The impetus for developing GnRH antagonists includes the desire to avoid the testosterone surge of GnRH agonists and the need for 2 agents initially (ie, an antiandrogen in addition to the agonist) to prevent that testosterone flare. The antagonists directly inhibit GnRH receptors in the pituitary gland and therefore produce a rapid suppression of testosterone, avoiding the testosterone surges that are associated with agonists.

The use of antagonists is particularly appropriate in certain circumstances. I would worry about the risk of an agonist-induced testosterone flare in patients who have a heavy burden of disease (eg, bone metastases and symptomatic disease). In addition, these antagonists may be especially important in those men who have a higher cardiovascular risk, as there have been some data to suggest that GnRH antagonists have more favorable cardiovascular outcomes compared with GnRH agonists.

Several presentations at AUA2021 were relevant to the GnRH antagonists. One involved relugolix, an oral GnRH receptor antagonist that was approved by the US Food and Drug Administration in December 2020 for use in advanced prostate cancer (abstract MP24-07). It is an oral agent, whereas the others are not. Saad and colleagues reported data from the HERO study, a multinational phase 3 trial. Men with advanced prostate cancer were randomized to relugolix (120 mg orally once daily) or leuprolide (3 monthly injections) for 48 weeks. Previously, Shore et al had reported that relugolix achieved rapid sustained suppression of testosterone levels and that, after 48 weeks of treatment, the risk of major adverse cardiovascular events was 54% lower in the relugolix group than in the leuprolide group. A subgroup analysis had suggested that this difference may have been even greater in patients with preexisting cardiovascular risk factors. At AUA2021, Saad and colleagues reported that the results indicated that the 2 agents had similar efficacy in lowering testosterone to the castration range, with no difference in castration resistance-free survival.

Another presentation at AUA2021 focused on testosterone recovery after androgen deprivation therapy (ADT), and this was an electronic health records network study of 66 million people by Bitran et al (abstract PD05-12). Among men with 2-year courses of ADT, testosterone suppression was still observed 5 years after cessation in many cases. They were unable to return to the eugonadal range. As noted in the abstract, this can have consequences such as metabolically adverse changes in body composition, increased insulin resistance, impaired bone health, and poor quality of life. The analysis found that GnRH agonists were associated with a greater long-term suppressive effect on testosterone levels compared with GnRH antagonists. To me, this was a surprising finding in that I am not certain as to what would account for this difference. Patients who are most likely to not recover testosterone were those who were older and those who were on ADT for a longer period, which are the 2 big risk factors for slow testosterone recovery or nonrecovery.