title: Olaparib combined with chemotherapy for recurrent platinum-sensitive ovarian cancer: a randomised phase 2 trial.
abstract: BACKGROUND
  The poly(ADP-ribose) polymerase inhibitor olaparib has shown antitumour activity in patients with platinum-sensitive, recurrent, high-grade serous ovarian cancer with or without BRCA1 or BRCA2 mutations. The aim of this study was to assess the efficacy and tolerability of olaparib in combination with chemotherapy, followed by olaparib maintenance monotherapy, versus chemotherapy alone in patients with platinum-sensitive, recurrent, high-grade serous ovarian cancer.
  
  
  METHODS
  In this randomised, open-label, phase 2 study, adult patients with platinum-sensitive, recurrent, high-grade serous ovarian cancer who had received up to three previous courses of platinum-based chemotherapy and who were progression free for at least 6 months before randomisation received either olaparib (200 mg capsules twice daily, administered orally on days 1-10 of each 21-day cycle) plus paclitaxel (175 mg/m(2), administered intravenously on day 1) and carboplatin (area under the curve [AUC] 4 mg/mL per min, according to the Calvert formula, administered intravenously on day 1), then olaparib monotherapy (400 mg capsules twice daily, given continuously) until progression (the olaparib plus chemotherapy group), or paclitaxel (175 mg/m(2) on day 1) and carboplatin (AUC 6 mg/mL per min on day 1) then no further treatment (the chemotherapy alone group). Randomisation was done by an interactive voice response system, stratified by number of previous platinum-containing regimens received and time to disease progression after the previous platinum regimen. The primary endpoint was progression-free survival according to Response Evaluation Criteria in Solid Tumors version 1.1, analysed by intention to treat. Prespecified exploratory analyses included efficacy by BRCA mutation status, assessed retrospectively. This study is registered with ClinicalTrials.gov, number NCT01081951, and has been completed.
  
  
  RESULTS
  Between Feb 12 and July 30, 2010, 173 patients at 43 investigational sites in 12 countries were enrolled into the study, of whom 162 were eligible and were randomly assigned to the two treatment groups (81 to the olaparib plus chemotherapy group and 81 to the chemotherapy alone group). Of these randomised patients, 156 were treated in the combination phase (81 in the olaparib plus chemotherapy group and 75 in the chemotherapy alone group) and 121 continued to the maintenance or no further treatment phase (66 in the olaparib plus chemotherapy group and 55 in the chemotherapy alone group). BRCA mutation status was known for 107 patients (either at baseline or determined retrospectively): 41 (38%) of 107 had a BRCA mutation (20 in the olaparib plus chemotherapy group and 21 in the chemotherapy alone group). Progression-free survival was significantly longer in the olaparib plus chemotherapy group (median 12.2 months [95% CI 9.7-15.0]) than in the chemotherapy alone group (median 9.6 months [95% CI 9.1-9.7) (HR 0.51 [95% CI 0.34-0.77]; p=0.0012), especially in patients with BRCA mutations (HR 0.21 [0.08-0.55]; p=0.0015). In the combination phase, adverse events that were reported at least 10% more frequently with olaparib plus chemotherapy than with chemotherapy alone were alopecia (60 [74%] of 81 vs 44 [59%] of 75), nausea (56 [69%] vs 43 [57%]), neutropenia (40 [49%] vs 29 [39%]), diarrhoea (34 [42%] vs 20 [27%]), headache (27 [33%] vs seven [9%]), peripheral neuropathy (25 [31%] vs 14 [19%]), and dyspepsia (21 [26%] vs 9 [12%]); most were of mild-to-moderate intensity. The most common grade 3 or higher adverse events during the combination phase were neutropenia (in 35 [43%] of 81 patients in the olaparib plus chemotherapy group vs 26 [35%] of 75 in the chemotherapy alone group) and anaemia (seven [9%] vs five [7%]). Serious adverse events were reported in 12 (15%) of 81 patients in the olaparib plus chemotherapy group and 16 of 75 (21%) patients in the chemotherapy alone group.
  
  
  CONCLUSIONS
  Olaparib plus paclitaxel and carboplatin followed by maintenance monotherapy significantly improved progression-free survival versus paclitaxel plus carboplatin alone, with the greatest clinical benefit in BRCA-mutated patients, and had an acceptable and manageable tolerability profile.
  
  
  BACKGROUND
  AstraZeneca.
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON, Canada. Electronic address: amit.oza@uhn.ca.
authors.forename: Amit M
authors.initials: AM
authors.lastname: Oza
authors.affiliation: General University Hospital, Prague, Czech Republic.
authors.forename: David
authors.initials: D
authors.lastname: Cibula
authors.affiliation: Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
authors.forename: Ana Oaknin
authors.initials: AO
authors.lastname: Benzaquen
authors.affiliation: University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Poole
authors.affiliation: Erasmus MC Cancer Institute, Rotterdam, Netherlands.
authors.forename: Ron H J
authors.initials: RH
authors.lastname: Mathijssen
authors.affiliation: Netherlands Cancer Institute, Amsterdam, Netherlands.
authors.forename: Gabe S
authors.initials: GS
authors.lastname: Sonke
authors.affiliation: University of Milan-Bicocca, European Institute of Oncology, Milan, Italy.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Colombo
authors.affiliation: University Hospital, Hradec Kralove, Czech Republic.
authors.forename: Jiří
authors.initials: J
authors.lastname: Špaček
authors.affiliation: Sainte-Elisabeth Hospital, Namur, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Vuylsteke
authors.affiliation: Juravinski Cancer Centre, Hamilton, ON, Canada.
authors.forename: Holger
authors.initials: H
authors.lastname: Hirte
authors.affiliation: University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Mahner
authors.affiliation: Laval University, Quebec, Canada.
authors.forename: Marie
authors.initials: M
authors.lastname: Plante
authors.affiliation: Technical University Munich, Munich, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Schmalfeldt
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON, Canada.
authors.forename: Helen
authors.initials: H
authors.lastname: Mackay
authors.affiliation: AstraZeneca, Macclesfield, UK.
authors.forename: Jacqui
authors.initials: J
authors.lastname: Rowbottom
authors.affiliation: AstraZeneca, Wilmington, DE, USA.
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Lowe
authors.affiliation: AstraZeneca, Waltham, MA, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Dougherty
authors.affiliation: AstraZeneca, Waltham, MA, USA.
authors.forename: J Carl
authors.initials: JC
authors.lastname: Barrett
authors.affiliation: Prince of Wales Clinical School, University of New South Wales, Sydney, NSW, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Friedlander
mesh_terms: D061605:Administration, Intravenous; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics; D016190:Carboplatin / Q000008:administration & dosage; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D006801:Humans; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009154:Mutation; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local; D018297:Neoplasms, Cystic, Mucinous, and Serous / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000401:mortality / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage; D010793:Phthalazines / Q000008:administration & dosage* / Q000009:adverse effects; D010879:Piperazines / Q000008:administration & dosage* / Q000009:adverse effects; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D004791:Enzyme Inhibitors; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D016190:Carboplatin; D011065:Poly(ADP-ribose) Polymerases; D017239:Paclitaxel; C531550:olaparib