• Peter C Fong, Timothy A Yap, David S Boss, Craig P Carden, Marja Mergui-Roelvink, Charlie Gourley, Jacques De Greve, Jan Lubinski, Susan Shanley, Christina Messiou, Roger A'Hern, Andrew Tutt, Alan Ashworth, John Stone, James Carmichael, Jan H M Schellens, Johann S de Bono, and Stan B Kaye.
• Drug Development Unit, Royal Marsden National Health Service Foundation Trust, Sutton, Surrey, UK.
• J. Clin. Oncol. 2010 May 20;28(15):2512-9.

PurposeSelective 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 MethodsPatients 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.ResultsFifty 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).ConclusionOlaparib has antitumor activity in BRCA1/2 mutation ovarian cancer, which is associated with platinum sensitivity.

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