Use of LHRH Agonists Versus Antagonists in Prostate Cancer

Transcript:Raoul S. Concepcion, MD: Let’s get back now to this whole concept of, again, intermittent, continuous trying to get lower levels. Ash, from a delivery system, comment, if you will, your thoughts about using an agonist versus an antagonist. Are there clinical implications based upon the delivery systems of microsurges that may be associated with some certain LHRH agonists?

Ashley E. Ross, MD, PhD: More recently, degarelix has come to market, which essentially is an LHRH antagonist as opposed to the previous agonists. And, the difference is a couple fold. One, like you suggested, when you give an agonist, you can have a surge of the testosterone, and then each time you go to redose, there can be a surge. And, people have shown this sort of increase. It’s mild, but there is a certain increase around the time of redosing in the testosterone.

The second difference is that you’ll get some higher levels of FSH, as well, as there’s a feedback cycle with the agonist as opposed to the antagonist. With degarelix, the data shows two things. When the testosterone is suppressed and it stays lower, in my opinion, it stays there with none of these little blips. Now, I don’t think there has ever been any data showing the clinical significance of those microsurges that I can parse out. The FSH stays lower and goes lower. There’s FSH-receptor (FSHR) on microvasculature for tumors, and there’s some thought that possibly it could lead to more angiogenesis among the tumors, so maybe that would be good. It’s unclear. Degarelix does appear to delay the time to PSA progression maybe a little bit better than the LHRH agonists. So, that’s one thing that’s there. And then, when using the intermittent context, at least my take on the data, as a urologist, is that the testosterone recovery when it comes off seems to be a little bit faster than with the LHRH agonists. Whether that’s true or just the way that the patient populations were in those data sets, I’m not sure. But, maybe to throw it to the audience, I wonder if degarelix is a better drug for intermittent androgen deprivation therapy or not, or if they see a difference.

Raoul S. Concepcion, MD: Dan, you did a study, though, looking at Eligard, which is sort of this Atrigel delivery system. Talk about that because you check, after a 1-month injection, looking at Eligard with their Atrigel system versus traditional leuprolide acetate. Didn’t you find that you had longer levels of T suppression with the Atrigel delivery system?

Daniel R. Saltzstein, MD: Yes. It was a small study, 32 patients, 16 in each arm, and it was basically comparing leuprolide versus the Atrigel system, the IM versus the subQ. And, what we found was that the area under the curve, the duration that these patients were exposed to testosterone levels below castrate in one arm, was 28 days and in the other arm was 45 days. So, again, in the era of worrying about when payers are going to reimburse you for treatment options, it was a comforting level to know that this patient was still going to have a suppressed testosterone. You weren’t going to have a microsurge. We use a lot of degarelix also in our clinic. My issue with degarelix is not that it’s not a great drug—and I like the antagonist, don’t have to worry about the flare—but I have patients traveling 300 miles, and to come monthly for an office visit sometimes can be very restricting. And, so, it’s nice to have both an antagonist and an agonist in your armamentarium that you can use when you need to, depending on travel, cost, all those kind of issues.

Ashley E. Ross, MD, PhD: Just a small point on the degarelix. For my patients I’m using it in, it does also seem to cause more of a site reaction that’s definitely there and, for some patients, can be somewhat bothersome.

Jorge A. Garcia, MD: I actually have to disclose, I have never used degarelix. The reason why, I think that it may be a moot point to the extent of where we are, because there’s not really level 1 evidence to suggest that one antagonist is better than an agonist. I tell my patients that the goal of the game for them is castration. It doesn’t really matter how we get you castrated, but we need to get your testosterone suppressed. It’s a hard statement for patients with significant others, but it’s an important statement for them to understand that it’s not the injection, which is actually leading to the benefit. It is actually the fact that the injection is what we’re trying to accomplish. The importance of that is, and I remind you, degarelix was actually developed for one reason and one reason only, at the time. Bicalutamide back in the days was very expensive, and for those men with metastatic disease who were maybe having obstructive symptoms or bone pain, then you didn’t want to actually give them a flare within the first 21 days or 30 days. So, you needed to block them first with bicalutamide and then put them on an LHRH agonist. Degarelix replaced that, to some extent.

With bicalutamide, I don’t know the cost, to be honest with you, but I don’t really think it’s as expensive as it used to be. And, for rising PSA syndrome—only patients, there is not a flare concern in my opinion because they don’t have any symptoms, they’re not going to get into trials. For those patients who walk in the office with systemic disease, with symptomatic disease, then you do want to actually block them, combine them, and that’s what I do. But, I also remind you that the flare happens day 20 to 30, so you can start both agents, an LHRH agonist and a bicalutamide or an AR blocker the same day. And, when the patients flare, you will be blocked. In theory, you shouldn’t have a flare. So, that is the reason why I’m not sure that degarelix really, actually, is that relevant. I think, at the end of the day, what we’re talking about is we want to maintain your testosterone suppression and the question is, is it 20, is it less than 12, or is it 50? And, most of us would argue that no LHRH agonist nor antagonist can render someone’s testosterone undetectable. The new oral agents may be able to do that, but not the LHRH agonists that we have.

Alicia K. Morgans, MD, MPH: I want to add one thing, and I agree, so I use very little of degarelix. I guess we’re in similar practice situations and bicalutamide is very easy to get, and I do start them on the same day and have always done that. I would say that I am curious about the FSH flare because in the context of side effects, there’s a question of whether that may be involved in cardiovascular risk. I’m not sure how that may happen, but I think it’s something for us to study as well as cognitive function. So, I wonder if we may find, down the line, that our side-effect profiles may be different, and I don’t believe that they are, so strongly, that I’m using a different medication. And, for me, a lot of that thought process is also based around timing, and having people from 300 miles away coming every month is challenging. But, I am curious about that and eager to see where things stand. In 5 years, hopefully we can figure some of this out.

Raoul S. Concepcion, MD: I completely agree with you, Alicia. I think that, especially, because we’re diagnosing prostate cancer in men who are much younger. We’re seeing more high-risk disease. We know that those patients will ultimately fail definitive therapy. LHRH analogs are tough drugs. And patients from the cognitive dysfunction, from the cardiovascular effects, from the bone mineral density changes that we see, we set these patients up for some really potentially bad side effects. And, I think, as we move into this whole new post-MACRA world, APM (advanced alternative payment models) and MIPS (merit-based incentive payment system), as we will start to be reimbursed by how we utilize resources and quality of life issues, which is going to becoming more and more impactful. I think we all need to be very cognizant of these potential side effects.

Daniel R. Saltzstein, MD: That brings up an interesting point. Again, when I trained in urology, we were doing a lot of bilateral orchiectomies, and that’s how you achieve castrate. And you didn’t have to worry about flares and you knew your testosterone was continuously suppressed, and so were microsurges. I think there were some new data, from the SEER data that Soon presented, that shows that, actually, there’s less of a risk of fractures, less cardiovascular morbidity. And, I think, with the cognitive effects, some of the DVT (deep vein thrombosis) associated were similar. But, again, in this world of MACRA, and MIPS, and APMs, I have a feeling we might be migrating that way, at least in the metastatic patient, maybe not in the biochemical recurring patient.

Jorge A. Garcia, MD: One of the interesting things about side effects and, for that matter, cardiovascular specifically, is that if you look at—actually one of the first papers that actually brought this to our attention was actually the MGH paper looking at the Medicare fee for a program in Massachusetts—men who undergo castration medically or surgically, 3 months of lack of testosterone induces mild risk of developing cardiovascular disease by seven-fold. That’s huge, right? That’s huge. That’s the metabolic syndrome part. And, that, to some extent, data from 5 to 10 years ago is what pushed most of us to rethink the timing of utilization of these agents. But, it is related to castration, and that’s the part that is hard for me to understand how you can overcome that. And perhaps your point, Alicia, which is the FSH part, maybe that’s why we may be seeing a little bit more cardiovascular disease for those patients who get medically castrated and not who get surgically castrated. To me, I’m more the ‘early treated’ type, I have to admit, especially with the new data from STAMPEDE, from the ECOG data in the United States. I think that when you balance the benefit, the side effects, and the ratio between outcome improvement and quality-of-life improvement, just look at the ECOG quality-of-life data. At 3 months, someone who gets hormones and chemotherapy, it’s a drastic detriment in quality of life. At the end of the year, people who get hormones and chemotherapy, however you look at that data, have a better quality of life. So, you can improve these things. And, I think, the biggest issue is balancing that benefit and side effects with patients, and how you’re going to support them.

Alicia K. Morgans, MD, MPH: I’m on the group that put that paper out—or is hoping to, we’re working on the paper. But, I think that we were surprised by that, we’re encouraged by that. Better disease control may lead to better quality of life. At the end of the day, if we can control people’s cancer, I think they can feel better. And so, it’s always a trade-off, and thank you for the bringing that up.

Transcript Edited for Clarity