Shallow whole genome sequencing approach to detect Homologous Recombination Deficiency in the PAOLA-1/ENGOT-OV25 phase-III trial

The bevacizumab (bev)/olaparib (ola) maintenance regimen was approved for BRCA-mutated (BRCAmut) and Homologous Recombination Deficient (HRD) High-Grade Ovarian Cancer first line setting, based on a significantly improved progression-free survival (PFS) compared to bev alone in the PAOLA-1/ENGOT-ov25 trial (NCT02477644). We evaluated the analytical and clinical validities of the shallowHRDv2 test, based on shallow whole-genome sequencing, as compared with MyChoice on 449 PAOLA-1 tumor samples. The overall agreement between shallowHRDv2 and MyChoice was 94% (369/394). Less non-contributive analyses were observed with shallowHRDv2 (15/449; 3%) than with MyChoice (51/449; 11%). Patients with HRD tumors according to shallowHRDv2 (including BRCAmut) showed a significantly prolonged PFS with bev+ola versus bev (median PFS: 65.7 versus 20.3 months, hazard ratio (HR): 0.36 [95% CI, 0.24–0.53]). This benefit was significant for BRCA-non mutated tumors (40.8 versus 19.5 months, HR: 0.45 [95% CI, 0.26–0.76]). ShallowHRDv2 is a performant, clinically validated and cost-effective test for HRD determination.