Zachary Klaassen: Hi, my name is Zach Klaassen, urologic oncologist at the Georgia Cancer Center. I'm delighted to be joined on UroToday by my close friend and colleague, Dr. Avi Guha, who is a cardio-oncologist at the Georgia Cancer Center, Dr. Sagar Patel, who's a radiation oncologist at Emory University in Atlanta, Georgia. Gentlemen, thanks so much for joining us on UroToday.

Sagar Patel: Thanks, Zach. Appreciate the opportunity. Oops.

Zachary Klaassen: Absolutely. So today we're going to be discussing data from Dr. Patel presented at SUO 2025, the REVELUTION Study. And this is a really, really interesting study looking at some cardiac data for leuprolide versus Relugolix. And so before I have Dr. Patel get into that, I just want to have Dr. Guha maybe just mention you're a cardio-oncologist. What's the potential ramifications from a cardiac standpoint for these men that are starting on ADT for prostate cancer?

Avirup Guha: So great question. Get to see a lot of these men pretreatment and risk-stratify them all the time. So the first thing which I always talk about is just baseline risk factors. So a lot of the disease which happens in these men are because some of them are older, or most of them are older, and then they have other risk factors like hypertension, diabetes. There have been studies by colleagues in Canada in the RADICAL PC-1 study, which shows of the 3,000 plus men, at least one uncontrolled risk factor was found in about 99% of the patients. So it is not unusual to find uncontrolled risk factors. So we lead with that to make sure that we're not just thinking of prostate cancer or prostate cancer-related medications.

Here on the slides, we see some of the prostate cancer medicines, some of them are used in United States, some of them are not. And we see that at least to focus on those which are the big bullseyes are the ones where we look at those risk factors, as we all utilize a lot of androgen receptor antagonist or mostly the second-generation ARAs. We see that medications like enzalutamide, apalutamide can cause hypertension, abiraterone can cause a lot of hypertension. There's a risk factor monitoring for hypertriglyceridemia and diabetes, and hyperglycemia in patients who are going through treatment with Relugolix, apalutamide, and abiraterone, and just increased risk of ischemic heart disease and atrial fibrillation across the board, with mostly AFib increase in patients with abiraterone. So we just throughout their treatment and baseline monitor for these risk factors and keep a close eye on them while they're going through optimal cancer care.

Zachary Klaassen: Yeah, it's a great intro, and it'll lead into Sagar's discussion of REVELUTION. So, Sagar, phenomenal trial initially presented at American Heart Association, now at SUO. Maybe just walk through the trial design and the key outcomes and findings from the study.

Sagar Patel: Yeah, absolutely, Zach. Again, I appreciate the opportunity. And then just to kind of piggyback on some points Avi made, I think we've recognized through multiple observational studies over the past decade that cardiovascular risk seems to be highest with GnRH-agonists like leuprolide compared with other forms of testosterone suppression, even back to the orchiectomy days. And then the HERO trial, which we're all familiar with, published in the New England Journal in 2020, showed a lower risk of adverse cardiovascular events with a novel oral GnRH-antagonist, Relugolix, compared with GnRH-agonist, leuprolide. But the mechanism by which cardiovascular risk may be lowered with Relugolix is still unclear because we expect the hypogonadal metabolic dyslipidemic effects may be similar. So the REVELUTION trial was designed to test our hypothesis that ADT-associated cardiovascular risk is at least partly mediated by accelerated coronary atherosclerosis.

And we hypothesized that it would be more prominent with the GnRH-agonist versus the GnRH-antagonist Relugolix. So REVELUTION was a single-institution parallel cohort and open-label randomized trial of men with localized prostate cancer receiving definitive pelvic radiotherapy with or without ADT. And I'll go through the scheme in a second, but just some logistics. We enrolled these patients across four hospitals affiliated with Emory, and the trial was completed between June '22 to March '24. And the randomization for the hormone therapy group was stratified according to their cardiovascular risk. We used the ASCVD 10-year risk score, and we stratified them by low borderline versus intermediate and high. And then all patients underwent a baseline coronary CT angiogram and a 12-month coronary CT angiogram. And these studies were blinded to treatment arm and then analyzed using a commercially available platform to measure coronary plaque, which was led by HeartFlow, which is very commonly utilized by cardiologists across the country.

Here's the schema, and again, it was a three-arm trial. So if you focus on the top two arms, these were men with localized prostate cancer who had planned ADT, meaning they had unfavorable intermediate, high, or very high risk prostate cancer, and they had intent to undergo at least six months of ADT. And they were randomized one-to-one to either radiation plus Relugolix with standard dosing versus radiation with leuprolide, which were administered via three-month injections. And we enrolled 65 patients in the hormone therapy arms. You can see 31 were randomized to Relugolix, 34 to leuprolide. And in parallel, we also enrolled a parallel prospective control arm for men with lower-risk prostate cancer who were eligible for definitive radiotherapy without hormone therapy, and they received radiation alone, but also underwent a baseline coronary CT angiogram before treatment initiation and then again 12 months after. So the total study population had 31 patients receiving radiation plus Relugolix, 31 receiving radiation plus leuprolide, and 28 patients receiving radiation alone.

This was the analyzable cohort who underwent a baseline pretreatment coronary CT, and then again, a 12-month coronary CT. And these were our primary outcomes or our main outcomes of interest. Our primary endpoint was change in total plaque volume. So this was a summation of the total coronary plaque across all major coronary vessels. And then the secondary endpoints were plaque subtypes, including non-calcified plaque volume, calcified plaque volume, and low-attenuation plaque volume. And as Dr. Guha and cardiologists are aware, these plaque subtypes have differential risks in terms of major adverse cardiovascular events, specifically non-calcified plaque and even low-attenuation plaque being softer plaque, more vulnerable, more at risk for acute events like an MI. And again, this was assessed by serial coronary CTs done within a week before treatment initiation and then again 12 months after. And then the 12-month mean difference was estimated for the change in each of these plaque volumes using an analysis of covariance regression model. And we did adjust the model for age, statin use, and respective baseline plaque volume. And this image on the bottom right is just a schematic on how the HeartFlow artificial intelligence platform works by essentially segmenting the CT and doing reconstruction, and then using Hounsfield units to measure plaque volume along the coronary vessel wall.

And this is a lot of data, but this is essentially the main data to take home. And I've highlighted the primary endpoint, total plaque volume at the top. So I'll review that first, but you can see in the rows within total plaque volume highlighted in yellow, we have the no ADT arm, the leuprolide arm, and the Relugolix arm. Without getting too busy in the details, I'll just share that this table presents the baseline total plaque volume, the month 12 total plaque volume, and the crude difference, but it's good for the audience to focus in on the adjusted mean difference, which is the column second to the right. What we saw here is that using the no ADT group, so those men who receive radiation alone without hormone therapy as a reference, we saw that leuprolide resulted in an estimated difference of plus 79 millimeters cubed of coronary plaque volume. While Relugolix resulted in an increase of only 10 millimeters cubed.

Now, the increase with leuprolide was statistically significant while the increase with Relugolix of 10 millimeters cubed was not significant. This was our primary endpoint. That total plaque volume was significantly increased with leuprolide of at least six months duration, while this change was not seen with Relugolix. And then within the various plaque subtypes or secondary endpoints, these are the three rows below that are not highlighted. We have non-calcified plaque volume, calcified plaque volume, and low-attenuation plaque volume. We see the exact same trend except smaller numbers, because again, these are just plaque subtypes that, in summation create total plaque volume. But just to quickly review, we saw that non-calcified plaque volume was significantly increased with leuprolide compared with no ADT of approximately 72 millimeters cubed, while Relugolix resulted in a non-significant marginal increase of 7.2 millimeters cubed, which is shown right here. And then we see the same trend for calcified plaque volume of a significant increase of approximately 20 millimeters cubed, while Relugolix resulted in a non-significant increase of nine millimeters cubed, and then same for low-attenuation plaque volume, leuprolide resulting in a significant increase, while Relugolix did not.

To summarize that, it was a busy slide, but just to break it down, in our opinion, or to our knowledge, REVELUTION is the first clinical trial to really identify biologic basis for the cardiovascular risk differences we've observed between ADT drug pathways and multiple observational studies in the past, including the post-hoc analysis of the HERO trial comparing leuprolide versus Relugolix. And then what we found is that leuprolide was associated with significant near-term coronary plaque progression while Relugolix was not, and that plaque progression was primarily driven by non-calcified plaque. And this is important because, as Dr. Guha and cardiologists know, non-calcified plaque tends to be a higher risk plaque subtype that's more associated with major adverse cardiovascular events. And so our results support the hypothesis that cardiovascular risk from ADT is at least partly driven by accelerated coronary atherosclerosis, which again appears more prominent with leuprolide compared with Relugolix. And we believe this corroborates prior clinical data, specifically from HERO that does show greater risk of MACE with GnRH-agonists, especially leuprolide.

Zachary Klaassen: Wonderful. Sagar, that was beautifully presented. I like how you broke that table down for listeners as well. And so just with a short course of ADT, we're seeing these, I'll call it drastic changes at the coronary artery level. So maybe Avi, put this into context for how radiation oncologists, urologists, medical oncologists should be talking to our patients about risk. And certainly, my practice sends a lot of patients to see you. When should we be making those referrals, maybe just from a practical perspective, lay it out for our listeners?

Avirup Guha: So a little bit, I mean, I was going to present a little bit of caveat for the data just so that we get it in the perspective of how we see it in total, of whatever exists in the space. So obviously, first of all, congratulations to Sagar and the entire Emory group for pulling out a trial, which is extremely mechanistic. It is very relevant. It shows what we have always thought it would be, where adding androgen deprivation therapy increases plaque progression. Interestingly, Relugolix did not lead to plaque progression of the bad kind, so to speak, the non-calcified plaque volume. There's data to suggest that it is related to major adverse cardiovascular events. There is, however, the caveat that in the same study, patients who had use of statin actually didn't have significantly increased plaque volume when they were on ADT using leuprolide. And to put that into perspective, patients...

There were two trials which were done. The HERO trial, obviously, which was positive, which from the standpoint of major adverse cardiovascular events, where they necessarily didn't really look for statin utilization, and it was much lower than what one would see in a trial like PRONOUNCE, which was the trial where we had another GnRH-antagonist, which is degarelix, utilized along with leuprolide. And in that comparison, there was no difference between degarelix and leuprolide in terms of major adverse cardiovascular event. The trial was stopped early, but the interesting thing was that because that trial had co-management with cardiology and oncology, the overall event rate was half of what is known in epidemiological studies, and that the utilization of statin was significantly higher than the HERO trial. So what I suggest or take together with all the data available is REVELUTION supports the importance of atherosclerotic surveillance and preventive therapy, particularly statin optimization when any ADT is introduced.

However, any treatment choice should remain grounded in individualized multidisciplinary discussion that integrates oncologic priorities, baseline cardiovascular risk, and patient preference. So that leads to what do we do when, I think your question about when I'm risk-stratifying these patients, when they have been sent to me. So we actually do not have a calculator to have you send the patients to me. So it is still based on a lot of gestalt of how you send patients to me. A lot of these patients have existing cardiovascular disease, so you cannot use the existing cardiovascular disease calculators, which are meant for patients who have not had heart disease yet. So we are actually working, you are on the paper, Sagar is on the paper, we are working with PCF to generate this white paper on when to refer. So I'm not going to get into too much detail of something which is not published yet, but when I've seen these patients, what I would do is I would use the ABCDE criteria, where we talk about the awareness of all the things we talked about, that ASCVD is common with these medicines, and you need to be protected against it.

I use aspirin in patients who have calcific coronary disease, which is very easy to identify. I'm going to quickly jump to C. So C is where we see the cardiac imaging, because these patients, a lot of them have PSMA PET-CT scans, and the CT scan helps me look at their heart, even though it is meant for the cancer. And I can look at coronaries, I can see calcific coronary artery disease, calcific abdominal arteries, and that helps me encourage them to use aspirin. We also work with the JNC 8 guidelines for maintaining their blood pressure, because, as you saw in the previous slide, which I had shown, that blood pressure increases common with several of these agents, we have a robust smoking cessation clinic here and several other places, including Emory, and we really strongly counsel. We use the American Heart Association Cholesterol Guidelines to keep the LDL. I think I try to keep it lower than 70 as a secondary prevention measure, but you can argue it be less than 100 as a primary prevention measure as well. 70 is better than 100 as shown in many cardiovascular studies, and perhaps very relevant to this specific study, where we see plaque progression.

And then the diet is American Heart Association diet, and the same is the exercise, which is embedded in the Life's Essential Eight. We give the Life's Essential Eight guidance from the American Heart Association to these patients and maintain diabetes with the ADA guidelines, with the A1C less than seven for those who have diabetes, and try to treat prediabetes in some of these patients who are starting androgen deprivation therapy. The other things which I italicized on this slide, I'm not going to talk too much except drug choice. That's the discussion now is whether we are ready for making a drug choice. So the European guidelines, even prior to Sagar's study based on the HERO trial, have given a 2B indication for patients with ischemic coronary artery disease to utilize Relugolix. We obviously are awaiting an outcomes-based trial, which would help strengthen that 2B recommendation to perhaps a 1 or even 2A recommendation at some point in time. So that's where I stand with my workup for these patients.

Zachary Klaassen: Oh, that was fantastic, Avi. I think the shout-out to the listeners is if you have cardio-oncologists in your cancer center, use them because even before we had this data that Sagar presented, we know that these patients are at risk of all these things of being on ADT and ARPI. So Sagar, just before we wrap up, what's sort of next for REVELUTION? Are we doing additional analyses, other stuff planned?

Sagar Patel: Yeah, absolutely. I mean, we've developed a really robust infrastructure here at Emory with the multidisciplinary team, so we certainly are capitalizing on that. I think there's two main future directions we want to take advantage of and pursue. One is that we need to have longer follow-up to really correlate these plaque changes with actual risk of major adverse cardiovascular events like myocardial infarction, sudden cardiac death, heart failure. So that's ongoing. That's important. We want to know, all right, so what? An increase in coronary plaque volume, what does that mean at two years, three years, four years? So that's important. I think in an ideal world, we also validate larger cohorts.

This was a single-institutional design. It supports our hypothesis. It creates biologic plausibility for data we've seen in HERO and other trials, but I do believe we as a group need to validate this data in a larger multi-institutional cohort. But what's ongoing is I think that testing cardiovascular risk, including atherosclerosis, is very important in men receiving intensified ADT, including ADT plus a second-generation ARPI, as Avi discussed in his opening. We've seen in the LATITUDE and STAMPEDE trials that cardiovascular risk is certainly elevated when we add on a second-generation ARPI. So that's the basis of REVELUTION two. REVELUTION two is a trial ongoing that we're doing right now for men with very high risk, node-positive, low metastatic volume who are eligible for pelvic radiation, but combination ADT with abiraterone acetate and prednisone. So these patients are randomized one-to-one to leuprolide with abiraterone versus Relugolix with abiraterone.

The design is the same in the sense that they get a baseline coronary CT angiogram as well as again at 12 months. And we want to look at coronary plaque progression over this 12-month period while on therapy. We're also doing very intense ambulatory blood pressure monitoring to look at just peripheral cardiovascular and hypertension while on treatment. So we believe this is an important study. I think it's the future direction as a whole because we, as a field, are utilizing second-generation ARPIs more commonly, even in the localized setting with ongoing trials. So I think that's the future. So we want to look at the cardiovascular risk exacerbation when we combine ADT with the second-generation ARPI and whether this risk can be lowered with Relugolix.

Zachary Klaassen: That's super important work. I think both just the follow-up of REVELUTION, but also this REVELUTION two study, that's going to be fantastic. So we'll keep an eye for both of those updates. Gentlemen, fantastic conversation. Maybe just a quick closing statement from each of you. I'll start with Avi.

Avirup Guha: So again, excellent, excellent work so far. Excited to see what REVELUTION two shows, and I'm sure plaque progression would be higher. I think there's a lot of future for the field when it comes to the emergence of the importance of cardio-oncology and prostate cancer. I think as these men live longer, we have a chance of making a big difference in their lives, both from the cancer and cardiovascular standpoint. There's a role of Relugolix in metastatic space as well, which I think we should at some point in time discuss of how that space can be utilized because metastatic patients are now surviving like five, 10-plus years. And I see several of them who are five years out of their initial diagnosis, and they're still doing just fine, but dealing with cardiovascular disease. But I think if you have patients with prostate cancer, please refer them to cardio-oncology based on whatever risk stratification you can use, and hopefully we'll have some better tools in the future, but this is very promising. I think this is leading into the future of cardio-oncology as a field and also the future of how prostate cancer treatment should be like.

Zachary Klaassen: Awesome. Sagar, you get the final word, my friend.

Sagar Patel: All right. So I think I got two take-home points. I think one, just to summarize REVELUTION and what we're excited about, just to reiterate, I think we're excited because it's a mechanistic trial. It's, to our knowledge, the first that really has shown drug-specific pathway toxicity and the differences between ADT drugs. And our study supports the differences that we're seeing in HERO, which I think is first of its kind. It's needed because there's been a lot of skepticism out in our community regarding the cardiovascular risk differences between the drugs observed in HERO. So that's one. Two, it's the point that you and Avi have made. I think in our clinics, and Zach, you and I can attest to this, our cardiovascular risk is underassessed, undermanaged. So we need to be more aware. We need to utilize our colleagues in cardio-oncology that we fortunately have with Dr. Mandawat at Emory.

You guys have with Dr. Guha at Augusta, and hopefully, more centers are building cardio-oncology programs because, as Avi mentioned, these patients are surviving prostate cancer. We want to minimize that other-cause mortality. And then the third point I do want to add is that I do believe testing the space in the metastatic patients is important. What we've seen, and we've actually published an initial analysis in JACC Advances that the coronary burden seems to be higher in men with higher-risk prostate cancer. So you could extrapolate that perhaps men with metastatic prostate cancer may have the highest baseline cardiovascular risk. So I think testing this concept, assessing cardiovascular risk reduction with drug-specific pathways in the metastatic patients, is important.

Zachary Klaassen: No, that's well said. Great wrap-up. Gentlemen, thank you so much for joining us and educating our UroToday community. Really appreciate your time and expertise.

Sagar Patel: All right. Thanks, Zach.