Long-Term Responders on Olaparib Maintenance in High-Grade Serous Ovarian Cancer: Clinical and Molecular Characterization

Abstract

<b>Purpose:</b> Maintenance therapy with olaparib has improved progression-free survival in women with high-grade serous ovarian cancer (HGSOC), particularly those harboring <i>BRCA1/2</i> mutations. The objective of this study was to characterize long-term (LT) versus short-term (ST) responders to olaparib.<b>Experimental Design:</b> A comparative molecular analysis of Study 19 (NCT00753545), a randomized phase II trial assessing olaparib maintenance after response to platinum-based chemotherapy in HGSOC, was conducted. LT response was defined as response to olaparib/placebo >2 years, ST as <3 months. Molecular analyses included germline <i>BRCA1/2</i> status, three-biomarker homologous recombination deficiency (HRD) score, <i>BRCA1</i> methylation, and mutational profiling. Another olaparib maintenance study (Study 41; NCT01081951) was used as an additional cohort.<b>Results:</b> Thirty-seven LT (32 olaparib) and 61 ST (21 olaparib) patients were identified. Treatment was significantly associated with outcome (<i>P</i> < 0.0001), with more LT patients on olaparib (60.4%) than placebo (11.1%). LT sensitivity to olaparib correlated with complete response to chemotherapy (<i>P</i> < 0.05). In the olaparib LT group, 244 genetic alterations were detected, with <i>TP53, BRCA1</i>, and <i>BRCA2</i> mutations being most common (90%, 25%, and 35%, respectively). <i>BRCA2</i> mutations were enriched among the LT responders. <i>BRCA</i> methylation was not associated with response duration. High myriad HRD score (>42) and/or <i>BRCA1/2</i> mutation was associated with LT response to olaparib. Study 41 confirmed the correlation of LT response with olaparib and <i>BRCA1/2</i> mutation.<b>Conclusions:</b> Findings show that LT response to olaparib may be multifactorial and related to homologous recombination repair deficiency, particularly <i>BRCA1/2</i> defects. The type of <i>BRCA1/2</i> mutation warrants further investigation. <i>Clin Cancer Res; 23(15); 4086-94. ©2017 AACR</i>.