Considering the wide range of therapeutic options for localized prostate cancer (active surveillance, radiation beam therapy, focal therapy, radical prostatectomy, etc), accurate assessment of the aggressiveness and localization of primary prostate cancer lesion are essential for treatment decision making. National Comprehensive Cancer Network guidelines recognize Prostate-Specific Membrane Antigen (PSMA) Positron Emission Tomography/Computed Tomography (PET/CT) for the initial staging of high risk primary prostate cancer. The Gastrin-Releasing Peptide Receptor (GRP-R) is a neuropeptide receptor over-expressed by low-risk prostate cancer cells. We aim to perform the first prospective head-to-head comparison of PSMA and GRP-R targeted imaging at the initial staging to understand how PSMA-PET and GRP-R-PET could be used or combined in clinical practice Methods: This was a prospective, single-center, diagnostic cross-sectional imaging study using anonymized, masked and independent interpretations of PET/CT paired studies in 22 patients with (68)Ga-PSMA-617 (a radiolabelled PSMA-inhibitor) and (68)Ga-RM2 (a radiolabelled GRP-R-antagonist). We enrolled patients with newly diagnosed, biopsy-proven, prostate cancer. No patient had received neoadjuvant hormone therapy or chemotherapy. All patients underwent extended pelvic lymph node dissection. Histology served as reference. Results: On a lesion-based analysis (including lesions <0.1cc), (68)Ga-PSMA-617 PET/CT detected 74.3% (26/35) of all tumor lesions and (68)Ga-RM2 PET/CT detected 78.1% (25/32; one patient could not be offered (68)Ga-RM2 PET/CT). Paired examinations showed positive uptake with the two tracers in 21/32 lesions (65.6%), negative uptake in 5/32 lesions (15.6%), and discordant uptake in 6/32 lesions (18.8%). Uptake of (68)Ga-PSMA-617 was higher in ISUP ≥ 4 vs ≥ 1 (P < 0.0001); and ISUP ≥ 4 vs 2 (P = 0.002). There were no significant differences in uptake between ISUP scores for (68)Ga-RM2. Median (68)Ga-RM2 SUV(max) was significantly higher than median (68)Ga-PSMA-617 SUV(max) in the ISUP 2 subgroup (P = 0.01). Conclusion: (68)Ga-PSMA-617 PET/CT is useful to depict higher, more clinically significant, ISUP score lesions and (68)Ga-RM2 PET/CT has higher detection rate for low-ISUP tumors. Combining PSMA-PET and GRP-R PET allows to better classify intraprostatic lesions.< Leer menos