TY - JOUR
T1 - Poly(ADP)-ribose polymerase inhibition
T2 - Frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval
AU - Fong, Peter C.
AU - Yap, Timothy A.
AU - Boss, David S.
AU - Carden, Craig P.
AU - Mergui-Roelvink, Marja
AU - Gourley, Charlie
AU - De Greve, Jacques
AU - Lubinski, Jan
AU - Shanley, Susan
AU - Messiou, Christina
AU - A'Hern, Roger
AU - Tutt, Andrew
AU - Ashworth, Alan
AU - Stone, John
AU - Carmichael, James
AU - Schellens, Jan H.M.
AU - De Bono, Johann S.
AU - Kaye, Stan B.
N1 - Copyright:
Copyright 2011 Elsevier B.V., All rights reserved.
PY - 2010/5/20
Y1 - 2010/5/20
N2 - Purpose: Selective tumor cell cytotoxicity can be achieved through a synthetic lethal strategy using poly(ADP)-ribose polymerase (PARP) inhibitor therapy in BRCA1/2 mutation carriers in whom tumor cells have defective homologous recombination (HR) DNA repair. Platinum-based chemotherapy responses correlate with HR DNA repair capacity. Olaparib is a potent, oral PARP inhibitor that is well tolerated, with antitumor activity in BRCA1/2 mutation carriers. Patients and Methods: Patients with BRCA1/2-mutated ovarian cancer were treated with olaparib within a dose-escalation and single-stage expansion of a phase I trial. Antitumor activity was subsequently correlated with platinum sensitivity. Results: Fifty patients were treated: 48 had germline BRCA1/2 mutations; one had a BRCA2 germline sequence change of unknown significance, and another had a strong family history of BRCA1/2-associated cancers who declined mutation testing. Of the 50 patients, 13 had platinum-sensitive disease, 24 had platinum-resistant disease, and 13 had platinum-refractory disease (according to platinum-free interval). Twenty (40%; 95% CI, 26% to 55%) achieved Response Evaluation Criteria in Solid Tumors (RECIST) complete or partial responses and/or tumor marker (CA125) responses, and three (6.0%) maintained RECIST disease stabilization for more than 4 months, giving an overall clinical benefit rate of 46% (95% CI, 32% to 61%). Median response duration was 28 weeks. There was a significant association between the clinical benefit rate and platinum-free interval across the platinum-sensitive, resistant, and refractory subgroups (69%, 45%, and 23%, respectively). Post hoc analyses indicated associations between platinum sensitivity and extent of olaparib response (radiologic change, P = .001; CA125 change, P = .002). Conclusion: Olaparib has antitumor activity in BRCA1/2 mutation ovarian cancer, which is associated with platinum sensitivity.
AB - Purpose: Selective tumor cell cytotoxicity can be achieved through a synthetic lethal strategy using poly(ADP)-ribose polymerase (PARP) inhibitor therapy in BRCA1/2 mutation carriers in whom tumor cells have defective homologous recombination (HR) DNA repair. Platinum-based chemotherapy responses correlate with HR DNA repair capacity. Olaparib is a potent, oral PARP inhibitor that is well tolerated, with antitumor activity in BRCA1/2 mutation carriers. Patients and Methods: Patients with BRCA1/2-mutated ovarian cancer were treated with olaparib within a dose-escalation and single-stage expansion of a phase I trial. Antitumor activity was subsequently correlated with platinum sensitivity. Results: Fifty patients were treated: 48 had germline BRCA1/2 mutations; one had a BRCA2 germline sequence change of unknown significance, and another had a strong family history of BRCA1/2-associated cancers who declined mutation testing. Of the 50 patients, 13 had platinum-sensitive disease, 24 had platinum-resistant disease, and 13 had platinum-refractory disease (according to platinum-free interval). Twenty (40%; 95% CI, 26% to 55%) achieved Response Evaluation Criteria in Solid Tumors (RECIST) complete or partial responses and/or tumor marker (CA125) responses, and three (6.0%) maintained RECIST disease stabilization for more than 4 months, giving an overall clinical benefit rate of 46% (95% CI, 32% to 61%). Median response duration was 28 weeks. There was a significant association between the clinical benefit rate and platinum-free interval across the platinum-sensitive, resistant, and refractory subgroups (69%, 45%, and 23%, respectively). Post hoc analyses indicated associations between platinum sensitivity and extent of olaparib response (radiologic change, P = .001; CA125 change, P = .002). Conclusion: Olaparib has antitumor activity in BRCA1/2 mutation ovarian cancer, which is associated with platinum sensitivity.
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U2 - 10.1200/JCO.2009.26.9589
DO - 10.1200/JCO.2009.26.9589
M3 - Article
C2 - 20406929
AN - SCOPUS:77954032829
SN - 0732-183X
VL - 28
SP - 2512
EP - 2519
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 15
ER -