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

摘要: 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 whom cells have defective homologous recombination (HR) DNA repair. Platinum-based chemotherapy responses correlate with HR repair capacity. Olaparib is potent, oral PARP that well tolerated, antitumor activity carriers. Patients and Methods BRCA1/2-mutated ovarian cancer were treated olaparib within dose-escalation single-stage expansion of phase I trial. Antitumor was subsequently correlated platinum sensitivity. Results Fifty patients treated: 48 had germline mutations; one BRCA2 sequence change unknown significance, another strong family history BRCA1/2associated cancers who declined testing. Of the 50 patients, 13 platinum-sensitive disease, 24 platinum-resistant platinum-refractory disease (according to platinum-free interval). Twenty (40%; 95% CI, 26% 55%) Response Evaluation Criteria Solid Tumors (RECIST) complete or partial and/or marker (CA125) responses, three (6.0%) maintained RECIST stabilization for more than 4 months, giving an overall clinical benefit rate 46% (95% 32% 61%). Median response duration 28 weeks. There significant association between interval across platinum-sensitive, resistant, refractory subgroups (69%, 45%, 23%, respectively). Post hoc analyses indicated associations sensitivity extent (radiologic change, P .001; CA125 .002).