GnRH Antagonists: Current Evidence and Role in Prostate Cancer

Androgen deprivation therapy (ADT) has been a pillar in the management of prostate cancer (PCa) since the 1940s and remains a standard of care across different clinical scenarios of PCa. Gonadotropin-releasing hormone (GnRH) agonists are the most commonly used form of ADT because they have consistently proven to be effective. The arrival of GnRH antagonists, such as degarelix and relugolix, has introduced an alternative to agonists while offering distinct advantages. Antagonists achieve the rapid suppression of testosterone without the initial flare effect observed with agonists. Relugolix, an oral antagonist, has been reported to result in the rapid recovery of normal testosterone levels after treatment discontinuation and may be associated with a potentially lower cardiovascular (CV) risk than agonists. Moreover, antagonists provide an additional therapeutic option that enables an individualised treatment approach, aligning with the growing emphasis on personalised medicine. However, evidence regarding the superiority of antagonists over agonists in terms of clinical outcomes or side effects remains limited and, in some cases, contradictory. The effectiveness of antagonists, particularly in sustaining long-term testosterone suppression, and their safety profile, especially in relation to CV risks, remain debated. Although early studies indicate potential advantages, current clinical evidence is still evolving and requires further validation. This narrative review of the literature aims to provide a comprehensive update on the role of antagonists in PCa management, highlighting their potential benefits and limitations while addressing existing controversies. Despite the apparent advantages of antagonists, long-term prospective studies must be conducted to confirm their efficacy and safety, particularly when combined with other therapies, and to define their role across different disease stages.