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Matthew Cooperberg: All right, well, let's dive into our Q&A. So we've got our patient advocates who have been helping organize these journal clubs: Stan Rosenfeld, Bruce Zweig, Nathan Roundy, and Leszek Izdebski, and we are going to dive in. We'll get the slides back up here. And as a reminder for anyone else who has questions, please put them in the Q&A, with the one caveat that we cannot answer any personal medical inquiries as this is a public forum.

So this is a question from Harold Valinsky. Will enzalutamide and related meds have any application for low-risk patients who otherwise go on active surveillance? This is the question about the ENACT trial, which, yeah, I'm going to pitch that one to Dr. Shore and not touch it myself.

Neal Shore: Yeah, no, I'm happy to answer that. Keep in mind that, to level set for all of our friends listening, EMBARK was for patients who had previously undergone either having their prostates removed and then had radiation treatment or had primary radiation treatment. Okay? So 75% of the patients had undergone removal of the prostate, and then there was 25% of that 75% who had radiation after their surgery didn't work, and then there was a separate 25% who had failed radiation.

This first question by Harold Valinsky is about patients who theoretically would have the indolent, not aggressive form of prostate cancer, who would be appropriate, good candidates for active surveillance. And thanks to Matt Cooperberg at the turn of the century, he really led the charge that we in urology were overtreating and taking out too many prostates and radiating too many prostates in men who had indolent, meaning disease that, yes, we call it cancer under the microscope, but the likelihood of it ever really spreading is very, very low and almost, in some cases, non-existent.

But that said, we as a field, as a profession, were taking out too many prostates and over-radiating. So active surveillance strategies, thanks to leadership from Matt and others, have really taken off so much to the point, but we still think it can be better because, at the end of the day, there's a whole bunch of different reasons, but people get anxiety about not treating their cancer, the PSA fluctuations. They talk to somebody, and the next thing you know, even though they have the low-grade prostate cancer, the grade group one and two, the Gleason 6 and favorable intermediate 3+4, they end up having surgery or radiation.

So we did a study, and I don't want to confuse the audience, but we did a phase two study, not a registrational study, just a proof of concept, to see what would happen if you were in the low-grade, the grade group one, grade group two. And actually, 50% were grade group twos, favorable intermediate, and the other 50% were an enriched grade group one. So you had to have a certain amount, yet, of course, positive in percentage. And we said, "Okay, let's take 114 patients and give them enzalutamide monotherapy, like our third cohort in EMBARK, and give it to them for a year versus the same group, and we just watch them and we monitor their PSAs, monitor their biopsies." And we published the results in JAMA Oncology. And we demonstrated that the patients who received the enzalutamide, their PSAs went down dramatically, as you would expect, and we actually saw a decrease in their upgrading of their subsequent biopsies in terms of them going on to more aggressive disease. It was a concept study. It wasn't meant to be game-changing. It wasn't meant to be practice-changing.

Now, one of the things that came out of that study, to just bring it back to EMBARK and why EMBARK is so important, because, as Steve said, we presented the data April 28th at a plenary at AUA, and then we gave additional data at ESMO 2023, and then the FDA approved it on November 16th, 2023. So in essentially six months, we went from presentation to approval label expansion. That's a big deal, right? Everybody gets that. And it's in the path where the guidelines of the NCCN and the European Medical Authority also just approved it a few weeks ago. So that's not so easy to do unless the data is incontrovertible.

But one of the things that we saw in the ENACT active surveillance of 114 and the 355 monotherapy enza patients is we didn't do anything to try and prevent a side effect of when you just get that treatment, that therapy, blocking the androgen receptor without lowering testosterone. When you don't do that, you also have increased levels of estradiol and estrogen-like molecules, so you get breast enlargement rather significantly and breast tenderness and even nipple pain. But we didn't do any preventative strategies in ENACT nor in EMBARK. So that's an area that's really ripe for consideration to, as we say, mitigate or prevent those side effects.

As it relates, just to put a sort of a final capstone on the active surveillance, we're doing additional work with artificial intelligence and other specific molecular signals. We have a paper that's been published. I published it with Ted Schaefer from Northwestern and Ash Ross, where we looked at three other particular molecular signatures to try and better delineate who would really benefit in this indolent group. So the answer is we still don't have level one evidence. It's ongoing research.

Matthew Cooperberg: Well, maybe we can come back to surveillance at the end, but let's stay on the topic of the patients with the elevated PSA after primary treatment and rapid doubling time. And we should have, just to emphasize the point again, who these results are relevant to. So these are the patients who have recurred with a PSA that's doubling in less than nine months. So it's a subset of patients. It's not everybody with a recurrence. That's an important thing to keep in mind.

So, a number of questions, so why don’t we kick off now with our advocates, and you guys can claim your questions and fire away.

Bruce Zweig: Leszek, do you want to hit the first question?

Leszek Izdebski: Sure. It's a little bit different question from the current display question. I was really looking at recommendations, who are the best candidates for mono versus enza plus ADT in particular?

The adverse events are somewhat similar, but there are some differences there. So one of the questions that I had was, for example, the patients who value libido, typically ADT has put a significant negative impact on that. So there would be one group that potentially maybe could benefit from enza mono. The other one I was also wondering about, patients who are just frail. But looking at some of the things that you were showing related to fractures, not sure if that's really the right or wrong direction. And in general, patients who just don't tolerate ADT, is that the right thing for them to do, to try to ask the doctors about enza mono?

Neal Shore: I think those are fabulous questions, Mr. Izdebski, or Leszek. Maybe, Steve, you want to just go first? I'll go second? Those are tons of great questions in your inquiry.

Stephen Freedland: Yeah, I'll do a little bit. I mean, you have the real-world experience. I have the trial and the data and things, but you've actually used a lot of enzalutamide monotherapy, so I'll certainly let you chime in on your experiences. I do think one of the real advantages of the monotherapy is that it preserves sexual activity. I think that's a real game-changer for some patients. We're in the process of looking at that in EMBARK patients who were still sexually active upon entry into the study. It's not the majority of patients, but it's not none. And I think in that group we do see the benefits of the monotherapy relative to either ADT alone or enzalutamide combination. So I think for the young, sexually active person, that's a great way to go.

There are some patients who just refuse hormones, refuse castration. Another one that we don't talk a lot about is hot flashes; they are a lot less. And we all know that's a side effect of hormones. We don't talk a lot about it, at least in the medical field; it's kind of just assumed, but there are some patients that can be really bothered by the hot flashes. The problem is you don't know until you start, but I think you could start a patient on the combination. If they're really bothered by the hot flashes, know that you can stop the shot and just keep them on enza alone and still have significant benefits. So I think there are subsets. I don't think everyone is going to jump at monotherapy, but I think there will be subsets. And how does that compare with your real-world experiences there, Neal?

Neal Shore: I think you nailed it. And I would only say that I've got a lot of... It depends on how you want to define older, but I have a lot of older gentlemen who really are interested in their sexual function. And I think one of the things we've realized is there's a lot more to sexual function than just the notion of a stiff erection and penetration. And we're learning a lot more about that, the notion of libido and desire and cuddling and just sexual romantic thoughts. A lot of our questionnaires have really not been very good about that. But for those patients for whom that's important, I really like the monotherapy, because the data that we have clearly supports an improvement for those patients versus those who had testosterone suppression.

The other group are the ones who say, "Man, I had that testosterone suppression. I had those shots or," even if it was a pill, "the relugolix and I can't live that way. I can't. My level of fatigue, my level of hot flush was miserable." But there are some other things that we're looking into as well that are very unique to androgen deprivation therapy that you don't see with an AR monotherapy, which would be visceral adiposity, sarcopenia, bone demineralization, and all the things that Steve talked about.

So I think what I really try to do now since approval is I really have that really vaunted, full-throated conversation of patient-shared decision-making. It's the patient's choice. Here are your two options. The monotherapy LHRH, you could still have it, but it's really the inferior option, and that's what EMBARK teaches us for your patients with high-risk BCR.

Matthew Cooperberg: So just to follow up with that, first, the related question, which is there was no comparison between combination therapy and enza monotherapy. So first of all, out of curiosity, why was that not done? Is there any plan to do that as a post hoc analysis? And what can be said about combination therapy versus enza monotherapy?

Stephen Freedland: So I'll jump in, Neal, unless you want to answer. If you think about it, it's really two different trials that were kind of put together into one. So it's really enzalutamide combination versus ADT, monotherapy versus ADT. It was never designed to compare these two arms. It's not in a statistical analysis plan. There are no ongoing analyses to look at that. You can look at the curves, you can put them together if you want. The package insert for enzalutamide actually has all three curves in one graph. It's the only place you will probably ever see all three on one unless someone bootlegs it together.

And you can see, I mean, the enzalutamide monotherapy is a little bit in the middle. I mean, you can see that on the curves that you look at the things, but I think that's, to me, not the take-home message. The take-home message is we have two really good options that are both significantly better than what we've been doing in the past. And then it's up to the patient, the side effects, and some of those real-world things to discuss which is right of those two new options. That's certainly the way I look at it. I mean, Neal, what's your take?

Neal Shore: Absolutely. I look at it the exact same way. And it's an important discussion to have with the patient and their family and caregivers, and you make your call. And that's exactly what I've been doing. Just parenthetically, someone in one of the questions, I have used some prophylactic breast radiation. This usually can be accomplished in one or two days max, 10 gray, 12 gray, which is a very small dose, but there's really good data on the use of taking another pill. Not that always taking another pill makes everybody happy in this world of polypharmacy, if you're basically taking more than four or five pills a day, but there is a generic, inexpensive, once-a-day pill called a selective estrogen receptor modulator, or a SERM, called tamoxifen, which can really mitigate a lot of the breast enlargement and any pain or tenderness. And if you actually want to get really aggressive, you can get the radiation prevention and the tamoxifen.

And this is a way to really reduce, because we did see a lot of this in the ENACT trial and in EMBARK, because we didn't have in our protocol any mitigating strategies to prevent that. And so I'm doing that now routinely in all of my patients. When it comes to adding another medication, such as tamoxifen, I have to work with my pharmacy colleagues and look at some drug-drug interactions, which are not many. And it's an inexpensive, once-a-day drug.

Rana McKay: I think the other thing, too, to consider is there's no decision that, I think, can't be undone, I guess you can say. I think sometimes it can be very daunting to think about, oh, I'm going to be on therapy for this entire duration of time, or I'm going to be on continuous intermittent therapy. A lot of times, treatment is dynamic and we make real-time decisions based off what you all experience as patients. So just because we decide that we are going to embark on combination therapy with the two, it doesn't mean that we can't modify what we do. It doesn't mean that we can't make dose adjustments or dose interruptions. Now, there's a new oral GnRH antagonist called relugolix, which is really nice because it allows for more rapid T recovery, especially when we're doing an intermittent strategy. And so treatment is dynamic and modifiable based on what patients may experience. And in the trial, the patients that were enrolled, not 100% of the patients received 100% of the dose 100% of the time. And so treatment can be modified to really help suit the needs of the patient.

Stephen Freedland: And if I could just expand upon that, Rana, I think you hit the nail on the head. I mean, first off, hats off; relugolix is FDA-approved. Neal Shore led that clinical trial as well, first author in New England Journal. Game-changing study there as well. Congrats, Neal.

But something about EMBARK that we didn't get into in the presentation, to kind of keep it simple, is you got the therapy you got based upon randomization for nine months, and if you had a really good response, your PSA came down really low. Even as part of the trial, we actually stopped therapy. And if you were in one of the enzalutamide arms, it was 85% to 90% or higher chance you got that treatment break; whereas, if it's ADT alone, only two-thirds of patients did. And with the enzalutamide combination, the break that you got actually lasted longer. So yes, you got a little bit more intense treatment upfront, a little more side effects, no major effects on quality of life, but you're more likely to get treatment suspension, so de-intensification being off treatment, and the off treatment lasted longer. So there are other benefits built in that we just didn't, for the time, get to show the full story.

Matthew Cooperberg: So one of the other big questions that's already been alluded to and came up in our discussions leading up to this journal club is, what do we do now that we are in the PSMA era? As you said, PSMA was not broadly available when the trial was conceived and when patients were being recruited to it, but now, of course, it is. And we knew all along that many men who had, quote-unquote, "M0 disease" actually had mets that we just couldn't see with the bone scan. Well, now we can see them.

So if you have a negative bone scan or maybe you don't have a bone scan at all and you see a few spots on the PSMA scan, is that patient eligible for enza monotherapy? Do you think about them as an EMBARK patient, or are they a more traditional M1 patient? I'm going to ask all the panelists. I know there's no one answer to this question, but I think it's an important one. As we think about a lot of the trials that have been published in the last few years, what do we do with all these in the PSMA era?

Rana McKay: I probably would further break it down into oligo- and polymetastatic, and does somebody have disease that could be in—

Matthew Cooperberg: Define those.

Rana McKay: Yeah, that could be—

Matthew Cooperberg: Define those for our audience.

Rana McKay: Oh. Oh. Oh, sorry, sorry. So did the PSMA scan show disease just in a couple of spots, like less than five spots, that could be targeted with radiation, or does it show disease in multiple spots, where it doesn't really make sense, or it's not feasible actually to do spot radiation to all the areas? Because I think practice is evolving that we don't have level one evidence on exactly what to do, that for individuals who just have a couple of spots, doing spot radiation to those areas with or without hormonal therapy and giving people at least an opportunity to be off treatment could certainly be an option that could be entertained. So I like to kind of make that distinction before wedding somebody with conventional imaging that is negative but a PSMA is positive to lifelong hormonal therapy as we would in the metastatic setting.

Stephen Freedland: I would agree with that. And I think about three buckets with PSMA. And Rana talked about two: a few spots versus a lot of spots; there is that third bucket of no spots. And so, to me, and that's where I'm not here to market or push enzalutamide, but it doesn't really matter whether you have no spots, some spots, or lots of spots; enzalutamide is approved. And so if we think you're traditional metastatic, we have data that enzalutamide... We also know apalutamide, darolutamide with chemo, docetaxel alone, abiraterone. We have a lot of drugs. Enzalutamide's one of them. But if we think of this as non-metastatic, we have enzalutamide. I mean, Rana talked about the spot welding as sometimes we'll call it, the radiation if you have a couple of spots.
And to me, the take-home from EMBARK is, when you are ready for systemic therapy, when you're ready for something beyond some radiation, some surgery that treats the whole body, we now know how to do that, which is intensified androgen deprivation therapy, enzalutamide, ADT plus some other drug. We still don't 100% know when to do it in the disease course.

Bruce Zweig: So, just a question for Neal. Do you then sometimes give enzalutamide monotherapy to patients who are getting the sort of spot welding oligometastatic treatment to a couple of metastases, or do you wait and see how the radiation works first?

Neal Shore: Yeah, I appreciate that question. This was asked recently at the Advanced Prostate Cancer Consensus Conference, and it's very interesting; there was really no consensus on how you do that. When you do this, quote, "spot welding" on the PSMA PET or even arguably unconventional imaging, do you do an AR pathway inhibitor drug, an ARPI? Which, by the way, there was unanimity from the voters to get rid of ARSI and NHA and ARTA. It was actually almost unanimous to call all these, apa, enza, daro, abi, ARPI. So that's going to come out in the paper. So that'll be helpful to avoid this confusion of this word salad or acronym soup.

But your question, I'll tell you what I do. I typically do not. I like to see. And if it's oligo, Greek for few, and in my definition, it's usually three or less, but some people push it to five, I like to see: is my SBRT, is my spot welding radiation, and I check the PSA pretty soon after, six weeks, eight weeks, 10 weeks. Is it going down? If it's going down, we have earlier phase two studies that basically taught us that that helps you delay the onset of systemic therapies, and typically that was testosterone suppression.
So I'm kind of a purist in that regard, but there are many who would say, "Hey, I want to try to radiosensitize," and so I'll add an ARPI and/or add a testosterone-lowering agent. But then you get the side effects, and then you don't really know until you stop those systemic drugs, did my focal spot radiation, was that the reasoning for my success?

Matthew Cooperberg: You mentioned darolutamide. There are a couple of questions in the Q&A about daro and apalutamide. There's some sense that daro may cause less fatigue. Obviously, it's not tested in this space yet, but any thoughts about daro as an alternative for patients who have a lot of fatigue on enza?

Rana McKay: Well, there is a study, right, that is currently... Is it still accruing or is it... I think it's still accruing. The ARASTEP study that is exactly in this space that is looking at answering that question of darolutamide in this context. That study doesn't integrate PSMA PET imaging, and to enroll you need to have PSMA PET-positive disease. But I think it's coming; darolutamide in this space, I think, is coming.

Bruce Zweig: The way the world works, you've studied a certain population and given them the enzalutamide monotherapy, and so it's approved in that specific group, but some patients might be interested in the possibility of expanding beyond the study group, to do sort of an off-label trial of their own or to try to talk their oncologist into maybe trying the monotherapy, especially if preservation of sexual quality and things is important. Can you talk about that a little bit as a possibility or, going forward, if you think the world's going to be there in a few years?

Stephen Freedland: The one thing I can comment on, I mean, off-label, obviously, a lot of it happens. It's hard to know where things are going to go. But one thing I like about what the FDA did is they defined high risk as up to the clinician for this PCR. So yes, we did a clinical trial, yes, we had very strict criteria of PSA going up at a certain rate, and PSA had to be up above a certain level and things, but ultimately, the definition of high risk is left up to the clinician and the patient.

So invariably, there's probably going to be some enzalutamide used for patients who would not have technically qualified for EMBARK. And I think in time we're going to be able to look at those patients, see how they did, and see if that's the right answer to treat those patients that way or not. But from the trial, we don't know because they weren't included. But I think many drugs slowly expand out. And obviously, once they go off patent life and the costs go down, then it's a lot easier for them to spread to other places as well.

Nathan Roundy: So, in terms of this risk of seizure, does that cause a man to lose his driving privilege, and would switching to darolutamide maybe be able to get him back on the road again?

Neal Shore: So, as Steve pointed out, it's a good question you ask because, for apa and enza, both of those drugs cross the blood-brain barrier and stimulate a certain receptor, and they have clearly been shown to have a risk of causing seizures. So if you have a seizure history or you're on drugs that can increase your seizure risk, you shouldn't be taking enza or apa. That's not true of darolutamide. Darolutamide in animal models has been shown not to cross the blood-brain barrier, and in all of their trials, they never excluded patients who had a seizure history or were taking medications that could lower your seizure potential risk.

I think the licensure issue of driving, I can't really comment. I'm not an expert on that. I think that probably varies amongst states and probably with the advice of a neurologist. But it's important to recognize if indeed you have a seizure potential and you want to be on an ARPI, darolutamide is the better choice. You could also take abiraterone because it doesn't cross the blood-brain barrier either.

Nathan Roundy: And one last question. What about the guy who had cryotherapy or HIFU or some other curative therapy and he's got PSA rising, does he qualify for this enzalutamide?

Neal Shore: So that's a great question. So if he had total gland ablation, cryo, not focal, but full HIFU, full cryo, and then presumably had no local recurrence and had BCR, biochemical recurrence, I would think the answer is yes, he would qualify as high risk. And we said high risk is a doubling time of less than or equal to nine months. The European Association of Urology defines high risk as less than or equal to 12 months. In the label, high risk is not defined. It's really left to the decision, I think, of the physician and the patient.

Nathan Roundy: And for the 85-year-old guy who's been on ADT for five years, can he switch over to enza monotherapy if he wants to try to improve his quality of life?

Matthew Cooperberg: This is exactly where we leave from what the trial tells us to what happens in the real world and what you can get insurance companies to cooperate with. That 85-year-old who's been on hormonal therapy for five years, you stop the hormonal therapy and the testosterone very frequently does not come back for years anyway. So long-term ADT in the elderly population has its own problems because what we intend to be intermittent therapy often is permanent.

I think the idea of... And there was a question in the Q&A about using enza during the off cycles of ADT. I mean, I'm sure all kinds of things are going to happen in clinical practice to the extent that insurance is going to cover it, and we're going to have to watch this space and hopefully continue to study those types of additional downstream endpoints. I mean, I think there will be all kinds of use cases for it, some of which are going to work, some of which are not.

And I will say, too, the one other thing to point out is that enza is still an expensive drug, and there are still 20% co-pays for many men, many patients who do not have supplemental coverage. And this is true of all the ARPIs, or however we're going to designate them; they're all quite expensive. And the financial toxicity considerations are going to become quite salient as well as we use these drugs earlier in the course of the disease. So it'll be a fascinating space to watch for those of us that are into this kind of health services research territory of tracking how treatments actually get used once the New England Journal paper has come out, the guidelines are approved, the FDA has said, "Okay," and then we track what actually happens in the real world, which is a completely different situation in many, many cases.

Leszek, last question from you.

Leszek Izdebski: Yeah, but only a quick question. You defined high risk as doubling time and other things. Did you look also at Decipher and similar types of indicators?

Stephen Freedland: We did not use that in the study is the short answer. I mean, a lot of people are using that to define high risk post-treatment, pre-treatment. I think it may in time. We know with salvage radiation, there's some data that high-risk Decipher benefits more from hormones than not after surgery, but in the EMBARK study we didn't look at it. It probably plays into it, but we didn't look at it.

Matthew Cooperberg: Well, any concluding thoughts from each of the panelists? We'll start with you, Steve?

Stephen Freedland: Just thanks for the opportunity to talk to patients. I think this is really game-changing; we've all said it, and I appreciate everyone listening.

Rana McKay: That's fabulous.

Leszek Izdebski: Thank you very much.

Matthew Cooperberg: Wonderful.

Neal Shore: Thank you.

Matthew Cooperberg: Thank you all for joining us.

Nathan Roundy: Thanks for coming, yeah.

Matthew Cooperberg: And thanks to all the attendees. As with the first one, this will be on the UroToday website, probably in two sections again, one with the presentations and one with the Q&A. We will look forward to our next journal club. We are tentatively planning a very interesting article on focal therapy for the third quarter of this year. So, thanks again for joining us. Thank you very much to the panelists. Thank you to UroToday for sponsoring us. And we will see you soon.

Neal Shore: Okay, thank you. Bye.

Rana McKay: Wonderful. Bye-bye.

Leszek Izdebski: Thank you.

Stephen Freedland: Okay. Bye.