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Clinical Trial
. 2017 Aug 1;23(15):4086-4094.
doi: 10.1158/1078-0432.CCR-16-2615. Epub 2017 Feb 21.

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

Stephanie Lheureux  1 , Zhongwu Lai  2 , Brian A Dougherty  2 , Sarah Runswick  3 , Darren R Hodgson  3 , Kirsten M Timms  4 , Jerry S Lanchbury  4 , Stan Kaye  5 , Charlie Gourley  6 , David Bowtell  7 , Elise C Kohn  8 , Claire Scott  9 , Ursula Matulonis  10 , Tony Panzarella  11 , Katherine Karakasis  1 , Julia V Burnier  1 , C Blake Gilks  12 , Mark J O'Connor  13 , Jane D Robertson  3 , Jonathan Ledermann  14 , J Carl Barrett  2 , Tony W Ho  15 , Amit M Oza  16
Affiliations
Clinical Trial

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

Stephanie Lheureux et al. Clin Cancer Res. .

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: 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. ©2017 AACR.

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