title: Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial.
abstract: BACKGROUND
  Olaparib, a novel, orally active poly(ADP-ribose) polymerase (PARP) inhibitor, induced synthetic lethality in BRCA-deficient cells. A maximum tolerated dose and initial signal of efficacy in BRCA-deficient ovarian cancers have been reported. We therefore assessed the efficacy, safety, and tolerability of olaparib alone in women with BRCA1 or BRCA2 mutations and advanced breast cancer.
  
  
  METHODS
  Women (aged >or=18 years) with confirmed BRCA1 or BRCA2 mutations and recurrent, advanced breast cancer were assigned to two sequential cohorts in a phase 2 study undertaken in 16 centres in Australia, Germany, Spain, Sweden, the UK, and the USA. The first cohort (n=27) was given continuous oral olaparib at the maximum tolerated dose (400 mg twice daily), and the second (n=27) was given a lower dose (100 mg twice daily). The primary efficacy endpoint was objective response rate (ORR). This study is registered with ClinicalTrials.gov, number NCT00494234.
  
  
  RESULTS
  Patients had been given a median of three previous chemotherapy regimens (range 1-5 in cohort 1, and 2-4 in cohort 2). ORR was 11 (41%) of 27 patients (95% CI 25-59) in the cohort assigned to 400 mg twice daily, and six (22%) of 27 (11-41) in the cohort assigned to 100 mg twice daily. Toxicities were mainly at low grades. The most frequent causally related adverse events in the cohort given 400 mg twice daily were fatigue (grade 1 or 2, 11 [41%]; grade 3 or 4, four [15%]), nausea (grade 1 or 2, 11 [41%]; grade 3 or 4, four [15%]), vomiting (grade 1 or 2, three [11%]; grade 3 or 4, three [11%]), and anaemia (grade 1 or 2, one [4%]; grade 3 or 4, three [11%]). The most frequent causally related adverse events in the cohort given 100 mg twice daily were nausea (grade 1 or 2, 11 [41%]; none grade 3 or 4) and fatigue (grade 1 or 2, seven [26%]; grade 3 or 4, one [4%]).
  
  
  CONCLUSIONS
  The results of this study provide positive proof of concept for PARP inhibition in BRCA-deficient breast cancers and shows a favourable therapeutic index for a novel targeted treatment strategy in patients with tumours that have genetic loss of function of BRCA1-associated or BRCA2-associated DNA repair. Toxicity in women with BRCA1 and BRCA2 mutations was similar to that reported previously in those without such mutations.
  
  
  BACKGROUND
  AstraZeneca.
authors.affiliation: Breakthrough Breast Cancer Research Unit, Guy's Hospital Campus, King's College London School of Medicine, London, UK. andrew.tutt@icr.ac.uk
authors.forename: Andrew
authors.initials: A
authors.lastname: Tutt
authors.forename: Mark
authors.initials: M
authors.lastname: Robson
authors.forename: Judy E
authors.initials: JE
authors.lastname: Garber
authors.forename: Susan M
authors.initials: SM
authors.lastname: Domchek
authors.forename: M William
authors.initials: MW
authors.lastname: Audeh
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Weitzel
authors.forename: Michael
authors.initials: M
authors.lastname: Friedlander
authors.forename: Banu
authors.initials: B
authors.lastname: Arun
authors.forename: Niklas
authors.initials: N
authors.lastname: Loman
authors.forename: Rita K
authors.initials: RK
authors.lastname: Schmutzler
authors.forename: Andrew
authors.initials: A
authors.lastname: Wardley
authors.forename: Gillian
authors.initials: G
authors.lastname: Mitchell
authors.forename: Helena
authors.initials: H
authors.lastname: Earl
authors.forename: Mark
authors.initials: M
authors.lastname: Wickens
authors.forename: James
authors.initials: J
authors.lastname: Carmichael
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D018095:Germ-Line Mutation; D006801:Humans; D020714:Maximum Tolerated Dose; D008875:Middle Aged; 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