longer.

Alicia Morgans: Absolutely. So if you had to summarize your discussion, and kind of let us know, were there any take home messages that we should consider from these presentations?

David VanderWeele: Well, I really encourage people to be diligent and with doing molecular testing. I think, so far, it's not, yeah, we saw that there's worse prognosis. If you carry a mutation in an HRR gene, that prognosis is even worse. If you have a mutation, BRCA1 or 2 gene, we know that BRCA1 and 2 are excellent predictive biomarkers for response to a PARP inhibitor, so do the molecular testing. And at least so far, it seems like, even though the PARP inhibitors are being used in wider populations, hoping for synergy with other agents, so far, it seems like those who benefit the most are the ones with the BRCA1 and 2 mutations.

Alicia Morgans: So many questions still remain unanswered, but thank you for answering the ones that we asked today. And certainly, for giving us all some perspective on these really interesting oral presentations. And congratulations on your talk, and thank you for your time today.

David VanderWeele: Thank you.