Proliferation associates with greater sensitivity to androgen receptor pathway inhibition for metastatic prostate cancer

BACKGROUND Proliferation is a key biological feature of cancer and in prostate cancer is modulated by androgen receptor (AR) signalling. Cohort studies have suggested that highly proliferative tumors respond poorly to androgen receptor pathway inhibitors (ARPIs). To clarify whether tumor proliferation interacts with treatment benefit from adding abiraterone to androgen deprivation therapy (ADT), we assessed the Ki-67 proliferation index in prostate core biopsies from participants enrolled in the STAMPEDE platform protocol. METHODS Proliferation was assessed by Ki67 immunohistochemistry on tumors from patients randomized in two sequential but non-overlapping (ie no shared controls) phase 3 trials of abiraterone or abiraterone and enzalutamide conducted in STAMPEDE (NCT00268476), with 14-year survival outcomes. A standardised unweighted global assessment method was used. Survival analyses used Cox proportional hazards models adjusted for established prognostic factors. Ki-67 was examined both continuously and dichotomised at the median. Sensitivity analyses excluded samples exposed to ADT. RESULTS Ki-67 was successfully scored on cancers from 1,605 patients. Higher Ki-67 was strongly prognostic for shorter overall survival across disease states. However, in metastatic patients treated with ADT plus abiraterone, the adverse prognostic impact of high Ki-67 was substantially attenuated (aHR=1.06 per 10-percentage-point increase), with a statistically-significant treatment-biomarker interaction (p<0.001) confirming highly proliferative tumors derived greater treatment benefit. No interaction was observed in non-metastatic disease. CONCLUSION Ki-67 is an independent prognostic biomarker in advanced prostate cancer. In metastatic disease, higher proliferation predicts greater sensitivity to abiraterone added to ADT, suggesting a potential biological vulnerability of rapidly cycling tumors to intensified AR pathway blockade. TRIAL REGISTRATION: NCT00268476.