de Bono, JohannRamanathan, Ramesh K.Mina, LidaChugh, RashmiGlaspy, JohnRafii, SaeedKaye, StanSachdev, JasgitHeymach, JohnSmith, David C.Henshaw, Joshua W.Herriott, AshleighPatterson, MirandaCurtin, Nicola J.Byers, Lauren AverettWainberg, Zev A.2018-01-182018-01-182017-06de Bono, J., Ramanathan, R. K., Mina, L., Chugh, R., Glaspy, J., Rafii, S., … Wainberg, Z. A. (2017). Phase I, Dose-Escalation, Two-Part Trial of the PARP Inhibitor Talazoparib in Patients with Advanced Germline BRCA1/2 Mutations and Selected Sporadic Cancers. Cancer Discovery, 7(6), 620–629. https://doi.org/10.1158/2159-8290.CD-16-1250https://hdl.handle.net/1805/15029Talazoparib inhibits PARP catalytic activity, trapping PARP1 on damaged DNA and causing cell death in BRCA1/2-mutated cells. We evaluated talazoparib therapy in this two-part, phase I, first-in-human trial. Antitumor activity, MTD, pharmacokinetics, and pharmacodynamics of once-daily talazoparib were determined in an open-label, multicenter, dose-escalation study (NCT01286987). The MTD was 1.0 mg/day, with an elimination half-life of 50 hours. Treatment-related adverse events included fatigue (26/71 patients; 37%) and anemia (25/71 patients; 35%). Grade 3 to 4 adverse events included anemia (17/71 patients; 24%) and thrombocytopenia (13/71 patients; 18%). Sustained PARP inhibition was observed at doses ≥0.60 mg/day. At 1.0 mg/day, confirmed responses were observed in 7 of 14 (50%) and 5 of 12 (42%) patients with BRCA mutation–associated breast and ovarian cancers, respectively, and in patients with pancreatic and small cell lung cancer. Talazoparib demonstrated single-agent antitumor activity and was well tolerated in patients at the recommended dose of 1.0 mg/day.enPublisher PolicyTalazoparibpoly(ADP-ribose) polymerase inhibitorBRCA1/2 mutationArticle