Impact of Age on Efficacy and Safety of Relugolix in the Phase 3 HERO Study Versus Leuprolide in Men with Advanced Prostate Cancer - Fred Saad

June 16, 2021

The HERO study was a randomized, open-label, parallel-group study evaluating relugolix in men with advanced prostate cancer. Overall, 934 men with advanced prostate cancer underwent 2:1 randomization to receive relugolix 120 mg orally once daily after a single loading dose of 360 mg or leuprolide 3-month injections for 48 weeks. Subgroups analyzed by age were <65 years or ≥65 years and ≤75 years or >75 years. Assessments analyzed included: Sustained testosterone suppression to castrate levels (<50 ng/dL) from day 29 through 48 weeks, early and profound (<20 ng/dL) castration rates, PSA levels, and safety.  in this conversation with Charles Ryan, MD, Fred Saad, MD, FRCS, highlights a subset analysis reported from the phase 3 HERO study further characterizing the impact of relugolix across the age span in comparison to leuprolide in advanced prostate cancer presented at the ASCO 2021 Annual Meeting. The subgroups analyzed by age were <65 years or ≥65 years and ≤75 years or >75 years. Testosterone recovery (≥280 ng/dL) was also evaluated in 184 patients who enrolled in the testosterone recovery substudy. Dr. Saad highlights relugolix was not only non-inferior but instead superior to the analog in terms of sustained castration from day 29 up to week 48 and superior in terms of sustaining castration, achieving almost a five-fold reduction in the risk of subsequent major cardiac events in the patients on the antagonist relugolix versus leuprolide.  Relugolix is a first-in-class FDA-approved, oral, highly selective, GnRH receptor antagonist that is given once daily with an effective half-life of 25 hours for the treatment of adult men with advanced prostate cancer. In the phase 3 HERO study, relugolix demonstrated sustained testosterone suppression to castrate levels in 96.7% of men, superior to that of leuprolide, and a comparative 54% decrease in risk of major adverse cardiovascular events.


Fred Saad, MD, FRCS, Professor and Chief of Urology, Director of GU Oncology, Raymond Garneau Chair in Prostate Cancer, University of Montreal Hospital Centre (CHUM), Director, Prostate Cancer Research, Institut du cancer de Montréal/CRCHUM

Charles J. Ryan, MD. Medical oncologist and the B.J. Kennedy Chair in Clinical Medical Oncology at the University of Minnesota and Director of the Division of Hematology, Oncology, and Transplantation.

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Charles Ryan: Hello from ASCO 2021, Chuck Ryan here from the University of Minnesota. And I am joined today by Dr. Fred Saad, friend, and colleague, who is Head of Urology and the Medical Director of the Interdisciplinary Urologic Oncology Group at The University Hospital of Montreal, where he is also a Professor in the Department of Surgery and Director of Prostate Cancer Research at the Montreal Cancer Institute. Thank you for joining us, Fred. Good to see you.

Fred Saad: Good to see you again too.

Charles Ryan: So we're going to talk about abstract 5075, where the presenting author was Dr. Michael Cookson. And this is a subset analysis of the recent Relugolix HERO data, which looked at age and the impact of relugolix across the age span in comparing it to leuprolide. And tell us a little bit about this analysis. And I guess, before you do that, tell us a little bit about relugolix?

Fred Saad: Yeah, so relugolix was published last year in The New England Journal, based on the results of the analysis in comparing an oral antagonist to the standard of care, an injectable analog of LHRH. And the idea here was to at least show that it was non-inferior to what we are using as the standard of care, and maybe have an advantage of the antagonist properties that I think many of us are intrigued about. And so the study basically showed that it was not only non-inferior but actually superior to the analog in terms of sustained castration from day 29 up to week 48.

And much of this is because of the flare that happens with the analogs upfront. So it was actually superior in terms of sustaining castration and deep castration. But I think the reason it made it to The New England Journal was the results in terms of cardiac safety in the patients that came into the study. So basically, the patients who had a history of major cardiac events in the past, obviously, patients who had a major cardiac event within six months of coming into the study were ineligible.

Charles Ryan: Right.

Fred Saad: But there was almost a five-fold reduction in the risk of subsequent major cardiac events in the patients on the antagonist relugolix versus leuprolide.

Charles Ryan: Right. That is certainly important data and I think it is driving a lot of our rethinking the standard of care about how we do medical castration in a variety of settings. Relugolix in this context has the added advantage of having pretty rapid reversibility. Recovery of testosterone after completion of treatment looks to be a little bit better than with the leuprolide comparator. And that was the primary driver of this particular abstract presented here at ASCO 2021. And what types of differences were seen across the age span with regards to that recovery?

Fred Saad: Yeah. So obviously, I think we all recognize that when you castrate an elderly person, it takes them sometimes forever to recover their testosterone. And the inverse is often seen in younger patients. So overall in the first analysis, there was a very big difference. At 90 days, about half the patients recovered their testosterone in the relugolix group versus almost none in the leuprolide group by 90 days, when treated for 48 weeks, obviously. So here in the subgroups, patients that were under 65, about 80% actually recovered testosterone within 90 days versus about 17% with leuprolide.

Charles Ryan: So essentially, these results show that the rates of castration were pretty much the same regardless of age, as one might expect. But perhaps the greatest difference was noted in the recovery, testosterone recovery, 90 days or so after discontinuing. And that may be where there is a pretty distinctive advantage, especially when we layer in the cardiovascular risk.

Fred Saad: Yeah, absolutely. So we actually looked at different age groups. And patients below 65, where often they are very anxious to recover their testosterone when they don't need the effects of ADT, about 80% actually recovered within 90 days compared to about 17% with the leuprolide. So clearly, if you want testosterone to recover quickly, and which is often what we want when we stop ADT, there is a big difference in the young group, but also in the elderly. So in the 75-year-olds and older, just about 40% recovered within 90 days versus zero with leuprolide. [crosstalk 00:04:59]

Charles Ryan: It's speculation, I suppose, but that may drive some of the difference perhaps in long-term cardiovascular morbidity, if older patients have castrated levels of testosterone for longer, they're probably going to be at an increased risk for cardiovascular or cerebrovascular events. So when we consider this across a whole population of hundreds and thousands of men taking intermittent and hormonal therapy, or getting hormone therapy with radiation or something like that, we could see an impact on those outcomes perhaps. And that will be something that should be followed over time. Can you speak, just a little bit about how relugolix is being integrated into care and where these data might be driving the use of the drug either in Canada or elsewhere at this time? Or is it too early to know?

Fred Saad: I think it's still too early for Canada, but in the states, it looks like it's picking up quite a bit. I mean, I think a lot of us were intrigued by the data from antagonists but felt that the differences didn't justify the inconvenience of a monthly injection that was painful.

Charles Ryan: Right.

Fred Saad: And we've had patients develop some severe local reactions that asked us to stop this therapy.

Charles Ryan: Right.

Fred Saad: So I think we all looked for an alternative to what is presently available. So I think it's interesting.

Charles Ryan: Yeah. It is going to be interesting to see how it rolls out over the next year or two or three because what you do have is you do have the triad of efficacy, safety, and convenience, really, in many ways, all favoring relugolix over degarelix for sure, well, over the LHRH agonists, and perhaps even over degarelix with the monthly painful injection. [crosstalk 00:06:40] So it is a shift in our practice patterns, not having to schedule those injections.

Fred Saad: Yeah. But obviously, I mean, there are always the positives, but also I think we have to recognize the negatives. The negatives are if patients are not compliant, the half-life is relatively short. So you need to have patients compliant that are going to take their drugs. And even though I'm the co-PI of the study, I have to recognize that we still don't have a lot of safety data in combination. You led the abiraterone trials, there are a lot of things we use in late-stage disease that we still need to figure out the safety of combining these agents that go through the hepatic pathway, right?

Charles Ryan: Right.

Fred Saad: So there is still some work to do, but [crosstalk 00:07:23].

Charles Ryan: Yeah, for sure. Especially in the combinations of oral agents, I would agree with that entirely. But, and it is as you point out, important for us to know that our patients are getting the therapies we've prescribed for them. And when we actually see the needle go into the muscle, we know that it's there, but we do not know what happens when something reaches the medicine cabinet at their home. So agreed, a lot more to study, but at least it provides another option for our patients to think about. And I agree, we are seeing a pretty decent uptake of it here in the US.

Fred Saad: Yeah.

Charles Ryan: So all right, Fred. Well, great to see you. And we look forward to seeing you in person in the coming year, I hope. And thanks, as always for your insight into these important areas.

Fred Saad: Thanks a lot, Chuck, for having me.

Charles Ryan: Yeah.