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 preolaparib 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

Development of Olaparib for BRCA-Deficient Recurrent Epithelial Ovarian Cancer

“…For patients treated post-olaparib with platinum-based chemotherapy, the ORR was 40% (n ¼ 19 of 48 patients; ref. 25). The corresponding ORRs when incorporating CA-125 were 45% and 49%, respectively (25).…”

“…25). The corresponding ORRs when incorporating CA-125 were 45% and 49%, respectively (25). The length of the platinum-to-platinum interval with intervening olaparib was associated with an increased likelihood of response (25).…”

“…On the basis of the preclinical data, early essayists were concerned that treatment with PARP inhibitors would result in acquisition of secondary BRCA1/2 mutations that would limit the efficacy of subsequent chemotherapy, specifically, platinumbased agents. Ang and colleagues (25) collected data from 89 patients with BRCA-deficient ovarian cancer who had been previously treated with olaparib at daily dosages of 200 mg and higher. The ORR by RECIST to post-olaparib chemotherapy was 36% (n ¼ 24 of 67 patients).…”

“…The corresponding ORRs when incorporating CA-125 were 45% and 49%, respectively (25). The length of the platinum-to-platinum interval with intervening olaparib was associated with an increased likelihood of response (25). Tumor was available from 6 cases and subjected to massively parallel sequencing, which demonstrated no evidence of secondary BRCA mutations (25).…”

PARP inhibitors and more

“…They already tested no less than 89 patients in a retrospective review of patients with BRCA1/2 mutation carrier ovarian cancer (PBMCOC) who received chemotherapy following disease progression on olaparib, administered at 200 mg twice daily for 1 month or more (10). An increased platinum-to-platinum interval was associated with an increased OS and likelihood of response following post-olaparib platinum.…”