38MO Validation study of the ShallowHRDv2 assay for homologous recombination deficiency (HRD) detection in high-grade ovarian carcinomas (HGOC) in the first-line setting, from the phase III PAOLA-1/ENGOT-ov25 trial

Abstract

The bevacizumab(bev)/olaparib(ola) maintenance regimen was approved for women affected with BRCA-mutated (BRCAm) and HRD HGOC, based on a greater progression-free survival (PFS) compared to bevacizumab alone in the PAOLA-1/ENGOT-ov25 trial (NCT02477644). HRD status in this trial was determined by the centralized MyChoice CDx test by Myriad Genetics (MG test). Belonging to the second part of the ENGOT HRD European initiative we evaluated the analytical and clinical validity of the ShallowHRDv2 test, an assay that analyzes the genome-wide copy number alterations, as compared with the MG test on PAOLA-1/ENGOT-ov25 tumor samples. We performed shallow Whole Genome Sequencing (sWGS) with a mean coverage of ∼1x (XT-HS capture kit; Agilent) on 449 tumor DNAs from the PAOLA-1/ENGOT-OV25 trial. HRD status was determined using the shallowHRDv2 bio-informatics pipeline with a single cut-off at 20 Large scale Genomic Alterations. We further evaluated our test on 109 prospective samples from our routine practice. In the PAOLA-1 cohort, positive agreement for the ShallowHRDv2 vs. MG test status was 95% (196/206), negative agreement was 92% (173/188) and the overall agreement was 94% (369/394). Patients with shallowHRDv2-HRD-positive (including BRCAm) tumors showed a significantly prolonged PFS with bev/ola versus bev/placebo (median PFS: 44.8 vs. 20.3 months, hazard ratio (HR): 0.35 [95% CI, 0.23–0.54]). This benefit was still significant after exclusion of BRCAm tumors (41.7 vs. 18.6 months, HR: 0.47 [95% CI, 0.27–0.84]). Less non-contributive analyses were observed with the ShallowHRDv2 test (15/449; 3%) than with MG test (51/449; 11%). We confirmed the high overall percentage agreement of 91% (86/94) between ShallowHRDv2 and MG tests in the prospective cohort, with less non contributive results for ShallowHRDv2 (5% vs. 12%). The ShallowHRDv2 test is a robust, cost-effective, clinically validated & highly performant test for HRD determination and is a valid alternative to MG to detect HRD in ovarian cancers.