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Zach Klaassen: Hi, my name is Zach Klaassen. I'm a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. I'm delighted to be joined for an ESMO 2024 discussion with Dr. Neal Shore, urologist at the Carolina Urologic Research Institute. Neal, thanks so much for joining us again on UroToday.

Neal Shore: My pleasure, Zach. Thanks for inviting me.

Zach Klaassen: So we're going to discuss the EMBARK trial, which you and I have discussed on this platform before, but specifically a stratification by age, which I think showed some really important data points. So why don't you take us through some of the background of the trial as well as the trial design and the key results?

Neal Shore: Yeah, absolutely, my pleasure. So yes, our poster was the EMBARK trial, the post hoc analysis by age, mono-enza or enza with leuprolide for patients with BCR, and they were at high risk. I'm really proud of this trial because it adds to our knowledge regarding combining AR pathway inhibitors with LHRH monotherapy. And I think it's almost fair to say at this point that across the continuum from high-risk localized to BCR, to mHSPC, to CRPC, there's very little role left for monotherapy ADT. Our study demonstrated that. It led to a label expansion by FDA and EMA for our patients with quote "high-risk" BCR. In EMBARK it was less than or equal to nine months, the EAU definition is less than or equal to 12 months. We have actually shown data on that and it's pretty comparable too. And Ugo De Giorgi has presented that.

So our poster at ESMO 2023 this year, which was a wonderful ESMO, a lot of great things presented, a lot of important phase 3 trials, but our poster basically looked at a stratification, or the segmentation better said, of less than 70 or over 70 to sort of think about the older versus a more mature adult, but yet younger patients. So here's the schema. It should be very familiar to everybody. This one-to-one-to-one blinded enza-combo versus leuprolide Q3 months and a placebo, the enza-mono was open-label, obviously we were not going to give placebo injections, and a little over a thousand patients and one can see the population that we looked at in our statistical analysis plan.

So I think the bottom line, Zach, is when we look at the less than 70, over 70, by the three different cohorts, there's really a very nice balance as you would expect in the baseline characteristics, a little more prostatectomy in the younger patients than in the older patients. But overall, really a nice balance between the arms whether it was by age, doubling time or grade group. And so almost 50/50 in the less than 70 and the over 70. So we were happy to see that. And then when we look at the MFS for these patients, one can see here it's a little bit of a busy slide but there's clinically meaningful improvement in metastasis-free survival, which is a composite endpoint of radiographic progression and/or death from disease.

We clearly hit it on our statistical significance at MFS with a majority when we first presented and we published in New England, we were all really coming from the rPFS benefit, a smaller percentage of death. We're following those patients and we will report on that hopefully sometime next year. And so here you see the conclusion that combo bested mono-leuprolide. And then likewise, regardless of age, and then very nicely when we look at the monotherapy enzalutamide, which is very attractive to many patients and physicians because you decrease the T-suppression side effects that we see also regardless of age, less than 70, over 70, a benefit of the enza-mono over the mono-leuprolide. I mean, not as dramatic, but still there's a clinically meaningful benefit.

When we look at the treatment emergent adverse events, again, I like this table because it lets you sort of bifurcate the less than 70, the over 70, into three different cohorts and I don't think it's surprising to see that you do see some more side effects in older patients. Not too dissimilar from almost every phase 3 advanced prostate cancer study that I've been involved with, and frankly in bladder cancer as well. Sometimes we look at those cut points as 75 rather than 70 in bladder, maybe a little bit younger on the kidney side in metastatic things, but that's just a side comment. But we do see a little bit more, and that was the conclusion as you can see on the bottom. The types of treatment emergent adverse events, fatigue is clearly up there of any grade. Some musculoskeletal ache and some hypertension.

These are the areas and of course, no surprise, you'd see more of that in the elderly as well with more cardiovascular issues, more sedentary lifestyle, and just generalized aging issues. So the conclusions were there was clearly clinically meaningful benefit in the metastasis-free survival in the combo enza-LHRH as well as in the mono regardless of age. And we do see a little bit more on the AE profile, but what I really like about this is it's just expanding our toolbox, as we say, or our armamentarium for patients. So thank you.

Zach Klaassen: So Neal, thanks so much for presenting that and certainly we're in the EMBARK phase of looking at some of these subgroups and age is certainly an important one. What it told me looking at this is that obviously we're enrolling patients in this clinical trial that are elderly and we see great results with reasonable tolerability. So let's just say a 76-year-old patient comes to your clinic today and he's a candidate, he's high-risk BCR, he has reasonable health, are you treating him with ADT plus enza or are you treating him with enza-mono? Does that conversation change based on him being 76 versus maybe 56?

Neal Shore: Yeah, I appreciate that. It really doesn't, but there's different issues. Since the approval of EMBARK, the label expansion by FDA in November, EMA in February, so a 76-year-old versus a 56-year-old high-risk BCR... and I believe it should be high-risk, I'm not starting patients on anything if they have a doubling time certainly north of 12 months. And I check the doubling time. I think that's important. In EMBARK we were more rigid, it was less than nine months or equal to nine months. So with a 56-year-old, more than likely he is going to have increased interest in sexual activity. One of the things we've learned and we've published on this is we have some pretty blunt instruments or validated questionnaires, but I think it's pretty intuitive to everyone that not having T-suppression and just having AR inhibition with enzalutamide, you're going to maintain a better likelihood to have a quality or some level of sexual function and libido.

If that patient says, "You know what? That's not at all important to me and I just want to live as long as I possibly can. Give me the most powerful regimen that you have outside of a clinical trial," then I'm going to use the combination. Now in older, the 76-year-old man, you could get the same concepts. I've got a lot of 76-year-olds and some guys in their 80s too, sexuality is extremely important to them. Some not. Usually for that patient population, energy and fatigue are really an issue, unless they're just really super fit, have a great workout regimen, great nutritional balance. But that T-suppression can really kick in and have terrible quality of life issues.

And some of those folks, if they've had radiation for example and they've had ADT in the past, and they go, "You know what? I took that ADT. I didn't have any problems with it," on one hand, and then on the other hand they're like, "Oh my gosh, that was the worst thing ever. Please don't do that again." So that's the discussion that I'm having and it's a much more enjoyable discussion. It's more, so to speak, full-throated. What I really am happy most about is we're giving patients options. And it goes under this important rubric of shared decision making.

Zach Klaassen: I think it's interesting, we talk about personalization of medicine and often that's related to targeted therapy, whether there's mutations that we're targeting, but as we know in our clinics, everything's a personal discussion with the patient. And so to sit there, know what their goals are, have options for them, share decision making, I think that's really where we're at in 2024, isn't it?

Neal Shore: Absolutely. And one of the things is we do see more breast-related issues: breast enlargement, nipple tenderness, some nipple pain. In EMBARK, as in other monotherapy ARPI, mostly with enzalutamide, what we saw when you do that unopposed ARPI, you can get clearly an increased incidence in breast-related symptoms. But now in my clinic, and what we didn't do in EMBARK or in ENACT and other small studies of monotherapies, we didn't really offer or promote any preventative strategies. And so we're doing work on this. We have a paper coming out on strategies such as preventative radiation therapy, eight to 10 gray could be given in one setting, as well as the use of selective estrogen receptor modulators.

I'm now using low-dose tamoxifen, and there's great data on that from the 150 mg bicalutamide studies. So it really helps diminish some of the adverse event profiling of just monotherapy enzalutamide, and it's inexpensive. The DDI is very good. It's generic. And so there's a lot of really interesting work that's going on in that to help mitigate any of that issue.

Zach Klaassen: Excellent. Always great chatting with you, Neal. Any final take-home messages for our listeners based on this age stratification analysis?

Neal Shore: Yeah, thanks, Zach. Yeah, this is a perfectly reasonable discussion to have with your patients 70 and above or less, and it's the same kind of concept or theme if you have mHSPC.

Zach Klaassen: Right.

Neal Shore: And some would argue if you get PET scans, the BCR population that's PET positive and conventional imaging negative, maybe they fall into now a new... clearly it's a new category, but it's that same thing. And what's troubling to me is, still in parts of the world, clearly in the US, we're still doing too much monotherapy ADT in mHSPC. It's shocking. But now patients who have high-risk BCR are owed this discussion that they will benefit from combo enza-LHRH or enza alone, clearly is better than LHRH monotherapy.

Zach Klaassen: Yep, well said. I always appreciate your time and expertise, Neal. Thanks so much for doing this.

Neal Shore: Thank you.