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Zachary Klaassen: Hi, my name is Zach Klaassen, urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. We are in Chicago for ASCO 2025. Delighted to be joined, as always, by Dr. Steve Freedland, urologic oncologist at Cedars-Sinai in Los Angeles. Today we're going to be discussing data that Steve presented at ASCO, looking at a subgroup analysis of EMBARK, specifically the impact of prior definitive therapy in the enzalutamide monotherapy arm. So Steve, thanks as always, for joining us on here today.

Stephen Freedland: Thanks for having me, Zach. It's great to be here.

Zachary Klaassen: So before we get into this subgroup analysis, I know we looked at combo enza leuprolide in this exact same population for the definitive treatment just previously presented at GU ASCO. Just take our listeners through EMBARK. Again, at a high level, what was the primary outcome and what were the results?

Stephen Freedland: We know in metastatic disease, adding an AR pathway inhibitor to ADT improves outcomes. So the question is, can we take it one step earlier to a high risk biochemical reccurrence? So had surgery, radiation, or both. That didn't work. PSA is going up quickly. Basically, it's going to be tomorrow's metastatic patient. But can we treat them today with this intensified ADT?

So patients had PSA doubling times less than nine months, conventional imaging negative, randomized to enzalutamide plus ADT, ADT alone, or enzalutamide alone. And as previously presented, published now in the guidelines, that enzalutamide either with or without ADT delayed metastasis free survival, which is metastasis or death. So basically, kept the patients alive without known metastases for longer. So clearly is the standard of care. And it's interesting now learning a lot about trying to change practice. We do research. We publish papers. We get it in guidelines. But the hard work is actually educating people about this.

So that's why I spent a lot of the last couple of years, year and a half or so, going around the world talking about this, educating, going to grand rounds in Europe and Australia and Egypt. I mean, literally all over the place. And one of the questions I've gotten is, well, my patient had radiation only. Does this apply? My patient had surgery and for whatever reason couldn't get salvage radiation. Do these data apply? Does it matter how we got here? Or is it now that we're here, this high risk biochemical recurrence, conventional imaging negative, how you got here doesn't matter. So that was the impetus for this analysis.

Zachary Klaassen: And amongst all that travel, spending some time on your own today educating as well. So we appreciate that. Tell us about the outcomes from this subgroup analysis. As you mentioned, there's three cohorts. Radiotherapy alone, surgery alone, surgery plus radiotherapy. What were the outcomes for this enzalutamide monotherapy group?

Stephen Freedland: Yeah. So what we did is we looked at as is there a statistical interaction? Because you start to break down, EMBARK had a little over 1,000 patients. 1/3 of them on each arm. So we only have 1/3 of the patients in monotherapy. Now we're going to break it down by four primary treatment arms. You start to get some small numbers. So taking the individual hazard ratios with a grain of salt. Looking is there an interaction? Meaning does how you got there, surgery, radiation, or both, impact the efficacy of enzalutamide monotherapy? And the answer is it did not.

Zachary Klaassen: That's great.

Stephen Freedland: So the data we see as a whole meeting the primary endpoint, allow the secondary endpoints except OS, which we're still waiting for. Stay tuned. And then obviously timed resumption of hormonal therapy from the treatment break was worse with monotherapy. But all of those findings held no matter how you got there. So really, I think it's a nice message of once you're in this high risk conventional imaging negative BCR space, it really doesn't matter how you got there.

And it's interesting. You think back, we think about our mentors and how we got to where we are in our career. So Anthony D'Amico had shown this ages ago that the PSA doubling time in biochemical recurrence, whether you had surgery or radiation, if your doubling time is less than three months, those patients are really in trouble. So again, how you got there, not so important. Once you're there, you're there. We need to figure out what to do for you.

Zachary Klaassen: And the educating is finding those patients, identifying them, PSA doubling time again less than nine months. Not the 24, 30 months, those really high risk patients.

Stephen Freedland: Absolutely.

Zachary Klaassen: And so when you think about somebody comes into the clinic, they want enzalutamide monotherapy. You've had those discussions with them. You've broken it down, the risks and benefits, which we've talked about. Does this data change how that conversation happens? Or is it more just we're confirming what D'Amico told us years ago?

Stephen Freedland: Yeah. I'm not sure it changes the conversation, per se, but I think it gives you confidence of whether this is a surgery or radiation or both.

Zachary Klaassen: Doesn't matter.

Stephen Freedland: Doesn't matter. Exactly. They're here now. I need to focus on how do we prevent them from getting there. Don't worry about how they got there.

Zachary Klaassen: Awesome. Great conversation, as always, Steve. Any concluding remarks? Anything we haven't hit on that you want to touch on before we finish up?

Stephen Freedland: Stay tuned for updated OS at some point, hopefully coming soon.

Zachary Klaassen: And we'll be getting into your travel schedule. We'll be talking about it on UroToday.

Stephen Freedland: Absolutely.

Zachary Klaassen: Thanks, Steve.