Impact of Testosterone Recovery on Oncologic Outcomes in High‐Risk, Localized Prostate Cancer

BACKGROUND: Prostate cancer (PCa) is the only cancer in men to exhibit androgen sensitivity at diagnosis, which has allowed for the development of androgen deprivation therapy (ADT). However, outcomes in high-risk PCa (HRPCa) remain significantly worse than low risk disease and the use of ADT varies among treatment algorithms and medical specialties. In men treated with radiation, testosterone recovery after completing ADT has been associated with oncologic outcomes. However, the relationship between testosterone recovery and oncologic outcomes following ADT in surgically managed HRPCa remains unexplored. METHODS: Using pooled data from two large, phase III clinical trials (CALGB 90203 and SWOG S9921), we performed a retrospective analysis of men with HRPCa treated with ADT and RP. Subjects were classified as recovered or non-recovered based on study protocol-defined testosterone recovery thresholds. Primary and secondary outcomes were overall survival (OS) and modified event-free survival (mEFS), analysed utilizing time-to-event Kaplan-Meier estimates and Cox proportional hazards models. Additional secondary analyses repeated this on an unpooled, per trial basis and also looked at speed of testosterone recovery using early ( ≤ 6 months) and late ( ≤ 12 months, including early recoverees) recovery subgroups. RESULTS: Among 445 eligible patients meeting our inclusion criteria, 87.2% achieved testosterone recovery. No significant differences in OS (HR = 0.72, p = 0.400) or mEFS (HR = 1.24, p = 0.360) were observed between the recovered and non-recovered groups. Similarly, no significant differences were present when OS and mEFS were analysed separately in each individual trial's cohort. Finally, we also saw no differences in oncologic outcomes between the early and late testosterone recovery subgroups. CONCLUSIONS: Testosterone recovery status and speed were not significantly associated with oncologic outcomes in HRPCa patients treated with RP and ADT. These findings, the first to assess this question in a surgical cohort, provide a foundation for further research into treatment strategies, including intermittent ADT, and optimization of patient quality of life while maintaining oncologic efficacy.