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Alician Morgans: Hi, I'm so pleased to be here with Dr. Neal Shore where we're talking about the EMBARK trial that was recently presented at AUA 2023. Thank you so much for being here with me today, Dr. Shore.

Neal Shore: My pleasure.

Alician Morgans: Wonderful. So Neal, I know you've worked on this trial for years, and are so excited to be able to share the results of the study. Can you set it up for us and tell us who was the population, and what was the study trying to accomplish?

Neal Shore: Yeah, thanks very much. Yeah. This was a trial that we started first patient in 2015, last patient into 2018. We just had the first significant readout that met our primary endpoint in January 2023, so eight years in the making. The EMBARK study was designed to test whether enzalutamide plus leuprolide treatment, or enzalutamide monotherapy could prolong metastasis free survival compared with placebo plus leuprolide. This was for men with high risk biochemical relapse, and that could have occurred after surgery as the primary therapy, or radiation, or both.

We looked at a population that when we say high-risk BCR, that had doubling times of less than or equal to nine months. We wanted to investigate MFS because as you know, a prolongation of MFS is going to delay symptoms, it's going to delay the need for subsequent therapies, certainly additional therapies, such as taxane based therapies. So our criteria for the doubling time, as I said, was less than or equal to nine months, that patients had to have a PSA of greater than or equal to one, if they'd had an RP, or at least two points above nadir if they'd had a prior RT.

Alician Morgans: Great. They were randomized, as you said, to one of those three arms. Importantly, I think it's interesting for these biochemical recurrent studies, did investigators, or clinicians, and patients get their own PSAs? How did you monitor this? That seems like could be a challenge as you're trying to get to an MFS endpoint there.

Neal Shore: Yeah, that's a great point. So yeah, the randomization was one, to one, to one. Leuprolide plus a placebo versus leuprolide enzalutamide. Those two arms were blinded, and of course the third arm of monotherapy enzalutamide was not blinded. We followed these patients with traditional, or what we call conventional imaging, so they received a full body CT scan and technician bone scan every six months and a lab work every three months, as well as patient reported outcome questionnaires. We also had the PSAs performed centrally.

Alician Morgans: Great. So the patients wouldn't know necessarily if their PSA was rising unless the sponsor and your team kind of alerted them to that, just to try to keep things on track, I would imagine with the MFS endpoint.

Neal Shore: That's exactly right. So the patients were ideally blinded to their PSA results. If the PSA had dropped to less than 0.2, patients were able to go on and receive what we described as a treatment holiday, and then ultimately, we would stop therapy in all three arms and monitor them for PSA elevation over time. Then if they met certain criteria, then they would re-initiate the arm that they had already begun. So combination ENZA, LHRH or LHRH plus a placebo, or go back to the open label ENZA.

Alician Morgans: So that's really interesting too and important to highlight because that does it's quite a pragmatic study really reflecting what we do in the real world where we take these holidays, in many cases, when we're treating patients with biochemical relapse, no evidence of new radiographic evidence of metastatic disease. Very interesting. Certainly makes the study complex when you're trying to interpret the data. What did you ultimately find, Dr. Shore?

Neal Shore: Yeah, so we met our primary endpoint. The primary endpoint of the study was comparing the ENZA LHRH arm versus LHRH placebo. We had a hazard ratio of 0.42. Patients were... This was after five years of monitoring patients in both arms. The hazard ratio of 0.42 translates to a 58% reduction in the risk of metastasis or death, favoring the combination ENZA LHRH versus the monotherapy LHRH arm alone. I think this is remarkably important and impressive. As it concluded in the plenary presentation that with approval from appropriate rigorous review by FDA, this will be a new standard of care for high risk BCR patients.

Alician Morgans: That's a phenomenal thing for these patients and certainly for their wellbeing. I wonder, can you tell us anything about the enzalutamide monotherapy arm?

Neal Shore: Yeah, so the enzalutamide monotherapy arm, which was a key secondary endpoint also, met its endpoint of statistically significant. I will note that in the primary endpoint arm, the combination of ENZA LHRH versus LHRH alone, in addition to that hazard ratio being 0.42, that P-value was a 0.001 in the monotherapy arm. This was also statistically significant with a P-value of 0.005. The hazard ratio of monotherapy ENZA versus LHRH alone was 0.63, so a 37% reduction in the risk of metastasis or death in that arm as well.

Alician Morgans: So as you go forward and treat patients in your clinic, certainly these are therapies... Enzalutamide is a therapy that is already something that we access on a regular basis. I wonder, will this change, as you said, the standard of care, at least in your clinical practice?

Neal Shore: Well, I think this gives us really, that vaunted important opportunity to have more tools in our toolbox, and to at least now have a level one evidence of long-term data done in with a phase three trial, looking at two different options for high-risk BCR patients other than LHRH alone. We, of note, saw a very nice trend in overall survival but had not yet reached the statistical significance based upon our analysis plan. We will continue to follow patients. We're now looking for a total of 271 events before we complete our OS evaluation. We're about halfway there. I think that we'll get there probably sometime in the next one to two years, and we are continuing to follow those patients. I'm certainly cautiously optimistic that we will demonstrate OS as well.

As it relates to decision making in the clinic, we didn't find any new safety concerns or new signals with ENZA LHRH, and frankly, given other trials that we've done with monotherapy enzalutamide, we didn't find any new safety signals. You do see some gynecomastia and nipple tenderness discomfort, which we've known. But an interesting phenomenon in ENZA monotherapy is the avoidance of testosterone suppression. We have a lot of patient-reported outcome data, which we plan on a further evaluating and presenting at a congress in the future, but that was not presented at the plenary at AUA. We did go over very carefully the safety profile and the most common treatment-emergent adverse events. And again, as I said, there was really nothing unusual that you hadn't already been aware of with the multitude of trials throughout the prostate cancer continuum, starting with AFFIRM, and PREVAIL, and PROSPER, and ARASENS and ENZAMET. Now we add EMBARK to that list, and I think it's a pretty impressive, the full breadth of work of the clinical trial landscape for now, enzalutamide throughout the prostate cancer continuum.

Alician Morgans: It is very impressive, and I sincerely appreciate the time that you're taking to talk it through with us. Congratulations on a wonderful presentation, and thank you to your team, and certainly to the patients who participated in this, because as you said, I do think it gives us an opportunity to have a new standard of care for a patient population that is inherently challenging to study, but certainly one that needed our attention and now has it. Thank you so much for your time and your expertise.

Neal Shore: Yeah, thank you. Alicia. If I could just say one more thing, I'd be remiss if I didn't. I mean, to your point, I mean, eight years a global study. I was the co-PI on this with my good friend and colleague, Steve Freedland. All the investigators and the families across the globe who were involved in this, over 240 sites, 17 countries, and frankly, the medical affairs leadership at both Astellas and Pfizer over an eight-year period, it was really an amazing collaborative effort. So, thank you. I appreciate having the time to talk about it with you.

Alician Morgans: Well, thank you.