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Poly(ADP)-Ribose Polymerase Inhibition: Frequent Durable Responses in BRCA Carrier Ovarian Cancer Correlating With Platinum-Free Interval

Open access
Fong, Peter C., Yap, Timothy A., Boss, David S., Carden, Craig P., Mergui-Roelvink, Marja, Gourley, Charlie, De Greve, Jacques, Lubinski, Jan, Shanley, Susan, Messiou, Christina, A'Hern, Roger, Tutt, Andrew, Ashworth, Alan, Stone, John, Carmichael, James, Schellens, Jan H.M., de Bono, Johann S., Kaye, Stan B.·2010·Journal of Clinical Oncology

Abstract

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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Metadata

Authors
Fong, P. C., Yap, T. A., Boss, D. S., Carden, C. P., Mergui-Roelvink, M., Gourley, C., De Greve, J., Lubinski, J., Shanley, S., Messiou, C., A'Hern, R., Tutt, A., Ashworth, A., Stone, J., Carmichael, J., Schellens, J. H. M., de Bono, J. S., & Kaye, S. B.
Venue
Journal of Clinical Oncology
Published
2010-05-20
Volume
28
Issue
15
Pages
2512-2519
ISSN
  • 0732-183X (ISSN-L)
  • 1527-7755
OpenAlex
W1999659306
Cited by
1,010
References
8
FWCI
40.89
Type
journal article
Language
en
Open access
bronze

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CoChat. (2026). Citation check: Poly(ADP)-Ribose Polymerase Inhibition: Frequent Durable Responses in BRCA Carrier Ovarian Cancer Correlating With Platinum-Free Interval. https://app.cochat.ai/papers/10.1200/jco.2009.26.9589
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Fong, P. C., Yap, T. A., Boss, D. S., Carden, C. P., Mergui-Roelvink, M., Gourley, C., De Greve, J., Lubinski, J., Shanley, S., Messiou, C., A'Hern, R., Tutt, A., Ashworth, A., Stone, J., Carmichael, J., Schellens, J. H. M., de Bono, J. S., & Kaye, S. B. (2010). Poly(ADP)-Ribose Polymerase Inhibition: Frequent Durable Responses in BRCA Carrier Ovarian Cancer Correlating With Platinum-Free Interval. Journal of Clinical Oncology. https://doi.org/10.1200/jco.2009.26.9589

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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).

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