Zachary Klaassen: Hello and welcome to UroToday. My name is Zach Klaassen, urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. I'm delighted to have back on UroToday Dr. Steve Freedland, who is a urologic oncologist at Cedars-Sinai in Los Angeles, California. Today we're going to be talking about the EMBARK overall survival data, which Dr. Freedland presented at ESMO 2025. Some really exciting data in this disease space. So Steve, as always, thanks for joining us on UroToday.

Stephen Freedland: Thanks so much for having me, Zach. It's a pleasure to talk, and especially when we have such really exciting data to talk about.

Zachary Klaassen: We absolutely do. I think without getting to the punchline, we've got overall survival data in this space for the first time. So let's walk through some of your slides and we'll have a little Q&A after your presentation.

Stephen Freedland: Yeah. So I'm actually a consultant for many companies, including Astellas and Pfizer, the makers of enzalutamide.

So in terms of background, we know going back 20 years now that patients with biochemical recurrence and no evidence of metastatic disease on conventional imaging, if they have a really short PSA doubling time, that predicts a high risk of prostate cancer-specific mortality. That's the state of the art from 20 years ago. And the question is what can we do about it?

And that led to the EMBARK trial where we took these patients with PSA doubling times less than nine months, PSA greater than 1 ng/mL post-surgery, above the nadir plus 2 ng/mL post-radiation, conventional imaging negative, non-metastatic on conventional imaging. Randomized to enzalutamide plus ADT, ADT alone, or for the first time ever in a phase III trial, enzalutamide by itself. Patients were treated for 37 weeks, really important. And if the PSA was less than 0.2 ng/mL, they got a treatment break. So that's really important. We're not talking about lifelong therapy here. We actually get the opportunity to have a break. The vast majority of those treated with enzalutamide did get that break. And then obviously what we're presenting here is the overall survival. But just keep in mind that the primary outcome was metastasis or death, also known as metastasis-free survival.

And what we see here is really unprecedented survival benefit with a hazard ratio of 0.597, below 0.6, the greatest survival benefit by hazard ratio ever seen in a global phase III trial that looked at all the patients in the trial, not just cherry-picked a small subset. Really dramatic. It does take a few years for these curves to separate, which is not completely surprising. But the fact that you're getting a 40% reduction in the risk of death at such an early stage is really impressive. Just speaking to the power of this combination when used in the right patients early on.

And when we looked at the forest plot subsets, basically we see benefits across every single subset. There's really no subset of patients that did not benefit. That's the take-home message for combination therapy. And if we look at monotherapy, not as clear-cut the same story. We do see a suggestion of benefit. I mean, the hazard ratio is 0.83, it's not 1, but it did not reach statistical significance. And when we start to look at the subsets, most of them are below 1, favoring monotherapy. Again, none statistically significant. But if we look really, to me meaningfully, at those with PSA doubling times less than three months, the hazard ratio is 1.0.

Now, mind you, we are relative to ADT; we are relative to an active control. So we're not saying things are horrible or worse, they're just no better than ADT alone. Whereas in the PSA doubling times of three to six, six to nine months, we see hazard ratios in the mid-0.7s, again, suggesting that in still aggressive, but the lower end of that spectrum, there may be a role for monotherapy in those patients.

Safety. We know all of these treatments do have side effects, even ADT alone. Treatment-emergent adverse events, 98%. We look at the last line, the serious treatment-emergent adverse events related to study drug, less than 10% in all of them. It is more with enzalutamide plus ADT. There absolutely are side effects from these drugs. We did preserve quality of life, don't have time to show it here. But ADT alone has side effects. And if your drug works by blocking the androgen receptor, if it works, you should see more side effects. So if you don't see more side effects with an androgen receptor blocker, you have to wonder is it really blocking the androgen receptor? Enzalutamide clearly does. Survival benefit—you see a little bit more ADT-related side effects. And these are some of them. Again, you see more hot flashes, more fatigue, arthralgia. You see less of that with monotherapy because you have preserved testosterone, which gets diverted to estrogen and tells the brain you don't need hot flashes, but that does lead to gynecomastia and nipple pain. We gave no instructions in terms of the trial on how to prevent this. We think this can be prevented with breast irradiation and/or tamoxifen, but that needs to be studied.

Obviously we were able to publish this in some nice journals. New England Journal of Medicine for the primary paper, New England Journal of Medicine for the quality of life showing preserved quality of life, and this most recent overall survival update, also New England Journal of Medicine.

Zachary Klaassen: Steve, just absolutely fantastic data. The EMBARK trial, we've heard about it for several years now, and the benefit for metastasis-free survival was clearly shown in the combo and the enzalutamide monotherapy. When we look at our patients now, and we probably all have patients on this regimen for this exact indication, we've talked about less of a sexual side effect with monotherapy, perhaps more gynecomastia and nipple pain. With the equivalent metastasis-free survival, it was a discussion with the patient: "Hey, this is more of a side effect. What do you want to do?" Now we have overall survival, which shows a clear benefit with combo, and as you mentioned, directionality for enzalutamide monotherapy. But when I looked at this data that you presented, this obviously goes into the conversation now. How do you think we operationalize this with patients now that we have an OS endpoint in an early prostate cancer population?

Stephen Freedland: Yeah, I mean, it comes back to shared decision-making as everything we do in medicine, but particularly in prostate cancer, and really understanding what is it that they value. I mean, monotherapy did delay metastasis-free survival, delayed PSA progression, delayed need for next antineoplastic therapy, delayed what we call PFS2, which is the progression on the next line of therapy, delayed symptomatic skeletal-related events. So I mean, it hit a lot of secondary outcomes, including the primary, which was metastasis-free survival, and there's a suggestive survival benefit.

But yeah, I mean, if you have a patient with a PSA doubling time less than three months who's really worried "I'm going to die of this disease," they really should be on combination therapy. Unequivocally, I think that's the correct answer. But a patient with a little bit slower-growing tumor, still fast—I'm still talking EMBARK-eligible, PSA doubling time less than nine months, but a little bit slower—who says, "Look, sure, I want to live as long as possible. Who doesn't? But I really care about how I live and I want to maintain that sexual activity. I want to feel as well as I possibly can. And if I can get survival benefit, that's great, but I'm really worried about how I'm living," then that brings monotherapy onto the table, and you have that discussion with the patient.

Zachary Klaassen: Yeah, I think it's a great point. You mentioned the monotherapy hit a lot of the endpoints, which is important. And I think as you mentioned, that take-home message with the three months or less PSA doubling time, those are really the patients we're worried about that are going to progress. If those patients had a PSMA PET scan, they're probably already metastatic hormone-sensitive. So I think that ties to the doublet nicely.

Any concluding statements? Any take-home messages for our listeners, Steve?

Stephen Freedland: Yeah, I mean, it is just really hard to ignore this kind of data. I mean, we have an unprecedented 40% reduction in the risk of overall death. I know there's been some naysayers saying, "Look, you're going to be on therapy for a long time." True. I think we could in the real world consider multiple rounds of treatment suspension. That was not what was done in the trial. I think, for monotherapy, you could consider no treatment suspension. Again, not what was done in the trial, to try and boost that efficacy. But it's just really hard to ignore this very clear benefit we're seeing for our patients. So for the sake of our patients, this absolutely needs to be, at least combination therapy, the new standard of care, and in the right patient, potentially monotherapy.

Zachary Klaassen: Yeah, well said. Steve, congratulations to you, to Neal Shore, to the Pfizer and Astellas teams, to the patients that were involved in the trial, everybody. Just a huge undertaking for decades now, essentially. Another great presentation. And I know you've been busy with multiple aspects, and people wanted some of your time. We appreciate you joining us on UroToday.

Stephen Freedland: No, absolutely. Thanks for having me. It's great. We've got to spread the word. These are really unprecedented data that need to be out there.

Zachary Klaassen: Absolutely. Thanks so much, Steve.

Stephen Freedland: Thanks so much, Zach.