HERO Phase III Trial: Results Comparing Relugolix, an Oral GnRH Receptor Antagonist Vs. Leuprolide Acetate for Advanced Prostate Cancer - Neal Shore
• Relugolix achieved castration as early as Day 4 and demonstrated superiority over leuprolide in sustained testosterone suppression through 48 weeks
• Relugolix also had faster testosterone recovery after discontinuation and a 54% reduction in MACE
• Relugolix has the potential to become a new standard for testosterone suppression for patients with advanced prostate cancer serum testosterone suppression to castrate levels (< 50 ng/dL) through 48 weeks.
Neal Shore, MD, FACS, is the Medical Director of the Carolina Urologic Research Center. He practices with Atlantic Urology Clinics in Myrtle Beach, South Carolina
Alicia Morgans, MD, MPH Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.
Alicia Morgans: Hi, this is Alicia Morgans, GU medical oncologist and Associate Professor of Medicine at Northwestern University. I am so excited to have here with me today a friend and colleague, Dr. Neal Shore, who is the Director of the Carolina Urologic Research Center in Myrtle Beach. Wonderful to have you here with us today, Neal.
Neal Shore: Thanks, Alicia. Great to be with you.
Alicia Morgans: So I wanted to talk with you today about a really exciting virtual ASCO presentation that you gave with a simultaneous New England Journal of Medicine publication on the HERO trial, a Phase III trial looking at an oral GnRH antagonist. So Neal, can you tell us a little bit about why this study was done when we really had quite a robust set of options for androgen suppression in prostate cancer patients? Why did you feel that this was an important piece of work that needed to happen?
Neal Shore: Yeah, I really appreciate the question and the historical aspects of where we've been with testosterone suppression. And to be as concise as possible, yeah, everyone talks about the seminal work of Huggins and Hodges in the 40s. In 1966, they get a Nobel prize. The early 80s were able to formulate LHRH agonists. Challis had been working on an antagonist, but just was not from a pharmacokinetic and bioavailability aspect and a volume standpoint, able to create an antagonist. And so an agonist came into approval. The agonist started out as daily parenteral injections, went to monthly, three, four, six, and 12 months. And then it wasn't until 2009 that we saw the approval of degarelix, a monthly subcutaneous GnRH antagonist.
I started working on this oral molecule, oral delivery, once a day medication known as relugolix because it really became clear to me, a), an oral daily medication, obviously the simplicity and the attractiveness to many patients, but also it was an antagonist as opposed to an agonist. And there was a body of literature that was suggesting through our retrospective analysis, there's a nice paper by Albertson where we looked at six different comparator trials of agonist versus antagonist, which suggested an improvement or an avoidance in cardiovascular side effects. So that became very interesting to me. And in 2011, we saw a black box warning about the use of agonist therapy and the concerns regarding cardiovascular side effects. That on top of all the other things that we began to recognize. There's no free lunch when you suppress testosterone. So as I've been involved with, and I know you have too, ways to minimize side effects of testosterone suppression. So when we started doing this trial, that's what was really exciting to me. Could we demonstrate not only efficacy of the drug, but better safety and tolerability?
Alicia Morgans: I think that's a great reason to start a Phase III, which is what you ended up doing. Can you tell us a little bit about the trial design?
Neal Shore: Yeah. So the HERO trial was a multinational Phase III global study. It was an open-label parallel group. We had a two to one randomization, a little over 900 patients, and the patients really came from three buckets of advanced prostate cancer. They either had de novo metastatic hormone-sensitive prostate cancer, biochemical PSA relapse, or high-risk locally advanced prostate cancer and were deemed appropriate to be on testosterone suppression for at least a 48 week period. We randomized patients two to one. Patients received relugolix, a loading dose of three pills on the first day. And then after that, just 120 milligrams once daily with or without food. So satiety and feeding were not an issue versus leuprolide sub-q every three months. The primary endpoint was testosterone sustained suppression through the 48 week period, which is essentially the regulatory endpoint for all T-suppressive medications over the last few decades. But we also looked at some very important secondary endpoints, which I know we'll want to talk about, in addition to testosterone recovery. And of course safety, and specifically on cardiovascular effects.
Alicia Morgans: So what did you find for your primary endpoint? Was this medication, the relugolix, was it as effective as leuprolide in suppressing testosterone at that time point?
Neal Shore: Yeah. So our primary endpoint was a non-inferiority of sustained castration. And what we found was that relugolix achieved a sustained castration through the 48 week period in 96.7% of patients, as opposed to the leuprolide arm, which achieved it in 88.8% of patients. So because of that, we were able to look at the between group difference and a superiority threshold, if it met a non-inferior margin of negative 10% within that. And we did, it was 7.9%. So because of that, we're able to claim not only non-inferiority but also superiority. And the P-value was less than 0.0001.
Alicia Morgans: So that's incredible. Not necessarily what I would have expected. And so really important and interesting. One of the other endpoints, I know that you mentioned, and I know we have actually talked about this many times, is not just having T-suppression less than 50, but really having a more intensive androgen suppression so that testosterone would be even less than 20. Did you find that relugolix was able to get the testosterone down to even lower levels than that initial threshold of 50?
Neal Shore: Yeah. We looked at what some describe as profound testosterone suppression, meaning less than 20 nanograms per deciliter. And in the relugolix, by day 15, that profound castration was a little over 78% versus less than 1% in the leuprolide arm. And I think that that is very significant in terms of avoidance of clinical flair. And it still remains a point of controversy as to the inherent super physiologic surge that we see in all LHRH preparations, as well as the delay in lowering testosterone to what the ultimate suppression that you're trying to achieve to get clinical remission and even potentially avoid biologic progression.
Alicia Morgans: That's really important if the goal is ultimately, as we all know, to lower testosterone, that this was able to do it very quickly. So that's important and a great thing for patients. I also know that you looked at testosterone recovery because there are many times when we use androgen suppression or androgen deprivation therapies with a goal of having a discrete period of low testosterone, but then allowing patients to have recovery of their testosterone if they've had it maybe concurrent with radiation or as an intermittent therapy and biochemical recurrence, the goal is really to allow patients to recover their testosterone. When did you see this happening? Did patients recover their testosterone when the relugolix was stopped?
Neal Shore: Yeah. Well, we had seen an earlier signal that testosterone recovery in our Phase II studies was more rapid with the relugolix. And what we did in HERO, we took a subset of 184 patients through week 48, then they stopped either their relugolix arm or the leuprolide arm,184 patients. Fifty-four percent of the relugolix patients achieved a recovery T level of approximately 280 nanograms per ml. This is within eugonadal levels, whereas only 3% of patients in the leuprolide arm achieved a eugonadal level by day 90. And as you say, if you're treating patients with a limited, set time period with radiation or intermittent therapy, this is, I think, of tremendous clinical importance, subjective importance, to patient wellbeing.
Alicia Morgans: I completely agree. And I hope at some point, if you don't already have them, you'll have some patient-reported outcome data to tell us how patients feel in that recovery period, if they actually are starting to feel better when their testosterone recovers. It seems like they may. Is that something you'll look into in the future? Or do you have that information from this study?
Neal Shore: Yeah, we have a tremendous amount of data that we're going through. That certainly is extremely important, these patient-reported outcome data, which we'll further evaluate. We also, interestingly, have, as I mentioned, a third of our patients came from the metastatic de novo hormone-sensitive state. We're following those patients out, looking for the development in both arms of castration resistance. So we have a lot more to report. We're really excited to do so.
Alicia Morgans: That's great. Well, you mentioned earlier that a lot of the impetus behind this was, of course, ease for patients of taking an oral medication rather than the scheduled administration, but also the cardiovascular toxicity that we know is associated with GnRH agonists. And there's always been this question of whether that toxicity is not as great with an antagonist. We've not actually had data in a Phase III trial comparing these types of agents head-to-head to really answer that question. But I know you followed cardiovascular toxicity in this study. What did you find?
Neal Shore: So yeah, I really appreciate you bringing that up, and we've been doing so much more work now, so many of us who recognized the importance of cardio-oncology and its implications for adverse events for patients. And so what we found was we screened our patients at the beginning of the study to avoid patients being enrolled within a six month period if they'd had a major adverse cardiovascular event, which by definition is a non-fatal myocardial infarction or non-fatal stroke. But it looks to be, if you look at SEER population data and the typical types of patients, for example, in the US and other parts of the world, the MACE percentage population that gets started on ADT could be as high as 30% or even higher. We were about 14% in our study. But anyway, having said that, when we looked at the totality of our cardiovascular events, we saw adverse events of all types of 7.1% in the leuprolide arm versus 3.9% in the relugolix arm.
But of note, we had 6.2% MACE events in the leuprolide arm versus 2.9% events in the relugolix arm. So that's really rather dramatic. And if you looked at the patients in our 14% at baseline who had a MACE who received relugolix or received leuprolide, it's nearly a little more than a five times odds ratio enhancement in the leuprolide arm that they would have another MACE event. If they had not had a MACE event, still a one and a half time more likelihood in the leuprolide arm that they would have a MACE event. So the Kaplan-Meier that we presented at the ASCO presentation, and as well as in the New England article, demonstrates a 54% reduction in the risk of MACE events for the entirety of the study population.
Alicia Morgans: So that's really interesting and important. So a 54% lower risk of having those complications in those patients treated with the relugolix. So important for any patient who has a heart, which would be anybody. And also in an aging population of American men, where we know cardiovascular disease is actually a leading killer of many men with prostate cancer. Aside from prostate cancer itself, it is the leading cause of death. So that is really interesting and important and I look forward to hearing more.
The other comment I would make on that is that that's a relatively high rate of events in a single year of follow-ups. So it just really speaks to the fact that this is a high-risk population, even though these patients probably were a healthier population than we will see in the real world when we start using this agent, perhaps in the future or when we're treating our patients with whatever GnRH agonist or antagonist we choose to use. So a really, really important endpoint.
So as we think about this data, as you think about your presentation and your New England Journal article, do you have any final thoughts or summaries that you'd like to convey to listeners?
Neal Shore: Yeah. I'm really appreciative of all of the co-investigators and the coauthors, the steering committee and the support that we received globally. This is the first oral agent to suppress testosterone effectively. And it's an antagonist, so it goes right to the endpoint. There is no counter-intuitive surge. You obviate the risk of flare. I think because it's one pill once a day, it offers tremendous convenience. And now on top of what we were talking about, and very importantly, is our better understanding and the recognition of cardiovascular risks, which as you say, is tantamount to all aging men and women, but especially men with prostate cancer.
The other minor thing, but maybe it's not so minor, it's contemporaneous and topical, is in this era of the COVID pandemic, now patients can take a daily medical pill and don't necessarily have to be burdened by the worry of coming into a clinic and exposing themselves to the risks of infection during these very troubling times. And also reducing even the risk for the clinic health care team. So I think there's going to be a really great opportunity for discussion as to really how to optimize the use of this once-daily oral GnRH antagonist therapy.
Alicia Morgans: Well, I congratulate you and the team for doing some work to try to get another option to be available for patients for their androgen suppression. And I look forward to seeing if this ultimately becomes an FDA approved agent. But in the meantime, congratulations on the study, on the presentation, and on the paper. Thank you so much for your time.
Neal Shore: Thank you.