Pharmacodynamic Activity of [¹⁸F]-Fluorthanatrace Poly(ADP-ribose) Polymerase Positron Emission Tomography in Patients With <i>BRCA1/2</i>-Mutated Breast Cancer Receiving Talazoparib.

Abstract

We tested the ability of [¹⁸F] fluorthanatrace (FTT), a radiolabeled analog of poly(ADP-ribose) polymerase (PARP)-1 inhibitors, to demonstrate target engagement on positron emission tomography (PET) scans from patients with newly diagnosed primary breast cancer receiving the PARP inhibitor (PARPi) talazoparib. Seven patients with germline <i>BRCA1/2</i> pathogenic variants underwent [¹⁸F]FTT PET-computed tomography scanning at baseline, and five underwent repeat scanning 14 days after talazoparib initiation. Maximum uptake on PET was quantified in the primary tumor, involved nodes, contralateral pectoralis muscle, and lumbar vertebra body level 3, and compared between the two time points. Blocking of [¹⁸F]FTT was observed on the second scan. Potentially strong but nonsignificant correlations were found between changes in tumor volume (on ultrasound at 1 month <i>v</i> baseline) and percentage changes in tumor-to-muscle uptake ratio at 14 days from baseline (Spearman rank correlation coefficient <i>r</i> = 1; <i>P</i> = .083); and between the highest-grade hematologic toxicity and baseline bone marrow-to-muscle (B/M) uptake ratio (<i>r</i> = 0.72; <i>P</i> = .068) and percentage change in B/M ratio at 14 days from baseline (<i>r</i> = 0.87; <i>P</i> = .058). We conclude that [¹⁸F]FTT can image target engagement by PARPi, but larger studies are needed to determine whether [¹⁸F]FTT uptake can predict response to PARPi and whether uptake of [¹⁸F]FTT in bone marrow may be an early predictor of hematologic toxicity.