Talazoparib is a potent, orally bioavailable, poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor that is currently under development for the treatment of a variety of cancers. This exposure-response (ER) analysis characterized the relationship between talazoparib exposure and PFS in patients with locally advanced and/or metastatic breast cancer with germline breast cancer susceptibility gene (BRCA) mutations based on the phase 3 EMBRACA trial.
285 patients, who were treated with talazoparib and had available pharmacokinetic (PK) parameters from the phase 3 EMBRACA trial, were included in the analysis. There were 185 PFS events at the data cut of the analysis. The apparent talazoparib clearance (CL/F) for each patient was obtained from a population PK analysis. To account for dose modifications over time, the ER analysis used a time-varying exposure metric (Cavg,t) for talazoparib exposure. At each PFS event, the talazoparib exposures up to the time of the PFS event t were calculated for all patients at risk using average daily dose intensity up to time t and CL/F and correlated with the probability of having a PFS event using the Cox proportional hazards model. Other potential prognostic factors were also tested as covariates for PFS. The significant covariates identified in univariate analyses were further examined for significance in multi-variate analyses.
The ER analysis for PFS showed that there was a significant correlation between PFS and talazoparib exposure. A longer PFS was associated with higher talazoparib exposure. In addition, longer PFS was also associated with lower baseline lactate dehydrogenase. PFS was longer in patients without visceral disease than patients with visceral disease. A diseasefree interval of > 12 months was associated with a longer PFS than that of ≤ 12 months.
PFS was found to be associated with Cavg,t, and a longer PFS was associated with a higher talazoparib exposure. This supports using 1 mg QD, the maximum tolerated dose, as the recommended dose for talazoparib.
Clinical trial identification
Legal entity responsible for the study
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, Genentech; Advisory board participation: AstraZeneca and Pfizer, both uncompensated. Y. Yu, M. Elmeliegy, I.C. Tudor, A. Czibere, J. Zheng, D.D. Wang: Employment: Pfizer, Inc.