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Zachary Klaassen: Hi, my name is Zach Klaassen, urologic oncologist in Augusta, Georgia. Delighted to be joined on UroToday with Dr. Neal Shore, urologist in Myrtle Beach, South Carolina. Neal, thanks so much for joining us, again, on UroToday.

Neal Shore: Always a pleasure, Zach. Thanks for inviting me.

Zachary Klaassen: We're doing a case-based discussion today. So we're going to look at high-risk biochemical recurrence, which really has been talked about for the last probably two years or so. And this is based off of your senior author randomized clinical trial published in the New England Journal of Medicine, looking at the EMBARK trial. So we're going to talk about a couple scenarios where maybe utilizing the EMBARK trial is going to be beneficial for patients.

So I'm going to just discuss a brief case to set the stage here. This is a 67-year-old African-American male diagnosed with Gleason, 4 plus 4 prostate cancer in 2017. His PSA at that time was 12. This was 2017. So he had a CT and a bone scan, which was negative for staging given his high risk disease.

He ultimately elected, at the age of 59, to undergo robotic radical prostatectomy, bilateral pelvic lymph node dissection. His pathology was somewhat unfavorable at pT3bR1 at the apex, 15 negative lymph nodes.

So at that point, we hadn't had all these nice meta-analyses looking at adjuvant versus early salvage. We talked about adjuvant radiotherapy. He did not elect for adjuvant radiotherapy. But his PSA at three and six months post-op was undetectable. At nine months post-op, we started to see a bit of a signal, maybe early biochemical recurrence PSA of 0.04, 12 months, 0.12. At that point, he was referred for early salvage radiotherapy, did not elect for ADT at that point in time.

So he did well with the salvage radiotherapy. His PSA from 2019 to 2022 was undetectable. But we see, starting in January of 2023, up 0.15, three months later, 0.28, July 2023, 0.45, October, 0.78. We started to think about a PSMA PET scan in that summer time.

At that point in time, it was still somewhat difficult to get PSMA PETs. It was denied by insurance. It's a little bit certainly a lot easier now. So again, we did a CT/bone scan, which was negative. And in January 2024, his PSA had reached 1.09.

So when we look at this patient on the whole medical history, very healthy, hypertension, hyperlipidemia. He had his robotic prostatectomy 2017, had a slight family history, uncle with prostate cancer, had a RALP, no evidence of disease. He's married. He's sexually active, with some Cialis. He's a non-smoker, retired military, very active, plays golf three times per week.

So when we look at this patient, Neal, PSA doubling time calculated is about 4.2 months, his testosterone, 293. Really, what are his next steps? So I'd love for you to walk through some of the trial design for the EMBARK trial. And then we'll get into a couple scenarios of which direction this patient may go with this treatment.

Neal Shore: Yeah, I'd love to. What a great case. I mean, I see this-- I mean, this is a patient I see in Myrtle Beach all the time. And I know you see these patients in Augusta. Listen, we're golf meccas in--

Zachary Klaassen: That's right.

Neal Shore: --in Myrtle Beach. And we get a lot of really healthy retirees come in. They love golf. And sure enough, they fail active intervention, whether it's surgery or radiation. And we saw this in the EMBARK trial.

So yeah, this is a nice slide. I like the way you added some things to make it a somewhat clearer than our original presentation at AUA in a plenary a couple of years ago. We really wanted to look at these patients who had rapid doubling times. A lot of data clearly showed that they were at risk if a doubling time less than 10 months. We chose less than nine months in EMBARK.

You see the entry criteria, three-arm trial, sort of, two studies in one comparing intensified therapy of ENZA and an ADT and LHRH Q3 month versus a placebo LHRH. And those were blinded. The ENZA mono was 160 milligrams, the approved dose, unblinded. We were not going to give folks a placebo injectable.

We had our stopping point at a PSA nadir of less than 0.2. And there's been a lot of great data on that, how important that is now. When you look at a lot of the literature and the analyses on our mHSPC trials, inclusive of ARCHES, and TITAN, and LATITUDE, we're really recognizing, and now with ARANOTE as well, the importance of that nadir delaying PSA PFS.

But we had the stopping, we had the interruption. We had a primary endpoint of MFS. A sort of a little teaser I'll say to the audience, we're really looking forward to potentially having some OS data, some time to report on the final OS data sometime in the foreseeable near term. I'll leave it at that. We did present OS data as a key secondary endpoint. It was trending positively. But we needed more events.

And so we're really proud of the study. We feel like it's changed the options for patients, which I think we're going to discuss, because the two arms, combo versus LHRH for mono ENZA both bested monotherapy LHRH.

Zachary Klaassen: Absolutely. And when we look at this case, and I think it's important just to go back to that entrance criteria and see how our patient fits in that criteria. So again, this study accrued before PSMA PET scan. We could have a whole discussion, aside from what we're talking about today, about PSMA PET in this area.

But he had negative conventional imaging. So that's one check mark. He had a PSA greater than 1 after a radical prostatectomy, 1.09. PSA doubling time less than nine months, so really that high-risk BCR population, his was 4.2 months. And his testosterone, just to make sure that that's not at a castrate level, was 293. So he really fits this criteria of hitting all four of those criteria for the EMBARK trial.

So I broke this down into two scenarios. So scenario 1, like you said, it's a three-arm trial. There's two scenarios in my mind. And this first one is we have shared decision making. This is really important when we're talking to these patients about options in this high-risk biochemical recurrence setting.

So let's say him and his family, they want maximal therapy. They want the best cancer control. They want to get on therapy. They want a high probability of treatment suspension, as you mentioned, at that 36 weeks, if the PSA becomes less than 0.2. So maybe just walk us through some of these key slides of the ENZA plus leuprolide combination therapy, Neal.

Neal Shore: Sure. Well, here's our Kaplan‑Meier of the combination ENZA leuprolide Q3 month versus a placebo leuprolide. And this really, was very heartening to all of us. When you do this intensification, you add an ARPI such as enzalutamide to T suppression hazard ratio 0.42.

Curve separating starting around 20 months, getting wider and wider. And we see basically this rather impressive delta of an MFS of 87 versus 71, with a hazard ratio and a statistically significant. So that was really the first, that was the key first primary endpoint.

When you look at the forest plot here on all these secondary outcomes, everything is way to the left, favoring combination over a monotherapy leuprolide. We're clearly trending towards survival. We'll have that data later. But with-- look at the PSA progression so far to the left. And that leads to the development of resistant disease.

It leads to the development of additional antineoplastic therapies. And it didn't really matter whether or not the patients were symptomatic or not, first skeletal event. So obviously, super proud to demonstrate that intensification in terms of a clinically meaningful outcomes could benefit these patients.

And this also then goes on to tell you about the treatment suspension. And even the combo, as well as the mono in the green, we had a greater percentage of patients who had that really key predictive factor of a PSA of less than 0.2. And the treatment suspension longest in the combination, shortest in ENZA mono, remember, in the ENZA mono, we don't see testosterone suppression. So you're going to see a PSA come back elevated, which was a re‑initiating point in the study. PSA is greater than 2 in the RP group, greater than 5 in the RT group.

Zachary Klaassen: Yeah. So that's great. I mean, this is exactly what this patient is looking for in scenario 1. Let's look at scenario 2. So same patient. He's sexually active. He's very active playing golf, as we mentioned. And let's say he really, at this point, is valuing preserving that sexual function as best as possible, knowing that he's going to be on therapy. He wants to preserve that energy and high activity on a day‑to‑day basis.

But he also doesn't want to compromise his cancer controls. He's a smart guy. I mean, he's really looking for an option where he can keep all three of these bullet points. So Neal, maybe just walk us through the ENZA monotherapy, and maybe why this scenario may fit a little bit better for him.

Neal Shore: So yeah. And here's just quickly, the MFS hazard for ENZA mono versus the placebo leuprolide as a hazard ratio of 0.63. It's also bests monotherapy leuprolide. So I love a case like this that you're presenting, because I now have close to 20 patients, since the approval, that I've started on ENZA monotherapy.

And you make an excellent point. It's shared decision making. And many of these patients who may have had ADT, if they had RT in the past, I asked them how was that experience. And if it was, hey, I didn't even know I was on the ADT, well, then that's one thing. But most patients will say the fatigue, the loss of libido, many other aspects to T suppression, which this audience is aware of.

And I really enjoy starting patients and giving them the option for ENZA monotherapy because our data and our patient reported outcomes, and I think, largely, too, our clinical experience, our empiric experience tells us that you're going to see less fatigue, less hot flash, and clearly, improvement in sexual parameters.

Zachary Klaassen: For sure.

Neal Shore: So I think this patient is ideal. Here's the forest plot, very similar to the combo. You see all the parameters favoring ENZA monotherapy. And again, we talked about earlier. We have the effect on T suppression. The top green is basically looking at ENZA mono. The bottom is the combo.

And we have a longer time on treatment suspension and combo, versus mono, the least on ENZA mono. But that's OK. I explained to patients that this interruption period gives them that ability to participate and augment the things that are important to them, fatigue, energy, sexual function. And for some patients, hot flashes can be very debilitating.

Zachary Klaassen: Yeah, absolutely. I think, Neal, we mentioned a couple of times. This is really shared decision making. It's really looking at the goals of what your patient and their family members are looking for. What their previous experience has been, as you mentioned, I think it's an important point. ADT during radiotherapy, how did you tolerate that? And really sitting down and showing them the data. You can get good cancer control. What sort of side effect profile are you looking at?

The one thing I want you to talk about before we wrap up, because I know you've published a lot on this, discussed it a lot at various venues, including APCCC. That ENZA monotherapy, the gynecomastia, is about 40% to 50% in the trial. Maybe just talk about some of the prevention strategies you've used for that monotherapy.

Neal Shore: Yeah. And in EMBARK, as well as another large phase II study that we did just giving monotherapy enzalutamide in enriched active surveillance population, we definitely see, if you give a monotherapy ARPI ENZA or the others, you're going to have unopposed increase in T and estradiol. And that causes a lot of breast‑related issues, enlargement, tenderness, pain.

We had no prophylactic strategies to prevent that. But we have a lot of really great literature from our colleagues, who've looked at prophylactic strategies for breast‑related symptoms, particularly in patients who are receiving 150 milligrams bicalutamide therapy. And so you could make some adjustments for a more powerful ARPI such as enzalutamide.

And there's been a lot of data looking at prophylactic radiation of the breast, 8 to 10 gray. It can be given in one to three sessions, or looking at a selective androgen receptor modulator SARMs and selective estrogen receptor modulators. We presented on this, as you said, at APCCC.

We have a paper coming out on this. There was a recent meta‑analysis on this as well that came out in EU. But we have a paper coming out. And the bottom line, take home for me, what I do now is I offer patients-- and this is my Neal Shore, the way of doing it, is I use a selective estrogen receptor modulator, tamoxifen, on a daily or even every other day basis.

It's generic. It's inexpensive. It has a very good DDI with enzalutamide. It's well tolerated. And I now have, like I said, close to I maybe upwards of 15, 20 patients. And I'm not seeing any breast‑related symptoms. And it's not expensive.

I had, prior to that, been using prophylactic radiation. And I still offer that to patients if they don't want to add another oral medication. We need more data. We need more prospective studies. But this is what I'm doing now.

We have paper coming out on this that we've submitted. And I hope it's published sometime during the summer on exactly what you're asking, all the different strategies to consider, and the discussion points with patients, if you're going to give monotherapy enzalutamide.

Zachary Klaassen: Wonderful, Neal. As always, great conversation going through this case. Appreciate the little teaser on the OS data at some point. We'll keep an eye out for that. And thanks, as always, for joining us on UroToday.

Neal Shore: Thank you, Zach.