title: Olaparib maintenance therapy in patients with platinum-sensitive, relapsed serous ovarian cancer and a BRCA mutation: Overall survival adjusted for postprogression poly(adenosine diphosphate ribose) polymerase inhibitor therapy.
abstract: BACKGROUND
  Maintenance treatment with the oral poly(adenosine diphosphate ribose) polymerase (PARP) inhibitor olaparib (Lynparza) in Study 19 (study number, D0810C00019; ClinicalTrials.gov identifier, NCT00753545) significantly improved progression-free survival in comparison with a placebo for patients with platinum-sensitive, relapsed serous ovarian cancer with a BRCA1/2 mutation (BRCAm), but an interim analysis revealed no statistically significant overall survival (OS) benefit. However, 23% of the patients receiving the placebo switched to a PARP inhibitor after progression. To investigate whether this had a confounding effect on OS, this article reports an exploratory post hoc analysis that excluded all patients from sites where 1 or more placebo patients received postprogression PARP inhibitor treatment.
  
  
  METHODS
  In Study 19, 136 of the 265 patients receiving olaparib or a placebo had a BRCAm. Sixteen patients treated at 11 of the 82 investigational sites received a PARP inhibitor after progression; these sites were excluded from this analysis, and 97 BRCAm patients at 50 sites were included. OS was assessed with a Cox proportional hazards model analogous to the primary study analysis. A supporting rank-preserving structural failure time (RPSFT) model analysis was undertaken for all 136 BRCAm patients.
  
  
  RESULTS
  The OS hazard ratio (HR) was 0.52 (95% confidence interval [CI], 0.28-0.97) for the 97 BRCAm patients, whereas for the interim OS analysis with all 136 BRCAm patients, it was 0.73 (95% CI, 0.45-1.17). The supportive RPSFT analysis HR was approximately 0.66.
  
  
  CONCLUSIONS
  The numerical improvement in the OS HR suggests that in Study 19, postprogression PARP inhibitor treatment had a confounding influence on the interim OS analysis for BRCAm patients. There is a degree of uncertainty due to the small sample size and the lack of data maturity. Cancer 2016;122:1844-52. © 2016 American Cancer Society.
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Ursula A
authors.initials: UA
authors.lastname: Matulonis
authors.affiliation: Kliniken Essen-Mitte, Essen, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Harter
authors.affiliation: Edinburgh Cancer Research UK Centre, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Charlie
authors.initials: C
authors.lastname: Gourley
authors.affiliation: Prince of Wales Hospital, Randwick, New South Wales, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Friedlander
authors.affiliation: University of Leuven, Leuven, Belgium.
authors.forename: Ignace
authors.initials: I
authors.lastname: Vergote
authors.affiliation: Mount Vernon Hospital, Northwood, United Kingdom.
authors.forename: Gordon
authors.initials: G
authors.lastname: Rustin
authors.affiliation: Royal Melbourne Hospital, Melbourne, Victoria, Australia.
authors.forename: Clare
authors.initials: C
authors.lastname: Scott
authors.affiliation: Evangelical Hospital, Dusseldorf, Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Meier
authors.affiliation: Chaim Sheba Medical Center, Tel Hashomer, Israel.
authors.forename: Ronnie
authors.initials: R
authors.lastname: Shapira-Frommer
authors.affiliation: Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
authors.forename: Tamar
authors.initials: T
authors.lastname: Safra
authors.affiliation: Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Daniela
authors.initials: D
authors.lastname: Matei
authors.affiliation: AstraZeneca, Macclesfield, United Kingdom.
authors.forename: Anitra
authors.initials: A
authors.lastname: Fielding
authors.affiliation: AstraZeneca, Macclesfield, United Kingdom.
authors.forename: Stuart
authors.initials: S
authors.lastname: Spencer
authors.affiliation: AstraZeneca, Macclesfield, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Parry
authors.affiliation: AstraZeneca, Macclesfield, United Kingdom.
authors.forename: Lynda
authors.initials: L
authors.lastname: Grinsted
authors.affiliation: University College London, London, United Kingdom.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Ledermann
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics; D018284:Cystadenocarcinoma, Serous / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D003627:Data Interpretation, Statistical; D018450:Disease Progression; D004311:Double-Blind Method; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D010793:Phthalazines / Q000008:administration & dosage*; D010879:Piperazines / Q000008:administration & dosage*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000008:administration & dosage*; D012008:Recurrence; D015996:Survival Rate
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C531550:olaparib
keywords: BRCA mutation; olaparib; ovarian cancer; overall survival; poly(adenosine diphosphate ribose) polymerase (PARP) inhibitor