Researchers in Canada have identified genomic drivers of resistance to androgen-receptor (AR)-directed therapies in men with metastatic castration-resistant prostate cancer (mCRPC). Annala et al. performed whole-exome and/or deep targeted sequencing of plasma-derived cell-free DNA samples from 202 treatment-naive men with mCRPC randomly assigned to abiraterone or enzalutamide. Defects in BRCA2 and ATM were associated with poor clinical outcomes independently of clinical prognostic factors and abundance of circulating tumour DNA. Deleterious alterations in TP53 were also associated with reduced time to progression.