Long-term responders on Olaparib maintenance in high-grade serous ovarian cancer: clinical and molecular characterization
Purpose: Maintenance therapy with olaparib has improved progression-free survival in women with high-grade serous ovarian cancer (HGSOC), particularly those harboring BRCA1/2 mutations. The objective of this study was to characterize long-term (LT) versus short-term (ST) responders to olaparib.Experimental Design: 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 BRCA1/2 status, three-biomarker homologous recombination deficiency (HRD) score, BRCA1 methylation, and mutational profiling. Another olaparib maintenance study (Study 41; NCT01081951) was used as an additional cohort.Results: Thirty-seven LT (32 olaparib) and 61 ST (21 olaparib) patients were identified. Treatment was significantly associated with outcome (P < 0.0001), with more LT patients on olaparib (60.4%) than placebo (11.1%). LT sensitivity to olaparib correlated with complete response to chemotherapy (P < 0.05). In the olaparib LT group, 244 genetic alterations were detected, with TP53, BRCA1, and BRCA2 mutations being most common (90%, 25%, and 35%, respectively). BRCA2 mutations were enriched among the LT responders. BRCA methylation was not associated with response duration. High myriad HRD score (>42) and/or BRCA1/2 mutation was associated with LT response to olaparib. Study 41 confirmed the correlation of LT response with olaparib and BRCA1/2 mutation.Conclusions: Findings show that LT response to olaparib may be multifactorial and related to homologous recombination repair deficiency, particularly BRCA1/2 defects. The type of BRCA1/2 mutation warrants further investigation. Clin Cancer Res; 23(15); 4086-94. (c)2017 AACR.
|ISBN||1078-0432 (Print) 1078-0432 (Linking)|
|Authors||Lheureux, S.; Lai, Z.; Dougherty, B. A.; Runswick, S.; Hodgson, D. R.; Timms, K. M.; Lanchbury, J. S.; Kaye, S.; Gourley, C.; Bowtell, D.; Kohn, E. C.; Scott, C.; Matulonis, U.; Panzarella, T.; Karakasis, K.; Burnier, J. V.; Gilks, C. B.; O'Connor, M. J.; Robertson, J. D.; Ledermann, J.; Barrett, J. C.; Ho, T. W.; Oza, A. M.|
|Responsible Garvan Author|
|Publisher Name||CLINICAL CANCER RESEARCH|
|URL link to publisher's version||https://www.ncbi.nlm.nih.gov/pubmed/28223274|