Approaching Cardiovascular Risk in Prostate Cancer Hormonal Therapy

With prostate cancer survival continuing to improve, the long-term cardiovascular consequences of androgen deprivation therapy (ADT) have emerged as an increasingly urgent clinical challenge, and one that has historically been overshadowed by the primary focus on cancer control.

CancerNetwork® spoke with Faisal Mehmud, MD, MRCP, member of the Royal College of Physicians, about the cardiovascular risks associated with long-term hormonal therapy in prostate cancer, drawing on emerging biology, recent clinical data, and practical frameworks for patient management.

Mehmud began by explaining why cardiovascular risk in prostate cancer has historically been underappreciated relative to disease control. He then detailed the overlapping pathophysiological mechanisms, including worsened insulin sensitivity, dyslipidemia, QTc prolongation, and plaque biology, that drive cardiovascular morbidity in patients on ADT. He then described the mechanistic distinctions between GnRH agonists and antagonists, with particular emphasis on differential FSH suppression. He also discussed how data from the randomized phase 3/4 REVELUTION trial (NCT05320406)—which demonstrated significantly greater coronary plaque progression with leuprolide compared with a GnRH antagonist—have sharpened the clinical question of whether all forms of ADT are truly cardiovascularly equivalent.

He offered practical frameworks for risk stratification before starting therapy, actionable cardiovascular monitoring steps for clinicians without immediate cardiology access, and guidance on what patients and caregivers should be asking. He closed by describing the prospective studies needed to definitively establish cardiovascular differentiation with emerging GnRH antagonists, such as Teverelix trifluoroacetate (Teverelix TFA).

CancerNetwork: Why has the cardiovascular risk associated with ADT historically received less attention than cancer control outcomes?

Mehmud: Historically, the immediate priority in advanced prostate cancer has quite rightly been on controlling the disease directly. But our patients are often older men with hypertension, diabetes, dyslipidemia—particularly [elevated] cholesterol—and may have established vascular disease or a prior cardiovascular event. Now that we are seeing survival for patients with prostate cancer improving quite significantly, the cardiovascular consequences of long-term [ADT] are becoming increasingly important. The question has now evolved from, “Can we suppress and maintain suppression of testosterone?” to, “What can we do without unnecessarily adding to the patient’s competing cardiovascular risk?” Cardiovascular disease is a major competing cause of both morbidity and mortality in men with prostate cancer; and in some cases, more patients with prostate cancer die from cardiovascular disease than from prostate cancer itself.

What are the specific pathophysiological mechanisms at play, and how do they translate into the clinical events seen in practice, like metabolic syndrome, QTc prolongation, or major adverse cardiovascular events?

It is a complex situation. There are several overlapping mechanisms. Testosterone suppression itself can worsen body composition, insulin sensitivity, lipid profiles, and other metabolic risk factors. There are also treatment-specific effects that may go beyond testosterone lowering alone. With GnRH agonists such as leuprolide [Lupron], there is an initial stimulation of the receptor before downregulation, which produces a transient testosterone and gonadotrophin surge.

Antagonists, by contrast, block the receptor directly and avoid that initial stimulation. There is a growing interest in whether the 2 pathways have different effects on vascular inflammation and, in particular, plaque biology. GnRH receptors have been identified in vascular and immune tissues, and preclinical work suggests that agonist signaling could influence plaque instability and inflammatory pathways, though this remains an active area of investigation rather than a settled clinical question. For QTc prolongation, that is a separate issue clinicians need to be aware of with profound androgen deprivation, particularly in patients with other risk factors or medications that prolong the QT interval. I would treat that separately from atherosclerotic risk rather than bundling all cardiovascular toxicity under one mechanism.

What is the mechanistic difference between GnRH agonists and GnRH antagonists in terms of testosterone suppression, and what does that means for patients who already have underlying cardiac disease?

An agonist initially activates the GnRH receptor before eventually suppressing the axis, whereas an antagonist blocks the receptor immediately. Clinically, that means antagonists avoid the initial testosterone flare and achieve rapid suppression of testosterone and gonadotrophins. One potentially important additional difference is FSH [follicle-stimulating hormone]. Antagonists generally produce a much more profound and sustained suppression of FSH throughout the entire course of therapy compared with agonists; essentially complete FSH suppression vs partial suppression.

In a body with complete testosterone suppression but only partial FSH suppression, we believe that is a materially important contributing factor. How much it contributes to cardiovascular differentiation is still a hypothesis, but it is biologically plausible and interesting because FSH receptors have been implicated in both vascular and metabolic biology. For a patient who already has significant cardiovascular disease, these mechanistic differences are exactly why we need to be asking whether all forms of ADT are truly equivalent from a cardiovascular perspective, especially now that we are seeing very long patient outcomes with increasingly effective anti-cancer therapies.

Beyond avoiding the testosterone surge, there is growing interest in the idea that GnRH receptors are expressed in cardiovascular tissue itself, suggesting a potential direct cardioprotective effect from receptor blockade. How does Teverelix’s design engage with that biology, and what does that mean for its proposed safety profile in high-risk patients?

I would be cautious about calling this a proven direct cardioprotective effect, but what we can say is that there is a biologically plausible hypothesis. GnRH receptors have been described on cardiovascular and immune tissues, including the cells directly involved in atherosclerotic plaque biology. Continuous receptor stimulation with an agonist throughout treatment and direct receptor blockade with an antagonist are unlikely to be biologically identical. What has made this particularly interesting are data from the REVELUTION study, published earlier this year, coming out of Emory University in Atlanta.

In that randomized trial, patients receiving leuprolide had significantly greater progression of total and non-calcified coronary plaque volume at 1 year than patients who received an antagonist, despite similar testosterone suppression. That strongly raises the possibility that cardiovascular differences between agonists and antagonists may be pathway specific and not simply a consequence of testosterone lowering. This is highly relevant to Teverelix, because our central developmental question, which we will need to prove prospectively, is whether a long-acting injectable GnRH antagonist can provide effective, sustained androgen suppression while also demonstrating cardiovascular differentiation in men who are already at elevated cardiovascular risk.

Which patients should be prioritized for a cardiovascular risk conversation before starting hormonal therapy, and what should that risk stratification process look like in practice?

Every patient should have the conversation, but in particular, men with established atherosclerotic cardiovascular disease—prior myocardial infarction, stroke, heart failure—as well as patients with diabetes, poorly controlled hypertension, dyslipidemia, chronic kidney disease, and smoking history, especially those with multiple of these risk factors. The practical mistake in reality is to wait until a cardiac event occurs. Cardiovascular assessment should begin when the patient is being selected for treatment, not after the toxicity emerges.

At a minimum, I would want to know, for any patient in front of me: their cardiovascular history, blood pressure, smoking status, diabetes status, lipid profile, renal function, current cardiovascular medications, and whether they have had a prior, and especially recent, vascular event. Then, the question is: are those risk factors being optimally managed before, as well as during, ADT? That is the critical piece.

For clinicians who don’t have immediate access to a cardiologist, what are the most actionable steps they can take today to proactively identify and manage cardiovascular risk in patients on long-term ADT?

There is a lot that oncologists can do before involving a cardiologist. Measure blood pressure properly, check lipids, check HbA1c, ask about smoking, check weight and keep reviewing it, and assess physical activity. Make sure that any established cardiovascular disease the patient has is being treated according to standard guidelines. Review medications for interactions, and especially for QT-prolongation risk. Then, communicate actively with the primary care physician rather than allowing cardiovascular management to fall between oncology and primary care, as this is exactly the kind of thing that gets lost in the handoff. The objective is not to turn every oncologist into a cardiologist; it is to recognize the risk early, optimize the basics, and escalate the patients who truly need specialist cardio-oncology input, particularly now that we are seeing evidence of potential differentiation between agonists and antagonists.

What specific questions should patients and their caregivers be asking their treatment teams about cardiovascular risk at the time hormonal therapy is being considered, and how should those conversations evolve over the course of treatment?

I would encourage patients to ask a number of very direct questions. What is my cardiovascular risk before we start treatment? Could the type of hormonal therapy I am being offered affect that risk? What are we going to do to monitor that risk while I am on treatment? These conversations should not just happen at the beginning; they need to continue throughout the duration of ADT because blood pressure, glucose, lipids, and cardiovascular symptoms can all change during the course of treatment.

This is not a tick-box exercise at initiation. Patients are now receiving ADT for very long periods, and prostate cancer is increasingly becoming a chronic disease. We need to shift our mindset from thinking only about how long our patients are living to also asking what risks we are exposing them to while controlling their cancer. [These are] risks that could be managed effectively if we stay actively attentive to them.

What will the evidence base ultimately need to demonstrate for GnRH antagonists to be definitively established as the preferred option for managing cardiovascular risk in this patient population?

We are quite energized about the need to demonstrate definitively, in a randomized controlled study, that antagonists produce a different cardiovascular outcome for patients compared with agonists. Patients need ADT as their backbone treatment while other therapies are added on, and an increasing body of both real-world and clinical evidence is pointing in the direction that antagonists may be the safer option for high-risk patients. That is exactly why we believe it is critical to design a study that can establish this difference, learn from how others have struggled to generate the right evidence, and potentially utilize novel surrogate end points such as coronary plaque volume as a way to accelerate the pace at which we can demonstrate this. We have reached agreement with the FDA on a study design, and that study is moving forward.

Reference

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;11(5):459-463. doi:10.1001/jamacardio.2025.5586