Methylation and Mutation Assay to Personalize PARP Inhibitor Therapy

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PROJECT SUMMARY/ABSTRACT The overall goal of the current proposal is to develop a clinically useful predictor of PARP inhibitor (PARPi) sensitivity/resistance to spare toxicities and cost for patients unlikely to derive benefit. Our hypothesis is that a combined mutation and methylation analysis performed immediately before initiation of therapy will provide a useful predictor of PARPi response. To test this hypothesis, our approach is to combine a high throughput and quantitative methylation assay with mutational analysis of key homologous recombination genes. We will refine our assay using banked tumor tissues and formalin fixed paraffin embedded (FFPE) neoplastic samples from a phase 2 PARPi trial, then test these assays using samples from 4 large phase 3I randomized controlled trials (RCT) in OC that employ three different PARPi. We propose three specific aims: Aim 1: Develop a clinical grade, quantitative methylation assay and a combined methylation and mutation assay (MMA) to define those BRCA wildtype cancers with best response to PARP inhibitors. Aim 2: Validate MMA as a predictor of PARPi response in a randomized controlled trial of recurrent ovarian carcinoma. Aim 3: Validate MMA as a predictor of PARPi response in 3 randomized controlled trials for primary treatment of advanced OC.