Androgen deprivation therapy is the mainstay treatment of metastatic prostate cancer, achieved mainly by gonadotropin-releasing hormone (GnRH) agonists or antagonists.

To investigate the differential impact of GnRH agonists and antagonists on clinical safety and oncologic outcomes.

This meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. A literature search using the electronic databases (MEDLINE, Web of Science, Cochrane Library, and Scopus) included randomized controlled trials comparing the clinical safety and oncologic outcomes of GnRH agonists and antagonists. The endpoints of interest were the following: (1) treatment-related adverse effects (AEs), (2) prostate-specific antigen (PSA) progression, and (3) overall mortality. The relative risk (RR) was used as the summary statistic, and results were reported with 95% confidence intervals (CIs).

Eight clinical trials (20 published studies) comprising 2632 men met our inclusion criteria; of them, 1646 received GnRH antagonist and 986 had GnRH agonist. Treatment-emerging AEs occurred in 73% patients in the GnRH antagonist group and 68% in the GnRH agonist group (RR: 1.10, 95% CI: 1.04-1.15). Serious AEs occurred in 9.8% of the GnRH antagonist and 11% of the GnRH agonist group (RR: 0.92, 95% CI: 0.73-1.17). Antagonists were associated with higher injection site reaction rates (38%) than agonists (4.8%). GnRH antagonist was associated with fewer cardiovascular events (RR: 0.52, 95% CI: 0.34-0.80). There was no significant difference in PSA progression, but GnRH antagonist was associated with lower overall mortality rates than GnRH agonists (RR: 0.48, 95% CI: 0.26-0.90, p =  0.02).

Existing data indicate that GnRH antagonist use is associated with significantly lower overall mortality and cardiovascular events as compared with agonists. These findings should be interpreted with caution owing to the short follow-up duration and assessment of cardiovascular events as secondary endpoints in the included trials. Further studies are needed to validate or refute these observations. Injection site reactions were significantly higher in the GnRH antagonist group.

Gonadotropin-releasing hormone (GnRH) antagonist is associated with lower death rates and cardiovascular events than GnRH agonists, based on the data from trials with short follow-up duration. GnRH agonists are associated with lower adverse events, such as decreased libido, hot flushes, erectile dysfunction, back pain, weight gain, constipation, and injection site reactions. There were no significant differences in prostate-specific antigen progression or fatigue.