Poly(ADP ribose) polymerase (PARP) inhibition in peripheral blood lymphocytes (PBLs): Does it reflect PARP inhibition in tumor?

Abstract

3054 Background: PARP activity in PBLs or PBMs, measured as poly(ADP-ribose) (PAR) levels, has been used as a biomarker in the development of PARP inhibitors for dose selection. Results of a phase II study of olaparib in pts with BRCA-deficient ovarian or breast cancer showed that PARP inhibition in peripheral-blood mononuclear cells (PBMCs) plateaued at 100 mg given bid, but better antitumor activity was achieved with 400 mg bid dosing. The goal of this study was to compare PARP inhibition by PF-01367338 (formerly AG014699) in PBLs and tumor using data from a previous Pfizer study. Methods: In a phase I melanoma study, PF-01367338 IV infusion (1 to 18 mg/m2) was given daily with temozolomide for 5 days. For this analysis, PAR in PBLs was measured on Cycle 1 Days 1 or 4 at baseline pretreatment and 4-6 hrs after dosing (cohorts 6-9). Tumor biopsy samples were collected before dosing on Day -7 and 4-6 hrs after dosing on Days 1, 4 or 5 from patients dosed with 12 or 18 mg/ m2. Samples were analysed using a validated immunoblot assay for determination of PAR formation. PARP inhibition was calculated as percent change of PAR level from baseline. Results: Patients provided PBL and tumor biopsy samples for paired analyses to assess PARP inhibition by PF-01367338. Data are summarized in the table below. Conclusions: Similar percent reductions in PAR formation in PBLs and tumor tissue indicate that PARP inhibition by PF-01367338 in PBLs reflects that seen in melanoma tumors. Further investigation is needed to determine whether additional dose escalation would produce additional anti-tumor activity. PF-01367338 dose Median (range)PARP inhibition in PBLs (%) Median (range)PARP inhibition in tumor (%) Wilcoxon Rank-Sum 12 mg/m2 (n = 7) 87.5 (82.1 – 96.0) 90.6 (78.1 – 99.1) z=-1.086, p=0.2774 18 mg/m2 (n = 4) 85.7 (79.1 – 95.6) 91.3 (85.9 – 97.0) z=-0.866, p=0.193 * Wilcoxon rank-sum analysis for pooled data: z = -1.215, one-sided p=0.112.