PARP Inhibitors and Prostate Cancer: To Infinity and BeyondBRCA

The U.S. Food and Drug Administration recently approved two poly-adenosine diphosphate-ribose polymerase (PARP) inhibitors, olaparib and rucaparib, for treatment of biomarker-positive metastatic castrate resistant prostate cancer. The benefits of PARP inhibition have been well characterized in patients who have BRCA1 and BRCA2 mutations in several forms of cancer. BRCA1 and BRCA2 occupy key roles in DNA damage repair, which is comprised of several different pathways with numerous participants. Patients with mutations in other key genes within the DNA damage repair pathway may also respond to treatment with PARP inhibitors, and identification of these alterations could significantly increase the percentage of patients that may benefit from PARP inhibition. This review focuses on the potential for synthetically lethal interactions between PARP inhibitors and non-BRCA DNA damage repair genes. IMPLICATIONS FOR PRACTICE: The treatment potential of PARP inhibition has been well characterized in patients with BRCA1 and BRCA2 mutations, but there is compelling evidence for expanding the use of PARP inhibitors to mutations of other non-BRCA DNA damage repair (DDR) genes. This could increase the percentage of patients that may benefit from treatment with PARP inhibitors alone or in combination with other therapies. Understanding the significance of PARP inhibitor-sensitizing alterations in other common non-BRCA DDR genes will help guide clinical decisions to provide targeted treatment options to a wider population of patients.