In vivo visualization of PARP inhibitor pharmacodynamics

BACKGROUND: [(18)F]FluorThanatrace ([(18)F]FTT) is a radiolabeled poly (adenosine diphosphate-ribose) 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 [(18)F]FTT PET before and after initiation of PARPi treatment and in vitro via [(125)I]KX1 (an analog of [(18)F]FTT) binding to surgically removed breast cancer. RESULTS: Thirteen patients had baseline [(18)F]FTT PET. Nine of these then had resection and in vitro evaluation of [(18)F]FTT uptake with an analog and uptake was blocked with PARPi. Of the other 4 patients, 3 had [(18)F]FTT PET uptake, and all had uptake blocked with treatment with a therapeutic PARPi. Initial in vivo [(18)F]FTT tumor uptake ranged from undetectable to robust. Following initiation of PARPi therapy, [(18)F]FTT uptake was not detectable above background in all cases. In vitro tumor treatment with a PARPi resulted in 82% reduction in [(125)I]KX1 binding. CONCLUSION: [(18)F]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 [(18)F]FTT PET as a predictive and pharmacodynamic biomarker. TRIAL REGISTRATION: ClinicalTrials.gov identifiers NCT03083288 and NCT03846167. FUNDING: Metavivor Translational Research Award, Susan G. Komen for the Cure (CCR 16376362), Department of Defense BC190315, and Abramson Cancer Center Breakthrough Bike Challenge.