Relugolix in the Phase 3 HERO Study in Men with mHSPC - Bertrand Tombal

September 19, 2021

Alicia Morgans is joined by Bertrand Tombal who is highlighting two subgroup analyses from the phase III HERO trial reported at the 2021 European Society of Medical Oncology meeting. They discuss a subgroup analysis of the phase 3 HERO study assessing the efficacy and safety of relugolix versus leuprolide among men with advanced prostate cancer as well as a subgroup analysis assessing geographical efficacy and safety of relugolix versus leuprolide among men with advanced prostate cancer. Dr. Tombal presented both sets of data at this year's meeting. The phase III HERO study was designed to evaluate relugolix in men with advanced prostate cancer. Relugolix, the once-daily oral GnRH receptor antagonist, demonstrated suppression of testosterone to castrate levels in 96.7% of patients, and a 54% lower risk of major adverse cardiovascular events relative to leuprolide in the HERO study.


Bertrand Tombal, MD, PhD, Bertrand Tombal is Chairman of the Department of Surgery and Professor of Urology at the Université catholique de Louvain (UCL), Cliniques universitaires Saint-Luc, Brussels, Belgium

Alicia Morgans, MD, MPH Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts.

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Alicia Morgans: Hi, my name is Alicia Morgans and I'm GU Medical Oncologist at Dana-Farber Cancer Institute in Boston. I am so excited to have here with me today, Dr. Bertrand Tombal, who is a Professor and Chair of Urology at The Université Catholique de Louvain in Brussels, Belgium. Thank you so much for being here with me today, Dr. Tombal.

Bertrand Tombal: It's my pleasure. And by the way, you did it very well, Université Catholique de Louvain. Congratulations.

Alicia Morgans: Thank you very much. Thank you. So, Doctor Tombal, can you tell us a little bit about some of the data that you and the team presented at ESMO 2021. It was digging into subgroups who were treated within the HERO trial, which of course was a phase III trial that investigated the ability of relugolix to really lower testosterone levels. Can you tell us a little bit about what you did?

Bertrand Tombal: Interestingly, when the HERO trial was published, we had a lot of questions about... yeah, but you know you're pooling a lot of patients together, so, are you sure that it's actually working the same in every group, at every stage of the disease and then in every ethnicity you could dream of? Basically, the idea was to show that it suppressed testosterone and also PSA, and according to even the FDA and EMA rules, it's a good thing that we pooled a lot of different patients.

So, we did the analysis to reassure people that it is working, basically whenever you need hormone therapy and you start with normal testosterone. So, we did stratify the patients into three typical big groups you have today, which are the biochemical recurrence, which interestingly, is still a very prominent indication outside Europe. Maybe that in Europe, we tend to wait more and give metastatic-targeted therapy [inaudible 00:01:57] tanks of new imaging technology.

Then we had the metastatic patient and we had the locally advanced patient. And whatever parameter you look at, whether it's a proportion of patients with testosterone less than 50 or less than 20, so-called deep testosterone suppression, it's very similar.

And it's always interesting. It's always a little bit higher than in the leuprolide group. And what I like about the HERO trial is that it's a very, very simple trial. So, it's close to real-world evidence. So, you give these drugs to the patient and you see what their testosterone is doing. Then we did the same in another poster, by looking at a geographical area, Europe, Asia, South America, US only. And once again, no big difference.

That was an important question, and because we know that in terms of AR sensitivity, there may be some differences between Asians.  We know, for instance, that if you look at leuprolide... In Europe, I think in the US also, we use high-dose leuprolide. So the dose is twice the dose they use in Asia. So that question was relevant. So, I think that by doing that, now we can reassure everybody that whether you believe the patient is a good indication for an oral androgen deprivation therapy, the result will be extremely consistent from one group to another. And there is really no group where we can say, oh, in that group, leuprolide seems better.

No, in every single group it remained extremely fast, castration, and very sustainable castration. No big difference, either, in toxicity profile. We haven't done the complete in-detail analysis about the cardiovascular toxicity by all these groups, because then we get into low, low, low numbers. But there's not a big difference. And actually, the interesting part was cardiovascular in the US, because you know there have been other trials with drugs like [inaudible 00:04:13]. But once again, we see in the US a 50% reduction, not 53.8% versus a 7.2% reduction in the risk of cardiovascular disease. But we see that also in Europe and in Asia Pacific. So, clear, consistent, same toxicity profile, with that small benefit in terms of cardiovascular disease.

Alicia Morgans: I agree. I think it's really important because of course, we treat all kinds of patients in our practice. So, to be able to ensure that we can use drugs like relugolix regardless of whether the patient has a biochemical recurrence, locally advanced disease, metastatic disease, is absolutely critical. And of course, as we're increasingly seeing patients from around the world in our own areas and our own clinics, it's also important of course to ensure that any variations that might be occurring are really not. So, how does this affect your practice? Does it make you feel more confident that this is an option, regardless of patient type?

Bertrand Tombal: Oh, yeah. I think that the findings by EMA, if I'm right. like I said, in the urology clinic we have a lot of patients we don't want to give a lot of hormone therapy, because... I know that because of all the trials today, the debates around hormone therapy are driven to [inaudible 00:05:40], metastatic, high-risk, and things like that. But we as urologists, we see a lot of intermediate prostate cancer, a lot of minimal burden PSA [inaudible 00:05:51] recommends to which we want to give two, three months... three to six months of hormone therapy. So, we have a lot of patients where we really expect... we really have a benefit of an oral agent. So, on top of that, these are patients, if they don't tolerate ADT very well, that's not a drama if they have to stop it. I mean, you don't want this to happen to somebody with a high burden, a high volume metastatic disease.

You need to do everything to adapt. You do not want a guy to stop the treatment, but in a low volume and a situation where we don't know whether or not we should give hormone therapy, that drug will bring a very interesting option. Because we've got something that is fast, rapidly reversible. And then also another option that we are going to have to start to investigate is to do more rapid cycling of intermittent androgen deprivation therapy. So, these are ideas that people had for 20 years, but we never had the drug to do it. So, we hope that this drug will get better [inaudible 00:07:04]. Then we can start thinking about all these new hormone therapy strategies. And why not a more powerful combo with one of the AR antagonists? And I think it opens a whole new perspective that was not possible because we have these very long-acting [inaudible 00:07:24] depots.

Alicia Morgans: I agree. I think it's also important to have a drug where you can kind of predict more accurately when testosterone will recover for most patients. And having that occur relatively rapidly absolutely is important and much more convenient. And maybe not having the heterogeneity in terms of testosterone recovery with some of the prolonged recoveries that seem to happen with some of our GnRH agonists is helpful too. So, if you had to summarize this really important and interesting work, and thank you for taking the time, of course, for sharing your findings from your ESMO presentation, what would your summary be?

Bertrand Tombal: I would say that it really will comfort people, that the observation we have made with relugolix, the first oral antagonist with very promising aspect, we can confirm that its efficacy is totally independent on the stage of the disease and on the ethnicity of the patient. So, it should reassure everybody that it can be used broadly in a large number of situations.

Alicia Morgans: Great. So, thank you so much, again. Thank you to you, to your co-investigators, and of course, the patients who participated. We, as always, appreciate your expertise.