The HERO Study – Reviewing Major Adverse Cardiovascular Results - Bertrand Tombal

November 8, 2020

Contemporary Treatment Strategies For Androgen Deprivation Therapy In Prostate Cancer Lecture 
The HERO Study: Reviewing Major Adverse Cardiovascular Events (MACE) - Bertrand Tombal (12-minute lecture).

Independent Medical Education Initiative Supported by Myovant Sciences 


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. 

Michael Cookson, MD, MMHC, Professor, and Chairman, Department of Urology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma

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.

Read the Full Video Transcript

Alicia Morgans:  Hi, my name is Alicia Morgans and I am a GU medical oncologist and associate professor of medicine at Northwestern University. I am so pleased to have here with me today, Dr. Bertrand Tombal, who is a urologist in Brussels, Belgium. He is here to talk with us about some of the cardiovascular risks from a urologist's perspective of ADT in men with prostate cancer. Thank you so much, Dr. Tombal.

Bertrand Tombal:  Thank you. The pleasure is mine. Thank you for asking me to report on the cardiovascular result of the HERO relugolix trial. It's been waited for a long time.

Here is my conflict of interest. I've been interested in an HRH antagonist since the early 2000s. To me, it's like a top now with these new results.

I would like to entitle this based on George Orwell's, Animal Farm quotes, "All animals are equal, but some animals are more equal than others," because I really believe that this is what has been creating confusion around cardiovascular risk.

And what we have observed with the antagonist, is that clearly, and I'm so happy that we are going to speak with a cardiologist later on, are all ADT treatment men equal when vis-a-vis(with regard to) the risk of cardiovascular disease?

As you know, there are some very common mechanisms that we observe in everybody we put on hormone therapy. This is not new. This is a 2006 Matt Smith trial. Basically when you measure lean men's fat mass, actually what is happening is this. And you don't need to be a genius to know that the guy on the right is more at risk cardiovascularly speaking than the original one, David one.

And actually, there has been a lot of discussions. I'm sure we are going to address that with the cardiologist, with a colleague cardiologist, that there is an increase in the risk of diabetes, cardiovascular disease, even cardiac deaths with all forms of hormone therapy, except the anti-androgens.

But this is not what I want to speak about. What I want to speak about is actually what's happening in the subgroup of a patient who has preexisting coronary heart disease. Once again, this is not new. This is a prospective review by Anthony D'Amico in 2009 when they looked at a large number of men treated with brachytherapy plus neoadjuvant hormone therapy. And what is very important is that the hormone therapy duration is very short. It's the median duration of four months. We are not speaking about men on chronic ADT for years. We are speaking about men who are with localized disease, receiving six months of hormone therapy, three to six months, so a median of four months.

And actually, what Anthony shows is that if you have no comorbidities or one CV risk factor, such as hypertension, so basically in terms of all-cause mortality, there is no difference whether you receive hormone or not. But if you have non-coronary heart disease, there was a rapid increase in all-cause mortality happening between one year and two. Something that is happening rapidly in the subgroup of a patient, the group of patients who had previous cardiovascular disease.

Everything is going on, we are like in 2010, that's about the time the FDA and the cardiologists say, "Hey guys, be careful. If you put somebody on the hormone, you are going to have some change in the risk factor." They ask the company to change the inset package, to change the label. They say, "You should warn the physician." That's about the time that degarelix is hitting the market and the company was interested to see whether the cardiovascular side effect was similar between agonist and antagonist. And to be honest, this was actually requested by the FDA. It was not something that came out of the mind of the company of one of the regular advisors, including people you know very well like Neal Shore, like Fred Saad. We were a group of four or five. Actually, they gave the data to another urologist, Peter Albertson, and he asked his own statistician to look at a large group of patients, roughly 2,400 patients, included in six randomized trials, comparing degarelix to either goserelin or leuprolide.

In that study, that is where we started to define a CV event in a kind of a standard way. In that, the initial paper was an event of myocardial ischemia, coronary artery disease, myocardial infarction, cerebrovascular accident, angina pectoris, or coronary artery bypass at baseline. The first observation is that actually in all the degarelix trials, that was roughly 30% of the patients. That was quite a large group. And very interestingly, if you look at the probability of a CV, a cardiovascular event, or death in that subgroup of the patient, it was reduced by more than 50% with a hazard ratio of 0.44. So, everybody says, "Okay, that's the prospective data." Although this was prospectively acquired, one of the big problems is that the CV event was treated as a side effect and not an endpoint. I must say people didn't react quite seriously to this data.

So, then the second piece of evidence came in 2019, roughly seven years later with this very interesting Phase 2 from a guy in Tel Aviv, David Margel, who actually did a proper trial where he randomized in phase 2, 80 men with prostate cancer and preexisting cardiovascular disease. And they were randomized to receive GnRH-agonist or antagonist, relugolix for one year. You see the distribution of the preexisting cardiovascular disease, I guess that would be kind of typical for anybody working in cardiology. But what was very interesting, is the huge difference in the number of CV events in one year. Once again, that kind of concept of even with very rapid onset, something that is happening within one year. So 39, 41 patients, 13 cardiovascular events with the agonist, and only two with the antagonist. And when David looked at the major CV and cerebrovascular events, so MACCE, that include death, myocardial infarction, CVA, and heart catheterization, it was eight versus one. Evidence started building up and people, at least many people, especially in my country start to say, "Oh, we may have something here."

Then came the relugolix trial. Neal Shore and I were the PI's of that trial. When we started working with Myovant, which has the license for relugolix, we said, "Okay, that is interesting but we really would like that you focus also on having a proper evaluation of cardiovascular disease," because we want to be sure that we could eventually repeat what has been seen retrospectively in the relugolix program and by David Margel. This was a typical hormone therapy trial comparing relugolix, which is an oral antagonist, which is given at a loading dose of 360 grams and then 120 grams. And in the control arm, the standard control arm for such trial, which is leuprolide acetate three months [inaudible]. It randomized 934 patients with prostate cancer. And that is a classical primary endpoint of testosterone suppression. This is an absolutely typical disease all ADT drug has been developed.

Very briefly, the drug worked. It is actually suppressing testosterone very well. And interestingly, although it was not really what we expected because this is not really what FDA asked, the primary endpoint not only was met but clearly, relugolix can be called superior in terms of testosterone suppression. But once again, that is not what we are interested in.

So, we started to look in more detail at the adverse cardiovascular event. If you take the whole population, there is a roughly 50% difference between leuprolide and relugolix with 7.1% of the patients in the leuprolide experiencing a cardiovascular event versus 3.9. And actually 6.2 MACE and 2.9 MACE in the relugolix.

But this is a curve. This says the reduction over time. You see once again, something very similar that we saw in the degarelix Albertson data, a reduction of 0.46. And to me, that is something very interesting. It's all consistent, the hazard ratio is. It's always 0.40 something. That to me is really puzzling and making the data quite solid.

And more interestingly is the proportion of patients with MACE and the difference between relugolix and leuprolide because, indeed, in a patient who had a history of MACE, 17.8%, once again, one patient out of five, roughly in the leuprolide group will experience a MACE, and once again, I do insist on a one-year trial because it is the standard duration of this trial, with a hazard ratio of 5.8. In the group of the patients having no MACE, there is still a difference, but you see what is more important I would say is not necessarily the benefit of relugolix, but with the huge amount of patients, the huge proportion of patients who experience a major adverse cardiovascular event, once they have a history of MACE already. Clearly interesting.

Why? I will leave the cardiologist to discuss that. Actually, the short answer is, we have no idea. What we know is that there is a GnRH receptor in T-cells of atherosclerotic plaque, there is an FSH receptor. If you want to see the view of the urologist, you should read that nice paper by David Crawford. That is kind of [inaudible], but to be honest, we do not really have the final explanation.

Instead of making my own conclusion, I would like to read the conclusion of Tia Higano in the editorial of the New England Journal of Medicine, the result of the HERO trial that she said clearly, "To that end, it might be time to consider treating men who have pre-existing cardiovascular risk factor with a GnRH antagonist rather than an agonist even though no level one outcome data exists for the superiority of a GnRH antagonist over a GnRH agonist with respect to cardiovascular events or death from cardiovascular causes. The testosterone suppression data for GnRH antagonists are level one. Therefore it is likely that the anticancer effects of a GnRH antagonist will not be inferior to those of a GnRH agonist and may be beneficial in terms of cardiovascular events that may be life-limiting."

Thank you very much for listening to me.