Alicia Morgans: Hi. I'm so excited to be at ESMO 2022 where I have the opportunity to speak with Dr. Neal Shore. Thank you so much for talking today.

Neal Shore: A pleasure.

Alicia Morgans: I wanted to talk with you a little bit about PROpel, which of course, is a study of Olaparib and Abiraterone versus Abiraterone alone, in the first-line metastatic castration-resistant prostate cancer setting. And it was an all-comers trial that suggested a benefit, actually, across the entire population, with a more extreme or more pronounced benefit in patients who have HRR mutations. But, we'd love to hear your thoughts as we got an update on this data. As a urologist in the United States, what does this data mean to you?

Neal Shore: Well, thank you. I was very honored to be part of the study and it really came after we saw the positive findings of PROfound. And then, also another earlier study, large Phase II study known as Study 8. Demonstrating first with PROfound that monotherapy with Olaparib for HRR marker-positive patients clearly bested sequencing from one AR-pathway blocker to another. So, I think for my colleagues in urology and medical oncology, of course, we know that that sequencing maneuver is typically not very effective. But, yet, it's practiced commonly for a whole host of different reasons. Study 8, a very important Phase II study that was presented at ASCO prior to the pandemic, demonstrated rather nicely that combining Abi and Olaparib in an all-comers population had a benefit as well as, in the wild-type HRR. So, then led to PROpel, which was published in the New England Journal and has been previously presented. And I know you've talked about it with others, such as Noel Clarke and Fred on the program.

So, I think for my colleagues who are practicing advanced prostate cancer, the findings clearly demonstrate that in an all-comer population, not just the HRR mutation-positive, but the ones who are not positive, we see PFS benefit clearly. We don't see any new tolerability or safety signals. So, why do it? Why add another drug to another drug? Well, number one, they're two distinct novel mechanisms of action. I think that's important. We're always trying to optimize mechanisms of action to impede prostate cancer proliferation. But, also to reduce resistance. Invariably we see resistance and so that's one of the theoretical issues for combining two novel mechanisms of action, such as a PARP inhibitor and an androgen biosynthesis inhibitor.



So, additionally, as long as we're not adding significantly to side effects and intolerability, and with the caveat that we can get it, it's accessible and not overly costly ... If we could reduce resistance, keep patients on oral therapy for a longer period of time, which most prefer, but not preclude other uses of survival-benefiting therapeutics, which I don't. I don't think we do. We can certainly have in our armamentarium the ability to use taxanes, whether it's docetaxel, cabazitaxel, arguably radiopharmaceuticals, whether it's Radium-223 or Lutetium-617, products that are coming forward now with RLT.


So I think this is a very, very exciting ... And, it's certainly something that PROpel informs physicians, teaches us that there are no doubt patients who are going to do better with two versus one. As you said, and I'm sure both Noel and Fred have talked about, not unexpectedly, the mutation-positive patients, particularly the BRCA patients, really we see excitingly powerful results. But, we also see positivity when we look at this in the patients who are wild type.

Alicia Morgans: So, agreed, it's so important to have that benefit. And I wonder, is that enough benefit for you to think about, for some patients at least, integrating this combination into a first-line mCRPC setting?

Neal Shore: Yeah, I love that question. Right. Is it going to be for everybody, the entirety of the all-comer population? Are there going to be other things, in addition to their mutational status, what particular HRR mutation they have? Or if they don't have an HRR mutation, are there other biomarkers? Are there other indicators, metrics, histopathology, CTC, DNA counts? And I think that's an exciting area that we're looking at. Yeah, I like that idea. It goes under the rubric of more personalized care. And, of course, we can get a little bit more into the granularity of their allele status. But, I think that that's some of the really exciting work that's going forward.

Alicia Morgans: Okay. So, not necessarily ready at this point in time, but really interesting, exciting, and something that we might think about in the future. And as you've alluded to too, we don't yet have survival data, which may also help make that decision, thinking about whether the combination is worth it versus a sequence of these agents.

Neal Shore: Yeah, that's right. And I think for many of our colleagues, that's where it all ends. For me, the rPFS benefit is so powerful. And that's already been previously presented. I mean, it really is the most powerful rPFS benefit against, not a placebo control, but it was against Abiraterone monotherapy in PROpel. But, I appreciate that many of our colleagues want to see the final OS. It is still early. It's trending positively, but we have to wait.

Alicia Morgans: Very good. So, just one final question, I guess, and that's about tolerability. You mentioned no real new safety signals for the combination of these agents. In your experience, how well-tolerated are these agents in combination?

Neal Shore: Yeah. So I've had a very good experience. I've had combination trial experience, not only with Olaparib, but with other PARPs and with other AR-pathway blockers, in addition to Abi. Enzalutamide, for example. I think that these drugs, patients usually don't have problems with oral medications. The typical adverse event profiles that we talk about, whether it's with Enza or Abi or any other AR-pathway blocker, as well as the PARP inhibitors in general ... PARP inhibitors chiefly revolve around concerns regarding myelosuppressive effects. And, in terms of constitutional, there would be the GI side effect profile. Tends to be early on, tends to be very manageable. The nice thing about Olaparib, at least in the PROpel trial, as well as my experience with other PARP inhibitors, is you can dose reduce, you can dose interrupt. And you can work with patients around it. I've very infrequently had to discontinue because of an adverse-event tolerability issue. So I think my colleagues in urology and medical oncology who are comfortable with that, managing the patients, doing the right education upfront, it won't be a problem.

Alicia Morgans: All right. Well, very good. Well, any last thoughts or summaries you'd like to put out for folks?

Neal Shore: Well, just regarding combination therapy. I love the idea of it, only because we are always trying to diminish the development of resistance. Of course, when we go from castration-sensitive to castration-resistant, it's an inflection point in the biology of the disease. And as we go from a first-line therapy to second to third line, we know that the window, the timeline is narrowing. So, I think the ethics and the integrity for doing combination therapy is to try to prevent that resistance and avoid toxicity. And that toxicity is typically to avoid hospitalizations and emergency department visits. And that's very accomplishable with this type of combination AR-pathway, AR-targeted agents and a PARP inhibitor.

Alicia Morgans: Wonderful. Well, thank you so much for going through all of this. I appreciate your time and expertise.

Neal Shore: Thanks.