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Zach Klaassen: Hi, my name is Zach Klaassen. I'm a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia, and I'm delighted to be joined today by Dr. Neal Shore, who is at the Carolina Urologic Research Center in Myrtle Beach, South Carolina, who's going to be talking to us about EMBARK as well as some patient case scenarios. Thanks so much for joining us today, Dr. Shore.

Neal Shore: Thanks for having me, Zach.

Zach Klaassen: Fantastic. I think today what we'll do is we'll have you run through some of the key results from the EMBARK trial. And then you and I will discuss maybe some index patients, some nuances between treatment and patient selection.

Neal Shore: That sounds great. As you know, Zach, this was a long trial to get completed, and I always have to begin by thanking all the amazing trial sites all over the world on almost every continent. We took almost nine years to complete this study. And I'm really proud of the steering committee and all of the sites and the sponsorship that allowed us to do this. It's a pleasure to be here with you and review the EMBARK trial.

As the title describes, this was a phase three randomized study of enzalutamide or placebo plus leuprolide acetate. And a third cohort, enzalutamide monotherapy in patients who had high-risk biochemically recurrent prostate cancer. This trial took almost nine years to complete. I'm really indebted to not only my steering committee team, my co-principal investigator, Steve Freedland, but also all of the many dedicated sites all over the world that allowed for the achievement of this study.

EMBARK and the study design that you see here, we took a patient population that we described as being high-risk, biochemical recurrence, so effectively a PSA doubling time of less than or equal to nine months. And the patients had to have undergone either previously radical prostatectomy or radiation therapy or both. They had to have essentially a normal baseline testosterone level. Conventional imaging, a CT scan, a full-body CT scan, and a technetium bone scan showed no evidence of metastatic disease. Of course, this was nine years ago when next-generation imaging was really of minimal presence.

There were some restrictions on prior androgen deprivation therapy exposure. And you can see the stratification factors that are listed here based upon screening PSA and the doubling time, the more rapid, less rapid. But again, less than or equal to nine months prior to hormonal therapy. It was a three-cohort trial. Enzalutamide at the traditional 160 milligram oral daily dose, which we see was approved for mHSPC, nmCRPC, and mCRPC, whether pre- or post-chemotherapy.

And this was a combination arm against a placebo leuprolide acetate. Cohorts one and two were blinded. And then there was an open-label enzalutamide monotherapy cohort, and this was unblinded. Interestingly, we had at the end of 36 weeks in any of these three cohorts, if you needed to achieve a PSA of less than 0.2, you were able to undergo interruption or what some have called a treatment holiday. And then you restarted based on the PSA going above two. And if you had undergone experienced RP or greater than five, if you had experienced radiation therapy. And the concepts there were that you rarely see anybody ever developing metastatic disease at those low levels of PSA.

And so, we looked at obviously very rigorously throughout the study, PSA, testosterone, and conventional imaging at regular opportunities. The primary endpoint, metastasis-free survival by a blinded independent central review, that was the combination enza-leuprolide arm versus the placebo leuprolide arm. And then key secondary endpoints, you see them listed here: MFS for the enza-monotherapy versus leuprolide, PSA progression, time to first androgen deprivation therapy, and overall survival. And of course, safety.

I'll go right to the Kaplan-Meier curve, which is really the primary endpoint MFS, metastasis-free survival. And one can see a hazard ratio of 0.42 in the combination enza-ADT besting a placebo leuprolide acetate. Now mind you, this data was all presented in a plenary session at the AUA in 2023. Really less than a year ago as we're having this conversation. The p-value was highly statistically significant. And so you look at the Landmark three-year and five-year analysis, one sees the clear separation and the data that favors combination or intensified androgen receptor pathway testosterone blockade versus testosterone suppression alone.

And then the key secondary endpoint also was PSA progression. This is really quite impressive as you can see here, a hazard ratio of 0.07 favoring the combination enza-LHRH versus placebo-LHRH. And then another key secondary endpoint was the third cohort, the unblinded open-label enzalutamide monotherapy. And likewise, a hazard ratio of 0.63, statistically significant. What we have reported at the AUA plenary that even though the p-value for overall survival is currently at the interim analysis less than 0.05, it hasn't reached the statistical plan for significance yet. And we continue to follow patients for overall survival, where the upper bound is right now less than one. We're expecting to have enough events, essentially deaths, sometime in 2025. And we will report back on the overall survival results in the combination enza-LHRH as well as in the enza-monotherapy arm.

Ultimately when it came to safety and tolerability, there were no new untoward signals with the adverse reaction profile of enzalutamide. One thing that's important to note, we did see patients in the monotherapy enzalutamide arm who had an increase in breast enlargement known as gynecomastia, nipple tenderness, nipple pain. And one sees this, and we've seen this before in unopposed AR pathway inhibition, whether it's with other earlier generation androgen receptor pathway inhibitors, as well as in two other early-phase enzalutamide monotherapy studies when you don't have concomitant T suppression. We did see that.

Now it's important to recognize in our protocol, we never had any prophylactic or preventative strategies to try and prevent that. And that's an area of ongoing research. I'm happy to talk more about that, but greatly appreciate the opportunity to give a quick review of our trial. Really importantly, Zach, we published our findings in the New England Journal in October of 2023. We also had a patient-reported outcome presentation at ESMO 2023, a concomitant New England Journal of Medicine evidence publication.

And then in November of 2023, the FDA expanded the label of enzalutamide to now include patients with high-risk BCR who can now receive enzalutamide either in combination with LHRH or as enzalutamide monotherapy. A really very nice achievement for this trial and accomplishment all in the period of less than a year from the original presentation at AUA 2023.

Zach Klaassen: Neal, thanks so much for that great overview. And you're right, it has been a tremendous accomplishment. We've seen not only what you already listed in the accomplishments, but also the transformation of the NCCN guidelines in the 2024 update. And really bringing some organization to this very chaotic disease space up until this trial was presented. Thank you for that overview for our listeners.

I'd like to just delve into maybe some cases, so for the person in private practice or in the academic center, whether in the United States or across the globe, what would you say, other than the usual criteria that are included for getting into a trial like EMBARK, is the index patient that you're going to sit down and discuss the two options with?

Neal Shore: Yeah, I appreciate that. I think this speaks to a couple of things, Zach. Number one, for a patient with high-risk BCR in our trial, we said it was less than or equal to nine months. If you look at EAU and other guideline definitions, some would say a high-risk patient is less than or equal to 12 months. In the FDA label expansion, they leave it to the clinician. They just describe it as high-risk biochemical recurrence.

I think this falls under the mantra of patient-physician shared decision-making. I'm pretty comfortable with the label of thinking about this for patients with a doubling time of less than or equal to 12 months. In EMBARK, we were less than or equal to nine months, we were a little bit more rigid. One could argue that maybe even a more aggressive biology.

Zach Klaassen: Sure.

Neal Shore: Now, having said that, I think that we clearly see that monotherapy, LHRH, is no longer a standard of care. And so if you're going to invoke testosterone suppression, it should be done in the setting of combining it with an ARPI such as enzalutamide. I don't think it should be interchangeable, but I'm steadfast in respecting the trial. There are no other studies that have demonstrated the same effect.

There was an earlier study using apalutamide called the PRESTO trial, which only spoke to PSA, PFS but not MFS. Now, additionally, you have the opportunity to use enzalutamide by itself as monotherapy. And as we saw, the hazard ratio for that also bested LHRH alone. There are different side effects of the combination versus monotherapy.

In the combination, you'll see more hot flushes, you may have more fatigue, and you may see more sexual dysfunction. We're looking at some additional patient-reported outcomes and other analyses, which we haven't reported on yet, such as sarcopenic obesity, bone demineralization, and fractures, but with the enzalutamide monotherapy alone, as I mentioned in the introduction, we saw more breast-related symptoms, enlargement, nipple tenderness, nipple pain, but we did not have any prophylactic preventative strategies for that. It was not part of the protocol.

And I'm actually preparing a presentation upcoming at the APCCC, the Advanced Prostate Cancer Consensus Conference, on prostate cancer to address that. And there really are three strategies in today for our colleagues. We've learned from our colleagues outside the US, we've used 150 milligrams by apalutamide, where you see the same kind of phenomenon happen when you don't have concomitant T suppression.

You can initially consider eight to 20 grays of radiation to the breast tissue. This can be performed in literally one to two days. There are aromatase inhibitors which are relatively inexpensive now, such as tamoxifen, which can be given in different regimens, but once to twice a day and are overall pretty well tolerated. And there's even a third strategy where one can make a small subareolar incision and simply remove breast tissue. Now, the timing for these and the accessibility and some other considerations, I think, are areas ripe for research.

Zach Klaassen: That's great. So much good information there. The final question I want to ask you just related to patient selection. And I think the one that I think about in the clinic is you have a patient, you've identified they're a great candidate, PSA doubling times are appropriate. Which one are you going to give, enza plus ADT or enza alone? Is there a crystal ball at this point in time or do we need more data to really delineate who those patients are?

Neal Shore: Well, it's a really important question. We now have this luxury to offer patients either combination, what we typically refer to as combination enza plus an androgen deprivation therapy strategy. In EMBARK, we used a Q3 month LHRH agonist versus now offering the traditional standard 160 milligram daily enzalutamide dose, the same dose that's applicable throughout the continuum of prostate cancer.

I think that one needs to have a very balanced discussion about the trade-off of the side effects. I think that for there, the trial was not designed to compare the combination arm to the monotherapy arm. Both bested LHRH agonist alone. But I think, as I mentioned earlier, you want to have that full-throated discussion with the patient about the side effect profile. Areas of ongoing research, can we start with the enzalutamide monotherapy? And then if the patient progresses, add LHRH? Well, that needs to be studied.

Zach Klaassen: Sure.

Neal Shore: That's an interesting phenomenon. And so I think that there are a lot of gray areas and opportunities, maybe very straightforward if there was somebody who was completely say had no interest in maintenance of any sexual function, libido. And there are a lot of various aspects to that. The combination may be, I might lean more toward that. But now since its approval, I've gone with the monotherapy in multiple patients now who say, "Look, I want to maybe have the opportunity to intensify later on in the course of my therapy."

Zach Klaassen: That's great. We look forward to a lot of interesting data coming out of this trial. As you mentioned, we'll look forward to hopefully the survival data in the next year or two, as well as some of these other subgroup and exploratory analyses. Dr. Shore, thank you as always for your time and expertise discussing the EMBARK trial and patient selection.

Neal Shore: My pleasure, Zach. Thank you so much for having me.

Zach Klaassen: Thank you.