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Androgen-deprivation therapy (ADT) is the mainstay treatment for management of advanced prostate cancer. Reduced testosterone levels can be achieved by either medical castration or surgical castration. Medical castration had been a preferred way to achieve castrate levels of testosterone in countries where access to luteinizing hormone-releasing hormone (LHRH) agonists or antagonists is not limited. LHRH agonists had been more commonly utilized because of the flexibility of duration options available.

However, in the last decade there had been multiple meta-analyses published with conflicting reports on increased cardiovascular (CV) toxicity from LHRH agonists as compared with antagonists. The recent review by summarizes this discussion, especially in context with the newly approved oral LHRH antagonist relugolix and findings from the trial.

The authors highlight the lack of dedicated randomized clinical trials (RCTs) evaluating cardiovascular outcomes between LHRH agonists and antagonists. Most of the RCTs used to evaluate CV outcomes have done so as ad-hoc analyses and safety reports instead of designating CV outcomes as primary or secondary outcomes.

There were two studies that looked at CV outcomes more closely -- and the . In the study by Margel et al., no significant difference was observed in endothelial dysfunction, which was the primary end point, but the results did show increased major cardiovascular events (MACE) in the agonist group. The study had a small sample size of 80 patients and there was observed imbalance of diabetics in the treatment arms which could have accentuated the difference.

The HERO (relugolix) study collected MACE from safety analysis, but used MedDRA codes to assign adverse events that were not independently adjudicated or verified.

The current discussion as presented by the authors revolves around the PRONOUNCE study, which was the only large phase III study designed with MACE as the primary end point with patients being randomized to LHRH agonists or antagonists.

The study was terminated early due to slow accrual and event rates, but it had accrued 545 patients out of a planned 900 patients and attained the entire prespecified follow-up length for its primary outcome in the patients randomized on the trial. Regardless, the study failed to show a difference in the two arms for MACE events, all-cause mortality, myocardial infarction, and stroke rates.

Despite the study's weakness, I agree with the authors that it offers good evidence that in general CV risk is overrated for LHRH agonists and antagonists. The study was designed to ascertain CV events through central adjudication, which help isolate the confounders.

In summary, the evidence for CV risk associated with LHRH agonists is limited and should not dissuade oncologists and urologists from using them for medical castration. In my practice I use a personalized approach when selecting patients for agonist or antagonist. Patients who require immediate testosterone control, who are debating between intermittent or continuous therapy or who are afraid of adverse events of ADT are the ones for whom I use antagonists first versus patients who are okay with long-term control, and would prefer fewer visits to the clinic and less risk of complications with possible testosterone flare in the beginning, who receive agonists.

Most of my patients on long-term ADT are eventually able to switch to agonists because of the convenient administration schedule.

Parminder Singh, MD, is assistant professor of hematology/oncology at the Mayo Clinic in Scottsdale, Arizona.

Read the commentary here and an interview about it here.