BACKGROUND The efficiency of the Myriad Homologous Recombination Deficiency (HRD) test to guide use of PARP inhibitors has been demonstrated in several phase III trials. However its high failure rate and limited accessibility establish a need for a clinically validated laboratory developed test. PATIENTS AND METHODS A novel biomarker to identify HRD was developed using TCGA data and, as part of the ENGOT HRD European Initiative, applied to 469 samples from the PAOLA-1/ENGOT-ov25 phase 3 trial using the OncoScanTM CNV Assay. Results were compared to the Myriad myChoice Genomic Instability Score (GIS) with respect to the progression-free survival in the Olaparib+Bevacizumab and placebo+Bevacizumab arms. RESULTS Analysis of the TCGA cohort revealed that a normalization of the number of large-scale state transitions (nLST) by the number of whole genome doubling events allows a better separation and classification of HRD samples than the GIS. The Oncoscan+nLST test yielded a lower failure rate on the 469 PAOLA-1 samples (10/469 vs 59/469 inconclusive results) and positive and negative agreement values of 96% (204/213) and, 81% (159/197) respectively. In nLST-positive samples, the hazard ratio (HR) was 0.40 (95% CI: 0.28-0.57) compared with 0.35 for Myriad GIS. In tumors that were BRCA wild-type and nLST-positive, the HR was 0.53 (Myriad: 0.41). In this subpopulation the nLST test and the Myriad myChoice test yielded a similar 1-year PFS (87% and 88%) but a different 2-year PFS (52% vs 60%) upon Olaparib+ Bevacizumab treatment. CONCLUSION The proposed test is a viable alternative to the Myriad myChoice HRD test and can be easily deployed in a clinical laboratory for routine practice. The performance is similar to the commercial test but its lower failure rate allows a 10% increase in the number of patients who will receive a conclusive laboratory result.

The authors have declared no competing interest.

This study was partially funded by AstraZeneca, Cambridge, UK and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

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The Ethic Committee "Comite de Protection des Personnes SUD-EST IV" of Centre Leon Berard, 28 rue Laennec, 69373 Lyon gave ethical approval for this work.

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All data in the present study produced from the TCGA cohort are available upon reasonable request to the authors. All data in the present study produced from the PAOLA-1 trial data are unavailable.