Tri-modal PSMA PET/CT-MRI-US fusion biopsy for clinically significant prostate cancer: a prospective paired diagnostic study.

PURPOSE: Multiparametric MRI (mpMRI)-ultrasound (US) fusion biopsy misses 8%-20% of clinically significant prostate cancer (csPCa), leaving a detection gap that prostate-specific membrane antigen (PSMA) PET/CT may help close. Whether incorporating PSMA into an MRI-US fusion platform improves csPCa detection has not been evaluated in a prospective paired design. We compared tri-modal PSMA PET/CT-MRI-US fusion biopsy with MRI-US fusion biopsy and systematic biopsy. METHODS: In this prospective, single-center, and paired diagnostic accuracy study (STARD 2015; ChiCTR2400089436), 308 biopsy-naive men underwent tri-modal fusion biopsy, MRI-US fusion biopsy, and systematic biopsy in a single session. The primary endpoint was the absolute difference in patient-level csPCa detection (International Society of Urological Pathology grade group ≥ 2) between tri-modal and MRI-US fusion biopsies. RESULTS: Tri-modal fusion detected 4.9% more csPCa than MRI-US fusion biopsy (95% confidence interval 2.4%-7.3%; P < 0.001; number needed to biopsy 20.5). The most significant gains were observed for PSMA-positive lesions < 10 mm (8.3%) and Prostate Imaging Reporting and Data System (PI-RADS) 4 lesions (5.8%), and this benefit persisted in multivariate generalized estimating equation models. The PSMA imaging-based risk score (area under the curve, 0.933) showed higher discrimination than the PRIMARY and molecular imaging PSMA scores. In a retrospective simulation using the test set, a risk-guided approach would have avoided approximately 42% of biopsies while missing 2.3% of csPCa. Limitations include the single-center design and the small test set. CONCLUSION: Tri-modal fusion was superior to MRI-US fusion biopsy in detecting csPCa, particularly in small PSMA-positive and PI-RADS 4 lesions. A PSMA-derived risk score enabled effective stratification, and in the test set, a simulated risk-guided approach showed potential for biopsy reduction. These findings require multicenter validation before clinical adoption. TRIAL REGISTRATION: ChiCTR2400089436 (Chinese Clinical Trial Registry, http://www.chictr.org.cn/ , registered 2024-09-09).