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Daniel George: Welcome. Hi, folks from UroToday. I'm Dr. Dan George, professor of medicine and surgery at Duke University. It's my pleasure today to welcome Dr. Steve Freedland, who is a professor of urology at Cedars-Sinai. Steve, welcome.

Stephen Freedland: Thanks for having me, Dan.

Daniel George: My pleasure, my pleasure. We're here to talk about the EMBARK study, a really pivotal trial that has led to a new label expansion for our Enzalutamide. Steve, do you want to walk us through this study which you and Neal Shore have led and I think again made a real impact in the field?

Stephen Freedland: Oh, thanks. Yeah, I'd be happy to. I put together some slides here. Disclosures: I work with a lot of companies, including Astellas and Pfizer, the makers of Enzalutamide. So, in terms of background, EMBARK was within the biochemical recurrent space, so had surgery, radiation didn't work, PSA is now rising, and unfortunately, about a third of our patients who undergo surgery and radiation end up in this space. And certainly, those that have a short doubling time, less than nine months, are at high risk of prostate cancer mortality. We know in later-stage disease, including metastatic hormone-sensitive, AR pathway intensification has a survival advantage. So that was the question: Can we apply that to an earlier stage, high-risk non-metastatic biochemical recurrence, including Enzalutamide monotherapy? So not even doing ADT, just Enzalutamide monotherapy.

So this is the study design. Basically, patients with biochemical recurrence less than nine months, PSA had to be greater than one after surgery or nadir plus two after radiation, and they were randomized to one of three arms: Enzalutamide plus Leuprolide, and it's a combo, placebo plus Leuprolide. So just ADT alone, or again this pretty novel Enzalutamide monotherapy, and they were treated for 36 weeks. PSA was assessed and if less than 0.2, treatment was actually suspended.

So they actually had the opportunity to go off therapy if they got a good response. And then once the PSA hit predefined thresholds, they went back on that same treatment they originally got. The primary outcome being metastasis-free survival. Between the combo and ADT alone, Enzalutamide monotherapy was the secondary outcome, as well as overall survival and other things. Again, keeping it high level here. So for here we have the primary outcome, really significant clinically, statistically significant separation. Curves start to separate as early as 18 months, which is pretty impressive for metastasis-free survival. Keep getting bigger and bigger. A 58% reduction in the risk of metastasis or death with the combo relative to ADT alone.

If you look at monotherapy, those curves don't quite separate as early, but still relatively early, keep getting more and more separated. Hazard ratio 0.63, so a 37% improvement in metastasis-free survival. So again, really impressive data. One of the questions we have is unlike advanced patients, metastatic hormone-sensitive, castration-resistant, these are asymptomatic patients. So if not for a blood test, we wouldn't even know they have cancer. No symptoms, hasn't spread. So we don't expect our therapies to improve quality of life, but we don't want them to worsen quality of life. And so that's the thing we looked at here. Two primary measures: We looked at the time to confirm deterioration in quality of life because they're all getting something. They're getting ADT. The quality of life is going to drop a little bit from ADT; time to first deterioration and all relative to ADT alone, whether you looked at pain, FACT-P total score, we looked at combination, monotherapy, all of these cross one. Basically saying there is no statistically significant difference in global quality of life.

There's some nuances there that maybe we get into in the Q&A, but again, keeping it at a high level here. So we're improving oncological outcomes, we're not worsening quality of life. The next question is, well, how about the side effect profile? So if we look at that in any global phase three, you twist your ankle, you get a headache, whatever, it's going to be an adverse event. So they're extremely high, 97% in all groups. But if we really focus on the grade three, it is a little bit higher in the Enzalutamide arms than the ADT, but not dramatically. If we get into the serious AEs, again, it is a little bit higher, 31 versus 28; for grade three it's 32 here, not dramatically, but there is a little bit of toxicity, some side effect profile, which we know about. If we look at those that lead to dose reductions, it's actually relatively low, 7%, four and a half percent.

It's actually a little bit higher in monotherapy. Keep in mind, monotherapy is open label, so people knew what they were getting, which may have influenced things, but really we'd like to think monotherapy has fewer side effects. But the data really say it's different side effects. It's not fewer, but it's different side effects. And maybe again, we can get to that in some of the questions, but at a high level, no real new safety signals. So I think in summary that we do know in this patient population doubling time is less than nine months. So high risk biochemical recurrence. Enzalutamide combination, hazard ratio 0.42, 58% reduction. There's a trend towards improved survival as well. Hazard ratio of 0.59, still ongoing. P at 0.01, but not statistically significant the way we designed the study. Monotherapy also benefits, trends towards improved survival there as well. Did not negatively affect quality of life, no new safety signals.

And now as you mentioned, Dan, it is FDA approved and actually is in the guidelines now. So really, I would say it is now the new standard of care for this high-risk BCR, not all BCR, but specifically this high-risk BCR population. And we had the opportunity to publish this primary outcome in the New England Journal and then the quality of life was New England Journal of Medicine Evidence almost simultaneous. That's what we got. So excited to kind of talk to you about what this all means in the real world.

Daniel George: Absolutely, Steve. Great work and a long study. I mean, this is probably what was designed nine, ten years ago. And then to actually activate it, accrue it, and then see this kind of follow-up time, it's really remarkable. So a great testimony.

Stephen Freedland: Yeah. First, the patient then was in late 2014, so we're coming up on 10 years. So it is. It's a long natural history, and that's what happens when you go early, even though we're selecting patients at high risk, they are going early. And I think that's going to be one of the challenges: ADT works decently in this patient population, it's just we can do better. And I think that's the message, is we have options, we can do better, not impact quality of life. The likelihood of getting that treatment suspension is extremely high with the Enzalutamide groups. So it's not lifelong for 10 years of therapy type thing.

Daniel George: I think that's a really key point. And I want to start with a question around adoption because you and I have looked at this in terms of metastatic hormone-sensitive prostate cancer, really strong data, even overall survival benefit. It's in all our guidelines, and yet when we look at our real-world adoption of this combination therapy, we'll call it, it's relatively low. Do you think we're going to run into challenges with the adoption of this EMBARK data into practice? What is it that's going to resonate here to help overcome the hurdles to kind of broad adoption of this data?

Stephen Freedland: I think there are going to be challenges. So I mean, I think the data are strong, but I think in the metastatic hormone-sensitive, we have, I don't want to say stronger data, but we have more data. We have multiple drug options all showing similar, as you say, overall survival. We're not quite there with EMBARK yet. So I think it's, I don't want to say easier to ignore, but you have one study trying to drive practice rather than half a dozen studies that are out there. So I think doing things like this, getting people aware, trying to promote it at meetings. I'm very fortunate. I'm actually traveling the world this year trying to educate providers about the options now to do it. So I think there's going to be some challenges. I think in some ways it's going to be harder. It's an earlier stage disease. Survival is better than what we're seeing in the metastatic hormone-sensitive population.

So there are some challenges. I think there are some things that give me some optimism that we can do this better. And one is Enzalutamide monotherapy, not that the side effects are less, but they're different. And just the fact that you don't have to undergo ADT, which we like to call ADT, but our patients call it castration. Right. They call it what it is. And that's a barrier for a lot of people, that they just don't want that, and I can't blame them. Right. So I think that we can have effective therapies that don't involve castration, I think, is exciting.

And the treatment holiday, if you look at the Enzalutamide, either one, it was over 85% got a treatment suspension. And the duration of that, especially in combination, was over 20 months. So you get nine months of therapy, you get 20 months off therapy. And in a PSMA world, which is what EMBARK was not, it was not around when we started the study, but if you can identify a couple of spots on PSMA, maybe radiate those at the same time, do you need the systemic therapy? Lots of unanswered questions, but if we do, again, let's be aggressive and then stop, we may be able to buy a lot more than 20 months off therapy. So I think that's going to resonate with people. So I think there's some greater challenges on the one hand, but some optimism on the other that we can get this better adopted.

Daniel George: That's great. I want to follow up on a couple of key points you brought up here. First on the monotherapy. So walk me through. Who's the ideal patient for monotherapy in your mind? Who do you feel like that's the right fit?

Stephen Freedland: Yeah. So it really comes down to the side effect profile. The efficacy is there; it's better than ADT, which is our current standard. Patients often choose therapies based on side effects. As a surgeon, when I have an opportunity to operate and someone doesn't want it for BPH, or whatever it is, like a knee arthroscopy because they're worried about side effects, they're choosing side effects over efficacy. So we see that trade-off play out every day in the clinic in the real world. So when we look at the side effect profile, the two things that really stand out for monotherapy are fewer hot flashes, which we often blow off as, "Oh, you're just going to get hot flashes." But there's a subset of people really bothered by that in the real world. So I think it's going to play out for that.

But the key one is better preserved sexual activity, sexual function. So we're still analyzing that. That came out in the New England Journal of Medicine Evidence, presented at some meetings. So to me, it's the younger patients, the sexually active patient. Keep in mind these are post-surgery, post-radiation patients. So sexual activity is not always perfect in that sense. They've undergone treatment that can affect that. But for that younger sexually active person really afraid of castration in their mind, I think this could be a really effective option for them.

Daniel George: That's great. That's great. And do you do prophylactic breast irradiation for those patients?

Stephen Freedland: Yeah, so the yin and the yang, right? We talked about the benefits of the monotherapy. The downside is more breast enlargement, breast tenderness. The EMBARK study didn't really prescribe anything in terms of how to manage that. We certainly know from the Bicalutamide monotherapy days that breast irradiation done beforehand, prophylactically, can be quite effective. Aromatase inhibitors probably aren't within the wheelhouse of most urologists, but as a medical oncologist could, something you may be very comfortable doing. Or if it does get to be bad, subareolar mastectomy is a one-hour outpatient operation. But I think the breast irradiation really brings this back to multi-D management of prostate cancer, which brings the radiation oncologist in, in a new way, but especially with PSMA, spot radiation brings them to the table in a good way.

Daniel George: Now the other thing you brought up was PSMA, and I just want to touch on that because I think it's really important because EMBARK obviously predated the wide access to PSMA imaging. And importantly, the endpoint here was conventional imaging metastasis, which is a validated, pretty well-accepted surrogate for overall survival. And obviously, we'll see that data later, but PSMA is integrated into our practices now. How do you use PSMA data in terms of deciding if this is an EMBARK patient or if this is more like an ARCHES type patient, someone with metastatic hormone-sensitive disease because we see something on PSMA PET? Where do you draw the line, and does it matter in terms of intermittent versus continuous? I mean, how do you use this PSMA data in those settings?

Stephen Freedland: Yeah, it's a great question. And to me, that's probably the most crucial aspect of how we actually use the EMBARK data in the real world. So, PSMA is here; it's used widely. We're not even doing conventional imaging here. It's PSMA and management based on that. So, to me, try to think about things in buckets in a simplistic way. So you have a patient with high-risk biochemical recurrence, you do your PSMA and, simplistically, there are three options. You see tons, you see a little, or you see nothing in a very simple world, right? So if you see tons, then it's probably more like an ARCHES patient. Study after study, TITAN, you go down the list, they need intensified ADT. Okay. They need intensified ADT. And then the question is, do you bring in chemo or not? That's a whole other question, which I don't want to get into because we don't know the answer yet.

How to define high volume on a PSMA is a whole different story. But nonetheless, they need intensified ADT. Do you give them a treatment break if they have a very good response? Perhaps. We don't know. But to me, that's a pretty straightforward one. You're not going to radiate anything. You're just using intensified ADT plus or minus chemo. If we see nothing, there's nothing to radiate; that's an EMBARK patient. And there's actually a real-world study that took patients who would've met EMBARK criteria, but 80% were PSMA positive. The 20% are PSMA negative. We know even in the late stage, there are just tumors that just don't make PSMA. I mean, you look at VISION, 15% of patients screened failed because they didn't have PSMA positivity. So there's just bad disease that sometimes doesn't show up on PSMA. They need intensified ADT.

So then it's really this middle bucket: you see a little bit where we can do radiation, targeted metastasis-directed therapy. And then the question is, do you need systemic therapy at all? And if you do, do you need intensified systemic therapy? There have certainly been trials, STOMP, ORIOLE, that looked at delaying ADT, but this is not the average PSMA positive. This is the selected doubling time, less than nine months. And you actually sit and talk to people. How often do you have these patients? We do metastatic therapy, and it's curative for these really high-risk, short doubling times. And the answer is very rare.

So to me, we know in the salvage local radiation, if you have a high DECIPHER score, your PSA is above 0.7, you do better with ADT, some data suggest you do better with intensified ADT. To me, it makes sense to do intensified ADT with the metastasis-directed therapy and then stop at nine months if you have a good response. If you say, "Look, I want to do this metastasis-directed therapy alone," that's fine. Chances are they're going to fail, and then you're going to repeat the PSMA six months later, and that's going to be now widespread at that point. And lo and behold, they're going to need intensified ADT. So they're getting intensified ADT at some point. Might as well do it early. And again, it's nine months and then you stop. That's the beauty. We're not committing someone to lifelong therapy here. I think that's a really important point.

Daniel George: Well, Steve, thank you so much. These were great insights into, first off, the EMBARK study, a really pivotal trial, really filling a void in our natural history of prostate cancer, this key biochemical relapse state and again, confirming combination therapy over monotherapy. And then really walking us through what I think are the challenges of implementing this data into practice. And I'm sure we'll be learning and talking a lot more about this in the next couple of years. Thank you so much for leading this work. We really appreciate it. On behalf of UroToday, thank you all very much for listening.