RT Journal Article
SR Electronic
T1 Efficacy of Chemotherapy in <em>BRCA1/2</em> Mutation Carrier Ovarian Cancer in the Setting of PARP Inhibitor Resistance: A Multi-Institutional Study
JF Clinical Cancer Research
JO Clin Cancer Res
FD American Association for Cancer Research
SP 5485
OP 5493
DO 10.1158/1078-0432.CCR-13-1262
VO 19
IS 19
A1 Ang, Joo Ern
A1 Gourley, Charlie
A1 Powell, C. Bethan
A1 High, Hilda
A1 Shapira-Frommer, Ronnie
A1 Castonguay, Vincent
A1 De Greve, Jacques
A1 Atkinson, Tina
A1 Yap, Timothy A.
A1 Sandhu, Shahneen
A1 Banerjee, Susana
A1 Chen, Lee-May
A1 Friedlander, Michael L.
A1 Kaufman, Bella
A1 Oza, Amit M.
A1 Matulonis, Ursula
A1 Barber, Louise J.
A1 Kozarewa, Iwanka
A1 Fenwick, Kerry
A1 Assiotis, Ioannis
A1 Campbell, James
A1 Chen, Lina
A1 de Bono, Johann S.
A1 Gore, Martin E.
A1 Lord, Christopher J.
A1 Ashworth, Alan
A1 Kaye, Stan B.
YR 2013
UL http://clincancerres.aacrjournals.org/content/19/19/5485.abstract
AB 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. Clin Cancer Res; 19(19); 5485–93. ©2013 AACR.This article is featured in Highlights of This Issue, p. 5259