Michael Cookson: Thank you very much, Dr. Shore, that was an excellent presentation. It is my pleasure to introduce my co-moderator, Dr. Alicia Morgans. She's a Medical Oncologist and Associate Professor of Medicine at Northwestern University's Feinberg School of Medicine and we're going to talk a little bit today about the HERO Trial.

Alicia Morgans: Great, thanks so much, Mike, and thank you so much, Neal, for such a really nice review of the HERO data, and congratulations to you and the team for getting that work done and giving us, potentially, another option for androgen deprivation. As you think about this data, there are several parts, I think, that are particularly compelling if I were in a patient's shoes, and one of those is the testosterone recovery after cessation of the treatment. Of course, the cardiovascular events as well. Can you dig a little bit into the testosterone recovery? Do you find that that's something that will be helpful to patients, and in what clinical settings might that be most useful?

Neal Shore: Yeah, no, thank you, Alicia. Yeah, some of our patients, as we all have seen, the T suppression is rather clinically and personally for patients, very debilitating. The level of fatigue, they can get around usually the hot flashes, we have various over the counter strategies and oral strategies, but the fatigue, clearly the loss of libido, and just generalized energy is, for some patients, remarkably debilitating. And so I think if you're doing an intermittent strategy if you believe that that's appropriate for the patient, or you're doing four to six months regarding an intermediate-risk patient receiving radiation treatment, or 12 months, 18 months, two years, for someone who's high risk, very high risk, or even arguably three-year strategy, depending upon the data you want to go behind, patients really look forward to getting back, even borderline elevated levels of testosterone.

In my experience, it makes a dramatic difference if somebody is, even if they don't return to completely eugonadal, but they're above the castrate level, there's just a little bit more energy in the tank. And so I think this is getting to be a really important appealing aspect to selection. And we actually saw this in two of our earlier phase 2 studies. So the on/off switch is quicker in terms of T recovery. I think it will be something that we can start off with patients and say, "Hey, I can stop this if you find this overly debilitating," and that sometimes is something we experience as well. But the problem with parenterals, whether it's IM, subcu, implant, is there's no pulling it back. There's no stopping it.

Alicia Morgans: Yeah, I completely agree with that. And just sort of to follow up on that, what are your thoughts about really relying on the patient to take a daily oral, again, if this is an approved medication in the future, versus having the ease of just using an injection? I know from my perspective, I like the patient to have that autonomy to be able to take medications. I see that in the advanced setting, patients are completely capable of taking pills. But everybody's a little different in how they interpret that and whether they feel comfortable really relying on the patient to take a daily oral. I'm just curious what your thoughts are?

Neal Shore: Yeah, I think that's important, and it's a fair question. But as we've all come to see, not only in GU oncology, and look at the great advances we've seen in CRPC therapies of oral oncologics or oncolytics that we're using, the AR pathway inhibitors, and how well they do, and these are oftentimes with or without food, more than one pill a day, and our patients are pretty compliant with them. And a lot of its education upfront. We see this oral agents in kidney cancer, we see a lot of other oral agents throughout the entire field of oncology.

So you're absolutely right. There may be some patients who have challenges in remembering to take pills. And this is where the combined patient, nurse, physician, education is important. There are some other interesting strategies. Of course, in our trial, there was 99% compliance in both arms. It's a trial. We expect to see that. There are some strategies to improve upon that.

Overall, one can really look at oral compliance and really inculcate on that. I don't really see that as a problem. You know, so many patients are taking a lot of polypharmacy strategies. Drug-drug interaction will always be important, that needs to be further established. But for one pill once a day, I mean, we see our patients do a lot better compliance with BID therapies and also multiple pills on a daily basis, especially when it's going to improve their survival.

Alicia Morgans: I agree, and just to further follow up on something that also might improve their survival. You mentioned the importance of cardiovascular disease in prostate cancer, which I think we've known about for a long time but didn't necessarily have a strategy to reduce other than addressing risk factors, which is absolutely critical. When we saw the data from the HERO trial and saw that the risk of cardiovascular events was lower in the relugolix arm as compared to the leuprolide arm, the first question that I got talking to colleagues was, "Well, how would that be possible? What do you think is actually driving that?" I'm just curious to hear your thoughts, as you think through this. I know you've thought about this, actually even before the trial launched, which is why you included this as something that you wanted to look into. Why do you think this is the case?

Neal Shore: Yeah. Super important question. There's been a lot of work that's been done on FSH, follicle-stimulating hormone, and its effect on cardiac myocytes in terms of plaque stability. That's one theory. But I don't know that we've completely delineated the exact etiology for this, but that's certainly an appealing notion and many have worked on that. At the end of the day, as I mentioned, there's the FDA labeled warning that was put in for all the LHRH agonists, but not for even degarelix, a parenteral antagonist. Some prior retrospective work done by Peter Albertsen and presented, a meta-analysis also showed a better safety signal on cardiovascular events with an antagonist degarelix versus the agonist.

A recent phase 2 paper out of Israel with about 80 patients also showed a similar odds ratio when one compared an LHRH agonist to degarelix. And then here we have our phase 3 trial which clearly demonstrates the improvement in cardiovascular toxicity. As I mentioned, that one potential mechanism of action, there may be others, and I think we look forward to, or I look forward to, some of our really astute colleagues on the preclinical and basic science aspect, getting better understanding of that cardiac attribution.

Alicia Morgans: I agree. And I'll send it over to Mike to ask you some more questions.

Michael Cookson: All right. Well, as we sort of wrap this up, Neal, the strengths of this study are pretty impressive and I would say quicker down T level, more sustained level, of testosterone suppression, faster rebound. Those are really good. You talked about the cardiovascular. What would you perceive as a weakness of this class medication and what are the barriers to adoption if it were to become available in the US?

Neal Shore: Well, first and foremost for me, I just think the cardiovascular enhanced safety profile is just why I would use this in preference to an LHRH agonist, kind of full stop. Having said that, barriers would be if someone had particular challenges in swallowing. This is a small pill, it's not a large capsule, and it's only one pill. So any sort of issues with dysphasia and swallowing. But those are extremely uncommon, particularly in one small pill.

The other thing that we need to look at in the data, we are looking at this, is further drug-drug interaction with other approved oral oncolytics. We have data that we'll be presenting fairly soon in combination with AR inhibitor such as enzalutamide, and we're working on additional trials and studies to demonstrate its safety with other concomitant medications. Short of that, and obviously the traditional concerns around accessibility vis-a-vis costs, would really be it. During the time of COVID, it's particularly appealing that one would not have to come in for injections and exposures to a clinic, and one could take a once daily pill at home.

Michael Cookson: Yeah. One of the things that I've noticed, and I'm sure you have over the years, is sometimes there is a slow uptick in change. This is going to be a major way of changing the role of the urologist in administering these therapies. Do you perceive any difficulties there, going from the traditional injections to these oral agents?

Neal Shore: Yeah, no, I think that's a fair question. I mean, we've been very comfortable as urologists and then medical oncologists and radiation oncologists, since the early eighties, using daily to monthly to three months to four months to six month parenteral agonists. So I understand that. And sometimes it's challenging to try new things, but to improve is to change, and to be perfect is to change often. That's a Churchill quote.

And sometimes it's not easy. We get very comfortable in these ways. But it's not just about going from a parenteral to an oral. Look at the other data, the suppression of T, the rapidity of that suppression, the PSA correlation, the recovery when you want to use it in those types of select patients. And most importantly to me, is the cardiovascular safety. So if you're going to use T suppression, regardless of the group, whether it's locally advanced, biochemical recurrence, or metastatic, that is kind of the selling point of most significance for me.

Michael Cookson: Well, thank you very much. On behalf of Dr. Morgans and myself, Neal, thank you very much for this excellent presentation and discussion on the really exciting results from the HERO Trial, and we look forward to further discussions down the road. Thanks a lot.

Neal Shore: Thank you.

Alicia Morgans: Thank you, Neal.