Author(s): Fong PC, Yap TA, Boss DS, Carden CP, MerguiRoelvink M,
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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.
This article was published in J Clin Oncol
and referenced in Journal of Cancer Science & Therapy