Acquired Resistance to Poly (ADP-ribose) Polymerase Inhibitor Olaparib in <i>BRCA2</i>-Associated Prostate Cancer Resulting From Biallelic <i>BRCA2</i> Reversion Mutations Restores Both Germline and Somatic Loss-of-Function Mutations.

Abstract

PARP1/2 inhibitors are effective against BRCA2-deficient tumors. The PARP inhibitor (PARPi) olaparib received FDA breakthrough designation for treatment of metastatic castration-resistant prostate cancers (CRPC) carrying mutations in <i>BRCA1/2</i> or <i>ATM</i> genes. Emergent resistance to PARPi has been associated with tumor-specific BRCA2 mutations that revert the normal open reading frame rescuing homologous recombination. We describe a case of metastatic CRPC with germline <i>BRCA2</i> mutation with acquired resistance to olaparib related to biallelic <i>BRCA2</i> reversion mutations of both the germline and somatic loss of function alleles detected by circulating tumor DNA testing. We also summarize a retrospective analysis of 1,534 prostate cancer cases with ctDNA analysis showing a 1.6% incidence of germline <i>BRCA2</i> mutations. Within the germline <i>BRCA2</i>-positive cases exposed to platinum chemotherapy or PARP inhibition, the prevalence of reversion mutations was 40%. This report documents the frequency of reversion mutations in a large cohort of prostate cancer patients carrying of BRCA mutations. It also shows the potential utility of ctDNA analyses for early detection of reversion mutation driving tumor resistance.