In Vivo Visualization Of Parp Inhibitor Pharmacodynamics

BACKGROUND. [F-18]FluorThanatrace ([F-18]FTT) is a radiolabeled poly (adenosine diphosphateribose) polymerase inhibitor (PARPi) that enables noninvasive quantification of PARP with potential to serve as a biomarker for patient selection for PARPi therapy. Here we report for the first time to our knowledge noninvasive in vivo visualization of drug-target engagement during PARPi treatment.METHODS. Two single-arm, prospective, nonrandomized clinical trials were conducted at the University of Pennsylvania from May 2017 to March 2020. PARP expression in breast cancer was assessed in vivo via [F-18]FTT PET before and after initiation of PARPi treatment and in vitro via [I-125] KX1 (an analog of [F-18]FTT) binding to surgically removed breast cancer.RESULTS. Thirteen patients had baseline [F-18]FTT PET. Nine of these then had resection and in vitro evaluation of [F-18]FTT uptake with an analog and uptake was blocked with PARPi. Of the other 4 patients, 3 had [F-18]FTT PET uptake, and all had uptake blocked with treatment with a therapeutic PARPi. Initial in vivo [F-18]FTT tumor uptake ranged from undetectable to robust. Following initiation of PARPi therapy, [F-18]FTT uptake was not detectable above background in all cases. In vitro tumor treatment with a PARPi resulted in 82% reduction in [I-125]KX1 binding.CONCLUSION. [F-18]FTT noninvasively quantifies PARP-1 expression. Early results indicate ability to visualize PARPi drug-target engagement in vivo and suggest the utility of further study to test [F-18] FTT PET as a predictive and pharmacodynamic biomarker.