PET Imaging of a [ 18 F]-radiolabeled PARP Inhibitor Monitors the Therapeutic Efficacy of Talazoparib in Small Cell Lung Cancer Patient-Derived Xenografts

Introduction— Inhibitors of poly-(ADP)-ribose polymerase (PARP) are promising therapeutics for small cell lung cancer (SCLC). We tested whether PARP inhibitor (PARPi) target engagement as measured by a radiolabeled PARP inhibitor ([ 18 F]PARPi) has the potential to predict drug efficacy in vivo. Methods— Tumor growth inhibition during daily talazoparib treatment was evaluated in mice engrafted with SCLC patient-derived xenografts to evaluate talazoparib efficacy at multiple doses. Mice were intravenously injected with [ 18 F]PARPi radiotracer at multiple time points after single doses of oral talazoparib to quantitatively assess the extent to which talazoparib could reduce tumor radiotracer uptake and PET/CT activity. Tumors were harvested and tumor PAR level was measured by ELISA. Results— A dose range of talazoparib with differential therapeutic efficacy was established, with significant delay in time to reach 1000 mm 3 for tumors treated with 0.3 mg/kg (p=0.02) but not 0.1 mg/kg talazoparib. On PET/CT with [ 18 F]PARPi, reduction in [ 18 F]PARPi uptake after talazoparib dosing was consistent with talazoparib clearance, with reduction in PET activity attenuating over 24 hours. Talazoparib target engagement, measured by maximum tumor PET uptake, increased in a dose dependent manner (3.9% vs. 2.1% ID/g for 0.1 and 0.3 mg/kg at 3 hours post-talazoparib, p=0.003) and correlated with PARP enzymatic activity among individual tumors as measured by total tumor PAR (p=0.04, R=0.62 at 1 hour post-talazoparib). Conclusions— PET imaging using [ 18 F]PARPi has the potential to be a powerful tool in treatment monitoring by assessing PARP inhibitor target engagement in real-time.