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Matthew Cooperberg: Hi, I am Matt Cooperberg. It's a pleasure to welcome you all to our second installment of the UroToday Journal Club for prostate cancer patients. As you all hopefully remember from the first one, a journal club is a format we've had in medicine for many years in which we take game-changing recent publications in the medical literature and discuss them among an internal group, either of physicians or physicians and researchers, or it's a group of us together with trainees, medical students, residents, and fellows to try to get the findings of important papers out into the world and into practice as quickly as possible. So in this format, we have tried to adapt this with the idea of getting the same results out to the patient community faster and in an easily digestible format. So we are asking the lead authors of these game-changing studies to join us together with a discussant to give an additional opinion.

So the first one we discussed, the ProtecT trial of surgery versus radiation therapy versus watchful waiting for localized disease. In this second journal club, we're going to be looking at the recently published EMBARK trial, which randomized men between traditional hormonal suppression therapy, androgen deprivation with leuprolide, to enzalutamide, which is the novel androgen receptor antagonist, or a combination of the two treatments. The EMBARK trial was led by Dr. Steve Freedland at Cedars-Sinai, and Dr. Neal Shore, who's medical director at Atlantic Urology. It's our privilege to have both of them joining us today to talk about the papers, and we're also joined by Professor Rana McKay, who's an associate professor at the University of California San Diego in medical oncology, and will give us an additional perspective about the trial and its implications.

We're also joined by four of our lead patient advocates from UCSF who have been instrumental in helping get this journal club launched and have been helping us choose the articles and organize the Q& A sessions. So it's also a pleasure to introduce Bruce Zweig, Stan Rosenfeld, Leszek Izdebski, and Nathan Roundy. So without further ado, we'll pass it over to Doctors Freedland and Shore to kick us off.

Stephen Freedland: Thanks so much, Matt, and thanks for inviting us to be here. It's an exciting time and looking forward to the discussion. As you said, we've given this talk many times to other physicians and trainees, but excited to talk with you all directly, the patients, the people impacted by this.

Neal Shore: This is game-changing. So I think it's fabulous to be talking to your audience today. People use the word game-changing probably a little bit too liberally. For the audience, whoever's listening, this is game-changing and I say that with a perspective of having been involved in over 400 clinical trials. This is truly game-changing and it's great and I hope that Steve and I can explain to you why this is a really significant option alternative. It's not even really an alternative. What we're going to tell you is, the standard of care no longer is appropriate, which is monotherapy, ADT, androgen deprivation therapy.

Stephen Freedland: So basically Neal and I, as well as many of the investigators involved in these, as Neal said, truly practice-changing studies. We work with a lot of companies and specifically we work with Astellas and Pfizer who are makers of enzalutamide and supported this study. So I just want to put that out there. What we do know is for patients who walk in the door with prostate cancer, often they can do active surveillance, which is great if picked up early, it's low risk. But many patients will undergo surgery or radiation. It's kind of the tried and true standard approaches we've been using for decades for this disease. And unfortunately, despite that, the treatments are not always curative. So about somewhere between 20 and 50% of the time, patients will have a recurrence of the cancer detected by a blood test, PSA starts to rise, and we call that biochemical recurrence, BCR.

We know those that are high risk BCR, where that PSA is going up really fast, they're at high risk of developing metastatic disease, tumor spreading and dying of prostate cancer. And we know in more advanced stages of prostate cancer, if we give one of these new drugs, an androgen receptor pathway inhibitor, something that blocks the androgen receptor, androgen receptor signaling inhibitor goes by a lot of different names such as enzalutamide, we actually can improve outcomes. Get patients to live longer, maintain their quality of life. So the question is, does that apply to these patients with this earlier stage disease, this high-risk biochemical occurrence? And that was the basis for EMBARK. So this was the trial design. We basically took patients with biochemical occurrence. PSA is doubling every nine months or less, and they were randomized to one of three arms.

They either got enzalutamide, this newer drug, it's been around for about a dozen years, but never tested in this space, plus leuprolide acetate, also known as androgen deprivation therapy that had been the de facto standard of care. Versus placebo, which is something that looks like enzalutamide but has no activity plus leuprolide. Versus actually enzalutamide alone. So without the androgen deprivation therapy for the first time. And patients were followed, after about nine months, we checked the PSA and if it was really low, we actually stopped treatment and waited for the PSAs to rise. And once they started to rise, which they often did, not always, then we would start them back on the treatment. And the primary outcome was metastasis-free survival or metastasis or death. And I can turn over to Neal in a couple of minutes to give us a little bit more context to what that means maybe from a patient perspective.

So just jumping into it, this is what we have as the primary endpoint, and this is on the Y-axis, the up and down, is the percent of patients that are basically alive without having the tumor spread. And you can see in the golden color there that we have the enzalutamide combination, the curve being much higher than the ADT alone. Those curves start to separate. And if we pick a random point in time at the five-year mark, we have 87% of patients alive without tumor spread in the combination versus 71%. So this is really in terms of medical research, very, very dramatic separation. And that's why Neal said this is really a game changer. It's not common we see curves that are really so separated and just keep separating more and more. But Neal, why don't you maybe from a patient perspective, what is an improved metastasis-free survival, what does that mean from our patient point of view?

Neal Shore: Yeah, we're fond in medicine of using a lot of phrases and acronyms that I think oftentimes patients find confusing. And so one of the really nice things that's really been a push is to have plain language summaries. And we've done a lot of that in this trial, in this study and others. It's important to not make the language so polysyllabic and confusing as well as the acronyms. So metastasis-free survival or MFS is a composite endpoint of either developing radiographic progression, and in our study we use what's known as traditional or conventional imaging.

And many of you listening, that's equivalent to a full-body CT scan, CAT scan, some people call it, as well as a traditional bone scan or the Technetium bone scan. Now that's very different, and I know we'll get into this in the Q&A, that's very different when you think about the new PSMA PET scans. They were not part of the study because when Steve and I and several others designed the study about nine years ago, the PSMA PET scans were just not very accessible and they were only available in a couple of places and weren't even available in the US.

So it was all based on conventional imaging. So the MFS, the metastasis-free survival, was the likelihood of developing either a progression radiographically or death. When we did this calculation, and we showed this, the overwhelming majority of the events, whether it's a progression radiographically or a death or progression events, overall survival is still too immature, statistically, but we are trending very positively and we are following all the patients in the study in all three arms. And we plan to report on this the overall survival analysis sometime in 2025.

Stephen Freedland: Thanks, Neal. That actually lends perfectly into our next slide, which is albeit immature, but as you see, the two curves are starting to separate as well. And this is overall survival. So this is not cancer spread or not; this is alive or not. And as you see, the curves are not quite as separated as we saw in the last one, but we are still following the patients and we're hopeful in a couple of years from now that we will have some updated data and be back here to talk to you about that. So we look at the hazard ratio, which is really the risk of dying, and we take that if it's at X percentage of a certain amount in the leuprolide alone, which had been the standard of care, how much is it reduced in the combination? And 0.59 means it's 59% of what it would've been.

So essentially, if you do one minus that, you get 41%. So it's about a 40% reduction in the risk of dying. And we in statistics in medicine have certain thresholds that we would call something statistically significant. You may have heard that term. We're not there yet with this. It's looking promising, but we still need to follow it for longer. So this was the monotherapy arm. So enzalutamide alone. Again, you see curves that are separating, they separate pretty early, they keep getting wider and wider, showing that, and you should look at the hazard ratio, it's less than one, shows a delay. The P-value there is statistically significant. So we can conclude that enzalutamide monotherapy, you don't even need ADT, just a simple pill, is going to make you do better than the traditional way we've been doing it with shots for decades.

And then if we look at overall survival for that, you start to see again some trends and it's really immature, but they're starting to separate towards the end, and we just need more data for that. So I'll explain this briefly, but I'll turn it over to Neal to again put this in the context that is relevant to the patient side. So this is what we call PRO analysis, up in the title, patient-reported outcomes. So this is the quality of life. Okay, great, tumors are spreading slower, patients seem to be living longer, but are they miserable and super unhappy or not? And so we looked at two different measures. One is pain. So it's always something you think about with cancer, that it could cause pain. And the other is just global quality of life. How do you feel?

And for each of these, without getting into, don't worry so much about the details, but if we look at those curves going across, any curve that overlaps that 1.0, basically it's saying that there is no statistically significant difference between whether they got enzalutamide with combination or monotherapy on the bottom with leuprolide alone. And we see all of those curves, we look at the crosshatch, they overlap with the 1.0. Saying, we can't statistically tell you that getting this drug is better or worse. Looks like it's the same in terms of your quality of life. And so maybe I'm sure we're going to have questions on this, but Neal, I'd love to hear your thoughts, from a patient perspective knowing that we can preserve your quality of life and delay your tumor. What does that mean?

Neal Shore: Yeah, I think that's a very important question. I usually always talk to my patients about what are the goals of therapy, and not in any particular order is prolonging survival, but also preserving your quality of life. What are the things that you like to do is another way of thinking about it in real-world terms, your ability to move and function and do your hobbies and to think and to avoid pain, increases in pain. And these are all kind of part of the subscales of the FACT-P score, your sense of well-being. And then so prolonging your survival, preserving your quality of life, and preventing complications of the therapy. And I do think we're going to want to spend some time breaking out a little bit more the specific differences in the side effect profiles.

I think that'll be very important for people to understand, comparing combination enzalutamide and androgen deprivation therapy. In this case, we used three-month leuprolide, that's what we call the combination cohort, versus the monotherapy cohort which was just enzalutamide. And these were all compared to the monotherapy of leuprolide. So there are different adverse events or adverse reaction profiles. I think we really want to have a really good full-throated discussion about that. And then the fourth concept is patient preference value. Are you risk-averse? Are you risk-seeking? Do you want to go for the gusto or do you prefer oral over injectables? Things of that nature.

Rana McKay: Just to kind of highlight a little bit, the FACT-P asks a lot of questions about physical well-being, social and family well-being, and emotional well-being. So it's a questionnaire that patients will complete that has almost 30 plus questions that ask these various things and they get a score. And so that's what we're looking at on the prior slide. Oh, this is the FACT-P. So kind of what is their total score that they answer on this questionnaire? Just to kind of break this up. And the BPI is a brief pain inventory. It's a short form of around nine questions. So patients will answer questions about are they having pain, where is their pain? And when they complete these questionnaires, they're kind of recalling what they experienced over the last week or couple of days.

Neal Shore: And I think it's important for the audience to recognize that these are typically almost never used in clinical practice, these are invariably used in clinical trials. So we try to measure these aspects. It's very cumbersome to try to do these on a regular basis in clinical practice.

Stephen Freedland: Great. And that's where I think on the next slide you see even more questionnaires that we had the patients complete, really put them through the wringer here, so to speak. But really wanted to understand the patient perspective, and again, anything where that crossbar, those arms are overlapping 1.0 means no significant difference. And really, the one thing that you see, so again, no major differences with the combination of sexual activity or urinary symptom bowel. You do see a little bit worse hormonal treatment symptoms, hot flashes, and other things, which kind of makes sense, it's more effective hormones. But again, incontinence, no difference, urinary symptoms. And if you look down to monotherapy, what's I think important and really maybe we get to more on the question is, that sexual activity seems to be better than ADT alone. And that's really, I think, one of the advantages of the monotherapy. But otherwise, no differences in sexual functioning, urinary, bowel, hormonal symptoms, other things.

And this is really the side effects. Again, we showed you the quality of life as measured with really detailed questionnaires is not really impacted. But what we do see is, first off, in a clinical trial, you twist an ankle, you get a headache, you get a stomach ache, it's an adverse event. So almost everyone at some point over a five-year study is going to have some adverse event, AE is what we call it. And then grade three or higher, that does start to be things that we start to get worried about. Pretty high in all the groups, but again, it's a five-year study, something, you get appendicitis and you get admitted to the hospital, that's something. So we look at treatment-related adverse events. Those are ones we can actually say we think the treatment caused or is related common.

And then the more serious ones there for the grade three, we do see a little bit higher with the enzalutamide 17.6 and in the monotherapy 16.1, versus the leuprolide alone is 8.8. But again, the flip side is, the vast majority of people are not having serious reactions to the drug. Adverse events leading to death is extremely low in all the groups. And it's always hard to know what's actually caused by the drugs. The discontinuation rates are low. And I think on the next slide we have a little bit more specifics about some actual things that patients would receive. So if we look at fatigue, very common with all of these drugs, 40, 50%. A little bit more on the enzalutamide arms, but the grade three, the things that would be more impactful in terms of quality of life, 4%, it's low. You see a little bit more falls, a little bit more fractures with a combination, actually less with the monotherapy.

You do see seizure risk. That is something with enzalutamide, you see about 1% of patients. So patients who've had a history of seizure or are predisposed to seizures for other reasons really shouldn't be on enzalutamide. But that's a relatively small percentage of patients. So I think in summary, and again, we'll get into a lot of this in the questions, we have a new standard of care. We have a drug, enzalutamide, that can be given with or without ADT. It prolongs the time people are alive without their tumor spreading.

Suggestively makes them live longer. Quality of life is preserved. And there are some side effects with the drug, and we're certainly happy to discuss those as well. But I think in the totality, this is why the FDA approved this drug for these patients. It's now in the guidelines. Guidelines of both the US and Europe that are widely used that this is the new standard of care for these patients.

Matthew Cooperberg: We use that word game-changing a lot. It's for anyone that doesn't really know the history of this, the idea of manipulating hormones to treat prostate cancer literally goes back to a Nobel Prize awarded to Huggins and Hodges in the mid-twentieth century, back when castration orchiectomy was the treatment for men with advanced prostate cancer. The idea of using medications to achieve the same end goes back to the 1970s. Leuprolide, which is kind of the standard of care here, goes back to the 1990s. And literally for decades, this has been the standard of care for men with progressive disease. Used in combination, used earlier, later, intermittent, continuous, this is really the first time in over a quarter-century, probably about 30 years, that we see any alternative. And it really is a big deal. So huge congratulations to Dr. Freedland, Dr. Shore, and the whole team for getting this trial done and for getting the result out there. So we'll now pass it on to Dr. McKay, who was going to make some comments.

Rana McKay: Thank you so much. I do 100% concur that this is, in fact, a practice-changing trial. And I think it mirrors everything that we've seen with hormone therapy escalation across the continuum of prostate cancer. In every setting where we have taken individuals who have high-risk features around their disease, they have a rapid PSA doubling time, they've got high-volume metastatic disease, they've got localized high-risk disease. In every situation where the clinical features are such that the disease is behaving more aggressively, we've actually demonstrated that adding additional hormone therapy, more potent hormone therapy, actually improves outcomes for patients.

We've done it in the localized setting with abiraterone from STAMPEDE. We've done it in the metastatic setting with Abi and Apa and Enza and lots of drugs in the metastatic setting. And now for the first time, we're doing it in the BCR setting, the biochemically recurrent setting. And what's also unique about this trial, why I think it's a critically important study, is because it actually tested the role of ADT monotherapy or an ARSI monotherapy. And this is a critically important thing for patients because when you include ADT, when you include that backbone of Lupron, that's therapy that's going to decrease your testosterone levels.

And so the combination, anything that includes Lupron or degarelix, relugolix, those kinds of drugs, they are therapies that drop testosterone levels to very, very low levels. And what's unique about this trial is there was an arm of enzalutamide alone, without the injectables or drugs that drop testosterone, and that's non-castrating therapy. Castrate is a terrible word for us to use amongst this group, but in actuality, it raises testosterone. It doesn't drop because the testosterone that you have just doesn't work because of the blocker. And so we've actually also demonstrated, that for patients that are in this situation, they can actually get enzalutamide as a monotherapy. And when you compare that enzalutamide as a monotherapy, it's at least better than Lupron. Now, what the study did not do was compare the enzalutamide monotherapy compared to the enzalutamide plus Lupron. It did not do that. It didn't make that comparison. So we can't say one is better than the other, but at least compared to just the Lupron alone, it is actually in fact better. And I think this is critically important for patients.

I think as we move forward in designing trials in this setting, we need to do it in concert with patients to make sure that the trials are being designed with the endpoints that matter to patients. And what's also unique about this trial is, it kind of does the intermittent therapy strategy, and patients can go on therapy in an on-off fashion. And when you look back, there was a cohort analysis that was completed by the UCLA group that took an EMBARK-like population. Because this study was conducted before we had PSMA PET imaging that was widely available. And most of the patients that went on this trial didn't necessarily have a PSMA PET scan before they enrolled.

And so there was a study that was done out of UCLA that took patients who had the same eligibility criteria as EMBARK and looked at what their PSMA scans would've looked like. And in actuality, probably a large bulk of the patients that enrolled in EMBARK had some evidence of PSMA PET disease on their imaging. And I think that kind of brings up the question of how do we integrate with PSMA PET and other approaches, whether it be radiation or other strategies to kind of ablate disease that we see on a PSMA PET. So I think in summary, this trial is absolutely practice-changing. Not only do I think we demonstrate that we make people have improved oncologic outcomes, but we don't actually compromise their overall quality of life, which is huge. So happy to entertain questions from the group, yeah.

Matthew Cooperberg: We're going to dive into our questions. I'm going to hit you with one just because I see a sequence meeting on the wall behind you there. So should we be sequencing these cancers and are there some cancers biologically that we can select for combination therapy versus monotherapy? Are we at that point or are we heading in that direction?

Rana McKay: I definitely think we're at that point. I mean, certainly for people that have metastatic disease, it is absolutely in the guidelines that all patients with metastatic disease should undergo both germline and somatic tumor profiling. And germline testing should be undergone for those people that have high-risk localized or recurrent disease. And so I do think we need to be integrating sequencing. I think over the next few years, my hope is that we will move beyond just PARP inhibitors and the DNA repair pathway, which is the key focus of why to do tumor genetic testing and potentially use the information we learned from the genomic profiling to identify who should potentially get chemotherapy, who should get hormonal therapy. Maybe there are other drugs that are out there that haven't yet made it into the clinic that are targeted that need to be tested. Yes.

Matthew Cooperberg: Give us a quick 20 seconds on germline versus somatic. What are those terms?

Rana McKay: Absolutely. So germline testing refers to, what is the genetic makeup of your normal cells. So it actually doesn't even test the tumor. We just get a tube of blood and you have infection-fighting cells that are just circulating in your blood, and we just genomically profile the normal cells to see if you were born with something to predispose you to a cancer. Now, why would you want to get this done? There's four main reasons why you would get this done. One, it's prognostic. The information that we get can give us insights into how your cancer may behave. It's two, predictive. Meaning there are certain mutations that we know are vulnerable to certain kinds of therapies. For example, BRCA2 mutations are sensitive to PARP inhibitors. It can also help inform cascade testing for family members. So if you are positive, then considerations for testing for first-degree relatives.

And it can also help inform screening for other cancers in you as the patient. If somebody has a BRCA2 mutation that they were born with, then they may need to undergo screening for breast cancer or pancreatic cancer because those cancers can come on in somebody who's BRCA2 mutated. So it's not just about family testing, there are actually other reasons to do the test that directly impacts you as a patient, which is why you should do it. Somatic tumor profiling refers to the tumor. It's testing the actual tumor itself. It's not what you were born with, but rather what's in the tumor. And we can do that by testing the blood because the cancer cells can sometimes shed DNA into the bloodstream. We can also do that by testing tissue. Whether that be an old prostate biopsy or prostatectomy specimen or maybe a fresh biopsy that we're doing. And that's to help inform what's actually going on in the tumor itself.