Testosterone breakthrough and outcomes during intensified therapy in metastatic hormone‐sensitive prostate cancer: the ARASENS and LATITUDE trials

Objectives To assess whether treatment‐period serum testosterone breakthrough >35 ng/dL is associated with clinical outcomes during intensified therapy for metastatic hormone‐sensitive prostate cancer. Patients and Methods We performed post hoc analyses of the experimental arms of the ARASENS (darolutamide plus androgen deprivation therapy [ADT] and docetaxel; ClinicalTrials.gov identifier NCT02799602) and LATITUDE (abiraterone acetate plus prednisone and ADT; NCT01715285) phase III trials. Cohort‐specific fixed‐window landmark analyses classified exposure as any eligible testosterone result >35 ng/dL after treatment initiation and through Day 147 in the LATITUDE trial or Day 266 in the ARASENS trial. Treatment‐initiation/Day‐1 and end‐of‐treatment measurements were excluded. Follow‐up began at the landmark. The primary outcome was overall survival (OS); the LATITUDE progression‐free survival (PFS) and the ARASENS time to castration‐resistant prostate cancer (CRPC) were progression endpoints. Multivariable Cox regression was primary; landmark and time‐dependent sensitivity analyses were also performed. Results At the landmark, 564 LATITUDE and 578 ARASENS patients were classifiable for OS. In the LATITUDE trial, breakthrough was associated with worse OS (adjusted hazard ratio [HR], 1.49, 95% confidence interval [CI] 1.07–2.08; P = 0.019); the PFS estimate was directionally similar but imprecise (HR 1.40, 95% CI 0.98–2.00; P = 0.065). In the ARASENS trial, the overall associations were not statistically significant for OS (HR 1.18, 95% CI 0.85–1.62; P = 0.322) or CRPC (HR 0.86, 95% CI, 0.60–1.23; P = 0.397). Exploratory piecewise modelling suggested time variation for CRPC (interaction P = 0.028). Conclusion Testosterone breakthrough >35 ng/dL was associated with worse post‐landmark OS in the LATITUDE trial, whereas the overall associations with OS and CRPC in the ARASENS trial were not statistically significant. These within‐cohort findings are exploratory and do not establish causality, a difference between treatment mechanisms, or a clinical testosterone target.