Real-World Effectiveness and Treatment Persistence of Darolutamide, Apalutamide, and Enzalutamide in Non-Metastatic Castration-Resistant Prostate Cancer: A Multicenter Study.

[INTRODUCTION] Three androgen receptor signaling inhibitors (ARSIs), darolutamide (DAR), apalutamide (APA), and enzalutamide (ENZ), are standard treatments for non-metastatic castration-resistant prostate cancer (nmCRPC); comparative real-world data on treatment persistence and safety remain limited.

[PATIENTS AND METHODS] We retrospectively analyzed 343 Japanese patients with nmCRPC treated with DAR (n = 92), APA (n = 64), or ENZ (n = 187) across 16 institutions. Oncological outcomes, including PSA progression-free survival (PSA-PFS) and PFS, were compared using multivariable Cox regression to adjust for baseline imbalances. Treatment persistence was evaluated by time to treatment discontinuation (TTD) and reasons for discontinuation.

[RESULTS] The ENZ group had significantly worse baseline characteristics than the other groups. After multivariable adjustment, DAR showed consistently favorable hazard ratios for PSA progression (HR, 0.55, P = .038) and disease progression (HR, 0.59, P = .047) compared with ENZ; however, these differences were attenuated and no longer statistically significant after PSM (PSA-PFS HR, 0.62, P = .119), suggesting broadly comparable oncological outcomes across agents. Median TTD was significantly shorter in the APA group (11.0 months) compared with the DAR (27.0 months) and ENZ (25.0 months) groups (P = .019). Discontinuation due to adverse events was significantly more frequent in APA (51.6%) than DAR (19.6%) or ENZ (18.8%), primarily due to skin rash. Among discontinuers, AEs were the primary reason in 82.5% of APA, 42.9% of DAR, and 41.7% of ENZ.

[CONCLUSION] In this real-world cohort, all 3 ARSIs demonstrated broadly comparable oncological outcomes, consistent with PSM. The principal differentiator was treatment persistence: APA was limited by markedly shorter TTD (median 11.0 months), primarily driven by skin rash; this difference was numerically preserved after PSM, though it did not reach statistical significance in the smaller matched sample. The high frequency of APA-related rash (46.9%) is consistent with prior Japanese/East Asian reports, including the integrated SPARTAN/TITAN Japanese analysis, and should be prioritized in treatment selection and patient counseling.