Background: The PAOLA-1/ENGOT-ov25 trial showed that maintenance olaparib plus bevacizumab increases survival of advanced ovarian cancer patients with homologous recombination deficiency (HRD). However, decentralized solutions to test for HRD in clinical routine are scarce. The goal of this study was to retrospectively validate on tumor samples from the PAOLA-1 trial, a decentralized HRD test based on low coverage shallow Whole Genome Sequencing (sWGS). Methods: The study comprised 368 patients from the PAOLA-1 trial. The sWGS test was compared to the Myriad MyChoice HRD test (Myriad Genetics), and results were analyzed with respect to Progression-Free Survival (PFS). Results: We found a 95% concordance between the HRD status of the two tests (95% Confidence Interval (CI) 92%-97%). The Positive Percentage Agreement (PPA) of the sWGS test was 95% (95% CI; 90%-97%) like its Negative Percentage Agreement (NPA) (95% CI; 89%-98%). Only 1% (95% CI; 0-3%) of its results were inconclusive. In patients with HRD-positive tumors treated with olaparib plus bevacizumab, the PFS Hazard Ratio (HR) was 0.38 (95% CI; 0.26-0.54) with sWGS and 0.32 (95% CI; 0.22-0.45) with the Myriad assay. In patients with HRD-negative tumors, HR was 0.98 (95% CI; 0.68-1.41) and 1.05 (95% CI; 0.70-1.57) with sWGS and Myriad tests. Among patients with BRCA-wildtype tumors, those with HRD-positive tumors, benefited from olaparib plus bevacizumab maintenance, with HR of 0.48 (95% CI: 0.29-0.79) and of 0.38 (95% CI: 0.23 to 0.63) with sWGS and Myriad test. Conclusion: The SeqOne sWGS HRD assay offers a clinically validated approach to detect HRD.

S. Beaumeunier, D. Bertrand, S. Brunel, N. Duforet, C. Gottin, N. Philippe, and J. Ruzicka have filed a patent application with the European Patent Office on June 24, 2022 (application number EP 22181091.4) and an international patent application with the WIPO on June 23, 2023 (application number PCT/EP2023/067179), entitled "DEVICE FOR DETERMINING AN INDICATOR OF PRESENCE OF HRD IN A GENOME OF A SUBJECT". M. Blum, C. Gottin, J. Ruzicka, T. Delhomme, J. Audoux, N. Duforet-Frebourg, D. Bertrand, N. Philippe are employees of SeqOne Genomics. M.-P. Wissler is employed by Cypath. She received consulting fees from AstraZeneca and she was a speaker for seminars sponsored by Amgen, AstraZeneca, MSD, Roche, and Servier. A. Jeanniard is employed by Agilent. E. Pujade Lauraine was a member of advisory boards for AstraZeneca, GSK, and Roche. He was on the IDMC board at Agenus and Incyte. He is employed by ARCAGY-research. I. Vergote discloses financial relationships with Agenus, Akesobio, AstraZeneca, Bristol Myers Squibb, Deciphera Pharmaceuticals, Eisai, Elevar Therapeutics, Exelixis, F. Hoffmann-La Roche, Genmab, GSK, Immunogen, Jazzpharma, Karyopharm, Mersana, MSD, Novocure, Novartis, Oncoinvent, OncXerna, Regeneron, Sanofi, Seagen, Sotio, Verastem Oncology, Zentalis, Oncoinvent AS, Amgen, Roche, Karyopharm, Genmab, Novocure. A. J. Gonzalez Martin discloses financial relationship with Alkermes, Amgen, Astrazeneca, Clovis, Eisai, Genmab, Gsk, Hederadx, Illumina, Inmunogen, Macrogenics, Mersana, MSD, Novartis, Novocure, Oncoinvent, Pharmamar, Regeneron, Roche, Sotio, Sutro, Takeda, Zaylab. He has also non-financial relationships with Aravive, GSK, MSD, Novartis, and Roche. N. Colombo received Grants or contracts from AstraZeneca, PharmaMar and Roche. She received payment or honoraria for lectures, presentations, or educational events from AstraZeneca, Tesaro, Novartis, Clovis Oncology, Merck Sharp and Dohme, GlaxoSmithKline and Eisai. She participated on a Data Safety Monitoring Board or Advisory Board for Roche, PharmaMar, AstraZeneca, Clovis Oncology, Merck Sharp and Dohme, GlaxoSmithKline, Tesaro, Pfizer, BioCad, Immunogen, Mersana, Eisai, Oncxema and Nuvation Bio. P. Alexandre received paid honoraria from GSK and Roche. K. Fujiwara received consulting fees and grant support from Pfizer, Eisai, Merck Sharp & Dohme, Taiho, Zeria, Chugai Pharmaceutical, Genmab, and Takeda Pharmaceutical Company, receiving grant support from Immunogen, Oncotherapy, and Regeneron, and receiving consulting fees from Novartis, Kyowa Hakko Kirin, Daiichi Sankyo, Mochida Pharmaceutical, and NanoCarrier. J. Maenpaa received honoraria from AstraZeneca and GSK.. K. Fujiwara received consulting fees and grant support from Pfizer, Eisai, Merck Sharp & Dohme, Taiho, Zeria, Chugai Pharmaceutical, Genmab, Takeda Pharmaceutical Company, Novartis, Kyowa Hakko Kirin, Daiichi Sankyo, Mochida Pharmaceutical, and NanoCarrier, and received a grant support from Immunogen, Oncotherapy, and Regeneron. P. Harter discloses grant supports from AstraZeneca, Roche, GSK, Genmab, DFG, European Union, DKH, Immunogen, Clovis. He did consulting activities for AstraZeneca. He was a member of advisory councils for AstraZeneca, Roche, GSK, Clovis, Immunogen, MSD, and Eisai. He did lectures for Amgen, AstraZeneca, GSK, Roche, Sotio, Stryker, Zai Lab, MSD, Clovis, Eisai.

SeqOne Genomics funded the retrospective study.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Ethics committee/IRB named Comite de Protection des Personnes at Centre Leon Berard (28, rue Laennec - 69373 Lyon Cedex 08) gave ethical approval for this work (decision numbered A 15-64).

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

The data can be requested from the clinical and translational departments of the non-profit ARCAGY-GINECO collaborative group.