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Dr. Alicia Morgans: I'm delighted to have with me here, Dr. Tom Keane, who is the professor and chairman of Urology at the Medical University of South Carolina in Charleston. Thank you for being with us today.

Dr. Tom Keane: Thank you very much, Alicia. It's a pleasure to be here.

Dr. Alicia Morgans: Great. Well, I wanted to talk to you and really pick your brain about ADT, but particularly GnRH antagonist therapy. I know that you have been involved with a lot of the studies that have looked at degarelix and its development, and I'm particularly curious about new findings in the cardiovascular world and wondering what you might be able to share with us about that today.

Dr. Tom Keane: Yes, well, thank you for that question. I think cardiovascular disease is an unrecognized risk. Well, it is presently recognized, but for a large number of years, it was not recognized. It's one of the main reasons I think that you need to assess the patients very carefully when you're going to put them on ADT.

It's very similar to fractures, if you like, in the way that we only really found out about fractures and ADT in the early '90s. Prior to that, if you mentioned it, people would look at you and say, "We've never seen that." And it's the same thing with cardiovascular disease. If you have 40 or 50 patients in your practice, you're probably not going to see a whole lot of problems because it is only roughly 2 or 3% of the patients who might have these problems.  Certainly, as we look at the death rates, they are significantly different between the antagonists and the other forms of ADT, which would be orchiectomy or the agonists.

So, when we put it all together, you need large numbers. Most of them are observational studies, and another question that's asked quite frequently is, "Well, why don't the randomized control trials show any difference?" Well, that's because they're randomized control trials, and in a lot of situations, they've corrected for cardiovascular disease. 

If we look at the two drugs, they're fundamentally different. If you're on an agonist, it only takes one change in the amino acid to make an agonist. You need to change seven amino acids to make an antagonist. But even more than that, when you're going to put a patient on ADT, you need to take a look at the patient and see how healthy they are because the sicker you are and the more complications that you have, the less well you're going to tolerate any of the treatments.

Now, with degarelix, there are some difficulties with degarelix, which people know about. Injection site reactions are 35%, 34% when they're on the first injection. That drops down to about 4% on patients on repeat doses.  But when we look at how frequently it's given, it's once every 28 days as opposed to a three-month or a four-month or even a six-month dose.

The issue is FSH; I believe it to be anyway. If you look at patients who have preexisting cardiovascular disease, there's only one head-to-head study, and that was the study which led to the approval of degarelix as an agent for advanced prostate cancer. It was compared to an agonist, and during the study there were differences noted, both in the ... Well, we all know it takes two to three days to render a patient castrate on an antagonist. It takes approximately a month on an agonist.

But when people looked at the cardiovascular side effects, there was a significant difference between the two groups. And it was highly significant, and this is by a paper by Albertson, et al, which was an overall 8% difference, which again, when you looked at the number of patients involved, there are thousands of patients who go on ADT on a regular basis, and most patients do not have a cardiac assessment performed. 

Now, Circulation published an article in 2017 which was a guideline for an ABCDE of what to do with a patient before you put them on hormonal therapy. Then, I've often heard the question asked, "Well, if it's FSH, if the patient undergoes an orchiectomy, one would expect the FSH to be very high, certainly initially. And would that not lead to more deaths for patients who are having orchiectomy as opposed to agonists?" And again, there was no data until just recently, and I think it was 2017 or early 2018. There was an article, again, published in JCO I think, which confirmed that the highest death rate is seen in patients who are actually having an orchiectomy, in terms of cardiovascular complications.

Now, what can we do to lessen it? Well, we take an accurate history. We can certainly control the cardiovascular disease beforehand. Or we can watch very carefully for and make sure that if the patient has any signs or is showing any signs, if they are on an agonist, they should be switched to an antagonist, which leads me back to what I was talking about earlier, the randomized control trial which established degarelix as the main agent or the main antagonist.  That was a non-inferiority trial.

So as such, you can't really comment about whether or not one agent was better than the other. Both managed to produce a testosterone level of 50 or less. Now, again, 50 is an old value. Most oncology people would fully recognize the fact that you want to be 20 or below to have full castration, if you like. The data from Moretti. There's also data from Perachino and the results of the Canadian data which was 6-700 patients which showed all of these were patients who were on ADT for at least six months and more in most cases. And it quite clearly showed that if you reached a castration level between 50 and 35, you did worse than if you reached a level between 35 and 20. And the group who did best in terms of survival were those patients who got down below 20.  So, I think the jury's in on level of testosterone and castration. The lower you can go, the better.

So, getting back to the CS21 Study, there was at the end of one year ... It was a one-year study, and the reason it was a one-year study was because abarelix had a 20 to 25% escape rate at one year, and the FDA quite rightly wanted to make sure the same thing wasn't going to happen with degarelix.

So, at the end of one year they looked at the data, and they found the event rate in terms of PSA progression was significantly different between the agonist and the antagonist. There was an event rate of 0.22 for patients on the agonist, and it was 0.08 for patients who were on the antagonist. Then the FDA mandated that everybody should be put on an antagonist because, again, they wanted to get large numbers.

So that led to a crossover of the patients who had been on the agonist. They were then put on the antagonist. And in that group, the event rate, which had been 0.22, went down to 0.1, which was roughly the same as the patients who were failing the antagonist. We did see a difference in survival, but because that was not part of the study, they could not claim that degarelix was superior.

So, when I look at a patient and I'm trying to decide what do I put them on, again, I look in terms of how big are they. In other words, are they overweight or are they normal weight? Because ADT does induce obesity, and it's a different type of metabolic syndrome. Everybody recognizes now there is a metabolic syndrome, andropause, it's called by some, but there is a definite difference when you compare the metabolic syndrome caused by ADT when you compare it to the standard metabolic syndrome.

There's a difference in adiponectin. There's a difference in C-reactive proteins. There's also, as I mentioned earlier, FSH control is different. And by that, I mean the lower the FSH levels, the better. Why is that important? There's data from Radu, et al, which was published in the New England Journal of Medicine in 2010, and basically, they looked at FSH levels in metastatic prostate cancer. They found that FSH is up-regulated, then they did a study to look at the new vessel formation and the FSH receptors and where they were most active, and they found that they were co-localized together.

So, in other words, the FSH is exactly where the neovascularity is developing, and that's exactly where you need to be if you're going to be a metastatic deposit and you're going to grow. You want to be at the leading edge of the cancer. They showed that that's true, at least in the animal models that they looked at.

And again, when we look at people themselves, when we go back and we look at our patients, we also see that the patients who benefited most from the antagonist were the patients who had the higher volume metastatic disease, were the patients who had the highest PSA. And that led us then to finally take a look and see, well, should we be considering early treatment for some patients with advanced metastatic disease in combination with something else? And everybody saw the CHAARTED study, and they looked at it and said, "Okay, this is very interesting data." And my thought was, how would it have been if there had been an antagonist rather than an agonist being used at that time?

There's also something else very interesting about giving chemotherapy upfront with ADT. You've still, even when you're castrate-sensitive, if you are on ADT and your testosterone is low, you are not going to take in as much degarelix. In other words, the pharmacokinetics are completely different in a castrate patient than they are in a non-castrate patient, and that has led us now to develop a trial which we're currently ... It's a phase two trial. We're looking for 50 patients. I think we have 15 or 16 now accrued, with high volume metastatic disease, or at least metastatic disease. 

They're now starting on four cycles of docetaxel, then they're being castrated, and then they do two more, the theory being that the toxicity we know in the GETUG-15 study was significantly greater than even in the TAX 327 or in the Charter data. One of the possible explanations for that is that when they started the patients on ADT, many of them received their chemotherapy within two weeks or at least a month of going on the ADT when a lot of them may not yet have been castrate. That led to more toxicity, and the question that I'd like to answer is, okay, if there is more toxicity, could there be more efficacy also? So, this study may well provide an answer to that.

Dr. Alicia Morgans: That's great. I have seen that data, looking at castration-sensitive versus more of a castration-resistant population. There's some nice data suggesting that the AUC of docetaxel actually might be twice as high, so twice as high of an effective dose for patients who are in the castrate-sensitive state.

Dr. Tom Keane: Right.

Dr. Alicia Morgans: And then there are all these questions about the hormone-sensitive population. So, I applaud you for doing that work and for letting us know about it.

I think there might also be ... Based on the LATITUDE and STAMPEDE data with abiraterone, is there a study through the Alliance looking at degarelix plus or minus apalutamide in a hormone-sensitive population?  I think they may be doing that as well.

Dr. Tom Keane: I think there is, and if there isn't, there certainly should be because I do believe not all LHRH agonists are the same, and certainly an antagonist and an agonist are completely different agents. They have been used as the same agent, but I do not believe they're the same at all. I also don't like when I hear of patients who get started on the antagonist straight away because they get castrated quicker and then converted over to the agonist. Because as CS21 showed, that's going to complete reverse from what the data shows. It was a secondary endpoint. It wasn't a primary endpoint, but once again, there was a difference in how the patients did.

And one other thing that needs to be highlighted is that when, again, this was I believe a study by Albertson where they looked at the death rates for patients in the first year, and there is a distinct difference between the death rates for patients who are on the antagonist as opposed to the agonist. These patients weren't dying of advanced disease. These were newly diagnosed metastatic disease patients who were going on ADT for the first time. As you and I both know, very few patients die within a year of disease.

Dr. Alicia Morgans: That's true.

Dr. Tom Keane: So, there's something else.

Dr. Alicia Morgans: So back to the cardiovascular risk, which is really fascinating, and I actually worked with Javid and the team, the cardio-oncologists who put together the ABCDE paper.

Dr. Tom Keane: That was a great paper.

Dr. Alicia Morgans: Oh, thank you. I think that it's important as urologists, medical oncologists, to really maximize cardiovascular health, and often times, particularly in the highest risk patients, it's great or has been helpful to me to collaborate with cardio-oncologists or cardiologists who really can kind of take the reins in terms of blood pressure control, cholesterol management, because it is unusual, at least in GnRH agonists, and I'm not sure that I've seen the data with GnRH antagonists, but there's a difference in the cholesterol changes, for example.

Dr. Tom Keane: Absolutely.

Dr. Alicia Morgans: Where HDL goes up actually.

Dr. Tom Keane: Yep. Yeah.

Dr. Alicia Morgans: And so, having experts involved who know what happens in the setting of ADT is really useful. In your practice, particularly if you see an individual who's at heightened cardiovascular risk, do you really steer in the direction of a GnRH antagonist?

Dr. Tom Keane: Absolutely. I mean, it is my first choice. And there is a slide that I show in the presentation, which I think is on the website, which shows that if you are somebody who has cardiovascular disease preexisting, you should probably go on an antagonist. If you're also somebody who has more advanced disease, and again, this was a secondary endpoint, but it did show that the patients who saw the maximum benefit from the antagonists were the patients with metastatic disease, high-volume metastatic disease, and a higher PSA.

And the last thing I'd say is that if you're somebody who's going on ADT initially for the first time and you're going to get chemotherapy, again, we'll know some more data when the phase two trial is done, but I would like to see them getting docetaxel upfront for four cycles and then receiving ADT in the form of an antagonist because that takes two to three days to render them castrate, not a month. And you can then continue on with two more cycles afterwards in terms of the docetaxel.

Dr. Alicia Morgans: Yeah. So, I really thank you for bringing all these issues to light. I think we have work to be done and questions to be answered, but the differences exist between these agents, and understanding those implications, particularly in terms of cardiovascular disease and disease control, are really critical. And thank you for continuing the trials that are going to help us answer these questions. Do you have-

Dr. Tom Keane: I would say that it's also interesting to see that a lot more medical oncologists now are involved in ADT than there used to be. The people who really did the ADT were the urologists, and a lot of urologists still think of ADT as just render them down to 50. We've got to get the message out there that 50, while it may be acceptable to the FDA, should not be acceptable to us.

And I think the medical oncology people understand that. I think the urology people need to understand that, but we're the people who usually end up giving the ADT first, at least outside of the academic medical centers. It tends to be the private practice urologists, and there's absolutely nothing wrong with that because the urologists have been treating prostate cancer for years, but I do think they need to be aware of the differences between the compounds.

Dr. Alicia Morgans: Absolutely.

Dr. Tom Keane: And they're not at the present time. I particularly would tell them I do not like the switchover. Now, again, has any been trial done? No. There hasn't, but there is plenty of data out there, and you just have to look to see why it perhaps shouldn't be done. It may have to be in some cases because the biggest problem with the antagonists, and we have to face it, is the injection site reaction, but again, that drops down to 4% after the first dose.

Dr. Alicia Morgans: And that's really important for everyone to hear, too. I think emphasizing getting below 50 or getting below 20 in reality is important because really the 50 was set as an arbitrary number when the FDA was approving these drugs many decades ago and truly was an arbitrary number. So, whether that's the clinically relevant number or not, I think has been looked at and debated and many do agree that under 20 is probably better for our patients in terms of clinical outcomes.

Dr. Tom Keane: Yes.

Dr. Alicia Morgans:  Thank you for your insights.