Alicia Morgans: Hi, I'm so excited to be here with Professor Fred Saad to talk about the updated PROpel data that was presented at GU ASCO 2023. Thank you so much for being here.

Fred Saad: Always a pleasure.

Alicia Morgans: It's always a pleasure to talk to you and it's always nice to hear your perspective on what has become a bit of a controversial space in our field, this first-line mCRPC setting in which we're thinking about combining PARP inhibitors and AR targeting agents. And certainly, there's multiple studies now that are giving us information on this particular question. The latest update, at least in terms of the OS information and longest-running, I guess, follow-up is PROpel. Can you tell me a little bit about the study and the data that was just presented?

Fred Saad: Right. Very briefly, PROpel really wanted to address the first-line mCRPC question in patients that hadn't been treated with a novel hormonal agent in the mCRPC setting. So we took patients all-comer. And I just want to correct, it was prospectively gathered, the information on the mutational status. It just wasn't an entrance criteria or a stratification criteria. So patients were randomized to getting the standard of care for mCRPC first-line abiraterone prednisone versus abi and olaparib at full dose. And then the primary endpoint was rPFS based on approvals by FDA and all the other organizations. So the trial already reported a year ago that it was positive in terms of improving rPFS by 8.2 months compared to a standard of care. And that was surprisingly similar to the standard of care against placebo several years ago of 8.2 months difference, a 34% reduction risk of progression or death.

So what we've been updating since then is everybody's asking about, "Well, what about overall survival? What about the subgroups specifically whether they were mutated or not?" So these updated results now are telling us that in terms of overall survival, clearly, with only 800 patients against an active control could not be the primary endpoint. But we're seeing 7.4-month improvement in overall survival in the patients who got the combination compared to abiraterone and prednisone. But the size of the study makes it that it's a 0.55 P-value. It didn't meet its criteria because it's multiple cuts of the data, but that absolute difference is striking. So that's where we are today in terms of overall survival in those patients. And obviously, there are questions around the subgroups, which should not be the focus. And we've been talking about that, people focusing on the subgroups.

Alicia Morgans: So really just to recap that, so there was an improvement in overall survival. This was not statistically significant but was underpowered. And also, of course, we had to adjust the P-value for multiple testing. So that adds to the issues in terms of spending the alpha and needing a lower P-value. But the clear trend there, the apparent direction was that there was an improvement even in overall survival with this earlier intensification in an all-comers population. So this has led to a lot of controversy and a lot of discussion. And I'd love to hear your thoughts on the all-comers population and the patients who did not have the HR mutations because that's really where I think a lot of the controversy lies. And if you could also comment on the TELEPRO-II data, which also seems to show a similar perhaps synergy with a benefit to the combination of talazoparib and enzalutamide in an all-comers population versus enzalutamide alone in that first-line space.

Fred Saad: Yeah, absolutely. And it was very, very reassuring that TALAPRO-2 confirmed what we saw in PROpel, that there is activity in patients who don't harbor detectable mutations. We know there are limitations to how we test. We can make all the efforts in the world, we can't really figure out some of the patients, whether they harbor mutations that are undetectable or if there are mutations that we just don't know yet that we're not looking for. But it was very reassuring that their improvement in rPFS in an all-comer population was very similar to what we saw in PROpel. So that's number one. In terms of the subgroups, when a study is not even powered to look at individual subgroups, it always becomes an issue of saying, "I'm going to exclude a population from the opportunity of discussing." And clearly, we have lots of therapies that we don't consider for every patient who walks in the door, but I think it's up to us as clinicians and the patients to participate in that discussion.

So the trial is positive and we need to move forward in prostate cancer. We can't keep doing thousand-patient studies that are going to take forever with overall survival when we think about how much effort and time it took for placebo control trials to show overall survival differences. And I remind, enzalutamide took 1,700 patients. And their first cut in the New England paper was only 2.2-month survival difference. But because the study was so large, that 2.2 was statistically significant and led to what we now consider a standard of care, but we need to move forward, the field needs to move forward or else we're going to condemn ourselves to continuing to have only what we have.

Alicia Morgans: Well, and I agree with that. I think that, and I hope our colleagues do too, but I think it's important for us to recognize that the details at least of PROpel from my understanding that a vast majority of patients, they all had prospectively collected specimens for testing for their HR mutation, either wild-type or mutation status. And even though that was not used in stratification or randomization, this was something that was prospectively tested. What proportion of patients were really unknown in terms of their status because there were a large majority that had tissue-based testing, and then there were some patients who had ctDNA testing. What proportion were actually unknown in that population?

Fred Saad: So all patients supplied tissue and ctDNA, but even with those two, because one or the other could be positive to be considered a positive mutation, there was only 2% of patients where we could not determine the mutational status. So by adding ctDNA, you compensate for the fact that tissue is going to be an issue forever. Either the tissue's too old, not analyzable, patients can't get another biopsy of value. So there's repeatedly, and even TALAPRO-2, it's always in the range of about 30% of tissue is noninformative. It can inform you that you can't figure out what it is, but doesn't inform you whether they're mutated or not. And ctDNA is probably the way of the future as it continues to improve because the reality is patients don't all want to get a new biopsy, and the somatic testing has its issues.

Alicia Morgans: Well, I do think it's important to recognize it was really 2% of this entire population that was unknown, and a majority of patients did have that tissue testing, and there are limits to science. So I think that's important. Perfection can be the biggest enemy of the good in this situation, I think. In any event, what would your conclusions be with this updated data and thinking about all of these studies and the combination of a PARP inhibitor and AR signaling inhibitor in that first-line mCRPC space? What's the bottom line?

Fred Saad: The bottom line is for the majority of patients, like we saw in this study, they will benefit with an improvement of radiographic progression-free survival against a very, very active control arm. So, when we realize that many patients don't go beyond first-line therapy in mCRPC, it can be critically important for patients to get that opportunity to get the very best upfront. And we're seeing that now in hormone-sensitive disease. When you can do the very best upfront, down the road, things are much, much better. And the real world is not like our clinical trial. So the bottom line is many patients are likely to benefit.

Figuring out what your cutoff is to offer this to patients is going to be part of our role as physicians, but also the patients who need to be informed that there are other options besides what we've been using for the past several years. Another important thing is these trials, whether it's PROpel or TALAPRO or MAGNITUDE, does not intend to say that genomic testing is not necessary. It adds to the information to help the patient decide. So if you're mutated, the data is clearly to the advantage of starting as early as possible the combination. If you're not mutated, then you need to look at other factors that might make you decide and the patient decide that they want to do more than the standard of care.

Alicia Morgans: I really could not agree more. I think that it is so important for us to do this testing, do it the right way, make sure that if we can't get tissue to work, we're doing our ctDNA, get that information for the patient, and then we should absolutely engage those patients in shared decision making. When we're talking about advanced prostate cancer, this is one of the most important things, I think, to empower our patients to play a role in that decision. And having those options is going to be a key part of that. But I do want to say thank you so much for your expertise and for helping us weave our way through what has become an extremely challenging space in first-line mCRPC with these PARP inhibitors and AR targeted agents. It is not easy now, and you're helping us find our way. So, thank you so much for your time. I sincerely appreciate your expertise.

Fred Saad: Always a pleasure.