Real-World Effectiveness and Treatment Persistence of Darolutamide, Apalutamide, and Enzalutamide in Non-Metastatic...

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.

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.

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.

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.