PT  - JOURNAL ARTICLE
AU  - de Bono, Johann
AU  - Ramanathan, Ramesh K.
AU  - Mina, Lida
AU  - Chugh, Rashmi
AU  - Glaspy, John
AU  - Rafii, Saeed
AU  - Kaye, Stan
AU  - Sachdev, Jasgit
AU  - Heymach, John
AU  - Smith, David C.
AU  - Henshaw, Joshua W.
AU  - Herriott, Ashleigh
AU  - Patterson, Miranda
AU  - Curtin, Nicola J.
AU  - Byers, Lauren Averett
AU  - Wainberg, Zev A.
TI  - Phase I, Dose-Escalation, Two-Part Trial of the PARP Inhibitor Talazoparib in Patients with Advanced Germline <em>BRCA1/2</em> Mutations and Selected Sporadic Cancers
AID  - 10.1158/2159-8290.CD-16-1250
DP  - 2017 Jun 01
TA  - Cancer Discovery
PG  - 620--629
VI  - 7
IP  - 6
4099  - http://cancerdiscovery.aacrjournals.org/content/7/6/620.short
4100  - http://cancerdiscovery.aacrjournals.org/content/7/6/620.full
SO  - Cancer Discov2017 Jun 01; 7
AB  - Talazoparib 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.Significance: In this clinical trial, we show that talazoparib has single-agent antitumor activity and a tolerable safety profile. At its recommended phase II dose of 1.0 mg/day, confirmed responses were observed in patients with BRCA mutation–associated breast and ovarian cancers and in patients with pancreatic and small cell lung cancer. Cancer Discov; 7(6); 620–9. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 539