Michael Cookson:  It is my pleasure to introduce to you, Dr. Neal Shore. Neal is a Urologist and Medical Director at the Carolina Urologic Research Center. He practices with Atlantic Urology Clinics in Myrtle Beach, South Carolina. Dr. Shore has been a prolific investigator and was the lead author on the HERO Phase 3 trial published in the New England Journal of Medicine. It's a delight to have him here today to present that data. Neal?

Neal Shore:  Well, thank you very much, Mike. And, of course, it was a pleasure to have you involved in the study and all of our members who were a part of the steering committee. I'm really proud to be able to have an opportunity to review the results of the HERO Phase 3 study, which was, relugolix, an oral GnRH receptor antagonist, versus leuprolide acetate, the three-month formulation for advanced prostate cancer patients. Yeah, we were all really happy and none of this work could have been done to get to the new England Journal presentation and publication without the dedication of so many investigators and the patients and their families.

Just quickly an overview, the incidence and burden of advanced prostate cancer. Well, it's the most commonly diagnosed cancer in the United States. Of note, the actual cardiovascular mortality is now a leading cause of death in patients with prostate cancer, as opposed to prostate cancer-specific mortality. And that changed at the very end of the last century, but it's really quite an important thing to consider, and we will talk more about that.

ADT testosterone suppression, historically we've used LHRH agonists, and what's of note, there is the counter-intuitive significant super physiologic increase in FSH and LH and the correlative increase in testosterone before you achieve suppression, which is the goal. And so there is this negative feedback loop. Mechanistically, antagonists have always had a more appealing direct suppression of FSH, LH, and direct and faster suppression of testosterone.

So, in the Phase 3 trial, as you see here, here's the study schema, a little over 900 patients. This was phase 3, it was global, it was open-label, and it was a parallel-group study. We looked at, having done two prior Phase 2 studies demonstrating the safety and the efficacy of relugolix, this was the phase 3 trial. And so patients received a loading dose of 3 tablets of relugolix, but then after that only 1 tablet per day, versus the 22.5 Q3 month injection. Now, in Japan and Taiwan, because of their regulatory approvals, and perhaps related to the BMI in that nation, they had a lower dose that was used. The primary endpoint was testosterone suppression at week 48 and all throughout continuous monitoring, and secondary endpoints included early castration at days 14, 15, castration levels below 20 nanograms per deciliter, and also PSA and FSH responses. We also looked at a subset of patients for testosterone recovery, and I'll show you that.

The eligibility criteria, the inclusion, about half the patients had biochemical or PSA relapse, and the other half was divided between those with metastatic disease and with advanced localized disease. Some of the other requirements on ADT, of course, everyone had to have eugonadal levels at baseline, really good performance statuses. And here are some of the exclusion criteria that you can read. Of note, we excluded patients who had significant cardiac conditions, specifically an MI or a stroke within 6 months, or significant arrhythmia or uncontrolled hypertension. And I'll get back to that later. It's an important point because the results of our cardiovascular profile and the differential in the arms, I think, is very compelling.

So the demographics between the relugolix once-daily oral generation antagonist versus the LHRH Q3 month agonist balanced regarding age, regarding racial differences, it was a global study, regarding the regions that we chose. Largely, a nice balance.

In terms of clinical characteristics, I mentioned earlier, was about almost 50% in each arm for the PSA biochemical relapse, about a quarter in each group of newly-diagnosed metastatic or a high-risk locally advanced disease. The baseline PSA's balanced, eugonadal levels of testosterone balanced. And interestingly, you can see here that a cardiovascular risk factor was present in both arms greater than 90%, and these included aspects of hypertension, dyslipidemia, diabetes, or a prior history of MI or cardiovascular disease, stroke, peripheral vascular disease. A history of MACE, particularly important, and this included myocardial infarction, the CNS hemorrhage cerebrovascular outcomes. Now, remember, I said, we excluded patients who have had a MACE within 6 months, and many studies, especially in developed countries, would suggest that the history of MACE is at least 30% or upward in our patients in consideration for ADT. But we excluded patients who'd had a MACE within 6 months.

Here's the primary endpoint, the sustained castration levels, and it's really important to see here that in the relugolix arm, it was above the lower bound of 90%. We achieved a 96.7% for T suppression throughout the entirety of the 48-week monitoring, 88.8% for the leuprolide arm. So we met the non-inferiority criteria, and because we had a difference, an intergroup difference, of 7.9, in other words, within the -10% differential, we could also claim superiority. So in the trial, we achieved, on the primary endpoint, non-inferiority, and the secondary endpoint, superiority, and T suppression.

Other important secondary endpoints were, as I mentioned earlier, and these were all alpha-protected, included PSA declines at day 15, the T suppression at day 15, as well as profound T suppression, as defined by less than 20 nanograms per deciliter, the cumulative probability of suppression, even at day 4, as well as mean FSH levels, all favoring the relugolix over the leuprolide arm with highly statistically significant p-values, as you can see here with less than 0.0001 

This was an interesting aspect that we looked at. A subset of patients for a testosterone recovery. If you look on the x-axis, the parallel lines as a truncation of the timeline. So week 17, all the way is, it's condensing it for purposes of scale. But at week 49 when patients had stopped testosterone, had stopped receiving either daily relugolix or the leuprolide Q3 month, we looked at 184 patients, 53% of the patients in the relugolix arm had achieved eugonadal levels of testosterone within 90 days, and only 3% of patients had achieved that in the leuprolide arm. So, one can certainly think about the importance of that as it relates to functionality and quality of life, the applications for patients on intermittent therapy for T suppression, patients who are receiving adjuvant therapy as regarding radiation strategies.

The AEs, as you can see on this slide, balanced in terms of totality, balanced in terms of grade 3 or higher. Of note, you'll see the fatal adverse events, approximately 3%, versus 1% difference between leuprolide and relugolix. I'm going to go, now, into what I think, after this slide, the really interesting findings on cardiovascular toxicity. But looking at the greater than 10% in any treatment group, you see balanced on the flush, the fatigue, which is well-described in T suppression. Constipation, diarrhea a little bit higher. Obviously, these are sort of obverse findings of GI symptoms, but of note, the diarrhea was primarily grade 1, 2, did not require any discontinuation of therapy, and essentially a relative balance between arthralgia and hypertension.

This is the aspect of the study that many had thought wanted to be really looked at in a prospective way in a Phase 3 manner. I'm very proud of these, that we were able to accomplish this because there has been this notion because all of the LHRH agonists, at least in the U.S. have an FDA labeled warning regarding cardiovascular toxicity. And so what we were able to demonstrate here, is that the patients on the relugolix arm versus leuprolide, in terms of adverse cardiovascular events, 3.9% versus 7.1%. And a MACE, as you see the definition here, a non-fatal MI, non-fatal stroke, or any all-cause mortality, an approximately 3% to 6% favoring relugolix as opposed to leuprolide.

If you break that down and you look at the patients who actually had a history of a MACE event, the odds ratio favoring the less likelihood for developing another MACE event is nearly 5 times less so with relugolix arm versus leuprolide. And even if there was no prior history of MACE, it's a 1.5 times likelihood of developing a MACE with the leuprolide arm versus relugolix.

Looking at the Kaplan-Meier curve here, you see a 54% reduction in the risk of a MACE, favoring the use of relugolix over the leuprolide arm. And the curves separate very early, and this has been pointed out to me as a very important, and potentially very significant, observation by some of our cardio-oncology colleagues.

So, in conclusion, I am really proud of the work that was done by all of the investigators and the patients and the families for the HERO trial. And we had the privilege of presenting this for the first time at ASCO 2020 this year, as well as AUA 2020. A 96.7% response rate for men with relugolix for T suppression and that was sustained over 48 weeks. A superiority over leuprolide in sustained castration rates, testosterone, and profound rates of suppression at day 15. T recovery within eugonadal normal levels following discontinuation, clearly favoring relugolix over the leuprolide arm. And, as it relates to safety and tolerability, a 54% decrease in the risk of a major adverse cardiovascular event compared to leuprolide. So, I'll conclude with that. Thank you very much and thank you for inviting me, Mike.