Exploring The Impact of ADTs on Cardiac Risk in Prostate Cancer Treatment

In a conversation with CancerNetwork®, Yun Rose Li, MD, PhD, assistant professor and physician-scientist from the Department of Radiation Oncology at City of Hope, detailed the clinical catalyst behind the phase 2 IMPACT-ADT trial (NCT07202247). The study was born from a striking observation during Li’s prior research on intermittent fasting: a patient with no traditional cardiac risk factors experienced a ST-elevation myocardial infarction (STEMI) weeks after initiating androgen deprivation therapy (ADT). This event underscored a critical gap in oncologic care—the difficulty clinicians face when using existing criteria to predict which patients will develop acute cardiovascular events of testosterone suppression.

She further explained that as patients with prostate cancer live longer, the competing risk of cardiovascular morbidity moves to the forefront of clinical decision-making. Standard ADT, which is known to induce metabolic shifts—including insulin resistance, increased visceral adiposity, and sarcopenic obesity—may result in acute coronary events occurring within the first 6 months of therapy, often before significant, visible changes in body composition or muscle mass take place. To address these risks, the IMPACT-ADT trial—a collaboration with cardio-oncologist June-Wha Rhee, MD, funded by the American Heart Association—will evaluate 3 protective strategies: intermittent fasting, glucagon-like peptide-1 (GLP-1) receptor agonists such as semaglutide (Ozempic) or tirzepatide (Mounjaro), and the American Heart Association’s “Life’s Essential 8” guidelines.

According to Li, the decision to study GLP-1 agonists was driven by their increasing prevalence in standard medical practice and their established benefits in reducing cardiovascular disease. Although some concerns exist regarding muscle wasting, Li emphasized that the trial’s short-term focus prioritizes immediate cardiac protection during the high-risk initial phase of ADT. Furthermore, the study utilizes a multidisciplinary team, including board-certified endocrinologists, to monitor for gastrointestinal (GI) adverse effects (AEs). Although these symptoms can overlap with radiation-induced toxicities, early data suggest that GLP-1 agents are well-tolerated alongside definitive radiotherapy. Ultimately, the IMPACT-ADT trial seeks to provide an evidence-based framework to mitigate treatment-related risks and optimize long-term survivorship.

CancerNetwork: What was the background behind conducting the phase 2 IMPACT-ADT trial?

Li: This was initially inspired by my own patients from a prior study. What I am referring to is our phase 2 randomized study looking at intermittent fasting in patients undergoing pelvic radiotherapy. In that study, we were looking at the role of fasting vs nutritional counseling to mitigate radiation toxicity. While I was conducting that study, one of the earliest patients I enrolled on the study developed a full classical STEMI, and it happened a few weeks into him starting hormonal therapy. He had none of the major risk factors of someone whom we would expect to have a heart attack.

When that happened, it [prompted] me to think: “What are the long-term and short-term consequences of hormonal therapy?” Because of that patient, I started to look and follow other patients who were getting hormonal therapy. Even though I am a radiation oncologist, I trained at an institution where we are the ones prescribing hormonal therapy. This was an issue near and dear to my heart.

As patients are living longer and being diagnosed later with prostate cancer, competing risk in terms of morbidity and mortality becomes an ever more important issue at the forefront of how we think of clinicians. There are patients whom we think probably need hormone therapy, but we might be shortening their lifespan or causing significant harm to their overall quality of life. We must weigh this; should we do hormone therapy or not?

To make that informed decision, we need to know who’s going to be at risk. It’s easy to identify patients who are “clearly at risk”: they had a prior heart attack, they had prior stents placed, [or] they have a history of stroke. The patients who have no prior cardiac history may not even have diabetes and may not even be significantly morbidly obese. Those are the ones where we don’t know who is going to be at risk. That was one of the patients whom I initially met for my other study, and that made me think about how we can start to address these issues and identify risk factors.

That’s what prompted the development of the study and the strong collaboration with my [co-principal investigator], June-Wha Rhee, MD, who is a cardio-oncologist at City of Hope. She and I are both physician scientists, and her research team is interested in ADT’s native effects on the heart and the cardiovascular system as well as being able to model those risk factors. When I started to run my study and see multiple patients come in with coronary artery disease and related risk factors plus those who did not have risk factors but then developed coronary artery disease, it prompted me to [think], “What are the risks in patients who are bearing that?” We don’t know. We’re not able to adequately inform them. That’s what motivated us to write this study.

Given the metabolic profile of patients on ADT, specifically regarding the risk of sarcopenic obesity, what was the rationale for choosing a GLP-1 agonist over other agents?

It was a question raised by the American Heart Association. Rhee and I wrote a grant that’s now funded by the American Heart Association. It was part of their Translational Collaborative Sciences Award (CTSA) program, specifically aiming to bring together clinicians across different disciplines to think about important questions to address in cardiovascular disease.

The reviewers brought up this question, too, [regarding] the concern about muscle wasting as a risk factor related to GLPs. Part of the reason we chose GLP as [treatment for] one of the arms of the study was fundamentally because more patients, regardless of whether we had the study or not, were coming in asking to be on the drug or be placed on the drug as a part of standard of care. We realized we had no information on the long-term or even short-term safety of putting patients on this agent. It was an important question to study, and it was almost chosen for us because of this new wave of interest in GLP agents. There has been a lot of data looking at GLP and reducing cardiovascular disease in patients with obesity and diabetes as prior risk factors. We thought that this would be a reasonable drug to study, as patients are already coming in and receiving them. Part of the rationale for the study was to look at patients getting short-term hormone therapy. We debated this back and forth to consider whether we should focus on short-term [therapy alone] or short-term and long-term hormone therapy.

To take a step back, patients with prostate cancer are recommended 6 months or longer [in] terms of hormone therapy, depending on how aggressive their prostate cancer is and their [phase of] disease. In different contexts, different durations of hormone therapy are recommended.

The reason we chose to focus on 6 months of hormone therapy is because, interestingly enough, the vast majority of patients who experience an acute coronary event are getting these events within the first 6 months, which is counterintuitive to how we think about the negative impact of ADT. We know ADT has negative effects on muscle mass [and] on visceral obesity. We know that it has effects on insulin resistance and glucose control, as well as circulating lipid profiles. All these things are negatively affected by testosterone suppression. It’s an overall systemic protection for men in terms of all these metabolic risk factors. If that’s true, then one would guess that the risk of cardiac events will continue to increase over time if patients are getting, say, 2 years [of therapy]. Then, why are all the events happening in the first 6 months?

Fundamentally, we are not that worried about how much muscle loss is happening in that initial phase. If I have a patient getting, say, 2 years of hormone therapy, it wouldn’t surprise me if, at 6 months into their hormonal treatment, I don’t observe substantial weight gain, muscle loss, or increase in adiposity. Interestingly, in such patients, it’s not uncommon that after the first 6 months, when their testosterone is recovering at 9 or 12 months, you start to see some of those things because their testosterone is still not fully recovered and they are technically suppressed.

[Regardless of what] is causing this increased cardiac risk, there is some disconnect between our understanding of what ADT does to the metabolism and what it also does to the cardiac system. There may be a discrepancy in terms of what’s putting patients at risk in terms of short-term coronary events and long-term coronary artery events; we strongly encourage patients to do resistance-based exercise. Strength training and resistance training are important for maintaining bone density as well.

Are there other specific AEs that you are monitoring more closely in patients undergoing concurrent radiation therapy?

GLP has its own risks related especially to the GI system, and radiation can sometimes cause GI-related toxicities. We have a closer eye on those kinds of things, whether that’s nausea or changes in bowel habits and loose stools. However, all patients [assigned] to the GLP arm are meeting routinely with a board-certified endocrinologist who specializes in managing GLP. That’s why we don’t necessarily need to monitor them so closely during radiation.

From a radiation standpoint, I don’t expect a whole lot more in terms of toxicity, partly because nausea is quite rare in terms of radiation-related [adverse] effects for prostate cancer; it happens in less than 5% to 10% of the patients we see, on average. More [often] than not, GLP tends to slow down bowel function; during radiation, we see more things like diarrhea and loose stools. They’re probably counteracting each other, if we were to guess. We haven’t seen anything so far in terms of patients I’ve treated; I’ve treated probably a dozen patients on GLP before, during, or after radiation as part of their standard of care. They’re getting GLP from their primary [provider] or from their endocrinologist, and those patients have not experienced [unexpected] toxicities.

Reference

Metabolic interventions (time-restricted eating, GLP1 Receptor Agonist, and heart healthy diet) to improve cardiometabolic health in prostate cancer patients during androgen deprivation therapy, IMPACT-ADT trial. ClinicalTrials.gov. Updated February 4, 2026. Accessed February 5, 2026. https://tinyurl.com/juvxzzbu