MEN with localised prostate cancer treated with the GnRH agonist leuprolide experienced significantly greater progression of coronary plaque over 12 months compared with those receiving the GnRH antagonist relugolix, according to a randomised clinical trial.
Androgen deprivation therapy (ADT) is a cornerstone of treatment for prostate cancer but has long been associated with increased cardiovascular (CV) morbidity. However, the biological mechanisms underpinning this risk remain unclear, and comparative CV safety data for GnRH agonists versus antagonists have been conflicting.
In this open-label trial conducted across four centres affiliated with a single academic institution in Atlanta, Georgia, 65 men with nonmetastatic prostate cancer and no prior exposure to ADT were enrolled. All participants were receiving pelvic radiotherapy and were randomised 1:1 to receive either leuprolide (a GnRH agonist) or relugolix (a GnRH antagonist) for at least six months. A total of 62 men (31 in each arm) completed baseline and 12-month coronary computed tomographic angiography and were included in the final analysis. The mean age was 68.5 years, and over half were taking statins.
Leuprolide Increases Total and Noncalcified Plaque Volume
The primary endpoint was change in total plaque volume (TPV) in the coronary arteries at 12 months. Secondary endpoints included changes in noncalcified plaque volume (NCPV), calcified plaque volume, and low-attenuation plaque volume.
After adjustment for baseline plaque burden, age, and statin use, leuprolide was associated with a significantly greater increase in total plaque volume compared with relugolix. The estimated between-group difference in TPV was +68.9 mm³ (95% CI 23.2–114.5; p=0.02). This effect was largely driven by increases in noncalcified plaque volume, with a between-group difference of +64.5 mm³ (95% CI 31.6–97.3; p=0.004).
No significant differences were observed between treatment arms in changes to calcified plaque or low-attenuation plaque volumes.
Implications for Cardiovascular Risk in Prostate Cancer
The authors suggest that accelerated progression of noncalcified coronary plaque may represent a mechanistic link between GnRH agonist therapy and increased CV risk. These findings indicate that, in men requiring ADT for localised prostate cancer, the choice of GnRH agent may have important implications for short-term coronary atherosclerosis progression and potentially longer-term cardiovascular outcomes.
Reference
Patel SA et al. Coronary plaque progression after androgen deprivation therapy in men with prostate cancer: a randomized clinical trial. JAMA Cardiol. 2026;doi: 10.1001/jamacardio.2025.5586.
