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

<div>Abstract<p><b>Purpose:</b> Preclinical data suggest that exposure to PARP inhibitors (PARPi) may compromise benefit to subsequent chemotherapy, particularly platinum-based regimens, in patients with <i>BRCA1/2</i> mutation carrier ovarian cancer (PBMCOC), possibly through the acquisition of secondary <i>BRCA1/2</i> mutations. The efficacy of chemotherapy in the PARPi-resistant setting was therefore investigated.</p><p><b>Experimental Design:</b> 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.</p><p><b>Results:</b> 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 <i>BRCA1/2</i> 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)].</p><p><b>Conclusions:</b> 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. <i>Clin Cancer Res; 19(19); 5485–93. ©2013 AACR</i>.</p></div>