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Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU medical oncologist and Associate Professor of Medicine at Northwestern University. I'm so excited to have here with me today, a friend and colleague, Dr. Ashley Ross, who is an Associate Professor of Urology also at Northwestern University. We are here to talk a little bit about our use of relugolix in the radiation setting, and pros and cons, some data or lack thereof regarding its use in this setting. Thank you so much for being here with me, Dr. Ross.

Ashley Ross: Thanks for having me once again. Thank you.

Alicia Morgans: Wonderful. So Ash, let's start first by talking about your thoughts regarding relugolix in the setting of definitive therapy for localized disease. How do you know if a patient is right for this sort of approach in terms of the intensification strategy around, concomitant ADT plus radiation, and is there an ideal candidate?

Ashley Ross: Yeah, so, as the audience well knows, relugolix was recently approved for usage. It is an LHRH antagonist, oral antagonist, and one of its, I think, important properties is from a testosterone side of it. It suppresses testosterone, but once the medication is stopped, a lot of men will have a recovery of their testosterone that happens relatively rapidly. If we look at some of the data from D'Amico and others about injectable LHRH agents, what they showed is it could take up to two years for men to recover to normal testosterone, even half the men to get there, whereas, with relugolix, that can... oftentimes you have half the men reaching that within a matter of months or even maybe a little bit less.

The other benefit for relugolix is as an antagonist, it appears to have fewer cardiovascular side effects. So when we are looking at a patient, and you are thinking about how do you intensify their primary treatments, they've been diagnosed with either intermediate-risk prostate cancer or high-risk prostate cancer, clinically localized, and we are going to add on androgen deprivation therapy, who is the right candidate for that, and to have relugolix versus an injectable. One part has to do with cardiovascular disease. Obviously, if they have a history of major cardiovascular events, you may gravitate towards relugolix. The other part I think is, for particularly the intermediate-risk patients, where we have a lot of questions, there is data now and there are trials that are ongoing through the National Radiology Group that are looking at, can we use genomics and other risk markers to figure out who really needs six months of ADT, who might need longer, who can do shorter?

And so when you have these guys that already are maybe questionable of how much benefit you're getting from the ADT, what you don't want to do is maybe compound that by having them have more side effects. And so for people who are maybe slightly on the younger side who have this intermediate-risk disease, but maybe they have unfavorable intermediate-risk disease from the virtue of having just one core, two cores, of four plus three equals seven grade group 3, and not multiple unfavorable features, you might say like, "We are going to do six months of therapy, and you're going to have recovery of your testosterone because we are going to use this pill."

The flip side is for this younger guy who cares more about testosterone, who has longer to live, the flip side is we don't have a lot of data about using relugolix in this setting. We know that it suppresses testosterone, there was a phase two trial that showed that in the setting. But we don't know if six months of suppression is enough, or if we should be extending the time period.

The reason I keep saying six months is actually because if I'm going to use it in that setting, the guidelines for injectables say four to six months. And so I'm going to build in a little bit at that tail by doing six months. And additionally, in my mind, I know I'm going to get a little bit longer time because testosterone suppression happens a lot faster. So I'm already building or baking in an extra, maybe effectively three months by doing a six-month time course and knowing they are going to get suppressed faster. But that is one setting in how I think about it. I think it's an unknown area, so I'd appreciate your thoughts on it as well. We can just think about the patient with intermediate-risk disease, localized.

Alicia Morgans: Yeah. I would completely agree. And I usually aim for about six months too. And certainly, it's patients who have cardiovascular risk factors. It's also patients who are really on the fence about whether they should be adding ADT or not. Because there are patients who recognize the data, see the data that we have that suggest that this population can have an improvement in their survival with this addition of ADT, but they say, as you mentioned, "That low testosterone is not worth it to me," or, "I have co-morbidities other than the cardiovascular disease that may be worsened with this issue," whether it's frailty, whether it is... I actually had a gentleman who had Parkinson's disease and he was concerned that the low testosterone could really worsen some of those symptoms. And also, of course, he had some movement issues anyway, so any lack of a loss of function in terms of his muscle mass was really concerning to him.

So there is a slew of patients who are really on the fence. And I think that the faster testosterone recovery is something that is really potentially a way for us to try androgen deprivation therapy in a population that otherwise may refuse. And then if we need to stop early, they have the opportunity to just stop taking the pill, talk to their physician about it, of course, but really have that conversation, stop taking the pill, and they have a much more rapid recovery than if we had given them a four or six or three-month depo injection. I don't know if you encounter those patients, but they seem to be relatively common in my practice.

Ashley Ross: Yeah, I do. And actually, one point that you are... and to expand on the point you're making that is excellent is, I wonder if one of the spots relugolix really fills for a lot of different situations clinically that we use ADT, is as the initial beginning of ADT. When I was talking, I talked a little bit about the younger patient who wants faster recovery. But I liked that you brought up that may be a patient with some more frailty or other comorbidities, and we don't know how much the ADT is going to hurt them. A, as you said, it's fast on. If we have to take it off, we can take it off without it being in some cases irreversible. And B, would be that there is some literature, now this has to be proven too, that a lot of the cardiovascular... the biggest lability in or the biggest area where there could be a damaged cardiovascular system might be at initiation of the LHRH agonist.

It has to be borne out whether you could decrease the amount of major cardiovascular events if you initiate with an antagonist and then switch. The data, I think is a little bit murky there. But some proponents say that's when plaques are unstable, that's when whatever, and it might give another boost to saying, maybe we should be starting a lot of patients on the relugolix, to begin with and then flipping them over if they are tolerating the ADT, et cetera. And that is when we would think about maybe leading into the hormone-sensitive, high-risk patient, who's going to usually get 18 to maybe up to 36 months of ADT. Where would you use relugolix there? It might be as a starting point to see how they are tolerating it, and then you could switch to an injectable for issues of cost or other things.

Obviously, you could go through the whole cycle there too. Because there is an issue where they go on, we have cardiovascular events upfront, frailty events upfront. Unfortunately, a lot of the cognitive events that I've seen in my patients tend to happen after six months, a year, or more, not the subtle things like did they develop earlier Alzheimer's, but the depression and things like that. I usually see that in my practice at about a year is the sweet spot, or a year and a half, and it can be hard to deal with. But that would be my how would I expand there.

Alicia Morgans: I agree. And I think it's interesting, in those patients who do need the longer-term ADT because they have high-risk localized disease, if they become profoundly depressed, again, we could stop the treatment and then allow them to recover. This is always weighing risks and benefits, but there are patients who do want to stop. And I think the average duration, even for these high-risk patients of exposure, is around 18 months, even though we do strive to get, I usually say two to three years. I think the guidelines say that the data is around 28 to 36 months. But if the average is really around 18 months, then even if we can make it 20 months or even 18, we are probably giving those patients the exposure that they would get, even if they were on an agonist therapy.

The other place where I think we should think about this therapy, and I'd love to hear your thoughts, is in the adjuvant or salvage setting for using radiation, we have a rising PSA or a PSA that never declines postoperatively, post-prostatectomy. What are your thoughts there?

Ashley Ross: Yeah, I mean, I think one place where at least I feel myself advocating for it, is there are people that post-prostatectomy will have an undetectable PSA and then it starts to rise and it's rising in the ultra-sensitive levels. So it's below 0.1 in many cases. And for those men, we don't really quite understand how their additional radiation should be given. So in the... there has been a few randomized control trials that suggest that radiation at that point, which those trials defined as adjuvant versus early salvage gives minimal benefit, a lot of those trials used no ADT, some of them use six months of ADT. We are still waiting for reporting of other studies that use six months with pelvic radiation or not.

And so here is a person who has a very low tumor burden because their PSA is under 0.1, but it's detectable, like say 0.05, 0.07. They had maybe higher-grade disease. There is some role in recent publications about roles of genomics, again, to determine, do they need radiation and ADT or not. And in this setting, I may want to say... It may help, maybe not. I kind of lean towards the ADT because you are of high-risk disease and I want it to synergize with the radiation, but I don't know how much harm I'm causing. In that absence of data, I think relugolix is a great choice because it could be on for the radiation therapy, it can be synergizing if needed, and it can come right off.

For my patients with elevated PSA after prostatectomy, like it's in the... say I do a prostatectomy and the first PSA is 0.2, 0.3. Usually, that's a context where the person has probably a pretty serious disease. There might be a lymph node that is positive. There might be a metastatic lesion somewhere. And for those patients, where I'm thinking more than the duration of their ADT might be extended, with some exceptions, I think relugolix, it's not at the forefront of my mind.

I'm usually using it when I'm... with that risk-benefit analysis, I don't know, am I really looking for an absolute risk reduction of like 2% or 3%? Is that worth it for this patient? Is this patient going to be the one in the 2% to 3%? That's when I'm really reaching for the relugolix.  When I think like, "well, I know the guy is going to be on this for a long time, maybe lifelong ADT." It's maybe not as important, except for the selective populations of cardiovascular risk and frailty.

So that is how I would parcel that together. And I do think that is an excellent location. The early salvage, let's say the early salvage space for people getting radiation is a good spot I think, to use relugolix.

Alicia Morgans: I completely agree. And the only thing that I would add is in those patients who may end up being on androgen deprivation for prolonged periods of time, I think that we really underestimate the cardiovascular risk factors that these patients have. And although they may not have a history of an MI or some other major cardiovascular event, at least in the HERO trial, which excluded patients who had had a major event within the preceding six months, 90% of those patients, or a little over that actually in both arms, had lifestyle factors or comorbid illnesses that could contribute to cardiovascular events. So it is something that I do talk to patients about, even though many, many of my patients end up on lifetime ADT because they ultimately, if they have that higher-risk disease may end up getting additional medications for intensification therapies like abiraterone or enzalutamide, which also may contribute to their cardiovascular risk.

And of course, as they have the changes that they will undergo in terms of their lipid profiles, their glucose sensitivity, they are going to potentially add more cardiovascular risk factors to what they are experiencing and their risk may go up.

So it is interesting. I think that as prostate cancer clinicians, our perceptions of cardiovascular risks are probably going to evolve over the next year or so, or even longer, as we recognize that maybe we do have a tool in our tool chest that can reduce or be associated with a lower risk of these cardiovascular events. And we don't have to necessarily reach for something that may be associated with raising the risk for these patients.

Ashley Ross: Yeah. I mean, I totally agree. And I think the main thing, and the audience has actually probably heard this on Urooday before, the reality is in my perspective that relugolix as an antagonist is very likely just a better drug. It causes very good testosterone suppression, less cardiovascular morbidity, you can take it off when you want. And the limiting factors are really cost compliance and drug-drug interactions. And we are generating more data as that goes. But, I hope that that data revolves around... In terms of cost, we will just have to see what happens over time.

But, for compliance and for the cardiovascular issues for these long-term ADT patients, I think a ripe area of research might be to look at when is this period of most risk? Is it upfront? Is it the whole time? I'd love to see them do that sort of study because that could actually take care of the cost and compliance. If you only had to do it for two months or three months, that kind of thing.

And the drug-drug interactions I know, or I think I know, that there are ongoing trials where they are combining relugolix, or people have taken relugolix with things like enzalutamide, darolutamide, apalutamide, abiraterone and they can get some early interaction data. So another kind of black box, in a little bit. But I think that data is very soon to come. I agree with you that... The subtext of what you were saying is it is a superior drug from a morbidity standpoint.

And the last final question we have is how are we... beyond assessing cardiovascular risk and managing it, how are we really managing it as urologists? And there might be clinics that are, or clinicians, that are more kind of savvy than I am that are making sure that they run the lipid panel upfront, checking the A1C, maybe even using some other markers that are emerging for reactive species, like CRP or something, making sure they've seen a cardiologist. There may be clinicians that are doing that upfront or thinking about programs they can put them in to maintain their cardiovascular risk factors. The reality for us as urologists, or at least for myself as a urologist, even though I think I'm thinking about this all the time, I still haven't operationalized this really well.

And in the past, it was because like you said, I only had one option. I knew that they needed the castration, and degarelix was difficult to get, and sometimes it made these big welts. And so I was always using some sort of agonist. But now with the extra option, I think I have to say, "Well, I have two options and there are these issues with cost and compliance. So I got to figure out who really needs to be in the relugolix where I can..." The only way to figure that out is to become, like you said, a better clinician, or do a better cardiovascular assessment and understand that risk. And again, to iterate, it would be wonderful to get studies going that are prospective, that can look at these things and really tease them out for us.

Alicia Morgans: Absolutely. And really understanding the biology too, underlying this, not just the phenotype, the clinical outcomes that we see, but really the underlying biology. Because like you said, that will help us understand, is this only an early event, is this an ongoing event? And you are a phenomenal clinician. So that's really not the message. The message is that we all as clinicians, I think need to evolve. And just like we had to evolve to really address bone health. And I think that we've made great strides in that area. We are now able to evolve in our understanding and our approach to cardiovascular health. And it is just another way, another opportunity for all of us to be better at what we do and support our patients even more. So thank you so much for talking through this with me today. And of course, for your ongoing collaboration in the clinic. I really appreciate your time Dr. Ross.

Ashley Ross: Thank you very much, Dr. Morgans. It's great to work with you and great to be on UroToday.