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

Abstract

<div>AbstractPurpose:<p>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. [<sup>18</sup>F]FluorThanatrace ([<sup>18</sup>F]FTT) is a PARPi-analog PET radiotracer that noninvasively measures PARP-1 expression. Herein, we evaluate [<sup>18</sup>F]FTT as a biomarker to predict response to PARPi in patient-derived xenograft (PDX) models and subjects with HRD HGSOC.</p>Experimental Design:<p>In PDX models, [<sup>18</sup>F]FTT-PET was performed before and after PARPi (olaparib), ataxia-telangiectasia inhibitor (ATRi), or both (PARPi-ATRi). Changes in [<sup>18</sup>F]FTT were correlated with tumor volume changes. Subjects were imaged with [<sup>18</sup>F]FTT-PET at baseline and after ∼1 week of PARPi. Changes in [<sup>18</sup>F]FTT-PET uptake were compared with changes in tumor size (RECISTv1.1), CA-125, and progression-free survival (PFS).</p>Results:<p>A decrease in [<sup>18</sup>F]FTT tumor uptake after PARPi correlated with response to PARPi, or PARPi-ATRi treatment in PARPi-resistant PDX models (<i>r</i> = 0.77–0.81). In subjects (<i>n</i> = 11), percent difference in [<sup>18</sup>F]FTT-PET after ∼7 days of PARPi compared with baseline correlated with best RECIST response (<i>P</i> = 0.01), best CA-125 response (<i>P</i> = 0.033), and PFS (<i>P</i> = 0.027). All subjects with >50% reduction in [<sup>18</sup>F]FTT uptake had >6-month PFS and >50% reduction in CA-125. Utilizing only baseline [<sup>18</sup>F]FTT uptake did not predict such responses.</p>Conclusions:<p>The decline in [<sup>18</sup>F]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.</p><p><i><a href="https://aacrjournals.org/clincancerres/article/doi/10.1158/1078-0432.CCR-22-3711" target="_blank">See related commentary by Liu and Zamarin, p. 1384</a></i></p></div>