Navigating ADT Choices: Agonists Versus Antagonists and the Role of AR Pathway Inhibitors

At the 2025 American Society of Clinical Oncology Genitourinary Cancers Symposium, a roundtable of expert panelists convened to discuss the latest research and practice updates related to metastatic hormone-sensitive prostate cancer (mHSPC). Dr. Tanya Dorff of City of Hope Comprehensive Cancer Center was joined by Drs. Dan Childs, Andrew Hahn, Cora Sternberg, and Vadim Koshkin in the discussion.

In the third part of the roundtable, the panel focuses on decision-making between AR antagonists and abiraterone in prostate cancer treatment, weighing factors such as reimbursement, patient preferences, cardiovascular risks, and drug interactions. The panel explores the clinical considerations for using relugolix versus traditional LHRH agonists, highlighting its benefits in testosterone recovery and cardiovascular risk mitigation.

View the next segment on Precision Medicine: The Future of ARPI-PARP Combos and PSMA PET Imaging.

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Dr. Dorff: What factors influence the decision to use an AR antagonist versus abiraterone? Is reimbursement an issue, or is the choice more influenced by comorbidities and other medications the patient is taking?

Dr. Koshkin: I believe reimbursement is a significant factor. For instance, I have encountered challenges with relugolix, and it is often easier to prescribe Lupron. It is not only simpler logistically but also more feasible for patients who would otherwise face a substantial copay. That has been my experience.

Dr. Dorff: In monotherapy, I see a meaningful difference between agonists and antagonists. However, once combined with a potent AR pathway inhibitor, we do not have conclusive data on whether that distinction remains significant. We did present a poster from the Optics Registry demonstrating that patients opt for relugolix because they appreciate having an oral option. I also have many patients who strongly prefer avoiding injections, which surprises me. Physicians, however, are more attuned to testosterone suppression and recovery, which may influence their use of relugolix in earlier disease stages rather than in long-term metastatic settings. Any thoughts on agonists versus antagonists?

Dr. Hahn: I agree with everything that has been said. Relugolix is particularly beneficial when quick testosterone recovery is desired. That is its biggest strength. Regarding cardiovascular risk, I always point out that if there were a substantial difference between these drugs, we would not still be debating it after 20 years. When differences are significant, they become evident quickly. That said, there may be a meaningful distinction when treating frail patients with ADT monotherapy, particularly if they have preexisting cardiovascular conditions or multiple risk factors. In those cases, an antagonist might be preferable.

There is a well-conducted systematic review and meta-analysis from the UK demonstrating that the odds ratio for adding an AR pathway inhibitor is approximately two for major adverse cardiovascular events. While the difference between agonists and antagonists is minor, layering an AR inhibitor on top creates a much more pronounced cardiovascular risk. Since we are using doublet therapy for most patients now, this becomes an important consideration.

Dr. Sternberg: When selecting a drug, patient age is a critical factor. If a patient is elderly or has cardiovascular issues, I am hesitant to prescribe abiraterone due to its association with increased cardiovascular events. Additionally, liver function abnormalities require careful monitoring. In our practice, we bring patients in every two weeks initially to monitor their labs when starting abiraterone.

Dr. Childs: Regarding relugolix, I find it particularly useful in cases where patients undergoing radiotherapy are reluctant to receive ADT due to concerns about side effects. Rather than having them refuse ADT altogether, I can offer relugolix as an option that allows for quicker testosterone recovery if they experience significant side effects. The HERO trial does suggest potential cardiovascular differences between agonists and antagonists, so I am more inclined to use relugolix as monotherapy in patients with recent cardiac events.

You also raise another important point. ADT is rarely used alone anymore. It is typically combined with an AR pathway inhibitor. While we lack definitive data, pharmacovigilance studies from the VA and other sources indicate that abiraterone may carry a slightly higher cardiovascular risk than the “lutamides.” Further research is needed, but I am already factoring this into my clinical decisions.

Dr. Dorff: I agree, and I wonder if we should involve cardiology earlier in the treatment process unless we plan to manage cardiovascular risk ourselves. I was intrigued to hear urologists discuss monitoring A1C levels in addition to bone density. While medical oncologists are generally aware of bone health, seeing greater ownership of cardiovascular risk assessment was quite interesting.

Dr. Hahn: Many people reference the PRONOUNCE trial, which aimed to evaluate major adverse cardiovascular events in agonist versus antagonist therapy. However, the study was stopped early due to slow accrual and a low number of events. Some interpret this as evidence that the cardiovascular risk issue is not significant, but I believe the key takeaway is that every patient in the study saw a cardiologist before starting ADT. This underscores the importance of cardiovascular risk mitigation and highlights the need for greater involvement from cardiologists. Managing cardiovascular risk has become increasingly complex, and it is difficult for oncologists to stay up to date while managing prostate cancer treatment.

Dr. Koshkin: Along those lines, I am curious: do you routinely involve cardiologists in patient management, and at what stage of treatment do you bring them in?

Dr. Sternberg: Most of my patients already have a cardiologist by the time they come to me. If they do not, I sometimes consult a cardiologist before initiating therapy.

Dr. Childs: During the first visit, we cover a great deal of information: treatment options, side effects, and potential toxicities. Addressing cardiovascular risk at this stage can be overwhelming for patients. That is why I schedule a one-month follow-up to assess toxicity and introduce discussions about bone density, lipid levels, and A1C testing. At that point, I often recommend that patients follow up with their primary care physician for further cardiovascular evaluation.

Dr. Hahn: In my practice, we check lipid panels and hemoglobin A1C during the initial visit and reassess them annually. We also calculate the ASCVD risk score. If a patient has preexisting cardiovascular disease, we refer them to a cardio-oncologist early. Otherwise, if we observe a significant increase in cardiovascular risk due to hormone therapy, we act quickly to involve cardiology. For patients without notable risk factors, we rely on their internist to manage these concerns.

Dr. Koshkin: My approach is similar. Working at a tertiary academic center, we have the advantage of access to cardio-oncology specialists, and I try to utilize that resource whenever necessary.

Dr. Dorff: I also make a concerted effort to evaluate drug-drug interactions, as they differ between abiraterone and AR antagonists, and even among the AR antagonists themselves. I carefully review the patient’s medication list to ensure that the prescribed therapy is compatible. At this meeting, Alicia Morgans presented a prospective trial examining cognitive function in patients receiving abiraterone versus enzalutamide. Surprisingly, the study did not show a difference between the two. That contradicts what we sometimes perceive in clinical practice. Are there any other side effects that influence your choice between abiraterone and the “lutamides?”

Dr. Childs: Dr. Morgans presented another key finding at this meeting, which aligns with what was observed in the ODENZA trial. In ODENZA, patients with metastatic castration-resistant prostate cancer were exposed to both darolutamide and enzalutamide and were allowed to express their preference. Ultimately, there was no significant difference in preference between the two, although there was a slight trend toward darolutamide. I had expected a stronger preference for darolutamide, and it turns out that patient preference was largely driven by fatigue. This makes me question whether our clinical impressions are correct or if we need better tools to assess these side effects.

Dr. Sternberg: That is an interesting point. I had thought enzalutamide was associated with more falls and fractures compared to abiraterone, while abiraterone raises greater concerns regarding cardiovascular issues. However, some patients simply cannot tolerate enzalutamide, requiring me to switch them to abiraterone instead.