title: Long-Term Responders on Olaparib Maintenance in High-Grade Serous Ovarian Cancer: Clinical and Molecular Characterization.
abstract: Purpose:Maintenance therapy with olaparib has improved progression-free survival in women with high-grade serous ovarian cancer (HGSOC), particularly those harboringBRCA1/2mutations. 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 germlineBRCA1/2status, three-biomarker homologous recombination deficiency (HRD) score,BRCA1methylation, 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, withTP53, BRCA1, andBRCA2mutations being most common (90%, 25%, and 35%, respectively).BRCA2mutations were enriched among the LT responders.BRCAmethylation was not associated with response duration. High myriad HRD score (>42) and/orBRCA1/2mutation was associated with LT response to olaparib. Study 41 confirmed the correlation of LT response with olaparib andBRCA1/2mutation.Conclusions:Findings show that LT response to olaparib may be multifactorial and related to homologous recombination repair deficiency, particularlyBRCA1/2defects. The type ofBRCA1/2mutation warrants further investigation.Clin Cancer Res; 23(15); 4086-94. ©2017 AACR.
authors.affiliation: Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Canada.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Lheureux
authors.affiliation: AstraZeneca, Waltham, Massachusetts.
authors.forename: Zhongwu
authors.initials: Z
authors.lastname: Lai
authors.affiliation: AstraZeneca, Waltham, Massachusetts.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Dougherty
authors.affiliation: AstraZeneca, Macclesfield, United Kingdom.
authors.forename: Sarah
authors.initials: S
authors.lastname: Runswick
authors.affiliation: AstraZeneca, Macclesfield, United Kingdom.
authors.forename: Darren R
authors.initials: DR
authors.lastname: Hodgson
authors.affiliation: Myriad Genetics, Inc., Salt Lake City, Utah.
authors.forename: Kirsten M
authors.initials: KM
authors.lastname: Timms
authors.affiliation: Myriad Genetics, Inc., Salt Lake City, Utah.
authors.forename: Jerry S
authors.initials: JS
authors.lastname: Lanchbury
authors.affiliation: The Royal Marsden Hospital and The Institute of Cancer Research, Sutton, United Kingdom.
authors.forename: Stan
authors.initials: S
authors.lastname: Kaye
authors.affiliation: University of Edinburgh Cancer Research UK Centre, Edinburgh, United Kingdom.
authors.forename: Charlie
authors.initials: C
authors.lastname: Gourley
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, and Garvan Institute for Medical Research, Sydney, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Bowtell
authors.affiliation: Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland.
authors.forename: Elise C
authors.initials: EC
authors.lastname: Kohn
authors.affiliation: Royal Melbourne Hospital, Melbourne, Australia.
authors.forename: Claire
authors.initials: C
authors.lastname: Scott
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Ursula
authors.initials: U
authors.lastname: Matulonis
authors.affiliation: Department of Biostatistics, Princess Margaret Cancer Centre, Toronto, Canada.
authors.forename: Tony
authors.initials: T
authors.lastname: Panzarella
authors.affiliation: Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Canada.
authors.forename: Katherine
authors.initials: K
authors.lastname: Karakasis
authors.affiliation: Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Canada.
authors.forename: Julia V
authors.initials: JV
authors.lastname: Burnier
authors.affiliation: Department of Pathology, Vancouver General Hospital, Vancouver, Canada.
authors.forename: C Blake
authors.initials: CB
authors.lastname: Gilks
authors.affiliation: AstraZeneca, Cambridge, United Kingdom.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: O'Connor
authors.affiliation: AstraZeneca, Macclesfield, United Kingdom.
authors.forename: Jane D
authors.initials: JD
authors.lastname: Robertson
authors.affiliation: Cancer Institute, University College London, and University College London Hospitals, London, United Kingdom.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Ledermann
authors.affiliation: AstraZeneca, Waltham, Massachusetts.
authors.forename: J Carl
authors.initials: JC
authors.lastname: Barrett
authors.affiliation: AstraZeneca, Gaithersburg, Maryland.
authors.forename: Tony W
authors.initials: TW
authors.lastname: Ho
authors.affiliation: Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Canada. amit.oza@uhn.on.ca.
authors.forename: Amit M
authors.initials: AM
authors.lastname: Oza
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010793:Phthalazines / Q000008:administration & dosage* / Q000009:adverse effects; D010879:Piperazines / Q000008:administration & dosage* / Q000009:adverse effects; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000008:administration & dosage; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C531550:olaparib