Efficacy of Chemotherapy in BRCA1/2 Mutation Carrier Ovarian Cancer in the Setting of PARP Inhibitor Resistance: A Multi-Institutional Study

Joo Ern Ang, Charlie Gourley, C. Bethan Powell, Hilda High, Ronnie Shapira-Frommer, Vincent Castonguay, Jacques De Greve, Tina Atkinson, Timothy A. Yap, Shahneen Sandhu, Susana Banerjee, Lee-May Chen, Michael L. Friedlander, Bella Kaufman, Amit M. Oza, Ursula Matulonis, Louise J. Barber, Iwanka Kozarewa, Kerry Fenwick, Ioannis AssiotisJames Campbell, Lina Chen, Johann S. de Bono, Martin E. Gore, Christopher J. Lord, Alan Ashworth, Stan B. Kaye*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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.
Original languageEnglish
Pages (from-to)5485-5493
Number of pages9
JournalClinical Cancer Research
Volume19
Issue number19
DOIs
Publication statusPublished - 1 Oct 2013

Keywords

  • DNA-SEQUENCING DATA
  • POLY(ADP-RIBOSE) POLYMERASE
  • SOMATIC MUTATIONS
  • SOLID TUMORS
  • OPEN-LABEL
  • CARCINOMAS
  • OLAPARIB
  • THERAPY
  • MULTICENTER
  • GUIDELINES

Fingerprint

Dive into the research topics of 'Efficacy of Chemotherapy in BRCA1/2 Mutation Carrier Ovarian Cancer in the Setting of PARP Inhibitor Resistance: A Multi-Institutional Study'. Together they form a unique fingerprint.

Cite this