Zachary Klaassen: Hi, 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's a urologic oncologist at Cedars-Sinai Medical Center in Los Angeles.

Today, we're going to be discussing a post hoc analysis of EMBARK that Dr. Freedland presented AUA 2025. Steve, thanks so much for joining us on UroToday.

Stephen Freedland: Zach, thanks so much for having me. It's always a pleasure to be here.

Zachary Klaassen: Always good to chatting with you about advanced prostate cancer, and I know this is a topic you know very well. EMBARK has really revolutionized how we look at high risk non-metastatic castrate-sensitive prostate cancer.

So maybe just by way of background before you get into some of the slides that you presented at AUA, just talk about some of the key findings from EMBARK.

Stephen Freedland: Yeah, no, absolutely. So EMBARK was high risk biochemical recurrence. I don't like to talk about it as non-metastatic, because in its era, it was conventional imaging negative. So I'm trying to promote this term CIN prostate cancer, Conventional Imaging Negative.

Because PSA, as you know, wasn't widely used 10 years ago when the study started. So those patients with short doubling time, PSA doubling time less than nine months, and randomized to ADT plus enzalutamide versus ADT alone versus enzalutamide alone. And primary outcome was metastasis-free survival, which is metastasis or death, and is a surrogate for overall survival.

And importantly, showed that enzalutamide either with or without ADT, improved outcomes. Improved metastasis-free survival, and importantly, this relatively asymptomatic patient population, it preserved quality of life.

Safety profile consistent with what we know about enzalutamide, and has now led to FDA approval, approval. In other countries, and it's in the NCCN guidelines. And really, I think, has become the standard of care for these high risk patients.

Zachary Klaassen: No, absolutely. And I think you presented some interesting data, because if patients had a good response, they stopped therapy at 36 weeks, 37 weeks. And basically didn't go back on therapy unless PSA started to increase.

And really, the goal here was to treat them and see if their testosterone would recover and get back to a quality of life. And so maybe pull up some slides and show us some of that key data with the testosterone recovery that you guys presented.

Stephen Freedland: Absolutely, be happy to. Thanks again, Zach, for the opportunity to present this. And first, obviously, a shout out to my co-PI Neal Shore, the rest of the investigators, Astellas and Pfizer, who sponsored the study. I am a consultant for both of those companies.

But let's jump into things here. As you said, EMBARK positive study, changing practice for these high risk biochem or current patients. And if they did, well, that's the nice thing, is unlike many where if you wait too late and they're now metastatic, we treat for life, here, we treat it for nine months, the PSA responded well, we would stop therapy.

And so the question is, how long does it take for the testosterone to recover? And does age affect that, given that in general, we generally no older age that testosterone takes a little bit longer to recover?

So study design, we kind talked about before. And, keeping in mind there were three arms. There was the enzalutamide combination, ADT alone, and enzalutamide monotherapy. But the monotherapy, you're not castrated. So testosterone never drops. So there's no recovery of testosterone. So we're not going to talk about that arm today.

And we follow patients while they were treatment suspended until they went back on treatment. And we measured testosterone every 12 weeks, used a testosterone above 175 to define recovery. And then we assessed whether age impacted things.

Now again, we use 175. And you might say, look, that's not my definition of normal. My definition is 250, which is fair. But the EMBARK study had patients as low as 150 for enrollment criteria. So if you walk in the door with a testosterone of 151, for example--

--you're not going to get back to 250 after nine months of treatment. So we used what we thought was a clinically meaningful threshold that would still account for these patients who come in with lower than normal testosterone.

So if we look at the time to recovery of testosterone, that 175, we look at the chart up at the top, it's only measured every 12 weeks, so median is either you got it this visit or the next visit. But if we look at the mean, it can be a little bit more averaged out. But eight to nine months on average is what it's taking.

Not a huge difference between combo and ADT alone. And if we look at what percent of patients recover to that 175, it's the vast majority, well over 80% in both treatment arms. And then there's a group of patients that get partial recovery. Very, very few patients, 1%, 2% of patients got no recovery at all. Still remain castrate, less than 50 the whole time.

So if we look at what is the impact of age, what we see, is the younger age here, recovery is about a month or so, half a month earlier in the ADT alone. Again, it's about a month earlier. Not dramatically different. A little bit quicker, not dramatic.

We look at the percent that recover and then younger than 70, it's about 90%, whereas it's closer to about 80% in the over 70. Still, it's the vast majority of patients in both groups. It's a little bit more in the younger group. And importantly, in the younger group, not a single patient had no recovery at all.

So those few patients that didn't recover were all over the age of 70. But again, not a huge difference by age, but what you'd expect. A little bit longer, a little less recovery. But still, the vast majority recovered.

If we look at T recovery over time, importantly, what we see here at week 37, there's still castrate. That's when we stopped the treatment. 12 weeks later, the vast majority of people are still castrate. So you don't see a lot of testosterone recovery. You see a big jump 24 weeks later.

By 36 weeks later, most of the patients are having now normal testosterone levels, per our definition, 175. I mean, if we look at the ADT alone, relatively similar looking curves, not dramatically different.

So in summary, what we can say, is the vast majority of patients do recover their testosterone to that 175. Whether you're treated with enza combination, ADT alone, whether you're less than 70, or over the age of 70, it does take a little bit of time. About somewhere in that six, eight, nine, months, somewhere in that range.

And that may help explain some of the quality of life data that we've seen previously in terms of the hormonal symptoms and the hot flashes and things, don't go away right away. Testosterone didn't recover, and our testosterone recovery data actually nicely mirror the timing of those hormonal treatment symptoms going away.

So in summary, most patients treated in this regimen can expect testosterone recovery, regardless of how they're treated, regardless of age.

Zachary Klaassen: So, Steve, fantastic presentation. I think when we look at this space and we talk about options with our patients, once we've identified that high risk biochemical recurrent patient, you and I have talked about risk benefits of enza plus leuprolide, enza alone.

But this really kind of gives us another couple of bullet points to bring to patients in terms of that fact that at about six to nine months, we should anticipate, especially if you're younger than 70 years of age, that you should be having a testosterone response.

For that, let's say that 55-year-old uro patient, so this patient, obviously probably active, high risk biochemical recurrence, how are you counseling this patient who's deciding between combo versus enza mono, thinking about testosterone recovery, that whole package? How are you talking to this patient?

Stephen Freedland: Yeah, it's interesting, because I think these data have helped put things in context. Because I'll tell you, before my discussions were, look, if you go on combination, you get, was it about 20 months of treatment suspension. Whereas if you go on monotherapy, it's about 11 months. So it's a lot longer on combo.

But if we take that 20 months and we minus the eight months to get testosterone back, about 12 months of normal testosterone, which is not that different than the monotherapy. So I think both of them, you can say in an ADT alone, that we really shouldn't be giving ADT alone to these high risk patients. That's clearly what the data show.

So either way, you're looking at about a year of normal testosterone until you go back on treatment. Keeping in mind, it's variable. Some patients, we have patients, this is to me, the amazing part. We have patients on monotherapy, so I know their normal testosterone. Four years later that have not gone back on treatment.

So it is variable. And I'm very curious to see what the PSA levels are in those patients. Really long-term NED. I don't want to use the cure word, but. NED from this nine months of hormones, I think we are seeing some, but we still have to tease out the data.

But I think it's saying, look, you're going to go on nine months of treatments, a few more months for it to wear off or not, and then about a year of normal testosterone until we have to start up again. And I think to me, the interesting question that EMBARK did not answer, and that's the beauty of EMBARK, any trial, is it opens up more questions than answers.

Zachary Klaassen: Right, right.

Stephen Freedland: So let's say it took two years now for them to go back on treatment, three years, and they get a really good response, as vast majority do on enza combination, do you do a second treatment suspension after another nine months?

Zachary Klaassen: We don't know.

Stephen Freedland: If they bounce back right away and almost got almost no time off treatment, that's certainly not someone that I would want to do a second treatment suspension.

Zachary Klaassen: Right.

Stephen Freedland: But they had a long time, perhaps you could think about it. I don't know. It's intriguing.

Zachary Klaassen: No, absolutely. There's so much to unpack from EMBARK, and this is another. And actually, we talk about actionable data coming home from AUA, I actually had this conversation with the patient in the clinic based off of your data, because these are questions that people are asking and they're trying to weigh the risks and benefits of whether they go in mono versus combo.

So always a good discussion. Any take-home messages, any final thoughts, Steve?

Stephen Freedland: Yeah I mean, I think the concern we have seen with older patients, hey, look, six months of hormones and they're never going to recover, they're going to be castrated for life, we're not seeing that. I mean, a handful of patients limited.

So I think we can get confidence the vast majority of these patients are going to recover at least some testosterone, if not fully. And so I think that should not be a concern for these patients by and large.

Zachary Klaassen: Yeah, absolutely well said. Steve, always enjoy chatting with you about prostate cancer. Thanks for your time on UroToday.

Stephen Freedland: Thanks for having me.