title: Iniparib plus chemotherapy in metastatic triple-negative breast cancer.
abstract: BACKGROUND
  Triple-negative breast cancers have inherent defects in DNA repair, making this cancer a rational target for therapy based on poly(adenosine diphosphate-ribose) polymerase (PARP) inhibition.
  
  
  METHODS
  We conducted an open-label, phase 2 study to compare the efficacy and safety of gemcitabine and carboplatin with or without iniparib, a small molecule with PARP-inhibitory activity, in patients with metastatic triple-negative breast cancer. A total of 123 patients were randomly assigned to receive gemcitabine (1000 mg per square meter of body-surface area) and carboplatin (at a dose equivalent to an area under the concentration-time curve of 2) on days 1 and 8--with or without iniparib (at a dose of 5.6 mg per kilogram of body weight) on days 1, 4, 8, and 11--every 21 days. Primary end points were the rate of clinical benefit (i.e., the rate of objective response [complete or partial response] plus the rate of stable disease for ≥6 months) and safety. Additional end points included the rate of objective response, progression-free survival, and overall survival.
  
  
  RESULTS
  The addition of iniparib to gemcitabine and carboplatin improved the rate of clinical benefit from 34% to 56% (P=0.01) and the rate of overall response from 32% to 52% (P=0.02). The addition of iniparib also prolonged the median progression-free survival from 3.6 months to 5.9 months (hazard ratio for progression, 0.59; P=0.01) and the median overall survival from 7.7 months to 12.3 months (hazard ratio for death, 0.57; P=0.01). The most frequent grade 3 or 4 adverse events in either treatment group included neutropenia, thrombocytopenia, anemia, fatigue or asthenia, leukopenia, and increased alanine aminotransferase level. No significant difference was seen between the two groups in the rate of adverse events.
  
  
  CONCLUSIONS
  The addition of iniparib to chemotherapy improved the clinical benefit and survival of patients with metastatic triple-negative breast cancer without significantly increased toxic effects. On the basis of these results, a phase 3 trial adequately powered to evaluate overall survival and progression-free survival is being conducted. (Funded by BiPar Sciences [now owned by Sanofi-Aventis]; ClinicalTrials.gov number, NCT00540358.).
authors.affiliation: Baylor Charles A. Sammons Cancer Center, Dallas, TX 75246, USA. joyce.oshaughnessy@usoncology.com
authors.forename: Joyce
authors.initials: J
authors.lastname: O'Shaughnessy
authors.forename: Cynthia
authors.initials: C
authors.lastname: Osborne
authors.forename: John E
authors.initials: JE
authors.lastname: Pippen
authors.forename: Mark
authors.initials: M
authors.lastname: Yoffe
authors.forename: Debra
authors.initials: D
authors.lastname: Patt
authors.forename: Christine
authors.initials: C
authors.lastname: Rocha
authors.forename: Ingrid Chou
authors.initials: IC
authors.lastname: Koo
authors.forename: Barry M
authors.initials: BM
authors.lastname: Sherman
authors.forename: Charles
authors.initials: C
authors.lastname: Bradley
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001549:Benzamides / Q000009:adverse effects / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D016190:Carboplatin / Q000008:administration & dosage; D018592:Cross-Over Studies; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D009362:Neoplasm Metastasis / Q000188:drug therapy; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D016019:Survival Analysis; D000093542:Gemcitabine
chemical_list: D001549:Benzamides; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D003841:Deoxycytidine; C090712:iniparib; D016190:Carboplatin; D000093542:Gemcitabine