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

• Published in: Clinical cancer research Vol. 29; no. 8; pp. 1515 - 1527
• Main Authors: Pantel, Austin R., Gitto, Sarah B., Makvandi, Mehran, Kim, Hyoung, Medvedv, Sergey, Weeks, Joanna K., Torigian, Drew A., Hsieh, Chia-Ju, Ferman, Benjamin, Latif, Nawar A., Tanyi, Janos L., Martin, Lainie P., Lanzo, Shannon M., Liu, Fang, Cao, Quy, Mills, Gordon B., Doot, Robert K., Mankoff, David A., Mach, Robert H., Lin, Lilie L., Simpkins, Fiona
• Format: Journal Article
• Language: English
• Published: United States 14.04.2023
• Subjects: Antineoplastic Agents - therapeutic use; Biomarkers; Carcinoma, Ovarian Epithelial - drug therapy; Female; Humans; Ovarian Neoplasms - diagnostic imaging; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - genetics; Pilot Projects; Poly(ADP-ribose) Polymerase Inhibitors - pharmacology; Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use; Positron-Emission Tomography - methods
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-22-1602

PARP inhibitors have become the standard-of-care treatment for homologous recombination deficient (HRD) high-grade serous ovarian cancer (HGSOC). However, not all HRD tumors respond to PARPi. Biomarkers to predict response are needed. [18F]FluorThanatrace ([18F]FTT) is a PARPi-analog PET radiotracer that noninvasively measures PARP-1 expression. Herein, we evaluate [18F]FTT as a biomarker to predict response to PARPi in patient-derived xenograft (PDX) models and subjects with HRD HGSOC. 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). A decrease in [18F]FTT tumor uptake after PARPi correlated with response to PARPi, or PARPi-ATRi treatment in PARPi-resistant PDX models (r = 0.77-0.81). In subjects (n = 11), percent difference in [18F]FTT-PET after ∼7 days of PARPi compared with baseline correlated with best RECIST response (P = 0.01), best CA-125 response (P = 0.033), and PFS (P = 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. 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.