Impact of Initial Prostate-Specific Membrane Antigen PET/CT Staging and Prostate-Specific Membrane Antigen–Targeted Biopsy on Treatment Decisions in Prostate Cancer: Results from the Phase 2 DEPROMP Trial

68Ga-PSMA-11 PET/CT (PSMA PET/CT) is used for staging advanced prostate cancer (PCa); however, its role in initial cancer detection and guiding localized treatment remains uncertain. The primary objective of this study was to assess the impact of upfront PSMA PET/CT on treatment decision-making based on imaging and biopsy-derived information. Methods: In this prospective, phase 2 interventional trial, 230 biopsy- and imaging-naïve men with suspected PCa underwent PSMA PET/CT and multiparametric MRI (mpMRI) before targeted ultrasound fusion and systematic biopsy. Randomized assessor teams independently reviewed histopathology and imaging data from either the mpMRI or the combined mpMRI plus PSMA PET/CT pathway and formulated treatment plans accordingly. Patient recruitment was conducted between 2021 and 2023. Results: Among 137 patients with PCa (9% low-, 35% intermediate-, and 15% high-risk disease), PSMA PET/CT altered management plans in 34% of patients, primarily modifying local treatment strategies, including lymph node dissection (16%), a nerve-sparing procedure (18%), and radiation field adjustments (28%). Systemic therapy escalation was rare (1%). In addition, 2% of patients initiated active treatment, 5% received adjunctive hormone therapy, and 7% underwent metastasis-directed therapy. Upfront PSMA PET/CT prompted treatment intensification at comparable rates in both intermediate-risk (31%) and high-risk (30%) PCa with high interrater agreement (Cohen κ, 0.71; 95% CI, 0.61–0.80). Prostate-specific antigen density of at least 0.15 ng/mL3 (odds ratio, 2.48; 95% CI, 1.22–5.06) and abnormal digital rectal examination (odds ratio, 2.12; 95% CI, 1.03–4.33) predicted PSMA PET/CT–driven changes. Conclusion: Early PSMA PET/CT staging altered treatment strategies for up to one third of patients with intermediate- and high-risk PCa by enhancing metastasis detection and local tumor characterization. Its effect on oncologic and functional outcomes warrants further investigation.