Read the Full Video Transcript

Thomas Keane: Good morning or good afternoon, depending on where you are. This is Tom Keane coming to you from UroToday. It's been a while since we've been on. I hope everybody is doing well and surviving what is a very strange time, whether you live in Europe, or the United States, or anywhere in the world. This has been the first pandemic I think that has stretched to much of the whole world, but it certainly is an interesting time.

Today, I have a particular pleasure in welcoming Professor Bertrand Tombal. I've known him for a long time. He is a professor of physiology and the Chair of the Division of Urology at the Université Catholique de Louvain. Bertrand is well known throughout Europe and the United States, and in fact, in most places in the world. He is an expert on GU malignancies, particularly prostate cancer. He has a particular interest in the hormonal therapy and management of advanced prostate cancer.

He is a personal friend, he is a wonderful speaker, and I'm very grateful to him for coming on to UroToday again. Bertrand, welcome.

Bertrand Tombal: Thank you. We are here to speak about the antagonist, and something which is to me still a mystery is why we actually do not use all these agents that are actually great agents. Maybe some of you remember, we had abarelix that actually was not used for the long term because it was creating an allergic reaction. Then we had degarelix, which was really the first of its kind. Then we had relugolix, which actually is giving more than just being an antagonist, it is the first really oral androgen-deprivation therapy if you exclude estrogen or molecules such as cyproterone acetate, that we had in Europe. And the whole trial has been published very recently. I would like to go through some of the main results of this trial, and highlight which to me, I believe, is really game-changing and so important.

Actually, the first thing is that we are living in a world when we speak a lot about abiraterone, enzalutamide, chemotherapy, olaparib, and we have that impression that the number one indication for androgen-deprivation therapy is de novo metastatic prostate cancer. That's not true from the urological perspective. We use a lot of monotherapy in early disease, rising PSA, biochemical recurrence, patients with slow volume disease, neoadjuvant, short-term neoadjuvant, prior or after a range of therapy. So we use these treatments for a short period of time. And actually, if you look carefully, the proportion of patients for which your intention is to give a definite duration of androgen-deprivation therapy, and then to stop, exceed by far the number of patients you start with the intention to give it forever. So that is important. We have been doing a lot of intermittent androgen deprivation therapy. It has disappeared with all the modern trials because people forgot that it is a valuable option. So, that question of starting and stopping androgen-deprivation therapy is very important. It is actually very relevant to the development of relugolix, which is an oral agent.

Okay. So actually, the only difference between an agonist and an antagonist actually is in this figure, in figure B. Actually, it is very strange that, and that may be one of the last exceptions, that to induce a treatment, we first do the opposite of what the treatment is supposed to do. So the goal of androgen-deprivation therapy is to suppress testosterone wherewith the drug we use, these are agonists, they actually first stimulate the receptor, and then they suppress it. And that caused something which is called the testosterone surge. There has been so much discussion about it, is it really relevant? I personally believe that first, it is relevant, and the second is, why would you live with this anomaly where you can not have it?

So I always like to take the analogy that you are driving a car, you have a brand new car, and the guy says, "Once you hit the brake, it's going to first accelerate, and then it's going to break." He is telling you, "Okay, we know that is what's happening and there have not been many accidents. And in most of the case, it's irrelevant." Yeah, but that's happening.

So relugolix is an antagonist. So meaning that it does suppress testosterone immediately. It does it very well. Actually, we could even say that during the period of the study, which is one year, it did it better than leuprolide itself, because these are very effective agents to suppress testosterone.

And then, the second advantage, but it is not an advantage of the antagonist, it's an advantage of the pill. Meaning when you stop the treatment, your patient will recover normal testosterone much quicker than with any agonist on the market. Because usually, it's a euphemism to say, I'm going to give you six months of hormone therapy, when you know that in reality, it may be one or two years. So this is basically relugolix in a nutshell. It is an antagonist, so it does suppress testosterone very rapidly. It is actually even probably much better versus leuprolide. We know that it is a little bit similar to degarelix in a trial that was done in the UK, by the radiation oncologist. And we knew already that degarelix was actually, if you look at the statistics, better than the agonist in suppressing testosterone, but the difference now with the pill is the rapid recovery. So in terms of pharmacology, this is the purest molecule you can go, and you can have, to do androgen-deprivation therapy, it's immediate, it's profound and it is fully reversible.

Then the question is, what is the benefit? In terms of side effects, this actually may be to a quite significantly different profile, because actually, hormone therapy has a very, very large spectrum of side effects. One part of the spectrum is actually visible. These are the side effects of hot flashes, fatigue, diarrhea, hypertension, but these are actually very similar because this pertains essentially to the long-term suppression activity. So meaning, once you are suppressing testosterone, you are using something that looks like a metabolic syndrome. But then there is a subgroup of patients that is probably more exposed to the consequence of the agonist. These are the patients with previous cardiovascular disease.

And this is something I have been very interested in because there is basically a very large lack of knowledge of exactly what are the cardiovascular complications of androgen-deprivation therapy? Because basically, if you suppress testosterone in everybody, they are going to get fat. They are going to get hypertension, hypercholesterolemia. So you don't need to be a genius to know that down the line, they can get more cardiovascular events.

But there is a subgroup of patients who have unstable activity in which we now have a great deal of argument. Most of them coming from Canada, actually from Hamilton, Canada. Where they have shown that actually, that increased rise in testosterone in patients with pre-existing cardiovascular disease, can actually activate a cascade at the level of the [inaudible] plague and lead to a very important increase in cardiovascular events. And actually, that is not new. Most urologists do a lot of testosterone replacement therapy, and we all know the controversy around the potentially negative effect of testosterone supplementation in elderly patients. So this is not new, this is known.

And actually in that trial, because we wanted to answer that question, together with Neal Shore, we insisted with the formality, with the company, that we looked at the cardiovascular events, what we call MACE, major cardiovascular events, and we properly stratified patients with and without any study of MACE. And what we see here actually is that basically, in all situations, patients treated with an agonist or an antagonist and no cardiovascular history, there is a minimal impact for the long term. Although if you look down on the [inaudible], on the number, you see a doubling of the rate of a cardiovascular events in the population who have no history. This is something.

In Europe, we just stopped the AstraZeneca vaccine because there was a 0.05 increase in thrombosis, where here, everybody seems to be okay with doubling the rate of major cardiovascular events. But if you go to the group of patients with a previous history of MACE, then the difference is dramatic. It goes from 3.6% to 17.8% with relugolix. So we are increasing by six. And once again, the reaction after this is unbelievable. It is like, oh, are you sure these data are true? So it really looked like the vaccine, actually. There are still a lot of people who believe that the vaccine has been invented and it doesn't work at all. So we are speaking about, in my country where we like good food, good beer, we are speaking about 30% to 35% of the patients will have a previous history of cardiovascular disease. We are speaking about 1.1 patients out of five, receiving an agonist that will get a new major cardiovascular event, versus less than 5%. So to me, that difference alone justified the fact that we should abandon agonists in this patient.

Because that's not new. This has been shown with degarelix by Peter Albertson, the retrospective analysis, but from prospective data. And most of them, there is a beautiful study done in Tel-Aviv by a very nice guy, a very nice urologist named David Margel who did the beautiful phase III. And what is striking is that we've got exactly the same number, 20% of patients on an agonist who actually have a previous history of MACE and will have a new cardiovascular event.

And this is not new either. This has been shown 10 years ago by Nanda working with the microdata, where he showed that patients receiving four to six months of neoadjuvant and androgen-deprivation therapy before brachytherapy, at a 20% increase in the next two years.

So I think to me, to summarize, relugolix is really... I'm sure in 20 years from now, this is going to be quoted as one of the seminal trials, as the Bolla trial, the Messing trial, basically showing us two very important data.

The first one is that yes, cardiovascular history is important, and an agonist by a very predictable mechanism, which is a rise in testosterone, a rise in [inaudible], do destabilize cardiovascular status in patients at risk of. And the second is that the idea of having an injection, which is a depot injection, may I remind you, these are a depot that dissolves slowly in your body, versus a pill, is a bad idea. Because if you want to decide when you start and when you stop the treatment, the pill is the way to go. That would be my summary of that very, very nice trial.

Thomas Keane: Excellent. Thank you very much. Perhaps you could say something about the speed of recovery as well. Because there was quite a difference even against the antagonist, with the speed of the testosterone recovery, which again, I think is a huge benefit.

Bertrand Tombal: So once again, I remember that I was contacted by the Myovant people like five, six years ago. I remember very well. It was at ASCO in Chicago with Neal Shore, and a company came to us and said, "We have that pill." You know It's a pill, so why would you be interested? I told them, "It's so important." Because the way these molecules work is that actually, in some patients, a six months injection can get you castrated for two years. I've been working a lot with, in Europe, a molecule called Eligard^®, which is actually, a very nice depot formulation, but that is very good when you want to castrate somebody forever. So I'd say having something that recovers rapidly, me as a urologist, where I would say probably 50% of my indication of hormone therapy are patients I know I'm going to treat for a few months, it is so important.

When you're looking at figure C, you see, I mean, you don't even need to apply any statistics. I mean, most of the patients will recover, a very rapid recovery, within, I would say, one to two months. Where actually, with the leuprolide depot, you see that at three months, we are still very low, and most of the patients are still pretty well castrated.

And I think that is important because when we speak with our colleague medical oncologists, they have a different view on hormone therapy. Radiation oncologists and urologists, we do appreciate these drugs for the short term. So tomorrow, to me, a pill like this would be the perfect companion for the guy who was going to receive brachytherapy on the patient. More and more we do stereotactic radiation therapy for oligometastatic disease, where it seems that six months of hormone therapy is still so important. We have the data of the GETUG 16 trial, with the MFS presented at ASCO GU '19. Six months of hormone therapy is agreed upon, and the magical number for many patients. But you don't want this to be lifelong, so you want something that is [inaudible]. So to me, that speed of recovery is really a game-changing argument in favor of relugolix.

Thomas Keane: Excellent. What are your thoughts about what we call adequate testosterone suppression? There's been a lot of debate, but surprisingly, in the US and in Europe, it is still considered 50 as being there, and that's nanograms. We still consider it 50, but most of us now talk about profound testosterone suppression. I don't like that phrase at all, because I think anything that is going to be of any use should be able to get down to 20 and below. And I think it's been shown by [inaudible], and also by the Canadians, in their randomized control trial, that those patients who hover around 50 do considerably worse than those patients who get down to below 20 and stay there. What's your opinion? I think that is a message that we have been very poor in getting out to both the urological and medical oncology population, that people consider 50 fine, and it's not.

Bertrand Tombal: Actually, the 50 nanogram per deciliter is one of these numbers that came in urology because of an inherent limitation. Actually, this is the same. Why do we give six cycles of BCG to a person with bladder cancer? It's because when he did the trial, he only got six vials.

In the Bolla trial, why is it three years of hormone therapy? Because when Michel Bolla asked AstraZeneca, he asked for five years, because the guy was treating breast cancer, and they say, "No, we can give you 36 months."

Actually, the 50 comes to the fact that like 15 to 20 years ago, this was the low-level limit.

Thomas Keane: Lowest level. Yeah.

Bertrand Tombal: You could test testosterone measurement with a sensitivity that would be acceptable for [inaudible] bodies, [inaudible] didn't even exist at that time.

So we always use 50. But then actually, we started to realize that first of all, there could be a lot of variation. Okay? And the second is that those who have studied the importance of the level of suppression, tend to show at large that there is a trend, there is a relationship between the depth of the suppression and the duration of the response. Meaning that the deepest you go, the longest you are going to keep your PSA down. And to me, the best examples still remain [inaudible] analysis on the intermittent androgen-deprivation therapy trial. They've tried very recently to look at more, to another endpoint that was not so successful. But actually, once again, it makes sense to lower testosterone to the lowest level you want.

The second argument for me is actually all the knowledge we have gained in castration-resistant prostate cancer. And actually, if you think about a drug like, abiraterone, it's been developed on the basis that some patients produce, do have an [inaudible]. So these trials have actually shown us that a very low level of testosterone is enough to trigger activity in prostate cancer cells.

So that's why I think that once again if you put everything together, it seems that you should go as low as possible. And that is where actually if you look at regular administration... So I'm not necessarily speaking in terms of a clinical trial, when you do your injections, typically I've had 20 a day. But when you look at real-world evidence, that testosterone suppression is not that good in the real life. So we have to keep that.

Five or six years ago, we looked at the proportion of patients that were referred to our center for castration resistant prostate cancer, that actually were having only a PSA progression, because the suppression was not maintained very well, but that one was quite, it was close to 10 people. And interestingly, in these patients, if you switch agonist or antagonist, I don't, but anyway, you find a way to lower the testosterone more, the PSA goes down.

Thomas Keane: Yeah.

Bertrand Tombal: I think it's very important to keep the testosterone, and to measure the testosterone. I should note that most tests today are good up to low and 20, and that is why with actually [inaudible], we spoke with [inaudible], have shown that you had to go lower than 32 nanograms per deciliter. And that is why together with Astellas Pharma at that time, we did a series of analyses comparing 50 versus 20, and we showed that 20 was better. That is where it started actually.

Thomas Keane: That's something that a lot of people, when I lecture and talk to outside urologists, and you ask the question, how often do you check the PSA, frequently or every three or six months? And then the next question is, well, how often do you check the testosterone? And often it's well, we don't, we just, we presume that they are still castrated because they are still on the treatment. And that is a message that needs to get out to a lot of urologists. That I'm a medical oncologist, you need to be checking the testosterone levels, because in a lot of situations, there can be an escape that we don't recognize, and I think that has been a big problem.

Bertrand Tombal: When I teach residents, I've got that beautiful case of a guy, which has been on ADT for a certain period of time. He pops up, and he's actually coming with pain, and he's got an increase in one bone metastasis, and his PSA is rising. And I ask everybody, "What would you do?" And people say, zytiga, or xtandi, radiotherapy? And then I say, "No, no, we did this. We checked testosterone. Actually, the guy had testosterone like 200 nanograms per deciliter, so quite normal. And then I say, "What would you do?" And then, people do hesitate and I say, "Okay, we just switch." We switched the patient to goserelin, to triptorelin, if I remember well, it was a few years ago. And actually, I would probably switch to degarelix to get an immediate effect.

Actually, what's very interesting is that the patient, we saw an objective response in the bone metastasis and the pain goes away. So I'd say, "You probably have avoided thousands of [inaudible] of treatment that he is going to need someday. I fully agree. But, at this point in time, starting enza or abbi was not appropriate, you just had to switch the agonists.

Thomas Keane: Yeah. I think that is very important for urologists, and also for medical oncologists. It has always surprised me that, and maybe it's because the urologists tend to be the first people who treat these patients, but a lot of medical oncologists don't seem to realize the differences between agonists and antagonists, and they are not aware as well of the side effects.

Now it's becoming more prevalent. People are starting to talk about, have you a history of liver disease, have you a history of cardiac disease? People are beginning to realize what it is, that it is preventable, and I think this trial highlights that. I would hope that it is going to be taken up by both the urological and medical oncologic community. Everybody moves on to the newer agents, the abiraterone, and the enzalutamide, the new chemo, and the new order in which they are being given.

But in fact, we need to go back to basics and take a look and see, make sure that the very start of the treatment is appropriate, and that we have the patient in the right place, and that the progression is not coming because of a lack of control of testosterone. I think that is one of the most important things that this trial has shown.

So also when you, with the medical oncology population, do you feel that there is still a lack of understanding that the pre-existing conditions are not considered enough by people who are managing androgen-deprivation therapy in these patients?

Bertrand Tombal: Oh yes.

Thomas Keane: In my experience is that a lot of people have no idea of the side effect profile of ADT and the fact that you need to know. Like in this trial, in the HERO trial, anybody who has had a cardiovascular event within six months was excluded, but they didn't exclude people who had a longer history than that. Thankfully, because we did get the information that we needed.

But it's not alone in cardiac issues, as I've mentioned, it's also in liver disease. And we see that with Grace Lu-Yao's work. And we also, if you go back to Radu in 2010, again, in the New England Journal, I mean his paper, over 700 patients that he had prostate biopsies on, and he was able to show us the differences, or what is going on within the cells, in that paper. And that was something that mentioned the fact that FSH was not well controlled. And that FSH was at the leading edge of the tumors as they were growing. And that is where you want them, that VEGF was co-localized with those FSH receptors. So there is your disease that needs the power to invade, that is where it is coming from. And that paper was largely ignored. So I think FSH is perhaps one of the things that we did know very little about, and nobody seemed to care much. I don't think that's going to change.

Bertrand Tombal: Clearly, and that's very funny because David Crawford was speaking about FSH 20 years ago.

Thomas Keane: Yeah.

Bertrand Tombal: Everybody was making fun of it and now everybody has realized, oh, maybe he was right. So, that's so funny. And we have all these trials showing they, and everybody started to discover that beautiful medical oncology paper from the French group. And the thing that is very important in bone metastases and finally Radu, and you save it, come on. It's some views that I mean, nobody, everybody says, oh no, FSH rise, we don't care about it. And then, there are so many things. It's the same for bone protection and all of the... There are so many saying we did except for one reason, it's easy to make a shot of six months. That's so easy to do.

But the question is, I mean, okay, it's easy, but is it good for our patient? And the more I go, we don't even speak about [inaudible]. We tell the patient, "You're going to get a monthly injection." So what? It can be done by a nurse, it can be done by anybody. We even had patients or wives who were going to do it. That's so important when we see the potential benefit associated with it.

My problem is that people are always asking for more trials. Because suddenly, when they don't like somebody or something, they say, "Oh, no, we need more trials." But every time we do a trial, it's positive. So, when is it going to stop? When do we have to show more than that?

Honestly, to do a cardiovascular trial would be, at some point... We asked David Margen [inaudible] trial, where he took patients with previous cardiovascular disease, he randomized agonist versus antagonist. Then I said, "Could we do that trial in my center?" The answer was no. Because actually, the ethical committee said you cannot repeat, at this point in time, this phase II data is enough. When you have a difference going from 5% to 17% and now, you have two trials. I mean, it's starting to get really dangerous to expose another 1000 patients, just to be sure that there is an increased risk. Because the problem here is not in the antagonist, it's in the agonist. Why would you treat another 500 people and cause 100 more cardiovascular events so that everybody would be easy? I think that we can live with the theoretical doubt that these are trials that we are just not going to know the endpoint. That would not be acceptable to me to do a large cardiovascular trial.

Thomas Keane: Well, I had the pleasure of presenting to Professor Challis a couple of years ago, which was a presentation that made me extremely nervous when you are talking to a Nobel Laureate, and he's the guy who actually developed the agonist. But he was working on the antagonist, and he told me that you only need to change one amino acid to make an agonist. You have to change seven amino acids to make an antagonist. And that may be the reason that we've been waiting so long. And you're right, I mean, the abarelix, that had an escape rate, and that led to the degarelix being developed. And the extension trial proved that when you converted the patients over from the agonist to the antagonist, there was a benefit. And now finally we have this trial, which I think you are exactly correct. How much more evidence do we need before people will say, when you're starting ADT, it should be an antagonist?

Bertrand Tombal: I remember very well, the first time I showed the cardiovascular data, it was actually at ESMO. A very famous European medical oncologist, it was the only medical oncologist, 5,000 people, ballroom session, and the guy stood up and he said, "I don't understand why you guys still use an agonist." So, I mean, because that is so obvious. I barely use agonists myself. I use antagonists, or I am a big fan of antiandrogen monotherapy. In Europe with privilege, we still have bicalutamide 150 monotherapy. I think in the future, I know this will slowly be replaced by antagonists and by AR monotherapy in selected patients. That is my prediction for the next 10 years.

Thomas Keane: Well, I want to thank you very much for this conversation. The presentation speaks for itself, but I think the real value is in the conversation because then you get the fine points. I hope the people who listen to this will realize that we are getting this from a world expert. Professor Tombal, thank you very much for agreeing to do this.

Bertrand Tombal: Thank you, and you are welcome.

Thomas Keane: It's been a pleasure.

Bertrand Tombal: Thank you. Bye-bye.