PMID- 28223274 OWN - NLM STAT- MEDLINE DCOM- 20180423 LR - 20220317 IS - 1557-3265 (Electronic) IS - 1078-0432 (Linking) VI - 23 IP - 15 DP - 2017 Aug 1 TI - Long-Term Responders on Olaparib Maintenance in High-Grade Serous Ovarian Cancer: Clinical and Molecular Characterization. PG - 4086-4094 LID - 10.1158/1078-0432.CCR-16-2615 [doi] AB - 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. CI - (c)2017 American Association for Cancer Research. FAU - Lheureux, Stephanie AU - Lheureux S AD - Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Canada. FAU - Lai, Zhongwu AU - Lai Z AD - AstraZeneca, Waltham, Massachusetts. FAU - Dougherty, Brian A AU - Dougherty BA AD - AstraZeneca, Waltham, Massachusetts. FAU - Runswick, Sarah AU - Runswick S AD - AstraZeneca, Macclesfield, United Kingdom. FAU - Hodgson, Darren R AU - Hodgson DR AD - AstraZeneca, Macclesfield, United Kingdom. FAU - Timms, Kirsten M AU - Timms KM AD - Myriad Genetics, Inc., Salt Lake City, Utah. FAU - Lanchbury, Jerry S AU - Lanchbury JS AD - Myriad Genetics, Inc., Salt Lake City, Utah. FAU - Kaye, Stan AU - Kaye S AD - The Royal Marsden Hospital and The Institute of Cancer Research, Sutton, United Kingdom. FAU - Gourley, Charlie AU - Gourley C AD - University of Edinburgh Cancer Research UK Centre, Edinburgh, United Kingdom. FAU - Bowtell, David AU - Bowtell D AD - Peter MacCallum Cancer Centre, Melbourne, and Garvan Institute for Medical Research, Sydney, Australia. FAU - Kohn, Elise C AU - Kohn EC AD - Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland. FAU - Scott, Claire AU - Scott C AD - Royal Melbourne Hospital, Melbourne, Australia. FAU - Matulonis, Ursula AU - Matulonis U AD - Dana-Farber Cancer Institute, Boston, Massachusetts. FAU - Panzarella, Tony AU - Panzarella T AD - Department of Biostatistics, Princess Margaret Cancer Centre, Toronto, Canada. FAU - Karakasis, Katherine AU - Karakasis K AD - Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Canada. FAU - Burnier, Julia V AU - Burnier JV AD - Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Canada. FAU - Gilks, C Blake AU - Gilks CB AD - Department of Pathology, Vancouver General Hospital, Vancouver, Canada. FAU - O'Connor, Mark J AU - O'Connor MJ AD - AstraZeneca, Cambridge, United Kingdom. FAU - Robertson, Jane D AU - Robertson JD AD - AstraZeneca, Macclesfield, United Kingdom. FAU - Ledermann, Jonathan AU - Ledermann J AD - Cancer Institute, University College London, and University College London Hospitals, London, United Kingdom. FAU - Barrett, J Carl AU - Barrett JC AD - AstraZeneca, Waltham, Massachusetts. FAU - Ho, Tony W AU - Ho TW AD - AstraZeneca, Gaithersburg, Maryland. FAU - Oza, Amit M AU - Oza AM AD - Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Canada. amit.oza@uhn.on.ca. LA - eng PT - Clinical Trial, Phase II PT - Journal Article PT - Randomized Controlled Trial DEP - 20170221 PL - United States TA - Clin Cancer Res JT - Clinical cancer research : an official journal of the American Association for Cancer Research JID - 9502500 RN - 0 (Antineoplastic Agents) RN - 0 (BRCA1 Protein) RN - 0 (BRCA1 protein, human) RN - 0 (BRCA2 Protein) RN - 0 (Phthalazines) RN - 0 (Piperazines) RN - 0 (Poly(ADP-ribose) Polymerase Inhibitors) RN - 0 (TP53 protein, human) RN - 0 (Tumor Suppressor Protein p53) RN - WOH1JD9AR8 (olaparib) SB - IM MH - Adult MH - Aged MH - Antineoplastic Agents/administration & dosage/adverse effects MH - Antineoplastic Combined Chemotherapy Protocols MH - BRCA1 Protein/*genetics MH - BRCA2 Protein/*genetics MH - Disease-Free Survival MH - Female MH - Humans MH - Middle Aged MH - Mutation MH - Neoplasm Grading MH - Neoplasm Recurrence, Local/drug therapy/genetics/pathology MH - Ovarian Neoplasms/*drug therapy/genetics/pathology MH - Phthalazines/*administration & dosage/adverse effects MH - Piperazines/*administration & dosage/adverse effects MH - Poly(ADP-ribose) Polymerase Inhibitors/administration & dosage MH - Tumor Suppressor Protein p53/*genetics EDAT- 2017/02/23 06:00 MHDA- 2018/04/24 06:00 CRDT- 2017/02/23 06:00 PHST- 2016/10/18 00:00 [received] PHST- 2016/11/14 00:00 [revised] PHST- 2017/02/06 00:00 [accepted] PHST- 2017/02/23 06:00 [pubmed] PHST- 2018/04/24 06:00 [medline] PHST- 2017/02/23 06:00 [entrez] AID - 1078-0432.CCR-16-2615 [pii] AID - 10.1158/1078-0432.CCR-16-2615 [doi] PST - ppublish SO - Clin Cancer Res. 2017 Aug 1;23(15):4086-4094. doi: 10.1158/1078-0432.CCR-16-2615. Epub 2017 Feb 21.