Long-term responders on olaparib maintenance in high-grade serous ovarian cancer: Clinical and molecular characterization
- Author(s)
- Lheureux, S; Lai, Z; Dougherty, BA; Runswick, S; Hodgson, D; Timms, KM; Lanchbury, JS; Kaye, SB; Gourley, C; Bowtell, DD; Kohn, EC; Scott, CL; Matulonis, UA; Panzarella, T; Karakasis, K; Burnier, JV; Gilks, B; O'Connor, MJ; Robertson, JD; Ledermann, J; Barrett, JC; Ho, TW; Oza, AM;
- Details
- Publication Year 2017-02-21,Volume 23,Issue #15,Page 4086-4094
- Journal Title
- Clinical Cancer Research
- Publication Type
- Journal Article
- Abstract
- 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: 37 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%). Long-term 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 the commonest (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 correlated with homologous recombination repair deficiency, particularly BRCA1/2 defects. The type of BRCA1/2 mutation warrants further investigation.
- Publisher
- AACR
- Research Division(s)
- Stem Cells And Cancer
- PubMed ID
- 28223274
- Publisher's Version
- https://doi.org/10.1158/1078-0432.CCR-16-2615
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2017-04-06 09:27:34
Last Modified: 2020-04-07 02:13:25