Highlights
In a landmark randomized clinical trial involving men with nonmetastatic prostate cancer (PCa), the GnRH agonist leuprolide was associated with a significantly greater increase in total coronary plaque volume (TPV) over 12 months compared to the GnRH antagonist relugolix.
The observed increase in plaque volume was primarily driven by noncalcified plaque volume (NCPV), a specific phenotype of atherosclerosis often associated with higher vulnerability and increased risk of acute coronary syndromes.
This study provides critical mechanistic evidence that may explain the divergent cardiovascular safety profiles observed between different classes of androgen deprivation therapy (ADT), offering a potential pathway for personalized treatment selection in patients with high cardiovascular risk.
Adjustments for age, statin use, and baseline plaque volume did not mitigate the findings, suggesting that the class of ADT is an independent driver of coronary atherosclerosis progression in this population.
Introduction: The Intersection of Urologic Oncology and Cardiovascular Health
Androgen deprivation therapy (ADT) is the cornerstone of treatment for many stages of prostate cancer, particularly when combined with radiotherapy for localized, high-risk disease. However, the survival benefits of ADT are frequently shadowed by its metabolic and cardiovascular side effects. For decades, clinicians have observed an association between ADT and increased risks of myocardial infarction, stroke, and cardiovascular mortality. As prostate cancer patients live longer due to oncologic advancements, cardiovascular disease (CVD) has emerged as a leading cause of non-cancer death in this demographic.
The biological basis for this risk has remained a subject of intense debate. Traditional theories point to metabolic shifts—such as weight gain, insulin resistance, and dyslipidemia—as the primary culprits. However, recent clinical attention has shifted toward the specific pharmacologic mechanism of ADT. There is a growing body of evidence suggesting that gonadotropin-releasing hormone (GnRH) agonists (like leuprolide) and GnRH antagonists (like relugolix) may have distinct cardiovascular safety profiles. The HERO trial (NCT03085030) previously demonstrated a 54% reduction in major adverse cardiovascular events (MACE) with relugolix compared to leuprolide, yet the underlying reason for this difference remained speculative. This new study, published in JAMA Cardiology, seeks to bridge that gap by examining the direct impact of these therapies on coronary artery anatomy using advanced imaging.
Study Design: The Atlanta Randomized Clinical Trial
To investigate whether ADT class influences the rate of atherosclerosis, researchers at four centers affiliated with a single academic institution in Atlanta, Georgia, conducted an open-label randomized clinical trial. The study enrolled 65 men with nonmetastatic prostate cancer who were candidates for pelvic radiotherapy and at least six months of ADT. Importantly, participants had no prior exposure to ADT, ensuring a clean baseline for observing the therapy’s effects.
Patient Population and Randomization
Participants were randomly assigned in a 1:1 ratio to receive either the GnRH agonist leuprolide or the GnRH antagonist relugolix. Of the 65 men enrolled, 62 completed the full 12-month protocol, including the necessary imaging. The mean age of the cohort was 68.5 years, and 56% were already on statin therapy, reflecting a typical clinical population with existing cardiovascular risk factors. The trial enrollment spanned from June 2022 to March 2024, with data analysis concluding in mid-2025.
Primary and Secondary Endpoints
The primary endpoint was the change in coronary artery total plaque volume (TPV) from baseline to 12 months, as measured by coronary computed tomographic angiography (CCTA). CCTA is a highly sensitive, non-invasive imaging modality that allows for the quantification of different plaque subtypes. Secondary endpoints included changes in noncalcified plaque volume (NCPV), calcified plaque volume (CPV), and low-attenuation plaque volume (LAPV), the latter of which is often considered a hallmark of high-risk, “vulnerable” plaque.
Key Findings: Quantifying Plaque Progression
The results of the trial revealed a striking divergence in how the two classes of ADT affect the coronary arteries. Patients treated with the GnRH agonist leuprolide experienced significantly more aggressive plaque progression than those treated with the antagonist relugolix.
Total and Noncalcified Plaque Volume
After adjusting for baseline plaque volume, age, and statin use, the leuprolide group showed a significantly greater 12-month increase in TPV compared to the relugolix group. The estimated difference was +68.9 mm3 (95% CI, 23.2-114.5 mm3; P = .02). When looking at the composition of this plaque, the difference was almost entirely driven by noncalcified plaque volume. The leuprolide group had an estimated increase in NCPV that was 64.5 mm3 greater than the relugolix group (95% CI, 31.6-97.3 mm3; P = .004).
Calcified and Low-Attenuation Plaque
Interestingly, there were no statistically significant differences between the two groups regarding the change in calcified plaque volume (CPV) or low-attenuation plaque volume (LAPV). While calcified plaque is often seen as a sign of “stabilized” or older atherosclerosis, noncalcified plaque is more metabolically active and susceptible to rupture. The fact that leuprolide specifically accelerated noncalcified plaque progression suggests a more acute and potentially dangerous shift in coronary health.
Expert Commentary: Mechanistic Insights and Clinical Implications
The findings from this trial provide the first randomized evidence that ADT class directly impacts the progression of coronary atherosclerosis. But why does a GnRH agonist potentially cause more harm than an antagonist? Several mechanistic theories have been proposed by experts in the field.
The FSH Hypothesis
One primary distinction between the two therapies is their effect on follicle-stimulating hormone (FSH). GnRH agonists initially cause a surge in LH and FSH before downregulating receptors, but they often do not suppress FSH levels as completely or as rapidly as GnRH antagonists. Some preclinical studies suggest that FSH receptors are expressed on vascular endothelial cells and that FSH may promote proinflammatory pathways and lipid accumulation within the arterial wall.
T-Cell Activation and Plaque Stability
Another theory involves the role of T-cells. GnRH receptors are found on T-lymphocytes. Agonists may stimulate these receptors, leading to the activation of T-cells and the subsequent release of cytokines that destabilize atherosclerotic plaques. Antagonists, by blocking these receptors, might prevent this inflammatory cascade. This is particularly relevant because the study found the difference was in noncalcified plaque, which is the subtype most influenced by active inflammation.
Reconciling with the PRONOUNCE Trial
Clinicians might point to the PRONOUNCE trial, which failed to show a difference in MACE between degarelix (an injectable antagonist) and leuprolide. However, experts note that PRONOUNCE may have been underpowered or limited by its specific patient selection. The current study uses a more sensitive surrogate marker—plaque volume—which can detect biological changes long before a clinical event like a myocardial infarction occurs. It suggests that while MACE outcomes might take years to diverge, the underlying pathology begins to shift within the first 12 months of therapy.
Conclusion: A Shift Toward Cardio-Oncology Collaboration
This randomized clinical trial marks a significant step forward in our understanding of the “cardio-oncology paradox.” By demonstrating that the GnRH agonist leuprolide is associated with greater coronary plaque progression than relugolix, the study provides a biological rationale for choosing GnRH antagonists in patients with pre-existing cardiovascular disease or high risk of atherosclerosis.
For urologists and radiation oncologists, these findings emphasize the importance of cardiovascular risk stratification before initiating ADT. For cardiologists, it highlights the need for vigilant monitoring of patients on GnRH agonists. As the medical community moves toward more personalized care, the choice of ADT may soon be dictated not just by oncologic efficacy, but by the need to protect the patient’s cardiovascular system.
Future research should focus on whether these imaging-based changes translate into long-term differences in clinical outcomes across broader populations, and whether aggressive lipid-lowering therapy can mitigate the plaque progression seen with GnRH agonists.
Funding and Trial Registration
This study was conducted at centers affiliated with a single academic institution in Atlanta, Georgia. The data analysis was completed in June 2025. The trial is registered at ClinicalTrials.gov under the identifier NCT05320406.
References
1. Patel SA, Yadalam AK, van Assen M, et al. Coronary Plaque Progression After Androgen Deprivation Therapy in Men With Prostate Cancer: A Randomized Clinical Trial. JAMA Cardiology. 2026; doi:10.1001/jamacardio.2025.xxxx (Published February 18, 2026).
2. Shore ND, Saad F, Cookson MS, et al. Oral Relugolix for Androgen-Deprivation Therapy in Advanced Prostate Cancer (HERO Trial). N Engl J Med. 2020;382(23):2187-2196.
3. Lopes RD, Higano CS, Sloane EM, et al. Cardiovascular Safety of Degarelix Versus Leuprolide in Patients With Prostate Cancer: The PRONOUNCE Randomized Trial. Circulation. 2021;144(16):1295-1307.
4. Bhatia N, Santos M, Jones LW, et al. Cardiovascular Effects of Androgen Deprivation Therapy in Men With Prostate Cancer. Circulation. 2016;133(19):1904-1914.
