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Alicia Morgans: Hi. I'm so excited to be here today with Professor Nick James, who is joining me from the Royal Marsden in London at ASCO GU 2025. Thank you so much for being here to talk with me.

Nick James: Pleasure as always.

Alicia Morgans: As always. And for talking with me about the PATCH trial. And you presented, of course, an update on this trial looking at AR pathway inhibitor combinations, but the PATCH trial in general is something that's been going on for a long time. Tell me about this.

Nick James: Yeah. So this is a really long-running program, and it stemmed from an idea that one of my colleagues at the Hammersmith Hospital had when we were junior doctors, which was that we stopped using oral estrogens in prostate cancer—largely, anyway—quite a long time ago because of the thromboembolic problems. But of course, estrogens are extensively used for HRT, and they're used as patches. And if you go down the patch route, you lose the thromboembolic problems that you have with oral estrogens. So he did a sort of dose-finding study, showed that you actually needed a few—three, in fact—HRT patches from the standard preparations to drop the testosterone down, but it did indeed drop testosterone as, of course, we've known since the 1940s.

And so that then grew into a program initially looking at things like quality of life, but then a more formal randomized program against standard ADT with a whole range of things looked at—so quality of life, bone density, cardiovascular profiles, things like that. So all of that has been published, actually a while ago. So the headline from the quality of life is that quality of life is broadly better on patches. You get less fatigue, better preservation of sexual interest, you get far fewer hot flushes—hot flashes, whatever you want to call them. And the one thing that's worse, as you might imagine, is gynecomastia. But you do get gynecomastia, of course, on standard preparations as well.

Bone density is preserved or increased, as opposed to decreased. And cardiovascular effects are, if anything, favorable rather than unfavorable compared to standard ADT. So all of that is published. And the problem the PATCH trial was having was that it had the same inclusion criteria as STAMPEDE. It was getting kind of squashed by it. And so, in the end, the two TMGs took the decision that we just merged them, and we merged it by adding a patch arm to STAMPEDE and shut the PATCH trial. And the plan is to—well, what we are doing is a meta-analysis of the two trials for the non-inferiority outcome, which is the primary outcome for the now-closed PATCH trial.

And so the first of the two—we split the non-inferiority into M0 and M1. So like STAMPEDE, we straddle the whole high-risk through to metastatic. And so we did the M0 analysis because we had enough events to present that at ESMO using MFS as the outcome. It's completely rock-solidly non-inferior. And the M1 non-inferiority will take a little bit longer because the more of the metastatic patients were in STAMPEDE previously, so there's not so many metastatics in there. But we should have that probably this meeting next year, I think—we'll have a non-inferiority primary outcome.

But one of the things that we felt was important was that obviously the treatment of metastatic prostate cancer has changed considerably. So again, we've previously shown that you could combine patches with docetaxel and get similar efficacy—I mean, not fully powered phase III, but it looks the same. And so we extended recruitment into the metastatic part of PATCH—the PATCH part of STAMPEDE, rather—to allow us to look at the interaction between ARPIs and patches. So that’s what I presented yesterday.

Alicia Morgans: Wonderful. Well, let me just reiterate, though, that in the data that was presented at ESMO last year, 2024, you showed that the PATCH versus an LHRH analog was actually—it absolutely basically lined up in terms of metastasis-free survival, which I think is just really important to share. And this was a big finding, big presentation at ESMO 2024.

Nick James: Absolutely.

Alicia Morgans: So now at this meeting, as you said, you were looking at that combination of AR pathway inhibitors and patches. Tell me, what did you find?

Nick James: So what we found was that patients were randomized to one or the other, and we were not able to randomize the ARPI. So they just got clinician’s choice of ARPI. So we had a mix of abiraterone, and enzalutamide, and apalutamide, which were the three drugs available during the recruiting period. And so there is the potential that they might not all be the same. I have to say it’s a limitation of the data. And this is a randomized phase II, if you like. And the outcome measure that we pre-specified was the PSA undetectable defined as less than 0.2 at 24 weeks. And essentially, it's completely identical—the response rates are the same.

The other thing we wanted to check, because we all got our endocrine books out and tried to figure out what would be the way that abiraterone would interact with an estrogen patch—the amides is probably easier because they're kind of doing the same thing—but steroid synthesis inhibitors, when you're giving a steroid and you've got complex changes in the steroid composition, we weren't quite sure what would happen. So we thought there is the possibility we might see funny interactions, but essentially, we didn't. We didn't see any unexpected adverse events.

And in particular, actually, one of the things we were very interested in—because separately within STAMPEDE, we've been looking at long-term cardiovascular effects, and we'll have some data coming out later in the year on that by essentially hooking the patient trial records to long-term NHS Digital records. So we've done that for about 8,000 patients in STAMPEDE now. But in essence, we know from meta-analysis—that we've done and published—that all of the AR-targeting therapies increase your cardiovascular risk. So we're very interested in the cardiovascular risk profile within this little subset. It's a small subset, but essentially, we saw less hypertension and improvements in lipid profiles and things like that on patches compared to the analogs.

And previously, we've shown that just without ARPIs, cardiovascular risk profiles improved with estrogen patches compared to analogs as well. So that holds up in this subset, where actually we know that the intensification is increasing cardiovascular risk. So we think it's particularly relevant.

Alicia Morgans: Absolutely. I think—especially if we think about maybe some of the more intense cardiovascular effects that can happen with abiraterone, at least this is what is suggested by some smaller studies and some database analyses in real-world populations—I think this is of such high interest and maybe even more important with abiraterone. I wonder, you did mention that you were specifically kind of trying to understand that complex hormonal interplay. Were you able to do any correlatives or blood work? I know this takes extra funding—it’s not always possible.

Nick James: No, we were not able to do that. So the study has limitations. But just going back to first principles, we know that estrogens work for prostate cancer. People got a Nobel Prize for that back in the 1940s. So we weren't really expecting to see differences in efficacy. Because we do have the testosterone data. We know that testosterone is suppressed to the same level as they are with the analogs. That was one of the early requirements to run the whole of the rest of the trial. And we do monitor that. But we haven't done a sort of complex endocrine steroid profile.

The other thing, actually, just to pick you up on something you said—so everybody has this perception that abiraterone has much more cardiovascular risk than the amides. But the meta-analysis we did suggested that's not true.

Alicia Morgans: Interesting.

Nick James: It suggests that it's a class effect. So people associate hypertension and abiraterone because, of course, if you don't give the right amount of steroid, the feedback loops and the mineralocorticoid drive your blood pressure up. But as long as you mitigate that properly, you shouldn't get hypertension with it—I mean, you do as a class effect of all the targeting the AR pathway. So you see it with the analogs as well. But it didn't seem to be particularly any worse with abiraterone.

Alicia Morgans: That's interesting. Some of the real-world data that I mentioned is obviously out of the US, and the data sets that we have here—it seemed to be a little bit of a differential, but these are not randomized, these are not prospective. And so that's one of the powers that you have within your study, to be able to look at these things in a way that's randomized and is more effective. So I will have to check out that literature as well.

Nick James: Yeah.

Alicia Morgans: So as you think about this PATCH study, the only other question I want to ask before we wrap up is, this was a relatively smaller phase II, as you said. With STAMPEDE normally thousands of patients, this is relatively smaller. Are you planning to continue this investigation or more work with an AR pathway inhibitor and the PATCH? Or how do we move forward from here?

Nick James: So the motivation for this was that—we've got this—if you look at newly licensed, or relatively recently licensed, AR-targeting pathway drugs that target the pituitary axis, all they've had to do—like degarelix—they just have to show that testosterone was suppressed out to 12 months compared to leuprolide in the trial of relugolix or whatever. They weren't required to show oncological outcomes. So we have all of that information already. We know that it suppresses testosterone just the same as the analogs do and very reliably. And we've documented all of that.

But we've got more than that as well, because we've got all the quality of life data, we've got the bone density data, we've now got an oncological outcome thing as well. So all of that is being put to the UK regulator with a view to getting the drug approved as an orphan indication. And we're also talking to small pharmaceuticals about how could we reformulate this so instead of having to put three HRT patches on and family doctors getting confused as to why they're prescribing HRT for men—all of that stuff—we just want a preparation that is one step and so on. So all of that work is in progress. I have to credit, actually, Ruth Langley, and Duncan Gilbert, and Hannah Rush, who you know, are the people doing the donkey work on this one. I'm just—

Alicia Morgans: You're just a spokes model for today.

Nick James: Yes.

Alicia Morgans: Well, this is so interesting and so important. I certainly have patients who are asking about this. I lied before, I said one more question. I do have one more question.

Nick James: I have one more thing I want to say as well.

Alicia Morgans: Wonderful.

Nick James: Which may be the same thing.

Alicia Morgans: We’ll do both. Now the gynecomastia is something that I just want to touch on. And is there a way that patients can think about prophylaxis, or prevention, or other mitigation methods? Because sometimes it doesn't bother people, but a lot of times that's something that's a little bit of a bother to patients.

Nick James: For sure. And I think—going back to when we were using a lot of monotherapy with bicalutamide, and this is going to resurface with monotherapy with enzalutamide, and other amides as well, I suspect, for this. Trials were done of breast bud irradiation to try and prevent the gynecomastia. And essentially, from those, what you find is that you do stop the tissue enlarging, but you don't stop the discomfort, which is actually what bothers a lot of men more than the actual gynecomastia. It very much depends on your lifestyle. I mean, if you live in Rio and like to go swimming on the beach in your bathing costume, growing a pair of breasts is not a great look, probably, whereas if you only ever get undressed to get in your own bath, you might not care very much. So I think how much the enlargement bothers people, as you rightly say, varies.

The pluses, though, are that if you're really bothered by fatigue, which a lot of men are, or by hot flushes, which a lot of men are, it's a really easy fix for that. And so I think—the thing that you can't do, I don't think, which we do with bicalutamide monotherapy (which I still use for low-grade PSA relapses as an intermittent therapy), is put them on low-dose tamoxifen. But it kind of makes no sense to block the estrogen pathway if you're using it as your primary therapy; the estrogens there with bicalutamide as a spin-off may matter. Yeah, I do feel a little uncomfortable about blocking it, but it might be part of how these drugs work. But anyway, that's—it obviously makes no sense if it's estrogen monotherapy to do that.

Alicia Morgans: Absolutely. It's interesting, though, all the approaches that we take to counteract all the things that we're doing. And so I would just love to give you the opportunity to share your final thoughts and what you want to communicate to the audience here.

Nick James: So my other thought was, as you know, we did this EAT-Lancet Commission—which you were involved with, so you obviously do know, but the viewers might not. And this was taking a global perspective on future trends in prostate cancer. So one of the things—there were a number of headline findings. One is that prostate cancer is going to get more common pretty much everywhere, simply because life expectancy is going up pretty much everywhere, but particularly in middle-income countries, where they've got a lot of younger men who are now not going to die so frequently of things they were dying from in the past, which is obviously very good news. There will simply be more 60- and 70-year-old men in 10 years’ time, 15 years’ time, than there are now, particularly in Africa, for example. The median age in Nigeria is 15. And so there will be a lot more prostate cancer, and we need cheap, effective ways of treating it.

And particularly, if you want to do short-course hormone therapy with radiotherapy, patches are quite attractive because they're much cheaper than injectables and they're self-administered, not injected by somebody else. So this sort of repurposing thing is quite important if you're paying for your own medication. It potentially gives you a cheaper route to getting the same outcomes, and potentially a better route in terms of quality of life as well.

Alicia Morgans: Absolutely.

Nick James: And actually even here, of course, a lot of people are stuck self-paying, aren't they, or co-paying, which they're not in the UK, to be honest. But again, for the same reason, it might be attractive. I mean, I don't know how the costs stack up here, but—

Alicia Morgans: That's true. But the other thing is that the differential side-effect profile is absolutely something of interest. And so between the cost and the differential side effects, to have the option I think is really important. And as we were talking earlier, I have patients who have already asked about this based even on the ESMO data and before your other publications. So I think this is an important advance and something that our listeners are definitely going to be interested in. I don't know how many medical oncologists and urologists are going to feel like they want to go out and prescribe an estrogen patch or a hormone replacement patch tomorrow, but I can say it's of interest, and it's probably something we should think about learning how to do.

Nick James: I think so because I mean, I think not least of which—you can safely just have a dabble with it. You can prescribe—if somebody's bothered by fatigue and hot flushes, it'll make that better. You don't even have to stop the other treatment. As you know, it takes ages to wear off anyway. And you've got a really easy way of monitoring that you find, because you just monitor the testosterone, which you probably do anyway.

Alicia Morgans: Yes. Well, thank you so much for sharing all this. Final thoughts, final message to the viewers?

Nick James: Yeah. It is that obviously we're here at a meeting where we're getting excited about bright, shiny new toys—SABR and new drugs and all the rest of it. But actually, this is a really old drug. The estrogen is the oldest anti-cancer therapy. And I think these results are really interesting and exciting.

Alicia Morgans: Wonderful. Well, thank you so much for taking the time to talk all of this through. It's always such a pleasure to talk to you, Nick.

Nick James: Thank you.