Abstract

Next-generation sequencing of circulating plasma DNA from CRPC offers an opportunity to monitor tumor genomic aberrations over the course of the disease. These studies have identified multiple independent clones with distinct genomic patterns showing complex dynamics over the lethal course of prostate cancer, partially related to treatment selection pressure. Clones harboring resistance-conferring AR mutations emerge in approximately 20% of patients treated with abiraterone and exogenous corticosteroids. These mutations are activated by ligands that persist in abiraterone-treated patients, including by prednisolone or dexamethasone at clinically relevant doses, and confer a survival advantage. Often sub-clones with alternative genomic aberrations, including AR amplification, are also present suggesting multiple mechanisms co-exist that lead to re-activation of AR signaling. These data introduce a management paradigm requiring sequential monitoring of advanced prostate cancer patients with plasma and tumor biopsies to ensure early discontinuation of agents when they become potential disease drivers and identify therapeutic targets that will allow selection of the next best treatment.