Efficacy of chemotherapy in BRCA1/2 mutation carrier ovarian cancer in the setting of PARP inhibitor resistance: a multi-institutional study

Clin Cancer Res. 2013 Oct 1;19(19):5485-93. doi: 10.1158/1078-0432.CCR-13-1262. Epub 2013 Aug 6.


Purpose: Preclinical data suggest that exposure to PARP inhibitors (PARPi) may compromise benefit to subsequent chemotherapy, particularly platinum-based regimens, in patients with BRCA1/2 mutation carrier ovarian cancer (PBMCOC), possibly through the acquisition of secondary BRCA1/2 mutations. The efficacy of chemotherapy in the PARPi-resistant setting was therefore investigated.

Experimental design: We conducted a retrospective review of PBMCOC who received chemotherapy following disease progression on olaparib, administered at ≥200 mg twice daily for one month or more. Tumor samples were obtained in the post-olaparib setting where feasible and analyzed by massively parallel sequencing.

Results: Data were collected from 89 patients who received a median of 3 (range 1-11) lines of pre-olaparib chemotherapy. The overall objective response rate (ORR) to post-olaparib chemotherapy was 36% (24 of 67 patients) by Response Evaluation Criteria in Solid Tumors (RECIST) and 45% (35 of 78) by RECIST and/or Gynecologic Cancer InterGroup (GCIG) CA125 criteria with median progression-free survival (PFS) and overall survival (OS) of 17 weeks [95% confidence interval (CI), 13-21] and 34 weeks (95% CI, 26-42), respectively. For patients receiving platinum-based chemotherapy, ORRs were 40% (19 of 48) and 49% (26/53), respectively, with a median PFS of 22 weeks (95% CI, 15-29) and OS of 45 weeks (95% CI, 15-75). An increased platinum-to-platinum interval was associated with an increased OS and likelihood of response following post-olaparib platinum. No evidence of secondary BRCA1/2 mutation was detected in tumor samples of six PARPi-resistant patients [estimated frequency of such mutations adjusted for sample size: 0.125 (95%-CI: 0-0.375)].

Conclusions: Heavily pretreated PBMCOC who are PARPi-resistant retain the potential to respond to subsequent chemotherapy, including platinum-based agents. These data support the further development of PARPi in PBMCOC.

Trial registration: ClinicalTrials.gov NCT00494442 NCT00516373 NCT00628251 NCT00679783 NCT00777582.

Publication types

  • Multicenter Study

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • BRCA1 Protein / genetics*
  • BRCA2 Protein / genetics*
  • Drug Resistance, Neoplasm
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use
  • Female
  • Germ-Line Mutation*
  • Heterozygote*
  • Humans
  • Middle Aged
  • Neoplasm Grading
  • Neoplasm Staging
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / genetics*
  • Ovarian Neoplasms / mortality
  • Ovarian Neoplasms / pathology
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Prognosis
  • Retrospective Studies
  • Risk Factors
  • Treatment Outcome


  • BRCA1 Protein
  • BRCA2 Protein
  • Enzyme Inhibitors
  • Poly(ADP-ribose) Polymerase Inhibitors

Associated data

  • ClinicalTrials.gov/NCT00494442
  • ClinicalTrials.gov/NCT00516373
  • ClinicalTrials.gov/NCT00628251
  • ClinicalTrials.gov/NCT00679783
  • ClinicalTrials.gov/NCT00777582