title: Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval.
abstract: OBJECTIVE
  Selective tumor cell cytotoxicity can be achieved through a synthetic lethal strategy using poly(ADP)-ribose polymerase (PARP) inhibitor therapy in BRCA1/2 mutation carriers in whom tumor cells have defective homologous recombination (HR) DNA repair. Platinum-based chemotherapy responses correlate with HR DNA repair capacity. Olaparib is a potent, oral PARP inhibitor that is well tolerated, with antitumor activity in BRCA1/2 mutation carriers.
  
  
  METHODS
  Patients with BRCA1/2-mutated ovarian cancer were treated with olaparib within a dose-escalation and single-stage expansion of a phase I trial. Antitumor activity was subsequently correlated with platinum sensitivity.
  
  
  RESULTS
  Fifty patients were treated: 48 had germline BRCA1/2 mutations; one had a BRCA2 germline sequence change of unknown significance, and another had a strong family history of BRCA1/2-associated cancers who declined mutation testing. Of the 50 patients, 13 had platinum-sensitive disease, 24 had platinum-resistant disease, and 13 had platinum-refractory disease (according to platinum-free interval). Twenty (40%; 95% CI, 26% to 55%) achieved Response Evaluation Criteria in Solid Tumors (RECIST) complete or partial responses and/or tumor marker (CA125) responses, and three (6.0%) maintained RECIST disease stabilization for more than 4 months, giving an overall clinical benefit rate of 46% (95% CI, 32% to 61%). Median response duration was 28 weeks. There was a significant association between the clinical benefit rate and platinum-free interval across the platinum-sensitive, resistant, and refractory subgroups (69%, 45%, and 23%, respectively). Post hoc analyses indicated associations between platinum sensitivity and extent of olaparib response (radiologic change, P = .001; CA125 change, P = .002).
  
  
  CONCLUSIONS
  Olaparib has antitumor activity in BRCA1/2 mutation ovarian cancer, which is associated with platinum sensitivity.
authors.affiliation: Drug Development Unit, Royal Marsden National Health Service Foundation Trust, Sutton, Surrey, UK.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Fong
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Yap
authors.forename: David S
authors.initials: DS
authors.lastname: Boss
authors.forename: Craig P
authors.initials: CP
authors.lastname: Carden
authors.forename: Marja
authors.initials: M
authors.lastname: Mergui-Roelvink
authors.forename: Charlie
authors.initials: C
authors.lastname: Gourley
authors.forename: Jacques
authors.initials: J
authors.lastname: De Greve
authors.forename: Jan
authors.initials: J
authors.lastname: Lubinski
authors.forename: Susan
authors.initials: S
authors.lastname: Shanley
authors.forename: Christina
authors.initials: C
authors.lastname: Messiou
authors.forename: Roger
authors.initials: R
authors.lastname: A'Hern
authors.forename: Andrew
authors.initials: A
authors.lastname: Tutt
authors.forename: Alan
authors.initials: A
authors.lastname: Ashworth
authors.forename: John
authors.initials: J
authors.lastname: Stone
authors.forename: James
authors.initials: J
authors.lastname: Carmichael
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
authors.forename: Johann S
authors.initials: JS
authors.lastname: de Bono
authors.forename: Stan B
authors.initials: SB
authors.lastname: Kaye
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005185:Fallopian Tube Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D018095:Germ-Line Mutation; D006801:Humans; D008875:Middle Aged; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D010534:Peritoneal Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D010597:Pharmacogenetics; D010793:Phthalazines / Q000009:adverse effects / Q000627:therapeutic use*; D010879:Piperazines / Q000009:adverse effects / Q000627:therapeutic use*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics
chemical_list: D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases; C531550:olaparib