Predictive value of the Leuven HRD test compared with Myriad myChoice PLUS on 468 ovarian cancer samples from the PAOLA-1/ENGOT-ov25 trial (LBA 6)

Objectives: The phase III PAOLA-1/ENGOT-ov25 trial (NCT02477644) evaluated first-line standard therapy including bevacizumab in advanced ovarian cancer with the addition of maintenance olaparib or placebo. Significant improved progression-free survival (PFS) was observed in homologous recombination deficient (HRD) tumors, with or without BRCA mutation (BRCAm), tested with Myriad myChoice PLUS (Myriad test) in contradiction to homologous recombination proficient (HRP) tumors, revealing the need for HRD testing in first line. As part of the ENGOT European HRD initiative, we developed the ‘Leuven’ HRD test. To the best of our knowledge, this is the first presentation of an alternative academic laboratory-developed HRD test compared with the Myriad test including an analysis of the predictive value for olaparib efficacy (PFS) in first-line ovarian cancer. Methods: The Leuven HRD test was first developed on ovarian cancer tumor samples of the biobank of the University Hospitals Leuven. Then, we analyzed formalin-fixed paraffin-embedded (FFPE) derived DNA from 468 available ovarian cancer samples of the PAOLA-1/ENGOT-ov25 trial. We performed capture-based targeted resequencing of ±90,000 genome-wide single nucleotide polymorphisms (SNPs) at ±40x coverage, and coding exons of BRCA1, BRCA2, RAD51C, RAD51D, PALB2, BLM, BARD1, BRIP1 and TP53 at ±400x coverage. All samples were analyzed using the Leuven HRD and the Myriad test. The BRCAm status, genomic instability score (GIS) and HRD status (comprising both the BRCAm and GIS status) were compared between both tests. The main objective was to compare the predictive value of both tests for predicting PFS in the olaparib versus placebo arm. The Hazard Ratio (HR) and associated 95% confidence interval (CI) were calculated with the use of a Cox proportional hazards model. Conclusions: A robust correlation between the Leuven HRD and Myriad myChoice PLUS test was observed. The Leuven HRD test showed in the PAOLA-1 trial a similar impact on PFS as the Myriad test. Subgroup analyses confirmed the PFS benefit with olaparib in patients with Leuven test BRCAm and HRD-positive/BRCAwt tumors. Objectives: The phase III PAOLA-1/ENGOT-ov25 trial (NCT02477644) evaluated first-line standard therapy including bevacizumab in advanced ovarian cancer with the addition of maintenance olaparib or placebo. Significant improved progression-free survival (PFS) was observed in homologous recombination deficient (HRD) tumors, with or without BRCA mutation (BRCAm), tested with Myriad myChoice PLUS (Myriad test) in contradiction to homologous recombination proficient (HRP) tumors, revealing the need for HRD testing in first line. As part of the ENGOT European HRD initiative, we developed the ‘Leuven’ HRD test. To the best of our knowledge, this is the first presentation of an alternative academic laboratory-developed HRD test compared with the Myriad test including an analysis of the predictive value for olaparib efficacy (PFS) in first-line ovarian cancer. Methods: The Leuven HRD test was first developed on ovarian cancer tumor samples of the biobank of the University Hospitals Leuven. Then, we analyzed formalin-fixed paraffin-embedded (FFPE) derived DNA from 468 available ovarian cancer samples of the PAOLA-1/ENGOT-ov25 trial. We performed capture-based targeted resequencing of ±90,000 genome-wide single nucleotide polymorphisms (SNPs) at ±40x coverage, and coding exons of BRCA1, BRCA2, RAD51C, RAD51D, PALB2, BLM, BARD1, BRIP1 and TP53 at ±400x coverage. All samples were analyzed using the Leuven HRD and the Myriad test. The BRCAm status, genomic instability score (GIS) and HRD status (comprising both the BRCAm and GIS status) were compared between both tests. The main objective was to compare the predictive value of both tests for predicting PFS in the olaparib versus placebo arm. The Hazard Ratio (HR) and associated 95% confidence interval (CI) were calculated with the use of a Cox proportional hazards model. Conclusions: A robust correlation between the Leuven HRD and Myriad myChoice PLUS test was observed. The Leuven HRD test showed in the PAOLA-1 trial a similar impact on PFS as the Myriad test. Subgroup analyses confirmed the PFS benefit with olaparib in patients with Leuven test BRCAm and HRD-positive/BRCAwt tumors.