Association Between Castration-resistant Prostate Cancer Progression Patterns and Survival Outcomes in Metastatic Castration-sensitive Prostate Cancer: A Post Hoc Analysis of the TITAN Trial.

BACKGROUND AND OBJECTIVE: In metastatic castration-sensitive prostate cancer, the prognostic implications of castration-resistant prostate cancer (CRPC) progression patterns under upfront androgen receptor signaling inhibitors remain unclear. We evaluated the prognostic impact of CRPC subtypes and baseline predictors using TITAN trial data (NCT02489318). METHODS: Patients from the intention-to-treat population were analyzed (n = 525 for apalutamide; n = 527 for placebo). Patients who developed CRPC (n = 499) were classified as prostate-specific antigen (PSA)-CRPC (PSA progression preceding radiographic progression) or radiographic CRPC (radiographic progression concurrent with or preceding PSA progression). The 24-mo cumulative incidence of CRPC subtypes was estimated and compared between treatment groups using the Gray test. Overall survival was compared using inverse probability of treatment weighting-adjusted restricted mean survival time (RMST). KEY FINDINGS AND LIMITATIONS: Apalutamide significantly reduced the 24-mo cumulative incidence of PSA-CRPC (19% vs 52%; p < 0.001) but not that of radiographic CRPC (13% vs 14%; p = 0.6) compared with placebo. In the placebo group, radiographic CRPC was associated with a significantly shorter RMST than PSA-CRPC. In contrast, this difference was not observed in the apalutamide group. Baseline visceral metastasis was associated with radiographic CRPC in both treatment arms. CONCLUSIONS AND CLINICAL IMPLICATIONS: Prognosis differed between PSA-CRPC and radiographic CRPC in the placebo group, whereas this heterogeneity was less evident in the apalutamide group. Although apalutamide reduced the cumulative incidence of PSA-CRPC, the cumulative incidence of radiographic CRPC remained comparable to that with placebo. Baseline visceral metastasis was associated with radiographic progression, suggesting that these patients may warrant closer imaging surveillance.