LAUSR

It is increasingly understood that the prevalence of inherited DNA repair mutations in men with recurrent or advanced prostate cancer (PC)—especially those in genes regulating homologous recombination—is higher than previously recognized. In a recent landmark study, Pritchard et al [1] reported that the frequency of germline DNA repair alterations in 692 unselected men with metastatic PC was 12%, while a second study of 150 men with castrationresistant PC (CRPC) found that the prevalence of inherited DNA repair mutations was 8% [2]. By comparison, germline DNA repair mutations are only found in approximately 4– 5% of patients with localized PC and in only 2–3% of patients from a general population without a cancer history [1]. While it is known that PC patients harboring germline DNA repair alterations have a generally worse natural history and earlier PC-related mortality [3], little is known about their responsiveness to systemic therapies including androgen deprivation therapy (ADT) and second-generation hormonal agents (abiraterone and enzalutamide). In this issue of European Urology, Annala et al [4] report results from a retrospective study in which 319 consecutive patients with metastatic CRPC underwent germline DNA sequencing using a targeted panel focusing on 22 DNA repair genes (ATM, ATR, BRCA1, BRCA2, CDK12, ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, FANCA, FANCC, FANCD2, FANCE, FANCF, FANCG, MLH1, MSH2, MSH6, PALB2, RAD51B, and RAD51C). In this patient cohort that was unselected for family history of cancer or age at diagnosis, the overall prevalence of inherited DNA repair gene mutations was 8% (24/319), the majority of which were mutations involving the BRCA2 gene (n = 16). In these patients with germline DNA repair alterations, the median time to castration resistance following ADT initiation was 11.8 mo, and the median