A Look at Established Paradigms in Androgen Deprivation Therapy in the Treatment of Advanced Prostate Cancer - Tom Keane

Tom Keane and Charles Ryan share in conversation about new developments and controversies in androgen deprivation therapy (ADT), answering questions on administering LHRH agonist and LHRH antagonist as well as sequencing new therapies on top of ADT in treatment for prostate cancer.

Biographies:

Thomas E. Keane, MBBCh, FRCSI, FACS, Professor and Chairman of Department of Urology at the Medical University of South Carolina

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

Read the Full Video Transcript

Charles Ryan: Hello. I'm joined by Dr. Tom Keane, who's Professor and Chairman of the Department of Urology at the Medical University of South Carolina. Always a pleasure to talk. Today we're going to talk about androgen deprivation therapy. There is, despite the fact that this is a 75/80-year-old treatment for prostate cancer, there are some nuances to it and some new developments and some new controversies about how we should be treating patients with androgen deprivation therapy. The topic is really, should we be giving LHRH agonists, LHRH antagonists? And we want to make sure we continue to think about this question, even though we're adding new therapies on top of traditional ADT. So, tell us about the state-of-the-art now.

Tom Keane: Well, nice to be here and thank you for asking me to discuss this topic. And, you're right. ADT has been in existence since Huggins in the 1930s, and as we look at it now, it has changed, and it's changing because the agonists, I personally believe, are not the appropriate therapy. Many oncologists- many urologists just go to the drawer and pick out whatever agonist they like. What they don't realize is that there are profound differences between the agonist and the antagonist. Number one, there's never been a study comparing agonists, among themselves, even though we have five or six different agonists currently on the market. And, they came from the era when testosterone of 50 was considered an appropriate castration level. Today it's not. I think if you look at our own guidelines, we haven't said much about it, but the Europeans have said about it, the St. Gallen have said about it, that it needs to be going to 20. Yet, our FDA still accepts 50, as does the European agency.

Tom Keane: So, I think we need to change what we're doing and we need to make sure that we get to the lowest point possible. One of the questions I frequently ask urologists and medical oncologists, "If you start somebody on ADT, how often do you check the testosterone levels?" Typically with urologists, they look blankly, and say, "What?" And the only time they check it is when the PSA starts to go up. That's not sufficient. That's not their fault in a lot of aspects, because we didn't have the technology to be able to go lower than 50 up until about ten years ago. The chemiluminescent techniques now that are available, we can get very accurate testosterone levels.

Tom Keane: Why would I use an antagonist as opposed to an agonist? Let's start off, first of all, with the structure. You have to change one amino acid to make an LHRH agonist. You have to change seven to make an antagonist. That's why it took so long to actually develop. The second thing you need to focus on is, yes, luteinizing hormone is important but so is FSH. Nobody ever thinks about FSH. It's the forgotten messenger if you like. The FSH control is significantly different between the agonist and the antagonist. That came out of the CS21 data, where they compared degarelix with leuprolide for a year.

Tom Keane: Why did they compare it for a year? Because the original abarelix, which was the original antagonist, at one year had a 25% escape rate. That was not seen in the CS21 data. Then what happened was the FDA said, "Okay, we want you to go out to three or four years, and we would like you to cross patients from the agonist to the antagonist in order to see how they do, so there is no escape." A couple of things happened when they crossed them over. Number one, the event rate for the agonists at the time was 0.22. The event rate for the antagonists at the time was .08. When they converted the agonists over to the antagonist, the PSA slope changed, and the event rate dropped to 0.1.

Charles Ryan: Let me stop you there. When they converted patients over from the LHRH agonists-

Tom Keane: Agonists.

Charles Ryan: ... to the antagonists, there was actually a clinical benefit that was observed-

Tom Keane: There was a clinical benefit.

Charles Ryan: ... in terms of PSA.

Tom Keane: There was a decrease in the PSA failure rates at that point. Also when you looked at the FSH levels, the FSH levels dropped a further 63%, when they converted from the agonist to the antagonist. Then we have to look and say, "Okay, well, what does that mean? FSH control?" There's a paper by Radu et al in the New England Journal in 2010, where they actually looked at FSH, and they looked where are the FSH receptors located. They were located right beside the area where VEGF was. Neovascularization was occurring. The FSH was right there, as was the VEGF, as was the leading edge of the tumor. If you think of it in military terms, where you do you want your troops? You want them at the leading edge of the attack, and that's exactly where the FSH receptors are located. That was another reason to take a long look at it and see what's going on.

Tom Keane: Then when you look it- There are metabolic consequences. The metabolic syndrome as we know it is, as men get older, they get the metabolic syndrome. If you have the LHRH agonist syndrome, if you like, that's different. There's different adiponectin. There's different HDL concentrations. It's subcutaneous, rather than visceral, fat that the patients develop. Again, it's less when we looked at the mice studies that are done. There's less obesity. There's less of this syndrome if you're on the antagonist.

Tom Keane: Then if we go back, and we look at the groups who had more advanced disease. The CS21 data was not all about- it wasn't all about metastatic disease, but the patients who saw the maximum benefit were the patients who had a higher volume metastatic disease. That's a third reason that you want to think about it. Again, when we look then at cardiovascular complications- And this was interesting- There was a study. There was no randomized control trial, but there is an observational study whereby they included all of the trials that had been done with degarelix, and then they compared them. This was by Albertson. Then they compared them to the agonist studies. They found that there was a 50% decrease in the rate of a cardiovascular event, the relative risk of a cardiovascular episode, and an actual 8-10% reduction in the rate of cardiovascular complications.

Charles Ryan: Do you think this is related to the FSH?

Tom Keane: Yes, I do, and interestingly the big question is, "Okay, how about something that looks directly at it?" At the AUA in 2017, there was a paper by Professor Margel, I think is his name. It was 59 patients. 29 were on the agonist. 30 were on the antagonist. At one year, there were 10 cardiovascular events-

Charles Ryan: Out of the 60 patients-

Tom Keane: ... out of the 60 patients. Nine of them were in the patients on the agonists.

Charles Ryan: Interesting.

Tom Keane: You put it all together, and you're looking at it saying, "Okay, let's figure this out, and see what's going on." We at MUSC- we've actually developed a trial on this that is currently accruing. The way we looked at it was I was having a chat one night with Evan Yu and we were talking about CHAARTED. He pointed out to me, "Why was there a difference between the results in CHAARTED versus the results in GETUG-15?" There were a number of reasons. Number one, there weren't as many high-risk patients in it. There were only half as many patients there. There was less advanced disease there, and also patients who progressed did not have the benefits of abiraterone and enzalutamide in that cohort, because they hadn't been approved yet.

Charles Ryan: Just to clarify, GETUG-15 was the French study in which it was ADT plus/minus docetaxel with a-

Tom Keane: Correct.

Charles Ryan: ... essentially lower volume of patients-

Tom Keane: Lower volume of patients and less advanced disease.

Charles Ryan: ... being treated.

Tom Keane: When he said this, there was also a big difference in toxicity. There were four deaths. There were very few deaths in CHAARTED, and then he looked back, and we both looked back at the original TAX 323 data. There was the same amount of neutropenic fever, and we were like, "This is strange. Why is there so much toxicity?" It turns out that there's a reason for it, and that's because if you are non-castrate, your liver is not protecting you from the docetaxel. If you are castrated- This is data from Frank et al in 2010, which showed that men who are castrated, the liver kicks out the docetaxel. If they are non-castrate, there's a 450% increased chance that you're going to get a neutropenic fever at the doses used.

Tom Keane: When we went back and looked at the timing of the ADT, it turned out, the GETUG-15 patients received chemo two weeks after they had started on ADT. 50% of them got their chemo, and at two weeks, they are not castrated-

Charles Ryan: They are not castrated.

Tom Keane: ... And they didn't use any GCSF. They didn't use any antibiotics, so they got a neutropenic fever, and that's where the four deaths occurred. Then the other question that comes up is if there's more toxicity, maybe there's more efficacy. So, we're doing a trial now at MUSC. We've so far accrued nearly 30 patients. It's for patients who present with newly diagnosed, metastatic prostate cancer. We have 76% of the patients are high volume, and so far we have 40% of the patients who are African-American. We've also opened it in Maryland, and it's open at the VA. We're planning on 50 patients and that, please God, we'll get there at that stage. That's going to be really interesting because they get four cycles of docetaxel up front. Then they get degarelix, which takes two days to render them castrate, and then they get two more cycles.

Charles Ryan: Very interesting. It's great to be looking back at established paradigms and rethinking them in terms of safety and in terms of efficacy in how we treat this disease. I think what you're getting at, with respect to the LHRH agonists and antagonists is a sign of our success as well, because a generation ago, we wouldn't have detected that cardiac signal perhaps-
 ... and patients were dying of their prostate cancer, and now we're focusing on living longer with it. These issues have always been important, but they're becoming just more important.

Tom Keane: I was at Emory when Holt Sanders produced one of the first papers documenting fractures in ADT patients on castration treatment, and everybody said, "That's rubbish. I've never seen one." The question was, "How many patients do you have on ADT?" 50, but the incidence is 1-2%, so of course, you're not going to know about it, but when we start looking at the big numbers, it gets very interesting.

Charles Ryan: Congratulations. Great work. It's really going to be interesting to follow this field. It is a really interesting confluence of the biology of the disease, endocrinology itself, and the availability of new agents. We'll continue to watch this space, and thanks for joining me today.

Tom Keane: Thanks, Chuck. It was a pleasure being here.
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