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Zachary Klaassen: Hi, my name is Zach Klaassen. I'm a urologic oncologist. We are live at GU-ASCO 2025 for UroToday. I'm delighted to be joined by Dr. Steve Freedland, who is a urologic oncologist at Cedars-Sinai, and has really been leading the charge on the EMBARK trial. Steve, thanks so much for joining us.

Stephen Freedland: No, it's great to be here. Thanks so much for having me, Zach.

Zachary Klaassen: So I know you've probably answered this 1,000 times, but maybe just a high-level view of EMBARK before we get into the subanalysis that you guys presented today.

Stephen Freedland: Yeah, no. Absolutely. So we know in metastatic hormone-sensitive prostate cancer, adding an AR therapy—whether it’s enzalutamide or others—significantly improves overall survival. So the question is, can we take it one step earlier? So we looked at patients with biochemical recurrence, conventional imaging negative—what I'm trying to call CIN, prostate cancer—conventional imaging negative, PSA doubling time less than nine months. They’re all biochemically recurrent, had surgery, radiation, or both. And the question is, does enzalutamide improve outcome in those patients?

So we had your standard ADT plus placebo (standard control), our ADT plus enzalutamide (we call it enza combo), or actually, for the first time ever in a phase III trial, enza alone (an AR monotherapy) in a phase III. First time ever.

Primary outcome was metastasis or death—what's called metastasis-free survival. And as previously reported, we saw significant benefits (delayed MFS) for both enzalutamide with or without ADT, suggestions of improved overall survival, preserved quality of life, no new safety signals. And this was published in the New England Journal, got FDA approval, EMA approval for the Europeans listening to us, and is in the guidelines. And to me, it really is the standard of care for these high-risk patients, no longer candidates for salvage radiation. And when they're ready to start systemic treatment—we still don't know when to start—but now, at least we know how to start.

Zachary Klaassen: And really, I mean, with this one trial, completely transformed that disease space. High-risk biochemical recurrence—we now have treatment options. And so that was over a year ago now. But now there's some really good subanalyses coming out, one of which you guys presented today, looking at two abstracts, one with the combo, one with the monotherapy, and looking at the effect of prior therapy, whether that be surgical or radiation.

So maybe just set up the rationale for looking at that, and maybe a little bit about the study design for that specific analysis.

Stephen Freedland: EMBARK, again, enrolled biochemically recurrent patients.

Zachary Klaassen: Yes.

Stephen Freedland: So it was either you had surgery or radiation. And if you had radiation, historically, there's not been as many salvage options—not a lot of patients undergo that, though we're learning there's a lot more salvage options now, I think, than in the past. So radiation.

But for surgical patients, a lot of them will get salvage radiation. So there's multiple paths to this biochemical recurrence ready for systemic treatment. And so the question is, did how you get there—surgery, radiation, or both—make a difference in how well enzalutamide worked? And intuitively, I wouldn't necessarily have hypothesized that they would be different.

Zachary Klaassen: Sure.

Stephen Freedland: But having now, as you said, EMBARK is the primary publication, is a little over a year now, and having gone around speaking, talking to people, this is one of the questions we get. So we really wanted to address this and see, are there differences by primary treatment?

Zachary Klaassen: So maybe just go through some of the high-level results, both for the combo and the monotherapy that you guys presented.

Stephen Freedland: Yeah. So the take-home message is, it didn't matter.

Zachary Klaassen: Yeah.

Stephen Freedland: They had surgery, radiation, or combination. And 50% of the patients in EMBARK had surgery and radiation, a quarter had radiation only, a quarter had surgery alone. So as you get to—you have combination, you have monotherapy, three different primary treatment groups, a lot of different secondary outcomes. You get some small numbers, not everything was statistically significant. But within the best global sense that we could get, all the hazard ratios were relatively similar to each other.

And it does really seem to be, whether you had surgery or radiation or both, that enzalutamide has benefits. And again, it's not necessarily surprising. We go back to the day Anthony D'Amico had looked at PSA doubling time, the less than three months as a surrogate for overall survival in both surgery and radiation patients, and it worked in both. If you look at guidelines to define high risk, most of them only include the doubling time less than 12 months often for surgical patients, not radiation. Never made sense why doubling time shouldn't be prognostic in radiation patients—D'Amico showed it is. And so you define a high-risk group, and in any high-risk group, whether it's metastatic, high-risk biochemical recurrence, we're seeing that these AR drugs really are potent at improving oncological outcomes.

Zachary Klaassen: Yeah. I think it's nice because, as you said, people are asking the question. And we're surgeons, but we see radiation patients. We don't know if that disease changes over time. So to see that data, at least, like you said, we didn't expect it to be different. But knowing that, I think, is nice. So if we take this subanalysis, do you think it changes people's opinion of how they give combo versus enza, or is it just something that checks the box, that it doesn't matter how they got there?

Stephen Freedland: Yeah. I think it's more, as you say, checking the box, that you don't have to think: did they have surgery, did they have radiation—"all right, I'm going to choose this drug over this drug." So it takes that question off the table.

And the whole who gets combo, who gets monotherapy, that's a huge debate. And I think it's a lot of patient preference things, and I think we're still understanding, still unraveling some of that data. I do think, as presented today at the session, that the questionnaires we use for quality of life probably don't capture the full patient experience.

Zachary Klaassen: That's right.

Stephen Freedland: So if we simply look at those measures, we don't see huge differences. You do see some sexual activity benefits from monotherapy over combo. But I think there's a lot of other patient factors and well-being that aren't captured in our questionnaires that do tend to favor monotherapy. At least, that's what I'm hearing anecdotally. And so I think there's a lot more to be written about the story.

And I think, to me, what's exciting about EMBARK is, as you said, in one study, I don't know if we've completely rewritten everything, but I do think we've changed the face of biochemical recurrence. But also, I think there's some paradigm-setting things in terms of nine months and then off treatment, which has been the case with Juanita Crook's biochemical recurrence paper, Laurie Klotz. But now people are starting to talk about that in metastatic disease, again, using the less than 0.2 criteria, not the old PSA below four criteria, for AR monotherapy. So I think there are some paradigm-shifting concepts that extend beyond BCR. And so it's been fun to be a part of this.

It's obviously a great shout-out to Neal Shore, my co-PI, huge team—Pfizer, Astellas—all the patients, the families, the PIs at each site. It's a huge, huge effort. But we now have this dataset and can analyze it and ask really paradigm-shifting questions. It's fun. It's a fun stage.

Zachary Klaassen: And we're seeing a lot of other trials in that disease space as well coming now. So it's a very hot topic. We haven't even touched on PSA—that's probably another conversation. There's a lot going on, particularly in that disease space. So thanks so much. Any take-home points for our UroToday listeners?

Stephen Freedland: So I think the key take-home is whether you had surgery, or radiation, or both, enzalutamide improves outcomes with high-risk biochemical recurrence.

Zachary Klaassen: Perfect. Steve, thanks so much for your time.

Stephen Freedland: Thanks for having me.