title: Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 study.
abstract: BACKGROUND
  Olaparib is a poly(ADP-ribose) polymerase inhibitor and cediranib is an anti-angiogenic agent with activity against VEGF receptor (VEGFR) 1, VEGFR2, and VEGFR3. Both oral agents have antitumour activity in women with recurrent ovarian cancer, and their combination was active and had manageable toxicities in a phase 1 trial. We investigated whether this combination could improve progression-free survival (PFS) compared with olaparib monotherapy in women with recurrent platinum-sensitive ovarian cancer.
  
  
  METHODS
  In our randomised, open-label, phase 2 study, we recruited women (aged ≥18 years) who had measurable platinum-sensitive, relapsed, high-grade serous or endometrioid ovarian, fallopian tube, or primary peritoneal cancer, or those with deleterious germline BRCA1/2 mutations from nine participating US academic medical centres. We randomly allocated participants (1:1) according to permuted blocks, stratified by germline BRCA status and previous anti-angiogenic therapy, to receive olaparib capsules 400 mg twice daily or the combination at the recommended phase 2 dose of cediranib 30 mg daily and olaparib capsules 200 mg twice daily. The primary endpoint was progression-free survival analysed in the intention-to-treat population. The phase 2 trial is no longer accruing patients. An interim analysis was conducted in November, 2013, after 50% of expected events had occurred and efficacy results were unmasked. The primary analysis was performed on March 31, 2014, after 47 events (66% of those expected). The trial is registered with ClinicalTrials.gov, number NCT01116648.
  
  
  RESULTS
  Between Oct 26, 2011, and June 3, 2013, we randomly allocated 46 women to receive olaparib alone and 44 to receive the combination of olaparib and cediranib. Median PFS was 17·7 months (95% CI 14·7-not reached) for the women treated with cediranib plus olaparib compared with 9·0 months (95% CI 5·7-16·5) for those treated with olaparib monotherapy (hazard ratio 0·42, 95% CI 0·23-0·76; p=0·005). Grade 3 and 4 adverse events were more common with combination therapy than with monotherapy, including fatigue (12 patients in the cediranib plus olaparib group vs five patients in the olaparib monotherapy group), diarrhoea (ten vs none), and hypertension (18 vs none).
  
  
  CONCLUSIONS
  Cediranib plus olaparib seems to improve PFS in women with recurrent platinum-sensitive high-grade serous or endometrioid ovarian cancer, and warrants study in a phase 3 trial. The side-effect profile suggests such investigations should include assessments of quality of life and patient-reported outcomes to understand the effects of a continuing oral regimen with that of intermittent chemotherapy.
  
  
  BACKGROUND
  American Recovery and Reinvestment Act grant from the National Institutes of Health (NIH) (3 U01 CA062490-16S2); Intramural Program of the Center for Cancer Research; and the Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Electronic address: joyce_liu@dfci.harvard.edu.
authors.forename: Joyce F
authors.initials: JF
authors.lastname: Liu
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: William T
authors.initials: WT
authors.lastname: Barry
authors.affiliation: Department of Medical Oncology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Birrer
authors.affiliation: Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Jung-Min
authors.initials: JM
authors.lastname: Lee
authors.affiliation: Department of Medical Oncology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Buckanovich
authors.affiliation: Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA.
authors.forename: Gini F
authors.initials: GF
authors.lastname: Fleming
authors.affiliation: Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Bj
authors.initials: B
authors.lastname: Rimel
authors.affiliation: Division of Hematology/Oncology, Beth-Israel Deaconess Medical Center, Boston, MA, USA.
authors.forename: Mary K
authors.initials: MK
authors.lastname: Buss
authors.affiliation: Department of Oncology, Fort Wayne Medical Oncology and Hematology, Fort Wayne, IN, USA.
authors.forename: Sreenivasa
authors.initials: S
authors.lastname: Nattam
authors.affiliation: Division of Gynecologic Oncology, North Shore University Health System, Evanston Hospital, Evanston, IL, USA.
authors.forename: Jean
authors.initials: J
authors.lastname: Hurteau
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Weixiu
authors.initials: W
authors.lastname: Luo
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Philippa
authors.initials: P
authors.lastname: Quy
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Christin
authors.initials: C
authors.lastname: Whalen
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Obermayer
authors.affiliation: Department of Biostatistics, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Hang
authors.initials: H
authors.lastname: Lee
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Eric P
authors.initials: EP
authors.lastname: Winer
authors.affiliation: Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA; Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Elise C
authors.initials: EC
authors.lastname: Kohn
authors.affiliation: Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, USA.
authors.forename: S Percy
authors.initials: SP
authors.lastname: Ivy
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Ursula A
authors.initials: UA
authors.lastname: Matulonis
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000077216:Carcinoma, Ovarian Epithelial; D002945:Cisplatin / Q000008:administration & dosage; D016001:Confidence Intervals; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D053208:Kaplan-Meier Estimate; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D010793:Phthalazines / Q000008:administration & dosage*; D010879:Piperazines / Q000008:administration & dosage*; D011799:Quinazolines / Q000008:administration & dosage; D018570:Risk Assessment; D016019:Survival Analysis; D016896:Treatment Outcome; D007211:Indoles
chemical_list: D002945:Cisplatin; D010793:Phthalazines; D010879:Piperazines; D011799:Quinazolines; C500926:cediranib; D007211:Indoles; C531550:olaparib