LAUSR

Purpose: Poly(ADP-ribose) polymerase enzyme inhibitors (PARPi) 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 and biomarkers to predict response are needed. [18F]FluorThanatrace (FTT) is a PARPi-analog PET radiotracer that non-invasively measures PARP-1 expression. Herein, we evaluate the ability of FTT uptake to serve as a biomarker to predict response to PARPi in patient-derived xenograft (PDX) models and patients with HGSOC. Patients and Methods: In PDX models, FTT-PET was performed before and after PARPi (olaparib), ataxia-telangiectasia inhibitor (ATRi), or both. Changes in FTT were correlated with tumor size changes. Patients with HRD and HGSOC that were enrolled in CAPRI (PARPi+ATRi), LIGHT (PARPi only), or off-trial (PARPi only) were selected for this single-center, prospective, cohort, IRB-approved study. FTT-PET/CT imagining was obtained from the skull base to the proximal thighs on an Ingenuity TF scanner (Philips Healthcare) 60-90 minutes after intravenous infusion of 8-12 mCi FTT. Subjects were imaged with FTT-PET at baseline and after ~1 week of PARPi monotherapy treatment. Target lesions (primary tumor and/or metastases) were identified at the time of the baseline imaging on correlative anatomic imaging using RECIST 1.1 and maximum standardized uptake value (SUVmax) data, normalized by body weight, was collected. Changes in FTT-PET uptake were compared to changes in tumor size, CA-125, and progression free survival (PFS). Results: A decrease in FTT tumor uptake after 1 week of PARPi treatment correlated with response to PARPi+ATRi treatment in PARPi-resistant PDX models (r=0.81-0.83, P=0.1-0.22). In HGSOC patients (n=13), percent differences in FTT-PET after ~7 days of PARPi compared to baseline correlated with the first RECIST response (r=0.60, P=0.034), best RECIST response (r=0.75, P=0.01), best CA-125 response (r=0.73, P=0.033), and PFS (r=0.67, P=0.027). All patients with >50% reduction in FTT uptake had >6-month PFS and >50% reduction in CA-125 (P=0.004 and P=0.016, respectively). Utilizing only baseline FTT uptake correlated to best RECIST response (r=-0.65, P=0.035) but did not predict response when corelated with other measures. Importantly, a decrease in FTT uptake does not appear to be associated with a reduction in tumor burden or apoptosis in response to drug cytotoxic activity at this early timepoint, indicating specificity for drug-target engagement. Conclusions: The decline in FTT uptake shortly after PARPi initiation compared to baseline provides an in vivo measure of drug-target engagement and shows promise as an early biomarker to guide PARPi therapy. FTT-PET has both pre-clinical and clinical applications warranting further study, including guiding PARPi combination therapy. Citation Format: Sarah B. Gitto, Austin R. Pantel, Mehran Makvandi, Hyoung Kim, Sergey Medvedev, Joanna K. Weeks, Drew A. Torigian, Chia-Ju Hsieh, Benjamin Ferman, Nawar A. Latif, Janos L. Tanyi, Lainie P. Martin, Shannon M. Lanzo, Fang Liu, Quy Cao, Gordon B. Mills, Robert K. Doot, David A. Mankoff, Robert H. Mach, Lilie L. Lin, Fiona Simpkins. [18F]FluorThanatrace ([18F]FTT) PET Imaging of PARP-inhibitor drug-target engagement as a biomarker of response in ovarian cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5610.