Castration-resistant prostate cancer (CRPC) is a prostate cancer that keeps growing even when the testosterone level is reduced to very low levels. Enzalutamide (Xtandi®) is an orally bioavailable, organic, non-steroidal small-molecule androgen receptor (AR) signalling inhibitor. The US Food and Drug Administration (FDA) approved enzalutamide for nonmetastatic and metastatic CRPC in July 2018. To date, enzalutamide is not yet approved by the European Medicines Agency (EMA) for the assessed indication.

The PROSPER trial assessed the efficacy and safety of enzalutamide versus placebo in patients with nonmetastatic CRPC and a rapidly rising prostate-specific antigen (PSA) level. Analyses showed that patients of the enzalutamide group had a statistically significant benefit in median metastasis-free survival (MFS) (HR 0.29, 95% CI, 0.24–0.35, p < 0.001); hence, patients who received enzalutamide had a 71% lower risk of metastasis or death than patients who received the placebo. Patients of the enzalutamide group also had a statistically significant delay regarding the median time to PSA progression (HR 0.07, 95% CI, 0.05–0.08, p < 0.001) and the median time to first use of subsequent antineoplastic therapy (HR 0.21, 95% CI, 0.17–0.26, p < 0.001). For overall survival (OS), only data from the first interim analysis is available; at that point of time, 11% of the patients of the enzalutamide group and 13% of placebo-group patients had died. The median OS was not reached in either treatment group. One third of enzalutamide-group patients had an adverse event (AE) of grade 3 or higher. Serious AEs were more frequent among patients of the enzalutamide group than in placebo-group patients (24% vs. 18%); 3% of enzalutamide patients had an AE that led to death, compared to 1% in the placebo group.

The administration of enzalutamide in patients with nonmetastatic CRPC and a rapidly rising PSA prolonged MFS and delayed PSA progression and the use of subsequent antineoplastic therapy. However, the clinical benefit of enzalutamide reflected in OS prolongation and an improvement of the patients’ quality of life (QoL) has not been established yet. Final analyses of the PROSPER trial and further ongoing studies may provide information about whether prolonged MFS also implies prolongation of OS. At any rate, the benefits of enzalutamide treatment need to be weighed against the risks, always considering the patients’ QoL. Additionally, a direct comparison of enzalutamide and apalutamide is needed to verify the optimal treatment for this patient population.