Elucidation of PARP inhibitor activity in BRCAwt recurrent ovarian cancer by hrr mutational gene profile analysis.

Abstract

5568 Background: Niraparib is an oral, selective poly(ADP-ribose) polymerase inhibitor (PARPi) approved for maintenance treatment of BRCA mutated ( BRCAmut) and BRCA wild-type ( BRCAwt) recurrent ovarian cancer patients (pts) who are in response to platinum-based chemotherapy. In the non-germline BRCA mutated (non-g BRCAmut) cohort of the ENGOT-OV16/NOVA trial, clinical benefit with niraparib vs placebo was seen in pts regardless of their Myriad myChoice HRD test status ( BRCAmut and homologous recombination deficiency [HRD] score), with a hazard ratio (HR) of 0.38 in HRD-positive (HRDpos) and 0.58 in HRD-negative (HRDneg) pts. To determine if treatment benefit in HRDneg pts may result from mutations in other homologous recombination repair ( HRR) genes, we examined the relationship between progression-free survival and other HRR gene mutations in the NOVA non-gBRCAmut cohort. Methods: A retrospective, exploratory biomarker analysis was conducted using all available tumor samples from 331 pts enrolled in the NOVA non-g BRCAmut cohort. Mutation status of HRR genes was evaluated using a 43-gene NGS assay (Myriad Genetics), including BRCA1/2 and 16 additional HRR genes. Results: In this exploratory analysis of the NOVA non-g BRCAmut cohort, niraparib demonstrated clinical benefit in pts with somatic BRCA mutation (HR, 0.27) and in BRCAwt pts (HR, 0.47). In addition, BRCAwt pts with other HRR gene mutations also derived benefit from niraparib (HR, 0.31), as did BRCAwt/ HRRwt pts (HR, 0.49). When BRCAwt/ HRRwt pts were categorized by HRD score, clinical benefit was also observed in both HRDpos and HRDneg pts, with HRs of 0.33 and 0.60, respectively. These results suggest that, although these biomarkers have good positive predictive value, they are not good negative predictors for niraparib benefit in this indication. Conclusions: This retrospective, exploratory analysis of the ENGOT-OV16/NOVA non-g BRCAmut cohort suggests that although pts with somatic BRCA mutation and other HRR mutations benefit from niraparib treatment, clinical benefit is also seen in HRDneg pts without HRR mutations, perhaps related to other genomic, epigenetic, or functional alterations within ovarian tumors yet to be defined.