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

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.

• Authors: 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 Assiotis, James Campbell, Lina Chen, Johann S de Bono, Martin E Gore, Christopher J Lord, Alan Ashworth, Stan B Kaye
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 19 Issue 19 Pg. 5485-93 (Oct 01 2013) ISSN: 1557-3265 [Electronic] United States
• PMID: 23922302 (Publication Type: Journal Article, Multicenter Study)

Chemical References

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

Topics

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