Diagnostic performance, safety, and biodistribution of [ ⁶⁸ Ga]Ga-OncoACP3 for PET imaging in prostate cancer: A phase I clinical trial.

3074 Background: Acid Phosphatase 3 (ACP3) is an emerging promising theranostic target in prostate cancer (PCa), expressed on PCa cells across most primary and metastatic lesions. ACP3 shows higher, more homogeneous expression than PSMA in low- and high-ISUP-grade tumours and in metastases, while not being expressed in healthy organs such as salivary glands, kidneys, and gastrointestinal tract. We present data from a multicentre, prospective phase I clinical trial investigating safety, dosimetry, pharmacokinetics, and diagnostic performance of [ 68 Ga]Ga-OncoACP3, a high-affinity ligand of ACP3 discovered from DNA-Encoded Chemical Libraries, in PCa. Methods: Twenty patients with a confirmed diagnosis of PCa were planned for enrolment in the study in two cohorts: Cohort A, 5 patients with primary tumour only; Cohort B, 15 patients with or without metastatic disease. Each patient received a single intravenous injection of [ 68 Ga]Ga-OncoACP3. PET/CT acquisitions were performed at 0, 10, 60 and 120 minutes after the injection with multiple blood and urine samples collections for pharmacokinetic and dosimetric analysis. Adverse events were recorded and graded according to CTCAE v5.0. [ 68 Ga]Ga-OncoACP3 PET findings were compared with PSMA PET (performed by all patients, according to clinical practice) and, when available, with follow-up data and histopathological findings. Results: All 20 patients completed [ 68 Ga]Ga-OncoACP3 PET imaging: 8 for initial staging, 10 for biochemical relapse, and 2 for advanced disease evaluation. No adverse events occurred. The tracer showed mixed hepatobiliary/renal excretion, with no uptake in salivary glands. PET-positive lesions showed rapid and selective tumour uptake shortly after injection, with increasing signal intensity at 60 and 120 minutes. All confirmed PSMA-positive lesions were evident at [ 68 Ga]Ga-OncoACP3 PET, in most cases with a higher tumour-to-background compared to PSMA PET. In three cases, [ 68 Ga]Ga-OncoACP3 PET detected additional PCa lesions, all confirmed by follow-up data or histopathology. No area of unspecific bone uptake at PSMA PET was evident at [ 68 Ga]Ga-OncoACP3. Conclusions: [ 68 Ga]Ga-OncoACP3 has an excellent safety profile and favourable pharmacokinetics, as well as promising tumour-targeting properties in PCa. [ 68 Ga]Ga-OncoACP3 may outperform current PSMA-targeting modalities across the whole natural history of the disease, and particularly in theranostic applications. Clinical trial information: NCT06840535 .