PMC

(A) Effect of talazoparib with JQ-1 in ASCL1 degradation. H2081 cells were treated with talazoparib (1 μM for 48 hours), JQ-1 (0.1 μM for 48 hours), or talazoparib + JQ-1 as indicated, and the cell lysates were subjected to immunoblot analysis using the indicated antibodies. Values were presented as means ± SD (n = 3). (B) Effect of talazoparib with JQ-1 in ASCL1 degradation in vivo. Mice implanted with H2081 cells were treated with talazoparib (0.3 mg/kg), JQ-1 (25 mg/kg), or talazoparib + JQ-1 as indicated, and the tumor extracts were subjected to immunoblot analysis using the indicated antibodies. Values were presented as means ± SD (n = 3). (C) Effect of talazoparib with JQ-1 in a time-dependent manner. H2081 cells were treated with talazoparib (1 μM), JQ-1 (0.1 μM), or talazoparib + JQ-1 in a time-dependent manner. Viability was measured using a CellTiter-Glo assay, and all values were normalized by the DMSO control (100%) in each time point and presented as means ± SEM (n = 3). (D) Antitumor effect of talazoparib with JQ-1 in a concentration-dependent manner demonstrated synergy. H2081 cells were treated with talazoparib, JQ-1, or talazoparib + JQ-1 in a concentration-dependent manner. Viability was measured using a CellTiter-Glo assay. Left: Cell death ratio; right: synergistic score. AVE, average. (E) Overview of H2081-implanted xenograft tumor models. (F) Synergistic effects of talazoparib with JQ-1 in vivo. Mice implanted with H2081 cells were treated with talazoparib (0.3 mg/kg), JQ-1 (25 mg/kg), or talazoparib + JQ-1 as indicated. Left: The image of representative tumors; right: tumor volume and weight. Values were presented as means ± SD (n = 6 to 10).

Pharmacokinetic profile of talazoparib in wild-type mice and ABCB1/ABCG2(−/−) mice. (a) Plasma concentration-time curve of talazoparib in female wild-type FVB mice (n = 5) or ABCB1/ABCG2(−/−) mice (n = 4) after oral administration of a single dose of talazoparib (0.5 mg/kg). (b) Plasma concentration-time curve of talazoparib in female wild-type FVB mice (n = 5) after oral administration of a single dose of talazoparib (0.5 mg/kg), 30 min after a single oral dose of novobiocin (50 mg/kg) or vehicle. (c) Plasma concentration-time curve of talazoparib in female ABCB1/ABCG2(−/−) mice (n = 5) after oral administration of a single dose of talazoparib (0.5 mg/kg), 30 min after a single oral dose of novobiocin (50 mg/kg) or vehicle.

A. Antitumor activity of temozolomide (30 mg/kg Dx5), talazoparib (0.25 mg/kg BID Dx5, or in combination against ‘sensitive’ Ewing sarcoma models. Combination A (temozolomide 30 mg/kg Dx5; talazoparib 0.1 mg/kg BID Dx5); Combination B (temozolomide 12 mg/kg Dx5; talazoparib 0.25 mg/kg BID Dx5). Graphs show growth of individual tumors in SCID mice. B. Antitumor activity of temozolomide (30 mg/kg Dx5), talazoparib (0.25 mg/kg BID Dx5, or in combination against ‘insensitive’ Ewing sarcoma models. Combination A (temozolomide 30 mg/kg Dx5; talazoparib 0.1 mg/kg BID Dx5); Combination B (temozolomide 12 mg/kg Dx5; talazoparib 0.25 mg/kg BID Dx5). Graphs show growth of individual tumors in SCID mice.

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.