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

Abstract

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. Biomarkers to predict response are needed. [18F]FluorThanatrace ([18F]FTT) is a PARPi-analog PET radiotracer that non-invasively 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. Methods: 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 to changes in tumor size (RECIST1.1), 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=0.77-0.81). In subjects (n=11), percent difference in [18F]FTT-PET after ~7 days of PARPi compared to 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. 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 pre-clinical mechanistic and clinical studies in subjects receiving PARPi +/- combination therapy.

Biomarkers of aging

“…For DNA damages, in vivo activity of PARP could be visualized by using 18 F-FluorThanatrace ( 18F-FTT) or 18 F-PARPi PET/CT imaging, which could indicate the responsiveness to PARP inhibitor treatment in patients with cancer (Pantel et al, 2022;Schöder et al, 2020). Besides, γH2AX (a phosphorylated DNA damage repair protein) activity could be visualized by using 89 Zr-anti-γH2AX-TAT radioimmunoconjugates to indicate the repairment of DNA double-strand breaks (Knight et al, 2017).…”

CD38‐Specific Gallium‐68 Labeled Peptide Radiotracer Enables Pharmacodynamic Monitoring in Multiple Myeloma with PET

“…These clinical observations suggest that real‐time, whole‐body measurements of CD38 expression using molecularly targeted PET radiotracers could provide more accurate information for guiding anti‐CD38 therapies in MM than current single‐time point and single‐lesion flow cytometry measurements. While molecularly targeted imaging agents have proven valuable for diagnosing and guiding treatment in breast, prostate, and various other cancer types, [ 39 , 40 , 41 ] their potential benefits have yet to be fully realized in the context of MM. Also, MM can be spatially heterogenous, and PET/CT is good at detecting extramedullary disease and focal lesions in the bone marrow.…”

Positron Emission Tomography Imaging of Tumor Proliferation and DNA Repair

“…High 18 F-FTT uptake prior to PARPi treatment in patients with high-grade serous ovarian carcinoma also predicted response. 42 Additional PARP-targeted agents have also been developed for PET imaging, and PARP PET imaging has been used to study the pharmacodynamics of PARPi drug target engagement in animal models of small cell lung cancer and evaluated in first-inhuman studies in patients with brain cancers and head and neck cancers. [43][44][45][46][47] These data together suggest the potential for PARP PET imaging to provide insights into better understanding in vivo PARPi behavior and improving patient selection for PARPi therapy.…”

“…In an ovarian cancer patient–derived xenograft mouse model, decreased 18 F-FTT uptake after treatment with PARPi confirmed PARPi target engagement. High 18 F-FTT uptake prior to PARPi treatment in patients with high-grade serous ovarian carcinoma also predicted response 42 . Additional PARP-targeted agents have also been developed for PET imaging, and PARP PET imaging has been used to study the pharmacodynamics of PARPi drug target engagement in animal models of small cell lung cancer and evaluated in first-in-human studies in patients with brain cancers and head and neck cancers 43–47 .…”