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Alicia Morgans: Hi, my name is Alicia Morgans, and I am a GU Medical Oncologist at Dana-Farber Cancer Institute. I'm so excited to have here with me today, Dr. Fred Saad, who is a Professor and Chair of Urology at the University of Montreal Hospital System. Thank you so much for being here with me today.

Fred Saad: It's always a pleasure, Alicia.

Alicia Morgans: Wonderful. So I wanted to speak with you today, Dr. Saad, about the PROpel trial, which is a really exciting Phase III trial for patients who are being treated in first-line metastatic castration-resistant prostate cancer. Can you tell us a little bit about the study?

Fred Saad: Sure. Maybe just briefly, some of the background, because this didn't fall out of the sky. So obviously, we are all working very hard to do better in the first-line setting of mCRPC. We are still using a monotherapeutic approach. There is no combination that has been proven to be effective, and there is no treatment that has actually been shown to be effective over a standard of care.

PROpel looked at pushing the envelope, in terms of combining abiraterone, which is pretty much, one of the standards of care in mCRPC first-line, and a PARP inhibitor, olaparib, in combination, based on the preclinical evidence that we maybe can potentiate the effects of each one alone when we put them together in patients that are metastatic castration-resistant. And a Phase II study in post-docetaxel showed that there was actually a benefit, regardless of whether or not you had mutations in your HRR. And so, the Phase III study took almost 800 patients, randomized one-to-one, to get abiraterone alone, versus abiraterone and olaparib. Obviously, prednisone was used in both arms, with a primary endpoint of delaying radiographic progression-free survival. And I think we all agree, this is a very important and clinically relevant endpoint.

Alicia Morgans: Absolutely, especially in patients with advanced disease. And I really want to just emphasize, that this included an all-comer population, so it did not require patients who had DNA repair defect alterations, like BRCA2, to enroll in the trial.

Fred Saad: Exactly. So we just went ahead and said, first-line patients that haven't been treated for mCRPC in the past but could have received docetaxel in the metastatic hormone-sensitive setting, could have visceral metastases, could have symptoms, even severe symptoms requiring opiates, and 20 to 25% of patients did come in with that. So really, addressing what is going on in the clinic. And exactly as you said, there was no requirement for testing to be eligible, and we just allowed it. And it gave us, I think, some of the best evidence of what is actually going on with the patients that we put in the first-line, and actually, 28% of patients, harbor mutations, BRCA, and others. So this is all mutations. And almost 70% had no mutations that were detectable. And so we really get an idea of what percent of patients harbor mutations, and also the outcome of patients with, or without mutations.

Alicia Morgans: Absolutely. And to your point, it's nice, in this metastatic CRPC setting, to have sort of almost a real world, or at least a real clinical trial type population, to help us define the prevalence of these alterations in our population, which is actually, something that we need in clinical practice. So another benefit of the study.

So let's dig into the results a little bit. You were aiming to understand whether PFS, progression-free survival, was going to be longer with the combination. What did you find?

Fred Saad: The results actually, surpassed our expectations. So we actually found, that in the whole patient population, it was over eight months improvement in radiographic progression-free survival. And surprisingly, that is pretty much the same as what we saw with abiraterone against a placebo, which was about eight months. And reassuringly, the patients on abiraterone, the control arm, had about a 16 month time to progression, which was almost identical to the 302 study that Chuck Ryan had led and published already, several years ago. So our control arm is really in line with the real-world data. And if we went to a blinded central review of imaging, it was actually over 11 months improvement, a 39% reduction in the risk of radiographic progression.

When we looked at the subgroups, it was all the subgroups that benefited from this combination, whether they had received docetaxel in the hormone-sensitive setting, whether they had visceral metastases, or not. And especially, whether they harbored an HRR mutation or not. They were all favoring the combination arm across the board, and especially in the young patients, they were favoring. But all of them were really on the left side of the non-significant line.

Alicia Morgans: This is really phenomenal because it allows us to use this therapy without that barrier of testing for genetic mutations before we can use the treatment. Of course, there are reasons for germline testing, even so in this population, but for a therapeutic reason, it lifts a barrier, which is important.

Fred Saad: Absolutely. I don't think, anybody should leave with a take-home message, that testing is not important anymore. It has a lot of implications for the patient, and for their families. It also allows us to maybe, follow patients differently when you know they are mutated because they reach this state much earlier, so the way we are going to react. And we need to do clinical trials in even earlier settings. And it also makes us reflect, is it only HRR mutations that are driving the benefit of a PARP inhibitor? There are things that we do not yet understand that we are going to continue to work on, biomarkers that go beyond just HRR mutations, to see why this synergistic effect is actually seen in this patient population.

Alicia Morgans: Well, and to that point, let's dig into the biology a little bit. This is, of course, what led to study eight, which was the study that Noel Clarke and the team worked on, that initially demonstrated this likely benefit across the board, regardless of the DNA repair defects status. Tell us a little bit, why would abiraterone really enhance the ability of olaparib to work in patients who do not have these alterations?

Fred Saad: Right. So the preclinical studies seem to suggest, that when you give a drug like abiraterone, and probably any of the other new-generation hormonal therapies, we create kind of a "BRCAness" environment, which makes PARP inhibitors more efficacious with, or without a mutation. And on the flip side, a PARP inhibitor has some activity in AR transcription, that may make actually, the abiraterone more effective.

So really, the theory behind this is, by putting them both together, we would do a better job than each user, either sequentially or alone. And that was looked at in study eight, like you said, we got a clear signal, but it needed to be shown in a Phase III study. So it was ambitious, it was a risky trial to do. But I'm very happy because, if you just think of patients post docetaxel in the hormone-sensitive setting, when you introduce a novel hormonal, the response rates are not so great. When you take patients that have visceral metastases, the response rates are not so great, so this is very reassuring when you take symptomatic patients. So this is nice that we might, eventually, have a first combination therapy that can be used in these patients that are, unfortunately, all destined to progress. Even more disappointing, many patients do not go into second-line therapy. We really have to concentrate on the very best we can do in the first-line setting in mCRPC.

Alicia Morgans: I would agree with that. And as we are making those decisions in the clinic, of course, we consider toxicities, which I know you assessed in this trial. And I'd love to hear your thoughts on the adverse event profile for these agents in combination, versus abiraterone alone. And if you could comment too, on cardiovascular events, which were something that was demonstrated in study eight, at a level that was a little bit higher than we might expect. Would love to hear your thoughts.

Fred Saad: Yeah. Obviously, abiraterone, olaparib, have adverse event profiles that are well known. The nice thing is, we didn't see any added adverse events that went beyond what we would have expected with each drug alone. If anything, it looked like they might be even tolerating it better, especially for the olaparib. It might just be a bias because we are taking patients earlier in their trajectory. We've always given it almost like a last resort. So patients overall, very few grade 3/4 adverse events in either arm, except for anemia, which was as expected, higher, but a 15% rate of grade 3/4, that was easily managed with supportive care. So this was very reassuring. And honestly, the patients we put into the study in our center, I had a hard time figuring out if they were on olaparib or not. It wasn't striking at all, and I'm very curious to unblind and know which patients were actually on because I really couldn't predict.

Alicia Morgans: That's wonderful to hear, but I just want to touch back on that cardiovascular signal. How did you and the team, as you were putting together this trial, deal with that adverse event from cardiovascular disease?

Fred Saad: Right. So you are absolutely right. In study eight, a very small study, you have to remember, it was about 70 patients in each arm. There was a higher rate of cardiovascular events in the patients getting the combination. And with such a small study, it could have been just bad luck, but we needed to look at this in the Phase III study. So we really didn't make any effort to exclude patients at risk. It was really based on the comfort level of giving them abiraterone, which we already know, we have to take into consideration cardiac state. And in this study, there was absolutely no difference in cardiovascular complications or arterial complications in the study. There were numerically more thromboembolic venous events, like a pulmonary embolus, that were incidental findings on a CT scan, but they didn't require discontinuation of therapy in the patients that we discovered this. So this is something that is continuing to be evaluated. But for now, very reassuring, in terms of cardiac toxicity.

Alicia Morgans: I agree. That absolutely is the right thing to do, the right thing to study. And I'm glad that you and the team did that. As you think about this, and you want to communicate a final message to the listeners, what would that be?

Fred Saad: Beyond PROPEL, I think we really need to do a better job of offering patients more effective first-line therapies in mCRPC. I think we are desperately behind having a first combination study. I don't think this is going to be the last, hopefully not, but we really need to be thinking better combination. And we also have to, I think, temper our expectations. We just have to remember, this is an 800 patient study against a very active control. Every drug that we are using today in mCRPC was compared against a placebo or an inactive control, and so, with generally, over 1,000 patients. So I think, rPFS, we have to start looking at this seriously, as being an endpoint that makes us change practice because if we are always waiting for overall survival, the field is continued to be monotherapeutic after monotherapeutic, which I think is not the future.

Alicia Morgans: I think that's a great message, and really, a message that I'm sure, resonates with patients. Because with each treatment change, besides the fact that many patients will actually fall off of that treatment journey, there is stress, there is pain and progression, and other complications that come when you have to make these shifts and try to approach the disease in a different way. So I commend you and the team. And I thank you and the patients for giving us this information. And thank you today, for sharing your time and your expertise.

Fred Saad: Thanks, it's a pleasure.