Alicia Morgans: Hi, my name is Alicia Morgans, and I'm a GU medical oncologist and Associate Professor of Medicine at Northwestern University in Chicago, in the United States. I'm so excited to talk with my colleague today, Dr. Charles Ryan, who is a Professor of Medicine and the Director of Hematology, Oncology, and Transplantation, at the University of Minnesota. Dr. Ryan and I are going to speak today about the recent approval of the oral GnRH antagonist, relugolix. Hi, Dr. Ryan, thank you for joining me.

Charles Ryan: Hello, Dr. Morgans. It's great to be here.

Alicia Morgans: Wonderful. So I wanted to get your impression, first thoughts, on this FDA approval, which we know was based on the Phase III trial, the HERO study. What are your first thoughts on this first oral GnRH antagonist?

Charles Ryan: Sure. You've already mentioned the one big aspect of this which is that this is an oral GnRH antagonist, which makes it different from leuprolide and goserelin, on a couple of different levels. I think it's exciting for a few reasons. One is, it's an opportunity for patients to be treated by a means other than coming into their physician's office for an injection every month or every three months. So that may be advantageous in terms of practice patterns and patient convenience. And I suspect there are going to be many patients out there who are going to prefer an oral therapy, because of the convenience aspect of things.

I also think that the fact that it's another GnRH antagonist is advantageous. And we can talk a little bit about the HERO study, which looked at a subset of patients who have a history of major cardiac events in their past, and that this may be an advantage for those patients as well. I think that this is a pretty significant breakthrough, in terms of practice patterns, and the way that we deliver androgen deprivation therapy in prostate cancer.

Alicia Morgans: Great. Yeah, I would agree. Well, now that you mentioned it, let's dig into the HERO data a little bit. So one thing I found really compelling about that data was that there seemed to be really nice testosterone suppression with this oral agent. Which I think was the primary endpoint of the study, certainly, and is one of the main drivers, I'm sure, for the FDA approval. But one of the things that you alluded to that I think was also really important is that patients seemed to have a lower chance of having a major adverse cardiovascular event when treated with relugolix, as compared to leuprolide. And that comparison, I think, was most exaggerated, or most clear, in those patients who had had a cardiovascular event in their past.

Now, I would say that patients who had major cardiovascular events within the six months prior to the trial initiation, were actually excluded from the trial. So it wasn't, that population may be a higher risk population, was not included. But for patients who had a past history of any cardiovascular event, there was a very clear and pronounced signal there. Does that affect you as you think about prescribing medications in the prostate cancer population?

Charles Ryan: Increasingly, it does. I think that the evidence has been mounting for many years. It continues to approach definitive status, with regards to the link between androgen deprivation therapy and cardiovascular events. So I think a therapy that is equivalent in terms of its ability to induce castration at a sustained level but may even have a hint at improving cardiovascular outcomes is going to be something that I'm going to give some serious thought to, in particular, in patients with a history of cardiac events.

Alicia Morgans: Yeah, I think me too. Because when I think about this population, which as we all know, is usually an older adult population, these men have really such a competing risk between cardiovascular events and prostate cancer, in terms of the most common cause of mortality in this population. So from my perspective, it's always going to be important, but particularly in those patients who I know have had cardiovascular events in the past. And it's interesting and consistent with data that we've seen from degarelix, though there hasn't been a Phase III prospective trial of degarelix really digging into the cardiovascular events. But at least on the smaller Phase II and other data, it's consistent. And so, it seems to be something that is important for the class, and thus important for patients, and certainly as I think about using these agents.

One of the other things that was really interesting about the HERO trial that I wanted to hear your thoughts on, was that there seemed to be a relatively rapid and consistent recovery of testosterone for those patients who were followed and then discontinued their treatment, either with leuprolide or relugolix. It seemed to be significantly faster than those patients who were treated with leuprolide, and I thought that was interesting. What do you think about that particular issue?

Charles Ryan: Yeah, so it is. And I think this is the third potential advantage beyond the oral availability, the fact that it's a GnRH antagonist. The third advantage is that people do recover more rapidly. I'm sure you've seen it. Right? Especially older patients, you put them on a GnRH agonist, and three, six, nine months after completing two years of hormonal therapy or something, they're still in the castrate range.

In the HERO study, what was interesting is, the primary endpoint of the study was testosterone suppression at 48 weeks. In the study, when they looked at the relugolix arm at 53 weeks, so four weeks after stopping the drug, the majority of them, the median testosterone levels had already risen to almost 200, from below 50. And the LHRH, the leuprolide arm, was still well below 50.

So I think that that's going to be important for a couple of reasons, quality of life, potentially the ability for us to analyze data on the efficacy of ADT across various settings in future clinical trials, but really it's going to be quality of life. And to the extent that this protection from cardiovascular events is real, that might even improve further the long-term cardiovascular output of patients. In other words, if the cardiovascular situation is due to the low testosterone, and the recovery from the low testosterone is faster, there's a possibility that we could see fewer longer-term cardiac events.

Alicia Morgans: Yeah. And I think to that point, there's still a lot of work to do, I think, in understanding whether this is really just a reduction of events as compared to leuprolide, or whether there's truly protection against cardiovascular events, and how testosterone levels, and other hormones, might come into play. So I think there's a lot more for us to understand. And certainly, as physicians and biologists, we always want to dig into those details. So a lot more for us to learn, but in the short term, I do think that that's a really positive and hopeful thing for patients, that they can have control over their medications, not having to go to the clinic to get injections on that regular basis, they can have maybe a lower rate of cardiovascular events, at least as compared to the GnRH agonist leuprolide. And certainly, then they can have this recovery of testosterone if it is the goal to discontinue therapy that we believe and see in the HERO trial, that there was a faster recovery. So, all positives.

I would just ask one more question of you, as a clinician who's taken care of many hundreds of men with this disease. Are you confident that men can take an oral agent and be reliable with that? And I'd love to hear your thoughts. I certainly have my own, but what do you think?

Charles Ryan: Yeah, I think that's a great question and a natural one in this setting. There have been some challenges to oral therapies in other contexts. I guess I would respond by saying we've become pretty adept at giving oral therapy in prostate cancer. Right? We're giving enzalutamide and abiraterone and other therapies, apalutamide, over a long-term basis. We trust our patients are taking them, and things like that. The barriers to oral therapy adherence can be many fold. People can forget, people can have adverse events or side effects, and just decide to skip doses here and there. Then things like copays have been shown to impact adherence to breast cancer regimens.

But, I think we've gotten over a lot of those barriers, but I think it's more of a reminder to those of us in the clinic that we need to talk to our patients about things, any problems taking these therapies that we should know about. And, it should be part of our discourse with them in the clinic visit.

It is worth noting that in the HERO study, some of the adverse events that did pop up, that are GI-related, constipation and diarrhea, for example, were slightly more common in the relugolix arm than they were in the leuprolide arm. But even though there was some evidence of diarrhea, that was pretty rare. There were not any cases of treatment discontinuation due to GI side effects. So I think that it's unlikely that a patient would have adverse events and stop taking this oral therapy. And I think it is a net positive for the field.

Alicia Morgans: I completely agree. And I think that it's important for us, as physicians, to really be aware of patient autonomy, and to give them the opportunity to take, or not take, their drug. That's not to say we want anyone to be untreated, but with the more rapid testosterone recovery, we can do a testosterone level and we can see, hey, it looks like his level is much higher than I would expect. Instead of being under 50, maybe it's 65. And then that's an opportunity for us, as physicians, to have a conversation with that individual, and ask exactly the questions that you've mentioned.

But, I think men with prostate cancer have been taking pills, even before abiraterone and enzalutamide, which they take really well, all the way back when they were taking nilutamide, and flutamide, and bicalutamide, which sometimes people still are using. And oral agents can be things that patients are very, very capable of taking. So, I have every confidence in our patients, and I really do look forward to using this agent.

Charles Ryan: There's a couple of nuances in the approval. Sorry to interrupt, but about this point, which is, it comes in 120 milligram tablets. And the dose is 120 milligrams once daily, after a loading dose of 360 on the first day. So basically, it's one pill. And if you think about a patient who's taking abiraterone, who'd be taking four pills, plus two of prednisone, he's already taking six pills. And so, it's a pretty small pill load, on top of what they might also be taking. Just thought I'd put that out there.

Alicia Morgans: That's a great point. We'll have to have another conversation, because this one is drawing on, about how this might be especially useful in patients who are taking combinations with abiraterone and enzalutamide. There is some signal that maybe those agents do have some increased risk of cardiovascular effects just on their own. And so, perhaps these different combinations will give us the ability to deliver all of these therapies, whether they're for mCRPC, or otherwise, in a safer way. So other final thoughts that you have to add, Dr. Ryan?

Charles Ryan: No, I would hope that those studies are being done, on cardiovascular effects in combination with abiraterone, et cetera. The label, by the way, is not limited to any stage of this disease. It's a pretty broad label for the treatment of adult patients with advanced prostate cancer. So we could expect, or we should expect, that there will be patients taking this with chemotherapy, with abiraterone, et cetera. I think it's a real opportunity for the type of research that you do, looking at quality of life and adverse events, and hopefully, moving that field forward, and demonstrating an overall benefit, in terms of not just efficacy, but also quality of life, and other factors for these men.

Alicia Morgans: Fantastic. Well, I appreciate you taking the time today, and I think we're all excited about this new approval. Just another option for men with prostate cancer, any advance is a good one, in my book. So thank you for your time today, and I look forward to using this drug in the clinic.

Charles Ryan: And you, always a pleasure.