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Accurately identifying patients with high-grade serous ovarian carcinoma (HGSOC) who respond to poly(ADP-ribose) polymerase inhibitor (PARPi) therapy is of great clinical importance. Here we show that quantitative  BRCA1  methylation analysis provides new insight into PARPi response in preclinical models and ovarian cancer patients. The response of 12 HGSOC patient-derived xenografts (PDX) to the PARPi rucaparib was assessed, with variable dose-dependent responses observed in chemo-naive  BRCA1/2 -mutated PDX, and no responses in PDX lacking DNA repair pathway defects. Among  BRCA1 -methylated PDX, silencing of all  BRCA1  copies predicts rucaparib response, whilst heterozygous methylation is associated with resistance. Analysis of 21  BRCA1- methylated platinum-sensitive recurrent HGSOC (ARIEL2 Part 1 trial) confirmed that homozygous or hemizygous  BRCA1  methylation predicts rucaparib clinical response, and that methylation loss can occur after exposure to chemotherapy. Accordingly, quantitative  BRCA1  methylation analysis in a pre-treatment biopsy could allow identification of patients most likely to benefit, and facilitate tailoring of PARPi therapy.

Methylation of all BRCA1 copies predicts response to the PARP inhibitor rucaparib in ovarian carcinoma