title: Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial.
abstract: BACKGROUND
  Olaparib is a novel, orally active poly(ADP-ribose) polymerase (PARP) inhibitor that induces synthetic lethality in homozygous BRCA-deficient cells. We aimed to assess the efficacy and safety of olaparib for treatment of advanced ovarian cancer in patients with BRCA1 or BRCA2 mutations.
  
  
  METHODS
  In this international, multicentre, phase 2 study, we enrolled two sequential cohorts of women (aged >or=18 years) with confirmed genetic BRCA1 or BRCA2 mutations, and recurrent, measurable disease. The study was undertaken in 12 centres in Australia, Germany, Spain, Sweden, and the USA. The first cohort (n=33) was given continuous oral olaparib at the maximum tolerated dose of 400 mg twice daily, and the second cohort (n=24) was given continuous oral olaparib at 100 mg twice daily. The primary efficacy endpoint was objective response rate (ORR). This study is registered with ClinicalTrials.gov, number NCT00494442.
  
  
  RESULTS
  Patients had been given a median of three (range 1-16) previous chemotherapy regimens. ORR was 11 (33%) of 33 patients (95% CI 20-51) in the cohort assigned to olaparib 400 mg twice daily, and three (13%) of 24 (4-31) in the cohort assigned to 100 mg twice daily. In patients given olaparib 400 mg twice daily, the most frequent causally related adverse events were nausea (grade 1 or 2, 14 [42%]; grade 3 or 4, two [6%]), fatigue (grade 1 or 2, ten [30%]; grade 3 or 4, one [3%]), and anaemia (grade 1 or two, five [15%]; grade 3 or 4, one [3%]). The most frequent causally related adverse events in the cohort given 100 mg twice daily were nausea (grade 1 or 2, seven [29%]; grade 3 or 4, two [8%]) and fatigue (grade 1 or 2, nine [38%]; none grade 3 or 4).
  
  
  CONCLUSIONS
  Findings from this phase 2 study provide positive proof of concept of the efficacy and tolerability of genetically targeted treatment with olaparib in BRCA-mutated advanced ovarian cancer.
  
  
  BACKGROUND
  AstraZeneca.
authors.affiliation: Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. william.audeh@cshs.org
authors.forename: M William
authors.initials: MW
authors.lastname: Audeh
authors.forename: James
authors.initials: J
authors.lastname: Carmichael
authors.forename: Richard T
authors.initials: RT
authors.lastname: Penson
authors.forename: Michael
authors.initials: M
authors.lastname: Friedlander
authors.forename: Bethan
authors.initials: B
authors.lastname: Powell
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Bell-McGuinn
authors.forename: Clare
authors.initials: C
authors.lastname: Scott
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Weitzel
authors.forename: Ana
authors.initials: A
authors.lastname: Oaknin
authors.forename: Niklas
authors.initials: N
authors.lastname: Loman
authors.forename: Karen
authors.initials: K
authors.lastname: Lu
authors.forename: Rita K
authors.initials: RK
authors.lastname: Schmutzler
authors.forename: Ursula
authors.initials: U
authors.lastname: Matulonis
authors.forename: Mark
authors.initials: M
authors.lastname: Wickens
authors.forename: Andrew
authors.initials: A
authors.lastname: Tutt
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D018095:Germ-Line Mutation; D006801:Humans; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D010793:Phthalazines / Q000627:therapeutic use*; D010879:Piperazines / Q000627:therapeutic use*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011446:Prospective Studies
chemical_list: D000970:Antineoplastic Agents; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C531550:olaparib