TALA is a potent PARP inhibitor. Efficacy and safety profiles of once-daily TALA 1 mg were established in advanced breast cancer patients (pts) in the phase 3 EMBRACA and phase 2 ABRAZO trials. Approximately 60% of pts experience dose modification due to an adverse event (AE). This analysis characterized the relationship between TALA exposure and grade 3 or higher anemia, neutropenia, and thrombocytopenia, the most common AEs leading to dose modification.
Safety and pharmacokinetic (PK) data from 367 TALA-treated pts (285 EMBRACA, 82 ABRAZO) were included in a pooled analysis. To account for dose modifications over time, individual time-varying concentration from time 0 up to the time of each safety event (Cavg,t) was calculated at each event time using average daily dose intensity and apparent TALA clearance as obtained from population PK analysis. The relationship between Cavg,t, as well as other potential prognostic factors and the selected safety events was evaluated using Cox proportional hazard (PH) models. Significant covariates in univariate analyses were further examined in multi-variate analyses.
Visual examination suggested a higher Cavg,t in pts with anemia and thrombocytopenia events vs pts without events. Cox PH models indicated that a higher risk of anemia and thrombocytopenia was associated with higher Cavg,t. For anemia, the HR (95% CI) for Cavg,t (ng/mL) was 1.3 (1.12, 1.4), P = 3.03. For thrombocytopenia, the HR (95% CI) for Cavg,t (ng/mL) was 1.2 (1.01, 1.3), P = 0.0394. A trend for association between higher Cavg,t and neutropenia was observed although the relationship was not statistically significant (P = 0.0633). Higher risk of all tested safety endpoints was associated with lower baseline hemoglobin. Higher risk of neutropenia was associated with lower absolute neutrophil count and lower body weight.
A higher risk of anemia and thrombocytopenia was associated with higher TALA exposure. This finding supports the proposed management of TALA-related AEs through dosing interruption and reduction.
Editorial and medical writing support funded by Pfizer Inc. were provided by Edwin Thrower, PhD, Mary Kacillas and Paula Stuckart of Ashfield Healthcare Communications, Middletown, Connecticut.
J.K. Litton: Institutional-contracted research: Pfizer, Novartis, EMD-Serono, AstraZeneca, GlaxoSmithKline, and Genentech; Advisory board participation: AstraZeneca and Pfizer, both uncompensated. N.C. Turner: Advisory board, honoraria and research funding: Pfizer and BioMarin. M. Elmeliegy, A. Czibere, Y. Yu, G.G. Wilson, I.C. Tudor, J. Zheng, D.D. Wang: Employment: Pfizer, Inc.