Phase I, dose-escalation, two-part trial of the PARP inhibitor talazoparib in patients with advanced germline BRCA1/2 mutations and selected sporadic cancers

Johann de Bono, Ramesh K. Ramanathan, Lida Mina, Rashmi Chugh, John Glaspy, Saeed Rafii, Stan Kaye, Jasgit Sachdev, John Heymach, David C. Smith, Joshua W. Henshaw, Ashleigh Herriott, Miranda Patterson, Nicola J. Curtin, Lauren Averett Byers, Zev A. Wainberg

Research output: Contribution to journalArticle

160 Scopus citations

Abstract

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. Treatmentrelated 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.

Original languageEnglish (US)
Pages (from-to)620-629
Number of pages10
JournalCancer discovery
Volume7
Issue number6
DOIs
StatePublished - 2017

ASJC Scopus subject areas

  • Oncology

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    de Bono, J., Ramanathan, R. K., Mina, L., Chugh, R., Glaspy, J., Rafii, S., Kaye, S., Sachdev, J., Heymach, J., Smith, D. C., Henshaw, J. W., Herriott, A., Patterson, M., Curtin, N. J., Byers, L. A., & 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-16-1250