AbstractImproved survival rates for prostate cancer through more effective therapies have also led to an increase in the diagnosis of metastases to infrequent locations such as the brain. Here we investigate the repertoire of somatic genetic alterations present in brain metastases from 51 patients with prostate cancer brain metastases (PCBM). We highlight the clonal evolution occurring in PCBM and demonstrate an increased mutational burden, concomitant with an enrichment of the homologous recombination deficiency mutational signature in PCBM compared to non-brain metastases. Focusing on known pathogenic alterations within homologous recombination repair genes, we find 10 patients (19.6%) fulfilling the inclusion criteria used in the PROfound clinical trial, which assessed the efficacy of PARP inhibitors (PARPi) in homologous recombination deficient prostate cancer. Eight (15.7%) patients show biallelic loss of one of the 15 genes included in the trial, while 5 patients (9.8%) harbor pathogenic alterations in BRCA1/2 specifically. Uncovering these molecular features of PCBM may have therapeutic implications, suggesting the need of clinical trial enrollment of PCBM patients when evaluating potential benefit from PARPi.