Purpose <p>Intermediate-risk (IR) prostatic adenocarcinoma is an heterogeneous subgroup of prostate cancer with discrepant progression and prognosis. These tumors can be subclassified based on the ISUP (International Society of Urology Pathology) score into favorable (ISUP 2) and unfavorable (ISUP 3) IR prostate cancer. Positron Emission Tomography / Computed Tomography (PET/CT) imaging targeting PSMA (Prostate Specific Membrane Antigen) is recommended for the assessment of high-risk prostate cancers. On the other hand, GRPR (Gastrin-Releasing Peptide Receptor) is over-expressed in low-risk prostate cancers (low ISUP score, low PSA and small tumor size). The aim of this study is to evaluate the relevance of PSMA- and GRPR-targeted PET/CT imaging for primary tumor stratification in newly diagnosed intermediate-risk patients.</p> Methods <p>22 patients with biopsy-confirmed intermediate-risk prostate cancer with no prior treatment and candidates for radical prostatectomy were imaged with [⁶⁸Ga]Ga-PSMA-617 (a radiolabeled PSMA-inhibitor) and [⁶⁸Ga]Ga-RM2 (a radiolabeled GRPR antagonist). Histology served as reference. Magnetic Resonance Imaging (MRI) was available in 18 patients.</p> Results <p>[⁶⁸Ga]Ga-RM2 SUVmax was significantly higher than [⁶⁸Ga]Ga-PSMA-617 SUVmax in ISUP ≤ 2 lesions (<i>p</i> = 0.027). [⁶⁸Ga]Ga-PSMA-617 SUVmax was significantly higher in ISUP ≥ 3 lesions than ISUP ≤ 2 lesions (<i>p</i> = 0.001)</p> Conclusion <p>These results suggest that the combined use of PSMA imaging and GRPR imaging is able to discriminate ISUP 2 from ISUP 3 prostate cancer and thus provides valuable information for treatment decision making.</p> Trial registration number <p>NCT03606837 (prospectively registered on 11/07/2019).</p>