Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU medical oncologist and Associate Professor of Medicine at Northwestern University. I'm so thrilled and honored to have here with me today some good friends and colleagues to speak about the HERO data. First, we'll start with having my co-moderator, Dr. Mike Cookson introduce himself.

Michael Cookson: Thank you, Dr. Morgans. I'm Dr. Michael Cookson at the University of Oklahoma, I'm Professor and Chair there and work at the Stephenson Cancer Center.

Alicia Morgans: Great, thank you for being here. And, Dr. Saad?

Fred Saad: Hi, I'm Fred Saad, Professor and Chairman of Urology at the University of Montreal Hospital Center and Director of GU Oncology and it's a pleasure to be among my friends and colleagues.

Alicia Morgans: Wonderful. Thank you for being here. And finally, Dr. Shore.

Neal Shore: Hi, Neal Shore, I'm the Medical Director of Carolina Urologic Research Center in South Carolina, and a pleasure to be with all of you.

Alicia Morgans: Wonderful. So as we start a conversation about the HERO Phase III trial, Dr. Shore, I'm going to ask you to remind all of us about the trial design and the key findings from this study, please.

Neal Shore: Sure, my pleasure. So this was a Phase III, two to one randomization comparing once-daily relugolix, an oral GnRH, antagonist versus parenteral Q3 months LHRH agonist therapy, leuprolide. A little over 900 patients were enrolled in this global study. As I said, a two to one randomization, about half the patients had biochemical PSA relapse and the other half were divided between patients with locally advanced high-risk disease or metastatic disease. The primary endpoints of the trial were T suppression cumulatively through week 48.

We also had very hierarchical, alpha-protected secondary endpoints looking at testosterone suppression at day 4, day 15, day 30, and corollary PSA responses as well. And in a subset of about 184 patients who stopped treatment in both arms after 48 weeks, we looked at testosterone recovery. Additionally, we looked at the importance of adverse events and safety tolerability profile, and one of the more important aspects of this study and for me personally, the most important was the decrease in cardiovascular toxicity in the oral daily relugolix arm.

Alicia Morgans: Wonderful, thank you for just recapping that for us, and let's get into some discussion. Dr. Saad, we talked momentarily before we started filming about the cardiovascular risk differences. Not that relugolix reduces the risk of cardiovascular disease from baseline, but that it does seem to be associated with a lower risk of cardiovascular events as compared to leuprolide, a GnRH agonist. What do you find most compelling about this information related to cardiovascular risks? And do you think that this is going to be important or useful to you as you're making clinical choices with your patients?

Fred Saad: So I have to admit, so Neal and I have been involved with this drug for many years, from the Phase I, Phase II, and now the Phase III. I have to admit that I wasn't completely convinced there was such a big difference between an antagonist and an agonist. So I was really looking forward to seeing in a prospective randomized fashion in a large enough study, whether it really makes a difference. And again, I have to really admit, I did not expect to see this kind of difference in such a short amount of time. So I think this was really quite revealing for somebody like myself, that wasn't at all convinced that there was much of a difference. So within a year of exposure, and even within the first few months, we saw separation of the curves of these cardiac events.

Why that is happening is still a question, but something is going on, especially in patients with risk factors for cardiovascular events, prior to coming onto the study. So there is something with early introduction of castration and whether it's an agonist or an antagonist really does look like it's making a difference. So this I think was very important in how I'm now viewing patients. We still don't have access to this oral agent. I still have a lot of issues with injecting patients with a painful injection every month. So I have to admit I haven't changed, but clearly, we're looking forward to having this opportunity to have an oral agent that's easy to take, and it has all the advantages of an antagonist, without the disadvantage of what is actually available to date.

Michael Cookson: Yeah. One of the things that I thought was interesting about the study and I know when Dr. Shore presented the study, it was clear that they excluded patients, that might be our average patients, maybe up to 25, 30% of patients who come to our clinic, who have had a major recent cardiac event. And those patients were excluded in the trial and yet, there was this cardiac, protective difference that was clearly seen. So it's possible that in the real world, we'll see even more benefit than we saw in the trial. I don't know if Neal wants to comment on that.

Neal Shore: No, I completely agree with that point. It's a really good point. We excluded patients in HERO trial who had had any form of a MACE event within six months. And so we ended up with about 14% of patients in both arms at baseline and in reviewing the epidemiology of developed nations where we have higher BMI's and maybe not as good exercise and conditioning programs, smoking, et cetera, the cardiovascular risks are greater than 90%, and probably the MACE risk is north of 30%. So I completely agree with your point. And I like Fred's comment, his honesty saying he needed to see the data. Having gotten involved very early on with the GnRH antagonist programs of abarelix and then degarelix, this notion of early T suppression, the counter-intuitive use of LHRH agonist, where we see super physiologic rates initially of T and FSH and LH, never really made sense to me.

And then later on with degarelix, we saw in meta analyses, there was a suggestion that there was less cardiovascular toxicity. In a recent Phase II study published in Journal of Urology by Marc Güell and others, also demonstrated the benefit of the degarelix over LHRH agonists in terms of cardiovascular effects. As Fred really appropriately points out, these patients are still at risk, but less risk with the oral GnRH antagonist and the whole field of cardio-oncology, Alicia, that you've been championing for many years, so many other aspects. I think this is now an important aspect for us to further think about so that our patients don't end up dying of a cardiovascular event prior to their prostate disease evolving.

Michael Cookson: Yeah, I think that's an important thing. And Neal, I mean, I don't know what you feel when you look at urologists across the country. I personally have not done as good a job managing the cardiac risk factors or assessing for those, prior to institution of ADT. And I think these type of results give us a new opportunity, Fred can talk a little bit more about the bone health, but you think about sort of ABCs and bone and cardiac need to be kind of on our minds while we think about initiating therapy and as we begin the therapy.

Fred Saad: Yeah. And to add to that, I mean, Canada is very conservative in their approach. So if we feel a patient is at high risk of something else going on, we actually don't even treat them. So I think we suffer sometimes from undertreating patients who deserve treatment because we're so worried about the other events. So this is actually very reassuring that we can probably more adequately treat patients that need treatment, but where we were worried about these adverse events that could occur in a patient with cardiac issues, or bone health issues. And so it's nice to know that we can still treat patients and not be as worried as we would be with what we have available. So I think it's great news.

Alicia Morgans: It is great news. And as we think about integrating this drug and generally, regardless of relugolix, actually just dealing with cardiovascular risk in our patients, I think it's really helpful to have sort of a way, a playbook almost, of how do you talk to patients about this risk, especially if it's not something you've normally been addressing. Mike, how do you bring this up when you're speaking to patients in clinic and how do you advise your trainees to really try to successfully integrate this type of counseling and attention to cardiovascular health in the care of their men with prostate cancer?

Michael Cookson: Yeah, I think it's going to be very similar to sort of a men's health clinic. I mean, we really need to do a better job of assessing their entire risk portfolio, not just their cancer. Many men in our area don't even have primary care or maybe just got a primary care when they got their diagnosis. So COVID's made that even worse, where patients aren't even getting routine checkups, but I think that the next time we place patients initially on ADT if they haven't had an assessment of their overall weight or their lifestyle, risk factors, exercise, smoking, all that, in addition, lipid profile and even a hemoglobin A1C, probably part of the discussion as we initiate the therapy. And then again, Neal pointed out, not all us have cardiologists that are as in tune to the side effect profiles of the ADT. But I think the emerging field of cardio-oncology will become increasingly important in our multidisciplinary approach.

Neal Shore: Can I just make a comment? It's so nice to be on a panel today with my great friends, Fred and Mike, and you, of course, Alicia. But, I look back on the arc of my career, and here you have Fred Saad who really shined a light on the importance of bone health and really almost single-handedly changed the way urologists had to think about the importance of the effects of testosterone suppression on bone health and how we were just ignoring it. And then Mike Cookson who said he's not doing such a good job. I think he's doing an amazing job. He established the AUA CRPC guidelines.

And I think what I take home from all of this is that if you're in a part of the world in the US, rural, suburban, and you don't have good PCP primary care access, cardio-oncology, cardiology access, globally this is an issue. We as urologists, as medical-oncologists, we have to take greater ownership and understand it's not just about suppressing the T, it's thinking about the totality of the patient's adverse event profile. We have to do better. We are doing better, but I think when we get new therapies and hopefully, relugolix will be approved soon by the FDA, this'll give us additional thoughts on our overall scope of cardio-oncology, bone health, neuro-oncology. We'll all do better and patients will do better.

Fred Saad: Yeah. And if I can just add, this has been a real eye-opener, but, just going back to basics. I mean, just how low and how well we control testosterone. I think we have repeated evidence that that actually helps to control the disease and delay the appearance of castration resistance, which is, we've done great job with castration resistance, but the best we can do is actually to try to delay that state of the disease or avoid it altogether. And I think the importance of testosterone suppression, how quickly we do it, and how well we do it, needs to stay in our mind. And I think we've all tried to contribute on the importance of actually measuring testosterone. And I think the results here, I mean, the primary results was actually linking to testosterone, and that was also a surprise just to how effective, and not only being non-inferior but actually being superior. And the bonus in terms of cardiac, I think really sets a really nice story of the importance of this kind of treatment.

Michael Cookson: Neal, Fred, those are great points. And I don't know if we kind of rushed into some of the benefits of the cardioprotective, but Neal let's kind of talk about the main primary endpoint again because I'm not sure everyone out there, especially with the travel difficulties and virtual meetings and stuff, may be not even aware of the primary results in some of the quicker, faster, better, and recovery. Can you speak to that a little bit?

Neal Shore: Sure. Happy to. So the primary endpoint was the cumulative testosterone suppression over a 48 week period. And essentially we saw that achieved in a little less than 97% of the patients in the oral relugolix, one pill daily arm, and about 88% in the leuprolide arm. So just by that criteria, we achieved the primary endpoint of non-inferiority. Looking at the intergroup difference of a negative 10%, and we came in at about a little over 7% difference, allowed us to claim superiority on the cumulative testosterone suppression.

And then other alpha protected secondary endpoints in a hierarchical analysis, looking at profound T suppression within a 30-day period, meaning T levels less than 20 nanograms per deciliter, as opposed to the FDA measure of 50 nanograms per deciliter. In addition to the PSA declines, the PSA fifties, the PSA nineties, as well as FSH response, all were highly statistically significant favoring the relugolix arm over the leuprolide arm.

So this continues to tell that story, and we talked about it early. It's not entirely clear as to why you have a potential less cardiac toxicity with relugolix. Perhaps it's related to the diminution in FSH. Perhaps it's related to the early lack of super physiologic LH FSH surge, testosterone surge. But, the data are the data, as they say. And it's hard to have a full-throated conversation I think, moving forward in the patient-physician shared decision making, especially with patients who have cardiovascular risk and over 90% of our patients had a cardiovascular risk in both arms. No surprise. Obesity, dyslipidemia, hypertension, in addition to the roughly 15% who had MACE. So, I think this is really important. I hope you're right, Mike, with the pandemic and the lack of ability to attend conferences and talk to our colleagues who've actually been involved in the trials like yourself. And Fred, I really appreciate having the opportunity to be on the program today and have this educational moment.

Michael Cookson: I'm going to ask Dr. Saad because he went and said, "I'm in the land of intermittency," that recovery, faster recovery, after discontinuing the therapy. Tell me how you think that'll play a role in your clinical practice.

Fred Saad: Well clearly when we're doing intermittent therapy or when you're combining ADT for a fixed amount of time with radiation, the first question patients ask is, "When am I going to get rid of these adverse events, these side effects? When am I going to regain my sexual function? When am I going to regain my energy?" So I think this was a very important part of the trial, is just looking at how quickly testosterone recovers. And it's amazing the speed at which it recovers, which is mind-boggling because we have always accepted that it takes months and sometimes years, to recover with what we currently use as an agonist. And so seeing this rapid rise where the majority actually recovered within three months and many even recovered within a month, their testosterone, is something that's really important for patient quality of life. Even if they're not very sexually active, the fatigue that comes with ADT is something that patients really want to get rid of as quickly as possible and the hot flashes and all the rest, so very reassuring.

Neal Shore: Yeah. If it's okay, if I could just add to amplify Fred's point, he and I were both involved in two prior Phase II studies where we presented that data at both ESMO and at AUA in oral podium presentations. And we published one of our studies so far in European Urology. But looking at the testosterone recovery specifically in the HERO trial, we looked at 184 patients that stopped treatment in both arms at the end of week 48, and 53% of patients in the relugolix arm had returned to normal u-gonadal levels of testosterone within 90 days, as opposed to only 3% in the LHRH arm. And it was clear that if you see that, one would see the benefits potentially of improved energy, sexual drive, libido, perhaps some cognitive benefits as well. So I think for intermittent stage or intermittent utilization of T suppression or adjuvant strategies with radiation, this is remarkably a compelling aspect to discuss with patients.

Michael Cookson: Yeah. And you know how much of our ADT usage in the United States and in Canada is really directed towards that short interval therapy, so, that's great.

Alicia Morgans: Absolutely. So as we start to wind down, I would love for each of you to pick a main point, a take-home point for the listeners because we've gone through quite a number and they're all really interesting and thought-provoking. So why don't we start with you, Dr. Shore? What is your primary take-home message to the listeners?

Neal Shore: Well, I think that we hopefully will soon have approval in the US by the FDA and hopefully around the world, based upon the work that Fred and Mike and others have been involved with regarding this novel, once-daily pill, GnRH antagonist. This will give us additional options within our armamentarium, as we always fondly like to say. And it's not just about having a once-daily pill, it's about having a more effective mechanism of action. It's about having less risk for developing cardiovascular toxicity, and in those patients who want an earlier T recovery, we have data that supports that.

And then on top of that, I know you asked me for one, I'm going to give you two is, I really do think it's important now in 2020 that we as uro-oncologists, medical oncologists, radiation oncologists, we have to think of the totality of the patient and all aspects and variables and metrics of their healthcare journey, not just T suppression and PSA decline. And that will help patients do better, live a better quality of life, live longer, and most importantly, reduce healthcare resource utilization. And that's going to be a continued important aspect for our global healthcare economy.

Alicia Morgans: Wow. Well, thank you for that one or five points, Dr. Shore, that was great. Dr. Saad, what would your take-home message be?

Fred Saad: So Neal elegantly summarized basically everything, but if I have to limit it, what we're looking for is to reduce T very quickly, and when it's not necessary for T to recover very quickly. And that's what our patients need, and that's what our patients ask for. So this is addressing those very important questions. This is extremely rapid within hours. We're seeing T go down and very shortly after we stop, the T goes back up and the patients feel better. And the bonus is we're doing that very effectively, and patients are at a reduced risk, a very important cause of death. The most common cause of death in many of these patients is cardiovascular. So I think this is addressing both our issues, efficacy, and safety.

Alicia Morgans: Fantastic. And you Dr. Cookson, what do you think?

Michael Cookson: Well, it's hard to add much to that, but I think, from a simplistic standpoint, sort of the ABCs. We have an oral antagonist, that antagonist calls to mind advantages that have been well pointed out, but we need to focus on bone health as well as cardiac health, to really improve the overall survival of men, both from a cancer standpoint, as well as from the other threats to their health, as they go forward on the hopefully longer and extended treatments for men with advanced disease.

Alicia Morgans: Well, thank you. Well, as I think about it, this is absolutely phenomenal cancer control, which we can see is similar to what we've been doing, but may turn on a little faster, appears to turn off faster too, so we get that bonus. Plus we're keeping men safe in terms of reducing that elevation of cardiac risk that we see with the GnRH agonists. And ultimately our patients are asking us, have been asking us for years, take care of all of me. And I think that this gives us an opportunity to do that, and to continue to focus on the other aspects of men's health that are going to affect their day-to-day lives. And it's the right thing for us to do, to take care of all of these things, to really get the best outcomes for our patients. So thank you so much for chatting about this today. I really, really appreciate your time.

Michael Cookson: Thank you.