Alicia Morgans: Hi, I'm so excited to be here with Dr. Elena Castro, who is joining me to talk about PARP inhibitors and their combinations, some of the data that we heard about at GU ASCO 2023, and that you discussed, in a really expert conversation, about how you integrate these new findings into the current landscape. So tell me a little bit about what you discussed, and sort of set the stage for us, Dr. Castro.

Elena Castro: Yes. Well, at this conference, we've learned about some studies, TRITON3, TALAPRO-2, and PROpel, that have really presented data that help us fill in some gaps that we have, regarding the use of PARP inhibitors for advanced prostate cancer.

So perhaps the easiest study to discuss first is TRITON3. That was a study of rucaparib in monotherapy for patients with alterations in BRCA1, BRCA2, and ATM. And what we've learned is that treatment with rucaparib, particularly for patients with BRCA alterations, results in improved cardiographic progression-free survival, compared to treatment with either docetaxel or a second hormonal treatment. For patients with alterations in ATM, we haven't seen any benefit. So this study is somehow helping us decide who are really the patients that get benefit from PARP inhibitors in immunotherapy.

Alicia Morgans: Oh, one of the things that I think you tackled in your discussion that was so interesting, is the consideration in patients who have these HRR mutations, regarding timing of a PARP inhibitor versus docetaxel. And I wonder if you can talk us through what your thoughts are after seeing the TRITON3 data.

Elena Castro: The TRITON3 data provides very relevant information about, that for patients with BRCA alteration, it is clear that the PARP inhibitor provides greater benefit than a taxane. And considering that these patients have poor outcomes, I think we should use a PARP inhibitor as soon as possible. Because if we don't do that early, the chances are that we may never get to use it.

For patients with ATM alterations, since they don't seem to benefit as much from PARP inhibitors, then perhaps we can use a taxane first. But there's more data that the TRITON3 study could provide, because patients who receive docetaxel cross over to rucaparib, and their patients who receive rucaparib that for sure received taxanes later, so an analysis of those data will provide very useful information.

Alicia Morgans: Absolutely. But I love the way that you frame that, because I do think that we know that these patients have such a poor prognosis, as compared to other patients in general, that having the opportunity to get something more effective to them earlier, rather than potentially missing that opportunity, is a really critical thing.

Elena Castro: Yes, I agree.

Alicia Morgans: Yes. So anything else you wanted to mention on TRITON3, before we move on to the next area of controversy?

Elena Castro: Yes. Well, I think TRITON3 also provided, for the first time, a direct comparison with taxanes, with docetaxel. So it allowed it to compare toxicity, because often, we hear about using PARP inhibitors to delay chemotherapy, just to avoid the side effects. And it was very important to get a head-to-head comparison. What we have seen is that, there are certain toxicities, such as nausea or anemia, which are more frequent with rucaparib than they are with docetaxel. This is reversible toxicity, and did not lead to treatment interruptions as much as other permanent toxicities from taxanes. But one in four patients required blood transfusion, meaning that we need to monitor carefully patients on PARP inhibitors.

Alicia Morgans: Absolutely. And that we need to be ready to do a blood transfusion, if that is the right thing for that individual. So thank you, certainly, for bringing that up.

Now, you also spoke about the TALAPRO-2 data, and you also helped us kind of put that in context with the other combination trials that we've heard about. I wonder if you can share a little bit of your thoughts on that?

Elena Castro: Yes. Well, we already have three trials investigating the combination of PARPi and ARPIs in first-line mCRPC. The TALAPRO-2 study has been presented in this conference for the first time. It's a positive study. There is a difference in rPFS, radiographic progression-free survival, from the combination of talazoparib plus enzalutamide, compared to enzalutamide alone. And although there is a benefit for the entire population, what we have seen is a difference in the magnitude of the benefit, depending on whether or not the patients have alterations in homologous recombination genes or not, and I think this is an important thing. In this study, the most frequent toxicity was also a hematologic toxicity, and about half of the patients experimented or presented with grade 3/4 anemia, also requiring blood transfusion. So I think it is very important that we identify who are really the patients that are going to benefit from this combination, and then use the combination. But being aware that there are toxicities that we need to monitor and be careful with that.

Alicia Morgans: Absolutely. And I think, especially because these are pills, it is really critical to reinforce that message. Because I think as you said before, this is not the patient that you can just put on an AR pathway inhibitor, an ADT, and say, "Well, I'll have you come back in two months or three months." These are really patients who you do want to monitor on that ongoing basis.

So just wondering now, this study, the TALAPRO-2 study, is positive for radiographic progression-free survival, with a combination of talazoparib and enzalutamide, versus enzalutamide alone, in an all comers population. When we do break out those subgroups, absolutely, the patients who have the BRCA1, BRCA2 seem to be driving a lot of that benefit. But one of the things that I think we've been talking about, at this meeting and certainly since the last meeting, when we saw similar data from PROpel, is that there does seem to be... There is certainly a signal for all comers, and does seem to be perhaps a benefit in those patients with wild type or lack of mutation, and this is statistically significant. So how do we make a choice about whether or not we might treat those patients or not, recognizing the toxicities? Is there a patient population that you might use the combination, or is this something that the benefits will just never outweigh the risks, from your perspective?

Elena Castro: Well, for the combination of talazoparib plus enzalutamide, I think is perhaps too early to decide whether we should start using this combination for these patients. Because we've seen data on radiographic progression-free survival, but this rPFS benefit not always translate in a benefit on overall survival. So we need to make sure that the patients that receive the combination will later benefit from other therapies, and that we are not harming them by giving this combination that will resort in shorter, or not benefit in overall survival.

Data on overall survival has been presented for the PROpel study. The overall survival for the entire population, at present, is not positive. So they have not reached the statistical significance. And we'll have also seen some analysis by subgroups, again, reinforcing the idea that in patients with alterations, there may be a benefit that is not so clear for patients without these alterations.

Alicia Morgans: So time will tell, is what I hear you saying, and what I think all of us are thinking, that we need to understand the data more clearly. And thank you for letting me put you on the spot. That is the question of the day. And no one knows the answer, because as you said, the data is not yet mature.

So as you think through this landscape, which is absolutely shifting, and as you think through really how we consider these studies that are testing first-line mCRPC, given the shifting landscape in mHSPC and non-metastatic CRPC, how do we really consider them, when everything around them may suggest that patients will already have received an ARPI before they get to that mCRPC setting?

Elena Castro: Exactly. And that is one of the major issues with these studies, is that the proportion of patients that had received a prior hormonal treatment with an ARPI is very small. So that the data we currently have do not allow us to conclude that patients who had already progressed to these agents will respond to the combination. So we have data for a population that is shrinking, and perhaps in a number of years, will not exist anymore.

Alicia Morgans: So we have to ask more questions, maybe the questions that are more relevant for today and get more data. Which is always the thing that keeps us in this line of work, I think, asking all of those questions, and trying to figure things out for our patients. So what is the bottom line? What would your conclusion be from all of the work that you saw today, and the discussion that you so expertly gave?

Elena Castro: I think one of the major points is that testing is important. Because at some point we have been discussing whether we could move away from testing patients, because we have combinations that will benefit all comers without regardless HRR status. And I think the data that has been presented in this conference points out in other direction. So testing is still important. HRR status is relevant, and we need to continue working on that direction.

Alicia Morgans: Well, thank you so much for sharing your expertise, both in the meeting, and certainly today. I always appreciate talking to you.

Elena Castro: It is my pleasure.