Background: 18F-Flotufolastat (18F-rhPSMA-7.3) is a prostate-specific membrane antigen (PSMA) ligand for the detection of prostate cancer (PCa). It targets the extracellular epitope of the PSMA molecule and is administered as a single intravenous (IV) bolus microdose. The molecular structure comprises a PSMA binding motif, a peptide spacer, an 18F-radiolabeled silicon fluoride acceptor moiety, and a gallium chelator complex. Recent studies have demonstrated the utilization of 18F-flotufolastat in newly diagnosed PCa is beneficial with high specificity for detecting N1 and M1 disease prior to surgery. While the evidence for utilizing PSMA imaging for staging of newly diagnosed PCa is growing, the impact on clinical management is yet to be examined. Here, we evaluate the sensitivity and specificity of 18F-flotufolastat for detection of N1 and M1 disease, with subsequent evaluation of management changes for patients with extraprostatic disease. Methods: This is a multicenter, prospective, randomized study comparing 18F-flotufolastat PET/CT to conventional imaging for staging men with high-risk PCa and the subsequent change in medical management of these men. High-risk patients are defined as grade group ≥3 (primary Gleason grade 4, or any Gleason grade 5), PSA ≥20, or clinical stage ≥T3. Inclusion criteria include males >18y with untreated biopsy-proven PCa with high-risk features as detailed above, and informed consent. Exclusion criteria are as follows: any prior therapy for PCa, previous imaging for staging of PCa, history of other malignancy, and significant comorbidity. All men will undergo conventional imaging techniques to complete staging. Physicians will then record the patients’ treatment plan (surgery, radiation including planned radiation fields, hormonal therapy, or other). The patients will then undergo PET/CT with a single bolus of 296MBq 18F-flotufolastat IV. Results will be reported to the responsible physician who will provide a final management plan. If treatment is planned post-18F-flotufolastat, the patient will receive treatment as follows: Standard of care surgical treatment of PCa, including PLND; or if the 18F-flotufolastat PET detects M1 lesion(s), a biopsy/surgery and/or additional imaging to confirm M1 lesion(s) will be required prior to treatment. The co-primary objectives of this study are the percentage of men with high-risk PCa upstaged to N1 or M1 disease, and the subsequent change in management. Clinical trial information: NCT05799248.