Translational and First-in-Human Positron Emission Tomography Targeting Prostatic Acid Phosphatase in Prostate Cancer Using the Ligand [68Ga]Ga-OncoACP3-DOTA

Prostate-specific membrane antigen (PSMA)-targeted theranostic agents have transformed prostate cancer (PC) management, but their performance is limited by variable PSMA expression and off-target uptake. We investigates the first-in-human positron emission tomography (PET) imaging of prostatic acid phosphatase (ACP3), a novel and highly specific PC target, using the radioligand [⁶⁸Ga]Ga-OncoACP3-DOTA. We analyzed and matched [⁶⁸Ga]Ga-OncoACP3-DOTA and [¹⁸F]PSMA-1007 PET scans in a cohort of 25 patients with PC. We compared the biodistribution and tumor uptake of the two tracers using the Wilcoxon rank-sum test and compared their performance. Superiority was defined as >10% more lesions detected or >50% higher lesional maximum standardized uptake value (SUV_max). [⁶⁸Ga]Ga-OncoACP3-DOTA showed low background uptake, including in the salivary glands and kidneys, with a significant difference from the high [¹⁸F]PSMA-1007 uptake in these organs (p < 0.002). Overall, SUV_max in localized or metastatic PC did not significantly differ between the two tracers. Better [⁶⁸Ga]Ga-OncoACP3-DOTA performance was observed in 11/25 matched scan pairs, and better [¹⁸F]PSMA-1007 performance in eight of 25 pairs. [⁶⁸Ga]Ga-OncoACP3-DOTA changed therapeutic management in three of six patients with biochemical recurrence, and in two of 12 patients with known metastases. Although the retrospective comparison is potentially biased, the intense and reliable tumor uptake and the low off-target activity of OncoACP3-DOTA provide a strong rationale for future exploration in trials on PET imaging and radioligand therapy with β- and α-particle emitters.