Shallow whole genome sequencing approach to detect Homologous Recombination Deficiency in the PAOLA-1/ENGOT-OV25 phase-III trial
Céline Callens, Manuel Rodrigues, Adrien Briaux, Éléonore Frouin, Alexandre Eeckhoutte, Éric Pujade-Lauraine, Victor Renault, Dominique Stoppa‐Lyonnet, Ivan Bièche, Guillaume Bataillon, Lucie Karayan‐Tapon, Tristan Rochelle, Florian Heitz, Sabrina Chiara Cecere, M.J. Rubio Pérez, Christoph Grimm, Trine Jakobi Nøttrup, Nicoletta Colombo, Ignace Vergote, Kan Yonemori, Isabelle Ray‐Coquard, Marc‐Henri Stern, Tatiana Popova
Abstract
The bevacizumab (bev)/olaparib (ola) maintenance regimen was approved for BRCA1/2-mutated (BRCAmut) and Homologous Recombination Deficient (HRD) high-grade Advanced Ovarian Cancer (AOC) first line setting, based on a significantly improved progression-free survival (PFS) compared to bev alone in the PAOLA-1/ENGOT-ov25 trial (NCT02477644), where HRD was detected by MyChoice CDx PLUS test. The academic shallowHRDv2 test was developed based on shallow whole-genome sequencing as an alternative to MyChoice. Analytical and clinical validities of shallowHRDv2 as compared to MyChoice on 449 PAOLA-1 tumor samples are presented. The overall agreement between shallowHRDv2 and MyChoice was 94% (369/394). Less non-contributive tests 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 also for BRCA1/2 wild-type 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 detection.