Phase I, Dose-Escalation, Two-Part Trial of the PARP Inhibitor Talazoparib in Patients with Advanced Germline BRCA1/2 Mutations and Selected Sporadic Cancers

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. 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.

Figure 1

Patient enrollment and disposition. Abbreviation: ECOG PS, Eastern Cooperative Oncology Group Performance Status.

Figure 2

PK and PD features of talazoparib. A–D, Mean concentration– time profiles of talazoparib. Linear mean talazoparib plasma concentration–time profiles over the initial 24 hours after dose and log-linear mean talazoparib plasma concentration–time profiles over the complete sampling interval following (A and B) single doses of talazoparib and (C and D) multiple daily doses of talazoparib. E–H, Dose proportionality of talazoparib PK and dose–response and exposure–response relationships between talazoparib and PBMC PARP activity. E, Plasma C_max following multiple daily doses ranging from 0.025 to 1.1 mg. F, AUC_0–24 following multiple daily doses ranging from 0.025 to 1.1 mg. Filled circles represent the mean value at each dose level, and error bars represent the standard deviations. Solid line represents the power model fit through the data. G, Dose–response relationship between talazoparib and PBMC PARP activity. H, Exposure–response relationship between talazoparib and PBMC PARP activity. Percentage baseline PBMC PARP activity defined as the mean of the predose PARP activity assessments during the multiple dosing assessment phase (i.e., predose assessments on days 15, 22, and 35 of cycle 1). Abbreviations: AUC_0–24, AUC from 0 to 24 h; IC₅₀, half maximal inhibitory concentration; ID₅₀, inhibitory dose 50%; PD, pharmacodynamic.

Figure 3

Percentage change in target lesion for patients undergoing treatment with talazoparib who have (A) gBRCA breast cancer and (B) gBRCA ovarian cancer. Positive values indicate tumor growth, negative values indicate tumor reduction, and the dashed line represents the definition of partial response from RECIST guidelines. Abbreviations: gBRCA, germline BRCA mutated; SLD, sum of longest diameter.