REVELUTION-2 Trial Is Evaluating Cardiovascular Risk With Relugolix Plus Abiraterone Acetate in High-Risk Prostate Cancer

To better understand the cardiovascular risks associated with hormone therapy in prostate cancer, relugolix (Orgovyx) plus abiraterone acetate (Zytiga) is being compared with leuprolide plus abiraterone acetate in the phase 3/4 REVELUTION-2 trial (NCT06650579), according to Sagar A. Patel, MD.

“This trial is great for all hormone therapy–naive individuals who meet the eligibility criteria, meaning they’re eligible for prostate-directed radiation plus 2 years of intensified androgen deprivation therapy [ADT],” Patel said in an interview with OncLive®. “We are excluding men with a recent cardiovascular event, such as myocardial infarction or percutaneous coronary intervention within 12 months. But short of that, assuming they’ve never received any hormone therapy, we believe this trial is an excellent option because it provides patients with an opportunity to get a deep dive into their own cardiovascular health and the implications of this treatment.”

Patel is an associate professor and the director of brachytherapy in the Department of Radiation Oncology and an associate professor in the Department of Urology at Emory University School of Medicine in Atlanta, Georgia.

In the interview, Patel discussed the rationale for REVELUTION-2, the details of the ongoing study, and the next steps for this area of research.

OncLive: What prior data that led to the initiation of REVELUTION-2?

Patel: [The initiation of] REVELUTION-2 stemmed from data from the [phase 2] REVELUTION trial [NCT05320406]. We saw an increase in cardiovascular morbidity in men with prostate cancer receiving hormone therapy.¹

There are also recent data suggesting that there’s a drug-specific action [according to] hormone therapy type. It wasn’t that all hormone therapies are similarly causing the same risk, but that it was a drug-specific interaction. That led us to pursue REVELUTION, which was a randomized trial between 2 competing forms of hormone therapy: gonadotropin-releasing hormone [GnRH] agonist vs antagonist. [Data from] REVELUTION suggested that the coronary plaque progression within 1 year is significantly worse after GnRH agonist such as leuprolide vs an antagonist, which was relugolix in that trial.

Before we even found those results and published them, recent data had suggested that when you add on a second-generation hormone therapy drug [such as] abiraterone acetate, cardiovascular risk is enhanced. This was based on 2 prior studies: the [phase 2/3] STAMPEDE [NCT00268476] and [phase 3] LATITUDE [NCT01715285] trials.

These were trials that really tested the inclusion of a second-generation hormone therapy drug such as abiraterone acetate in men with advanced prostate cancer. These trials found that when you add abiraterone acetate to standard hormone therapy, the risk of cardiovascular events is significantly higher, especially hypertension and cardiovascular disease such as myocardial infarction or sudden cardiac death.

We as a group felt that doing intensified dual-drug hormone therapy may be more toxic to the heart. That led to the inception of REVELUTION-2, which is a randomized study of men with more advanced prostate cancer than REVELUTION.

What are the key design features of REVELUTION-2?

REVELUTION-2 is [enrolling] men with high-risk or advanced prostate cancer, who are eligible for definitive radiation plus intensified ADT, specifically dual-agent hormone therapy with backbone ADT plus abiraterone acetate.² The [study will include] men with localized very high-risk prostate cancer, lymph node-positive prostate cancer, or low-volume metastatic prostate cancer. All these patients receive prostate-directed radiation therapy, and all are eligible for 2 years of ADT plus abiraterone acetate. All 3 of those patient populations are eligible and they will receive prostate-directed radiation plus 2 years of ADT plus abiraterone acetate and they’ll be randomly assigned to either leuprolide plus abiraterone or relugolix plus abiraterone acetate.

All patients will undergo a baseline coronary CT angiogram prior to treatment initiation, and another coronary CT angiogram 12 months later, during which time all patients will be on continuous hormone therapy. In addition, all patients will undergo ambulatory blood pressure monitoring. The trial provides a home blood pressure device that syncs to our data pool; [patients] will check it every morning, and we’ll have very granular blood pressure data on these patients. The hypothesis is that the addition of abiraterone acetate certainly enhances cardiovascular strain and cardiovascular stress with higher blood pressure, and perhaps relugolix, as a GnRH antagonist, may mitigate that risk compared with leuprolide.

Do you anticipate any barriers to enrollment?

Currently guidelines support that the population REVELULTION-2 is enrolling are recommended to undergo backbone ADT plus abiraterone acetate. Abiraterone acetate was one of the first second-generation androgen receptor signaling inhibitors brought to market, so our guidelines really support it. However, it’s a moving target, and as we’ve had more and more trials come out over the past couple of years, we’ve realized that these other second-generation hormone drugs could as well be indicated. We have extrapolated from other trials that they may have similar benefit and perhaps lower toxicity risk for certain individuals compared with abiraterone acetate.

One of the challenges we’re seeing in REVELUTION-2 is the evolving landscape of prostate cancer; for men who are eligible for dual-agent intensified hormone therapy, although the guidelines primarily support ADT plus abiraterone acetate, some patients may prefer or be better treated with these other second-generation hormone therapy drugs. As investigators, we are anticipating this in REVELUTION-2. We’re tracking that, and perhaps may be more pragmatic in the future, but right now we are aligned pretty closely with the guidelines that advocate for abiraterone acetate in this cohort.

What clinical questions or unmet needs does this study aim to address?

The overall awareness around cardiovascular survivorship has really grown in prostate cancer over the past decade. REVELUTION did a good job identifying a missing link to understanding the cardiovascular risk from hormone therapy. But now we’re facing a new landscape in prostate cancer where we’re doing more intensified ADT, with ADT plus the second-generation agents, and the cardiovascular risk and the survivorship implications of that are completely unknown.

We believe that REVELUTION-2 is right on time with the inclusion of this kind of treatment protocol in our patients to really ascertain what the additional cardiovascular risk is. If we identify in REVELUTION-2 that the cardiovascular risk is indeed exacerbated with leuprolide compared with relugolix, we’ll have more awareness around that.

In the future, we’ll be able to identify patients that we could perhaps triage to cardiovascular risk-reducing drugs, such as relugolix, which will overall improve long-term outcomes, survivorship, and all-cause mortality. As the overall landscape of prostate cancer is changing to [include] more dual-agent ADT, REVELUTION-2 will be able to validate the cardiovascular safety of leuprolide or identify potential other drugs that should be used in men at high cardiovascular risk.

What are the future research directions in this space?

We’re first to the space in this area in terms of cardiovascular risk. Other ongoing trials nationally are looking at toxicity risk with intensified ADT, specifically with bone health, cognitive health, and certainly quality of life [QOL]. But to our knowledge, REVELUTION-2 is the first, and perhaps only, to really home in on cardiovascular risk, specifically looking at granular blood pressure data, coronary plaque data, and other imaging biomarkers we can measure on cardiac CT.

We’re excited to fill that void, but across the country and across the world, a lot of data are going into the intensified hormone therapy space. We know it should improve oncologic outcomes, but how is it impacting survivorship? Many of these patients won’t die of prostate cancer. We really need to understand what the impact of these more aggressive cancer therapies will be on the overall QOL and survivorship of these patients.

References

1. Patel S, Yadalam A, van Assen M, et al. Coronary artery plaque progression after androgen deprivation therapy in men with prostate cancer: a randomized controlled trial comparing relugolix versus leuprolide. Presented at: Society of Urologic Oncology Annual Meeting; December 2-5, 2025; Phoenix, Arizona.
2. REVELUTION-2: Relugolix+abiraterone acetate (AA) versus leuprolide+AA cardiac trial. ClinicalTrials.gov. Updated February 24, 2026. Accessed May 13, 2026. https://clinicaltrials.gov/study/NCT06650579