Real-world safety and efficacy of enzalutamide versus darolutamide in nonmetastatic castration-resistant prostate cancer: a multicenter retrospective study

Background Although enzalutamide and darolutamide share a common mechanism of action targeting the androgen receptor pathway, they differ in their molecular structure and pharmacological properties, which may influence their efficacy and safety. However, real-world evidence directly comparing these agents in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) remains limited. Materials and methods In this multicenter retrospective study, data from 198 patients who received enzalutamide or darolutamide as their first androgen receptor signaling inhibitor (ARSI) during treatment of nmCRPC were analyzed. Adverse events (AEs) and prostate-specific antigen (PSA) responses were compared. Progression of PSA and development of metastases were assessed using the Fine-Gray subdistribution hazards model, adjusting for death as a competing risk. Results In the cohort, 94 (47%) patients received enzalutamide and 104 (53%) received darolutamide. Incidence rates of any-grade AEs and grade ≥3 AEs were similar between the two groups ( P = 0.968 and P = 1.000, respectively). The rates of any PSA response, decline in PSA ≥50%, and decline in PSA ≥90% did not differ significantly between the two groups ( P = 0.130, P = 0.687, and P = 0.171, respectively). In multivariable analyses, ARSI type was not significantly associated with progression of PSA [reference, enzalutamide; subdistribution hazard ratio (SHR), 1.153; P = 0.620] or development of metastases (reference, enzalutamide; SHR, 0.815; P = 0.510). Conclusions Enzalutamide and darolutamide had comparable safety and oncological outcomes in patients with nmCRPC. These findings support the use of either agent as an appropriate first ARSI treatment.