TY - JOUR
T1 - Efficacy of chemotherapy in BRCA1/2 mutation carrier ovarian cancer in the setting of PARP inhibitor resistance
T2 - A multi-institutional study
AU - Ang, Joo Ern
AU - Gourley, Charlie
AU - Powell, C. Bethan
AU - High, Hilda
AU - Shapira-Frommer, Ronnie
AU - Castonguay, Vincent
AU - De Greve, Jacques
AU - Atkinson, Tina
AU - Yap, Timothy A.
AU - Sandhu, Shahneen
AU - Banerjee, Susana
AU - Chen, Lee May
AU - Friedlander, Michael L.
AU - Kaufman, Bella
AU - Oza, Amit M.
AU - Matulonis, Ursula
AU - Barber, Louise J.
AU - Kozarewa, Iwanka
AU - Fenwick, Kerry
AU - Assiotis, Ioannis
AU - Campbell, James
AU - Chen, Lina
AU - De Bono, Johann S.
AU - Gore, Martin E.
AU - Lord, Christopher J.
AU - Ashworth, Alan
AU - Kaye, Stan B.
PY - 2013/10/1
Y1 - 2013/10/1
N2 - 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) and45%(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 OSof 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.
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 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) and45%(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 OSof 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.
UR - http://www.scopus.com/inward/record.url?scp=84886399807&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-13-1262
DO - 10.1158/1078-0432.CCR-13-1262
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C2 - 23922302
AN - SCOPUS:84886399807
SN - 1078-0432
VL - 19
SP - 5485
EP - 5493
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 19
ER -
