[¹⁸F]FluorThanatrace ([¹⁸F]FTT) PET Imaging of PARP-Inhibitor Drug-Target Engagement as a Biomarker of Response in Ovarian Cancer, a Pilot Study

Purpose: PARP inhibitors have become the standard-of-care treatment for homologous recombination deficient (HRD) highgradeserousovariancancer(HGSOC).However,notallHRDtumors respond to PARPi. Biomarkers to predict response are needed. [¹⁸F]FluorThanatrace([¹⁸F]FTT)isaPARPi-analogPETradiotracer thatnoninvasivelymeasuresPARP-1expression.Herein,weevaluate [¹⁸F]FTT as a biomarker to predict response to PARPi in patient-derived xenograft (PDX) models and subjects with HRD HGSOC. Experimental Design: In PDX models, [¹⁸F]FTT-PET was performed before and after PARPi (olaparib), ataxia-telangiectasia inhibitor (ATRi), or both (PARPi-ATRi). Changes in [¹⁸F]FTT were correlated with tumor volume changes. Subjects were imaged with [¹⁸F]FTT-PET at baseline and after ~1 week of PARPi. Changes in [¹⁸F]FTT-PET uptake were compared with changes in tumor size (RECISTv1.1), CA-125, and progression-free survival (PFS). Results: A decrease in [¹⁸F]FTT tumor uptake after PARPi correlated with response to PARPi, or PARPi-ATRi treatment in PARPi-resistant PDX models (r ¼ 0.77–0.81). In subjects (n ¼ 11), percent difference in [¹⁸F]FTT-PET after ~7 days of PARPi compared with baseline correlated with best RECIST response (P ¼ 0.01), best CA-125 response (P ¼ 0.033), and PFS (P ¼ 0.027). All subjects with >50% reduction in [¹⁸F]FTT uptake had >6-month PFS and >50% reduction in CA-125. Utilizing only baseline [¹⁸F]FTT uptake did not predict such responses. Conclusions: The decline in [¹⁸F]FTT uptake shortly after PARPi initiation provides a measure of drug-target engagement and shows promise as a biomarker to guide PARPi therapies in this pilot study. These results support additional preclinical mechanistic and clinical studies in subjects receiving PARPi ± combination therapy. See related commentary by Liu and Zamarin, p. 1384.