Purpose <p>Inhibitors of poly(ADP-ribose) polymerase (PARP), an enzyme with numerous roles in DNA damage response signaling, represent a class of anti-cancer drugs approved for treating solid tumors with defects in the DNA damage response. However, additional methods for identifying patients who would benefit from the use of PARP inhibitors are urgently needed. We evaluated a novel radiotracer, ¹⁸F-FluorThanatrace ([¹⁸F]-FTT), to noninvasively assess PARP activity with PET/CT before treatment and determine associations between uptake, tumor mutation status, and prior receipt of therapy including PARP inhibitors.</p> Methods <p>Fifty-two patients with solid tumors underwent whole-body (skull base to thigh) [¹⁸F]-FTT PET/CT scans before beginning PARP inhibitor treatment. The maximum standardized uptake value (SUVmax) was recorded for up to five lesions per patient. All recorded lesions were included in the analysis.</p> Results <p>Uptake of [¹⁸F]-FTT was confirmed in all 52 patients regardless of primary tumor type (20 breast, 12 ovarian, 7 prostate, 3 pancreas, and 10 other). Lesion-by-lesion analysis revealed significant differences in [¹⁸F]-FTT uptake by primary tumor type (<i>P</i> &lt; 0.001) and higher uptake in lesions with <i>BRCA2</i> mutations (<i>n</i> = 65) than in lesions with other genetic mutations (<i>n</i> = 26) (6.7 vs. 5.5, <i>P</i> = 0.03). Prior receipt of PARP inhibitor was associated with lower SUVmax (4.7 vs. 6.4, <i>P</i> = 0.001), and prior receipt of systemic therapy was also associated with lower SUVmax (4.0 vs. 6.0, <i>P</i> = 0.01).</p> Conclusions <p>[¹⁸F]-FTT PET/CT may be useful as a noninvasive quantitative assessment of PARP1 enzyme activity in patients with solid tumors; uptake of [¹⁸F]-FTT varies based on tumor mutational status and receipt of prior PARP inhihbitor therapy and/or systemic therapy.</p>