Introduction: The Cardiovascular Paradox of Androgen Deprivation Therapy
Androgen deprivation therapy (ADT) has remained the cornerstone of management for men with intermediate-risk and high-risk localized, as well as metastatic, prostate cancer (PCa) for decades. By suppressing testosterone to castrate levels, ADT effectively inhibits tumor growth and improves oncological outcomes. However, this therapeutic benefit comes at a significant metabolic and cardiovascular cost. Clinicians have long observed that men undergoing ADT experience an increased risk of cardiovascular (CV) morbidity, including myocardial infarction, stroke, and sudden cardiac death.
Recent years have seen a shift in the pharmacological landscape of ADT, moving from traditional gonadotropin-releasing hormone (GnRH) agonists (like leuprolide) to GnRH antagonists (like relugolix). The landmark HERO trial previously demonstrated that relugolix was associated with a 54% lower risk of major adverse cardiovascular events (MACE) compared with leuprolide. Despite these clinical findings, the underlying biological mechanism—specifically how these two classes of drugs differentially affect the coronary vasculature—has remained elusive. A new randomized clinical trial by Patel et al., published in JAMA Cardiology, provides critical insights into this mystery by examining coronary plaque progression through advanced imaging.
Highlights
– The GnRH agonist leuprolide is associated with significantly higher coronary total plaque volume (TPV) progression over 12 months compared to the antagonist relugolix.
– This progression is primarily driven by an increase in noncalcified plaque volume (NCPV), a phenotype of atherosclerosis traditionally associated with higher vulnerability and risk of rupture.
– There was no significant difference observed in calcified plaque volume (CPV) or low-attenuation plaque volume (LAPV) between the two treatment arms.
– These findings suggest that the cardiovascular safety profile of GnRH antagonists may be mediated by a relative stabilization or slower progression of soft coronary atherosclerosis.
Study Design and Methodology
This open-label randomized clinical trial was conducted across four centers affiliated with a single academic institution in Atlanta, Georgia. The study enrolled 65 men with nonmetastatic prostate cancer who were candidates for pelvic radiotherapy and ADT with a planned duration of at least six months. Participants were randomized in a 1:1 ratio to receive either the GnRH agonist leuprolide (administered via injection) or the GnRH antagonist relugolix (administered orally).
To precisely quantify changes in the coronary arteries, the researchers utilized coronary computed tomographic angiography (CCTA), a noninvasive imaging modality capable of characterizing plaque composition. Scans were performed at baseline and again 12 months after the initiation of ADT. The primary endpoint was the change in coronary artery total plaque volume (TPV). Secondary endpoints included changes in noncalcified plaque volume (NCPV), calcified plaque volume (CPV), and low-attenuation plaque volume (LAPV).
The analysis was rigorous, adjusting for baseline plaque volume, patient age, and the use of statins, which are known to influence plaque progression and stabilization. Of the 65 men enrolled, 62 completed the full 12-month follow-up and were included in the final data analysis.
Results: Quantifying Plaque Progression
The results revealed a striking divergence in coronary health between the two treatment groups. Men treated with the GnRH agonist leuprolide showed a significantly greater increase in atherosclerosis compared to those treated with the antagonist relugolix.
Total Plaque Volume (TPV)
After 12 months, the leuprolide group exhibited a substantially higher increase in TPV. The estimated difference between the groups was +68.9 mm3 (95% CI, 23.2-114.5 mm3; P = .02) in favor of relugolix. This suggests that the agonist treatment accelerated the overall burden of coronary artery disease significantly more than the antagonist treatment.
Noncalcified Plaque Volume (NCPV)
Perhaps the most clinically relevant finding was the change in NCPV. Noncalcified plaques are often referred to as “soft” plaques and are considered more prone to erosion or rupture than calcified, stable plaques. Leuprolide was associated with a significantly greater 12-month increase in NCPV compared with relugolix, with an estimated difference of +64.5 mm3 (95% CI, 31.6-97.3 mm3; P = .004).
Calcified and Low-Attenuation Plaque
In contrast, there were no statistically significant differences between the leuprolide and relugolix groups regarding the 12-month change in calcified plaque volume (CPV) or low-attenuation plaque volume (LAPV). This indicates that the primary driver of the difference in total plaque progression was the accumulation of noncalcified atherosclerotic material.
Mechanistic Insights: Why the Difference?
The study raises a fundamental question: why does a GnRH agonist promote more plaque progression than an antagonist? While both drugs achieve testosterone suppression, their mechanisms of action and secondary hormonal effects differ significantly.
The FSH Hypothesis
GnRH agonists work by overstimulating the GnRH receptor, leading to an initial surge in testosterone and gonadotropins followed by receptor downregulation. Crucially, follicle-stimulating hormone (FSH) levels often remain higher in patients treated with agonists compared to those on antagonists. Emerging evidence suggests that FSH receptors are expressed on vascular endothelial cells and may play a role in promoting inflammatory pathways and atherosclerotic progression. The more profound suppression of FSH achieved by relugolix might contribute to its relative vascular safety.
T-Cell Activation and Plaque Stability
Previous research has suggested that GnRH receptors are present on T-cells. Agonists may trigger a distinct inflammatory response within existing atherosclerotic plaques, potentially destabilizing them or accelerating the recruitment of lipids and inflammatory cells. This aligns with the study’s finding that the difference was concentrated in noncalcified (inflammatory-rich) plaque rather than calcified (stable) plaque.
Expert Commentary and Clinical Implications
For clinicians, these findings provide a biological rationale for the clinical outcomes observed in the HERO trial. For patients with prostate cancer who have a high cardiovascular risk profile—such as those with pre-existing coronary artery disease, diabetes, or multiple risk factors—the choice of ADT may be pivotal.
Dr. S.A. Patel and colleagues note that the rapid progression of noncalcified plaque within just 12 months is a sobering finding. In the context of oncology, where patients may remain on ADT for years, the cumulative effect on the coronary vasculature could be substantial. This study reinforces the importance of the “Cardio-Oncology” collaborative model, where the patient’s cardiovascular health is monitored as closely as their PSA levels.
However, there are limitations to consider. The study population was relatively small (N=62), and while the results were statistically significant, larger multicenter trials are needed to confirm these findings across more diverse populations. Additionally, the study was open-label, although the CCTA analysis was performed by blinded core laboratory personnel to maintain objectivity.
Conclusion
In men with localized prostate cancer undergoing radiation and ADT, the use of the GnRH agonist leuprolide is associated with significantly greater progression of coronary total plaque and noncalcified plaque volume compared to the GnRH antagonist relugolix. These results suggest that the cardiovascular advantages of GnRH antagonists may stem from their ability to limit the accumulation of vulnerable coronary plaque. As we move toward more personalized medicine, these findings support the consideration of GnRH antagonists as a preferred option for patients at high risk of cardiovascular events.
Funding and ClinicalTrials.gov
This trial was supported by institutional research funds and was registered at ClinicalTrials.gov with the identifier NCT05320406. Data analysis was conducted between March and June 2025.
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 Cardiol. 2026 Feb 18. doi: 10.1001/jamacardio.2025.5586.
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. Bhatia N, Santos M, Jones LW, et al. Cardiovascular Effects of Androgen Deprivation Therapy in Patients With Prostate Cancer. Circulation. 2016;133(15):1504-1514.
