Leuprolide Accelerates Coronary Plaque Buildup in Prostate Cancer Patients, Small Trial Finds

The Question

Prostate cancer doesn't usually kill men directly. Cardiovascular disease does. For men on androgen deprivation therapy (ADT), that distinction matters enormously, because the drugs used to suppress testosterone can damage the heart.

The two main options are GnRH agonists like leuprolide, given by injection every three months, and the newer oral GnRH antagonist relugolix. Leuprolide has been the workhorse of ADT for decades. Relugolix showed a lower rate of major cardiovascular events in the large HERO trial, but researchers couldn't fully explain why.

A small randomized trial published March 4, 2026 and reported by Univadis tried to answer that question directly by looking inside the arteries.

What the Trial Did

Researchers enrolled 65 men with non-metastatic prostate cancer who were receiving pelvic radiotherapy plus at least six months of ADT. Participants were randomized 1-to-1: leuprolide (22.5 mg injection every three months) versus relugolix (120 mg orally once daily, after a 360 mg loading dose).

The primary endpoint was change in total coronary plaque volume at 12 months, measured by coronary computed tomography angiography. Secondary endpoint: change in non-calcified plaque volume specifically.

What They Found

Coronary plaque increased in both groups. That's expected — ADT suppresses testosterone, and low testosterone is bad for cardiovascular health regardless of the drug class.

But the gap between the two groups was measurable and statistically significant. Leuprolide was associated with 68.9 mm³ more total plaque growth compared to relugolix at 12 months (p = 0.02), after adjusting for baseline plaque volume, age, and statin use, according to Univadis's summary of the findings.

The critical detail: the faster progression on leuprolide was driven specifically by non-calcified plaque. Non-calcified plaques are less stable and more prone to rupture. The study's authors noted that non-calcified plaques are closely associated with myocardial infarction and other serious cardiovascular events.

Testosterone suppression was comparable between groups at months three and six. That rules out the simplest explanation. Both drugs were equally effective at lowering testosterone, yet their cardiovascular fingerprints diverged. The trial's authors concluded this suggests the cardiovascular difference stems from something other than testosterone reduction itself — that the cardiovascular effect of ADT is drug-pathway specific and independent of testosterone suppression.

What This Doesn't Prove

Fairness requires stating the limits plainly. Sixty-five patients is a small sample. The trial was open-label, meaning physicians and patients knew which drug they were getting. Plaque volume on CT angiography is a surrogate endpoint — it predicts cardiovascular risk, but the trial was not powered or designed to directly measure heart attacks, strokes, or deaths. And 12 months is a short follow-up window for a disease process that unfolds over years.

The source also notes that most patients in this cohort had coronary artery disease at baseline, which may limit generalizability to healthier populations. Changes in statin dosing after enrollment were not recorded, which could have influenced plaque progression.

Urologists and oncologists who prefer leuprolide have legitimate reasons: decades of safety data, established dosing protocols, and the fact that many patients do fine on it cardiovascularly, particularly those without pre-existing heart disease.

Why It Still Matters

The HERO trial — a much larger study — had already shown fewer major adverse cardiovascular events with relugolix versus leuprolide. That signal was real. This smaller mechanistic trial adds a plausible biological explanation: faster non-calcified plaque progression on leuprolide may be the pathway through which the drug causes more cardiovascular events downstream.

The study's authors stated that, to their knowledge, this is the first study to identify a biological basis for the different cardiovascular risks observed with different types of ADT.

For men with prostate cancer who already carry cardiovascular risk — prior heart attack, diabetes, hypertension, existing coronary disease — the choice between these two drug classes is no longer purely a matter of convenience or cost.

Relugolix is more expensive than leuprolide, and insurance coverage varies. That practical barrier has kept many patients on injectable GnRH agonists by default. This trial adds evidence that the cost calculus may need to include cardiovascular outcomes, not just drug acquisition prices.

The Unresolved Question

What exactly is the biological mechanism separating the two drug classes if it isn't testosterone suppression itself? The trial's authors flagged that the mechanism remains unclear. A larger, longer trial powered for hard cardiovascular endpoints — not just imaging surrogates — would be needed to confirm the benefit and explain it. Whether cardiology and oncology societies will revise shared guidelines on ADT selection in high-cardiovascular-risk prostate cancer patients is the concrete next step to watch.

The study was led by Dr. Sagar A. Patel of Emory University in Atlanta and published in JAMA Cardiology. The trial received support from the Prostate Cancer Foundation, Pfizer, and Sumitomo Pharma Switzerland GmbH. Several co-authors disclosed financial relationships with Pfizer, Sumitomo, or other commercial sources.