DNA Repair Deficiency Is Common in Advanced Prostate Cancer: New Therapeutic Opportunities.

Abstract

: Advances in DNA sequencing technology have created a wealth of information regarding the genomic landscape of prostate cancer. It had been thought that BRCA1 and BRCA2 mutations were associated with only a small fraction of prostate cancer cases. However, recent genomic analysis has revealed that germline or somatic inactivating mutations in BRCA1 or BRCA2, or other genes involved in the homologous recombination (HR) pathway of DNA repair collectively occur in as much as 20%-25% of advanced prostate cancers. A synthetic lethal therapeutic approach using poly(ADP-ribose) polymerase inhibitor therapy has been developed for BRCA mutant- and HR deficient-related cancers (those with "BRCAness") and is being studied in multiple clinical trials. This article discusses the current understanding of the genomic landscape of prostate cancer, focusing on the occurrence of DNA repair mutations and the therapeutic opportunities that this presents. This review aims to update oncologists about the increased understanding of the genomes of prostate cancers and, in particular, the prevalence of mutations in DNA repair genes. These observations provide potential new therapeutic opportunities for the use of poly(ADP-ribose) polymerase inhibitors and other therapies, especially in advanced forms of the disease. Of note is the recent U.S. Food and Drug Administration breakthrough therapy designation of olaparib for the treatment of BRCA1/2- or ATM-mutated metastatic castration-resistant prostate cancer. The implications of this new knowledge for clinical practice now and in the future are discussed.