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

Background

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.

Methods

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.

Results

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%).

Conclusions

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.

Clinical trial identification

NCT02477644.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

M.J. Rodrigues: Financial Interests, Personal, Advisory Board: AstraZeneca, GSK, Immunocore; Financial Interests, Personal and Institutional, Advisory Board: MSD; Financial Interests, Institutional, Research Grant: BMS. E. Pujade-Lauraine: Financial Interests, Personal, Advisory Board: Roche, GSK, AstraZeneca; Financial Interests, Personal, Other: Agenus, Incyte; Financial Interests, Personal, Full or part-time Employment: Arcagy Research. D. Stoppa-Lyonnet: Financial Interests, Institutional, Funding: AstraZeneca. F. Heitz: Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, GSK, NovoCure, PharmaMar; Financial Interests, Personal, Invited Speaker: amedes, Clovis; Financial Interests, Institutional, Invited Speaker: Newoncology. S. Chiara-Cecere: Financial Interests, Personal, Advisory Board: Clovis, MSD, AstraZeneca, GSK; Financial Interests, Personal, Member of the Board of Directors: Clovis, MSD, AstraZeneca, GSK. N. Colombo: Financial Interests, Personal, Advisory Board, Various: Roche, PharmaMar, AstraZeneca, MSD/Merck, Clovis Oncology, GSK, Pfizer, Immunogen, Mersana; Financial Interests, Personal, Invited Speaker, Congress, Symposia, Lectures: AstraZeneca; Financial Interests, Personal, Invited Speaker, Lectures: Novartis; Financial Interests, Personal, Advisory Board, Lectures: Eisai; Financial Interests, Personal, Advisory Board, Advisory role: Nuvation Bio, Pieris; Financial Interests, Personal, Advisory Board, Advisory Role: Onxerna; Financial Interests, Institutional, Research Grant: AstraZeneca, PharmaMar, Roche; Non-Financial Interests, Personal, Other, Sterring committee member Clinical Guidelines: ESMO; Non-Financial Interests, Personal, Leadership Role, Chair, Scientific Committee: ACTO (Alleanza contro il tumore ovarico). I.B. Vergote: Financial Interests, Personal, Advisory Board, Consulting: Agenus (2021), Aksebio China (2021), AstraZeneca (2021-2022), Bristol Myers Squibb (2021), Deciphera Pharmaceuticals (2021), Eisai (2021), F. Hoffmann-La Roche Ltd (2021), Genmab (2021), GSK (2021), Immunogen Inc. (2021-2022), Jazzpharma (2021-2022), Karyopharm (2021), MSD (2021-2022), Novocure (2020-2022), Novartis (2021), Oncoinvent AS (2021-2022), Seagen (2021), Sotio a.s. (2021-2022); Financial Interests, Institutional, Advisory Board, Consulting: AstraZeneca (2019-2020), Deciphera Pharmaceuticals (2020), Elevar Therapeutics (2020), F. Hoffmann-La Roche Ltd (2019-2020), Genmab (2019-2020), GSK (2019-2020), Mersana (2020), MSD (2019-2020), Oncoinvent AS (2019-2020), Sotio a.s. (2019-2020), Verastem Oncology (2020), Zentalis (2020), Amgen (Europe) 2019, Clovis Oncology Inc (2019), Carrick Therapeutics (2019), Millennium Pharmaceuticals (2019); Financial Interests, Institutional, Research Grant, Contracted Research (via KU Leuven): Oncoinvent AS (2019-2020); Financial Interests, Institutional, Research Grant, Contracted Research (via KU Leuven): Genmab (2019); Financial Interests, Institutional, Research Grant, Corporate sponsored research: Amgen (2019-2020), Roche (2019-2020). I.L. Ray-Coquard: Financial Interests, Personal, Advisory Board: Roche, GSK, AstraZeneca, Mersana, Deciphera, Amgen, Oxnea, Merck Sereno, Agenus, Novartis, Macrogenics, Clovis, EQRX, Adaptimmune, Eisai, SUTRO, BMS, Adaptimmune, Daiichi Sankyo; Financial Interests, Institutional, Other, COLIBRI translational research: BMS; Financial Interests, Institutional, Advisory Board, translational research NEOPREMBROV trial: MSD; Non-Financial Interests, Personal, Principal Investigator: PAOLA1; Non-Financial Interests, Personal, Other, President: GINECO. All other authors have declared no conflicts of interest.