title: Phase I, Dose-Escalation, Two-Part Trial of the PARP Inhibitor Talazoparib in Patients with Advanced GermlineBRCA1/2Mutations and Selected Sporadic Cancers.
abstract: Talazoparib inhibits PARP catalytic activity, trapping PARP1 on damaged DNA and causing cell death inBRCA1/2-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 withBRCAmutation-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 withBRCAmutation-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.
authors.affiliation: Drug Development Unit, Royal Marsden Hospital, London, United Kingdom. johann.de-bono@icr.ac.uk.
authors.forename: Johann
authors.initials: J
authors.lastname: de Bono
authors.affiliation: Clinical Trials Program, Virginia G. Piper Cancer Center at Scottsdale Healthcare/TGen, Scottsdale, Arizona.
authors.forename: Ramesh K
authors.initials: RK
authors.lastname: Ramanathan
authors.affiliation: Simon Cancer Center, Indiana University, Indianapolis, Indiana.
authors.forename: Lida
authors.initials: L
authors.lastname: Mina
authors.affiliation: Division of Hematology/Oncology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Rashmi
authors.initials: R
authors.lastname: Chugh
authors.affiliation: Division of Hematology/Oncology, David Geffen School of Medicine at UCLA, Los Angeles, California.
authors.forename: John
authors.initials: J
authors.lastname: Glaspy
authors.affiliation: Drug Development Unit, Royal Marsden Hospital, London, United Kingdom.
authors.forename: Saeed
authors.initials: S
authors.lastname: Rafii
authors.affiliation: Drug Development Unit, Royal Marsden Hospital, London, United Kingdom.
authors.forename: Stan
authors.initials: S
authors.lastname: Kaye
authors.affiliation: Clinical Trials Program, Virginia G. Piper Cancer Center at Scottsdale Healthcare/TGen, Scottsdale, Arizona.
authors.forename: Jasgit
authors.initials: J
authors.lastname: Sachdev
authors.affiliation: Department of Thoracic Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: John
authors.initials: J
authors.lastname: Heymach
authors.affiliation: Division of Hematology/Oncology, University of Michigan, Ann Arbor, Michigan.
authors.forename: David C
authors.initials: DC
authors.lastname: Smith
authors.affiliation: Pharmacokinetics/Pharmacodynamics, BioMarin Pharmaceutical, Inc., Novato, California.
authors.forename: Joshua W
authors.initials: JW
authors.lastname: Henshaw
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Ashleigh
authors.initials: A
authors.lastname: Herriott
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Miranda
authors.initials: M
authors.lastname: Patterson
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Curtin
authors.affiliation: Department of Thoracic Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Lauren Averett
authors.initials: LA
authors.lastname: Byers
authors.affiliation: Division of Hematology/Oncology, David Geffen School of Medicine at UCLA, Los Angeles, California.
authors.forename: Zev A
authors.initials: ZA
authors.lastname: Wainberg
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000201:enzymology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D010793:Phthalazines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000097:blood; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D010793:Phthalazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C586365:talazoparib; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1