Ovarian carcinoma patients with a tumorBRCA-like genomic copy number aberration profile benefit from maintenance olaparib/bevacizumab therapy in the PAOLA-1 randomized controlled trial

Abstract

Background We previously established an ovarian carcinoma (OC) BRCA-like genomic copy number aberration profile classifier ('BRCA-like classifier'), which identifies tumors with deleterious mutations and epigenetic alterations in the homologous recombination pathway. We explored whether the classifier may also be predictive for therapies targeting tumors with homologous recombination deficiency (HRD) such as olaparib, a PARP inhibitor with synthetic lethal interaction with HRD, in combination with bevacizumab. Methods As part of the ENGOT (European Network of Gynaecological Oncological Trial groups) HRD initiative, the OC BRCA-like classifier was evaluated using tumor-derived DNA samples from 469 out of 806 patients enrolled in the PAOLA-1/ENGOT-ov25 trial. PAOLA-1 is a randomized, double-blind, international phase 3 trial (NCT02477644) including advanced high grade OC patients. Prolonged progression-free survival (PFS) and overall survival (OS) was observed for patients treated with maintenance olaparib and bevacizumab versus placebo and bevacizumab, and particularly for those patients tested HRD positive according to Myriad MyChoice CDx HRD test. Results Results were obtained for 442 patients (failure rate of 6%, 27 of 469 samples). A survival benefit from adding maintenance olaparib was observed in the 298 (67%) patients with a BRCA-like tumor (hazard ratio (HR) for PFS: 0.49, 95% confidence interval (CI) 0.37-0.65, p = 0.01; OS: 0.64, 95% CI 0.45-0.90, p < 0.01). No benefit was detected in patients with a non-BRCA-like tumor when treated with olaparib (HR for PFS: 1.02, 95% CI 0.68-1.51, p = 0.93; OS 1.48, 95% CI 0.94-2.33, p = 0.09). P values for interaction between BRCA-like status and olaparib for PFS and OS were both 0.004. Multivariate analysis revealed comparable results. The concordance rate with the Myriad test was 77% in samples that were successfully analysed with both assays. In the survival analyses, the CIs of the BRCA-like classifier and the Myriad test overlap. Conclusion The BRCA-like classifier is a high-sensitive predictive biomarker for survival benefit of olaparib/bevacizumab as maintenance therapy in advanced ovarian carcinoma with a low drop-out rate.