Sagar Patel: Thank you so much. I appreciate this opportunity. Yeah, so I'm excited to present the REVELUTION trial, which was an institutional investigator-initiated study we carried out at Emory. And just some background for this study. The morbidity from androgen deprivation therapy in men with prostate cancer is fairly well established. One of those particular morbidities and toxicities we are concerned about in clinic is cardiovascular. Several observational studies that were published in the 2010s show that cardiovascular risk may indeed be higher with gonadotropin-releasing hormone agonists such as leuprolide, compared with other forms of testosterone suppression, such as an orchiectomy. And then the HERO trial was published in 2020. This was a landmark study because of course, it led to the FDA approval of a new oral hormone therapy drug known as Orgovyx, which is a gonadotropin-releasing hormone antagonist. I think notably from the HERO study they did show that the risk of major adverse cardiovascular events was lower with the gonadotropin-releasing hormone antagonist Orgovyx compared with the agonist leuprolide. But the mechanism by which cardiovascular risk may be lowered with relugolix or Orgovyx is unclear because the hypogonadal metabolic and dyslipidemic effects from the two drugs are expected to be similar because they both are excellent testosterone-suppressing agents.
So the REVELUTION trial was designed to test our hypothesis that ADT-associated cardiovascular risk is mediated by accelerated coronary atherosclerosis, and we believe that it will be more prominent with gonadotropin-releasing hormone agonist leuprolide versus the gonadotropin-releasing hormone antagonist relugolix. This hypothesis has been informed by recent preclinical studies that essentially have identified GnRH receptors in peripheral inflammatory cells, including T-cells and monocytes. And we hypothesize that activation of this immune effector response through GnRH agonism leads to peripheral immune effector response, specifically at the coronary endothelium, which leads to plaque disruption and propagation, and that ultimately leads to major adverse cardiovascular events. This is the study design on this slide of REVELUTION. This again was a single-institution parallel-cohort open-label randomized trial of men with non-metastatic prostate cancer. All patients received some sort of pelvic radiotherapy to the prostate with or without the pelvic lymph nodes. And all patients with intermediate and high-risk disease were included. So some men received ADT, some did not, and I'll go through that distribution and schema in a second. But we enrolled across four centers affiliated with Emory, and the trial was completed over June 2020 to 2024.
The randomization for those patients receiving hormone therapy or ADT was stratified according to their atherosclerotic cardiovascular disease ten-year risk score. So that is a nomogram that's widely used in the cardiology realm, which provides an estimation, a 10-year risk score of their risk of having a major adverse cardiovascular event. All patients underwent a baseline and follow-up cardiac CT or a coronary CT angiogram. Those are synonymous, also known as a CCTA. And these CCTA imaging studies were blinded to treatment arm, and we ultimately analyzed it using a commercially available, well-validated automated measuring tool run by HeartFlow, which is used widely across cardiology clinics in the United States. So if you look at the schema, again, we enrolled men with non-metastatic prostate cancer. 94 men were enrolled. Those who were eligible for concomitant ADT, they all received hormone therapy for at least six months or longer depending on their cancer risk tier. And they were randomized one-to-one to either relugolix or leuprolide. Relugolix was delivered at standard dosing of 360 milligrams on day one, followed by 120 milligrams each day thereafter, and leuprolide was administered in three-month depots. And then all patients again underwent a baseline cardiac CT or CCTA, and then they underwent their treatment, and then they underwent another cardiac CT 12 months later. We also enrolled on a parallel prospective control arm patients with lower-risk prostate cancer who were eligible for definitive radiotherapy alone without planned ADT.
And we enrolled them prospectively pursuing the same procedures, including a baseline cardiac CT and then another cardiac CT 12 months after the baseline. We felt that inclusion of this radiation-alone arm would serve as a strong control to see the effect of patients receiving no hormone therapy. These were our outcomes of interest. So the primary endpoint was change in total plaque volume, and secondary endpoints were changes in plaque volume subtypes, including non-calcified plaque, calcified plaque, and low-attenuation plaque. And of course, Leslie, you and I aren't cardiologists. I learned through my cardiology collaborators and co-investigators the meaning of these, that these plaque subtypes are well-validated biomarkers that can predict the risk of major adverse cardiovascular events later down, and also provides a biologic mechanism because we can truly measure non-invasively whether coronary atherosclerosis changes with treatment or with an intervention. Again, these plaque subtypes were assessed by serial cardiac CT, which were complete at baseline or within seven days prior to treatment initiation, and then again 12 months after the baseline scan. And then we measured a twelve-month mean difference using analysis of covariance. And we did adjust this analysis for patient age, whether they were on a statin, and also their baseline plaque volume.
This image is just a schematic of how the automated quantification tool that HeartFlow runs. They use these scans; they reconstruct the scans, and then they have an automated algorithm that measures the actual volume of plaque within the coronary vessels. This is kind of our primary endpoint, which was a direct comparison of plaque changes between those patients receiving leuprolide versus those receiving relugolix. So I simplified this table compared with the one that will be published in JAMA Cardiology, but for viewers to see more easily the most important findings. On the first column shows the twelve-month crude difference in plaque volume between those receiving leuprolide versus relugolix. You can see that total plaque volume, the difference was higher with leuprolide of 56 millimeters cubed versus relugolix at 25. And then that trend was also similarly seen with non-calcified plaque volume, or NCPV, with the higher change with leuprolide compared with relugolix. And then the calcified plaque volume and the low-attenuation plaque volume, there was not a significant difference between the two arms, but the volume changes were relatively low. And then on the right column, you see the adjusted mean difference. This is the plaque volume changes that were also adjusted for age, statin use, and baseline plaque volume. Here we see that there was an estimated mean difference of 68.9 millimeters cubed of total plaque volume with leuprolide compared to relugolix, meaning patients on average had almost 70 millimeters cubed of increase of total plaque volume when they received leuprolide compared with those receiving relugolix. This total plaque volume change was mainly driven by non-calcified plaque, as the non-calcified plaque volume, or the NCPV, had a mean increase of 64.5 compared with relugolix when adjusting for age, statin use, and baseline plaque volumes.
Those two findings were statistically significant, the total plaque volume and the non-calcified plaque volume. In terms of the other plaque subtypes, we did see an estimated mean increase with leuprolide compared with relugolix, but that did not reach statistical significance. We also wanted to look at how these changes compare with those patients who did not receive hormone therapy, the radiation-alone arm. So this was a supplementary table that's also included in this analysis where we looked at the adjusted mean difference of each treatment arm using the no-hormone therapy arm as reference. Again, the no-hormone therapy arm was non-randomized, so this was more of a secondary analysis we were interested in. But what you can see here is that if you focus on the top rows of the TPV, or the total plaque volume, patients who received leuprolide had an adjusted mean difference, or an increase of nearly 80 millimeters cubed of total plaque volume compared with men not receiving hormone therapy. And that was statistically significant. While those patients who received relugolix had an estimated mean difference of 10.5 millimeters cubed increase in total plaque volume compared with those not receiving hormone therapy. And that was not significant. And this trend was consistently seen with each plaque subtype, including non-calcified plaque volume, calcified plaque volume, and low-attenuation plaque volume, meaning that leuprolide resulted in a significant increase in each of these plaque volumes compared with men not receiving hormone therapy, while relugolix did not result in a significant increase in each of these plaque volumes.
So the summary of REVELUTION to our knowledge REVELUTION is the first clinical trial to really identify biologic basis for cardiovascular risk differences observed between different ADT drug pathways in men with prostate cancer. And specifically GnRH-agonist leuprolide was associated with significant near-term coronary plaque progression, while the GnRH-antagonist relugolix was not. And the total plaque volume increase was primarily driven by non-calcified plaque volume. And that's a really important finding because recent large data in the cardiology world has shown that non-calcified plaque volume is a higher-risk plaque subtype. It's softer plaque. It's the type of plaque that's much more prone to acute changes, acute propagation leading to occlusion of a vessel in a subsequent MI. So the results of this trial support the hypothesis that cardiovascular risk from ADT is at least partly driven by accelerated coronary atherosclerosis, which appears more prominent with leuprolide compared with relugolix. And we believe this data corroborates prior clinical data showing greater long-term major adverse cardiovascular risk with GnRH-agonists such as leuprolide.
Leslie Ballas: Thank you, Dr. Patel. That is a really great study, and I am so excited to read the paper in JAMA Cardiology. We all know that ADT and sort of ADT combination therapies are effective in helping men who have prostate cancer throughout the spectrum of their disease, but induce a number of adverse effects; metabolic, weight gain, and cardiovascular with increasing cardiovascular events. I think for me, one question, as you mentioned, we're not cardiologists, and I don't think many of the people that will listen to this are cardiologists. Is there a critical cutoff in total plaque volume or NCPV that predicts more strongly for MACE, only because on the HERO trial there was 2.9% MACE with relugolix, 6% with leuprolide, and you have to sort of say to yourself, maybe you have to have a lot of plaque before something really significant happens.
Sagar Patel: Totally. Yeah. Leslie, that's a really important question, because what's the clinical implications of these findings? Do they really matter clinically? So actually recently, a large kind of multinational prospective study has been carried out in the cardiology world. It's called the CONFIRM-II trial, where they've taken a heterogeneous population and done pre and post or prospective cardiac CT, looked at changes in plaque volumes and correlated that with subsequent MACE. One kind of at least preliminary cutoff point is 50 millimeters cubed of plaque volume change that is significantly associated with an increased risk of MACE down the road, specifically at four years. So an increase of 50 millimeters cubed of total plaque volume is associated with an increased four-year risk of MACE. So that is a number that, again, it's early, it's based off the CONFIRM-II study. I think it needs to be validated in other cohorts, but that is an initial kind of threshold for which we believe that that enhances someone's risk for having an adverse cardiac event. And here in the REVELUTION study, the plaque increase with leuprolide at 12 months was again, above 50 millimeters cubed when you compared it with relugolix, and especially when you compared it with guys who did not get any hormone therapy.
Leslie Ballas: Thank you for that, because I didn't know that. I also wonder if there's a qualitative component to the way that plaque is formed that makes it more likely to cause MACE in the sense that in your really terrific schematic, you could have plaque that forms sort of parallel to the vessel, or you had one where it was kind of curving around the vessel. The only reason I ask that is if 50 millimeters cubed of plaque increases your risk of MACE, you would think that the men that got leuprolide on HERO, there were 622 men, there'd be more than 6% that had MACE, especially given the other sort of negative confounders that come with ADT.
Sagar Patel: Absolutely. Yeah. I think, Leslie, you bring up an important point that I think is really important for readers and the audience to be aware of that. This study was accrued and recruited from a notoriously co-morbid population in the Southeast US. So our cohort for REVELUTION is a higher-risk cohort than probably that represented in HERO, and that represented in other populations in the United States. I think if, when you look at our paper, the baseline plaque burden in our patients was quite high. Again, this study excluded men with any major adverse cardiac events within 12 months of enrollment, or excluded guys with prior coronary stents or CABG surgery. So we tried to get cardiovascularly healthy men, but even then the plaque burden was quite high. So I think that might be a reason why we are seeing a substantially stronger kind of signal for this than we may extrapolate in comparing with the HERO studies as well. And then the other point you brought up I think is really, really interesting because you're asking a really kind of anatomical question, where is this volume coming from? Is it more longitudinal?
Is it more kind of concentric that may result in MI? That's actually a future analysis we're working on. We're able to look at per-lesion changes. With our collaboration with HeartFlow, they've developed more sophisticated software to be able to hone in on a specific high-risk lesion and actually see how that specific lesion changes. So as opposed to getting this summative blood volume, we want to actually look at the particular plaque features and see how those are changing, whether it is more longitudinal, whether it is more concentric and inclusive. There's going to be more to come with that in the future.
Leslie Ballas: Is there any signal from subset analysis of the patients who are on a statin prior to initiation, and either ADT, whether or not they had a similar increase in plaque volume comparable to the other men who weren't on statins?
Sagar Patel: Yeah. Yeah. I mean, that's an astute question and one that we actually presented at the American Heart Association concurrently. It was a post-hoc analysis where we wanted to look at the association of statin use with these plaque changes. We interestingly found that baseline statin use did mitigate the plaque progression effects seen in men receiving leuprolide. It was quite substantial. While the effect of statin on relugolix was a bit minimal, because men receiving relugolix did not have much of a plaque progression change in any of these ways, but those men receiving leuprolide did have substantial mitigation of their plaque progression when they were on a statin.
Leslie Ballas: Yeah. It'll be interesting to find out whether that when put into effect on a large-scale population, maybe adding a statin, or more importantly in this population, optimizing statin use, would actually make a difference. As I'm sure you remember, there was a whole bunch of excitement about the addition of metformin for men on ADT because of smaller studies that showed that there was a benefit in terms of some of the metabolic problems that were associated with ADT. And then when they looked at the STAMPEDE data with metformin, they found really, it made very little difference.
Sagar Patel: Yeah. Yeah. I think you're spot on there. I think we certainly need to validate this in larger cohort. That's a future initiative that I think we need to get a multi-institutional study, look at this in larger numbers with more diverse population. And I think the effect in the attribution of statin is important, because a really cost-effective risk-mitigating therapy. The challenge though is, as you and I experience day to day, when we're seeing our patients, we're laser focused on their prostate cancer. We're risk stratifying their oncologic risk and using crude assessments of their cardiovascular risk. Things like prior MI, hypertension. But I think early cardio-oncology or early cardiology optimization may be an important answer to mitigating their long-term risk as well.
Leslie Ballas: Dr. Patel, you are singing music to my ears. We have a study that's just about to open at Cedars called the Heart-Safe Study. And we actually are using men who are also on an ARPI because of the increased risk even with ARPI, and randomly assigning them to either cardio-oncology visit, or a letter to their primary care doctor, letting them know that they're starting ARPI and ADT, and looking at what kind of intervention is done and if that makes any difference. And we're using cardio-oncology because of just the strong presence at Cedars. Although if we're able to discover that optimization can be done in a primary care doctor's office, then obviously then that's enough also.
Sagar Patel: That's exciting that you guys are carrying that out, because I think that is an important missing link in optimally caring for our patients, and it's getting their early cardiology input or primary care input, early optimizing these patients. So that's fantastic. And also, Leslie, that's a perfect segue and a plug for me to also share that our sister, or our follow-up, study for REVELUTION is the REVELUTION II study where we're doing a similar schema, but looking specifically at men with more advanced disease who are getting dual-agent intensified ADT with the second-generation ARPI, because that-
Leslie Ballas: We know that that-
Sagar Patel: Exactly.
Leslie Ballas: ... is a risk, like four-fold over no ADT and two-fold over ADT alone.
Sagar Patel: Exactly. Based on the STAMPEDE and LATITUDE studies, we know it exacerbates their CV risk. So our REVELUTION II study has a very similar schema, except men who are getting dual-agent ADT and ARPI, and we're doing pre- and post-cardiac CT assessments.
Leslie Ballas: This is great. Dr. Patel, thank you for sharing this. You have really opened up our eyes to the effects of these medications, which a lot of us prescribe sometimes without thinking about all of the effects. And so thank you for this amazing study and all that you're doing to healthcare for our patients.
Sagar Patel: Absolutely. Leslie, thank you so much for your time and this opportunity.