Background <p>Poly (ADP-ribose) polymerase inhibitors (PARPi) are approved for Breast Cancer gene (<i>BRCA</i>)-mutant HER2- breast cancer, and there is clinical interest in expanding indications to include homologous recombination deficient (HRD) breast cancers. Yet, response in these populations remains variable, suggesting clinical utility in developing a better biomarker to select patients for PARPi and predict response. Here, we evaluate a radiolabeled PARPi, [¹⁸F]FluorThanatrace ([¹⁸F]FTT), as a functional biomarker of PARPi response in breast cancer.</p> Methods <p>A single-arm prospective observational trial was conducted at the University of Pennsylvania. [¹⁸F]FTT-PET uptake was measured in 24 women with untreated primary breast cancer and correlated with tumor HRD score. In a separate cohort of ten subjects with metastatic HER- breast cancer, [¹⁸F]FTT-PET uptake was measured at baseline and after a short interval on a PARPi (a measure of drug-target engagement) and correlated to progression free survival (PFS).</p> Results <p>Here we show that baseline [¹⁸F]FTT-PET uptake does not correlate to HRD tissue score, supporting that [¹⁸F]FTT provides distinct information from genetic features. Baseline [¹⁸F]FTT-PET uptake and the change in uptake from baseline to after PARPi initiation significantly correlates to PFS in woman with breast cancer who received a PARPi (<i>ρ</i> = 0.74, <i>P</i> = 0.023 and <i>ρ</i> = −0.86, <i>P</i> = 0.012, respectively).</p> Conclusions <p>These early results suggest the potential of [¹⁸F]FTT-PET to select patients for PARPi treatment and monitor in vivo pharmacodynamics after therapy start. Absence of association with HRD scores supports [¹⁸F]FTT uptake as a novel measure that may be leveraged as a biomarker. Further studies are warranted.</p>