Mutations in TP53 or DNA damage repair genes define poor prognostic subgroups in primary prostate cancer

•We show that a substantial proportion of patients undergoing RPX for localized high-risk or locally advanced prostate cancer harbor mutations in DNA damage repair genes or TP53.•The presence of either a TP53 mutation or a mutation in a DNA damage repair gene conferred a significantly higher risk for a biochemical recurrence or PSA persistence.•TP53 and DNA damage repair gene mutations were not found to overlap in our patient cohort and an analysis of publicly available sequencing data showed that mutations in BRCA1/2 or ATM are enriched in TP53 wild-type tumors in two of three datasets.•Our findings underscore that mutations in TP53 or DNA damage repair genes can be detected in primary prostate cancer where they are associated with a more unfavorable prognosis. The significant negative impact on patient prognosis may be exploited to identify men with prostate cancer who may benefit from a more intensified treatment.