Comparative Parp Enzyme Inhibition Of Pf-01367338, Olaparib, And Mk-4827

e13552 Background: Within the past several years multiple PARP inhibitors have been entered into clinical trials, in a variety of tumors types with defective homology-directed DNA repair. An understanding of the degree of PARP inhibition produced by these inhibitors is critical in understanding potential drug effectiveness. Pharmacodynamic (PD) data, specifically PARP inhibition in peripheral blood lymphocytes (PBLs), have been reported for PF-01367338, olaparib and MK-4827, which provides an opportunity to compare the PD effect of these compounds. The objective of this study was to compare PARP inhibition following PF-01367338 daily IV dosing to those achieved by olaparib and MK-4821. Methods: PARP inhibition (percent change of PAR from baseline) data for PF-01367338 were obtained from the Phase 1 study of PF-01367338 given daily in combination with temozolomide for 5 days. Olaparib and MK-4821 data were obtained from the exposure or dose/response curves reported in the literature. Comparisons were made using PD data from PF-01367338 matched to those reported for each compound, including (a) the average PARP inhibition over the dosing interval for comparison with olaparib, and (b) the PARP inhibition at the end of dosing interval for comparison with MK-4827. Maximum inhibition (Emax), the endpoint used for the comparison of inhibitory performance, was either determined by PK/PD modelling (PF-01367338 and Olaparib) or obtained from the average inhibition at the dose levels where PARP inhibition in PBLs reached plateau (MK-4827). The corresponding range for Emax was obtained from observed data for the relevant comparison at the dose or exposure level(s) where Emax was achieved. Results: Comparison of Emax achieved (see table). Values for Olaparib and MK-4827 were read off the published figures thus approximate. Conclusions: PF-01367338 provides an average increase of 22-27% in PARP inhibition with less inter-patient variability compared to olaparib or MK-4827. Future studies are planned to determine if this finding translates into an increase in anti-tumor response. PF-01367338 vs. olaparib PF-01367338 vs. MK-4827 PF-01367338 Olaparib Difference PF-01367338 MK-4827 Difference Emax (%) 92 70 22 Emax (%) 92 65 27 Range 90-97 40-95 Range 92-99 40-82