PCa Detection in PI-RADS 4 and 5 Lesions: Comparison of [ ⁶⁸ Ga]Ga-PSMA-11 PET/CT–Guided Robot-Assisted Biopsy Versus mpMRI Cognitive-Fusion TRUS-Guided Prostate Biopsy

Lesions with a Prostate Imaging-Reporting and Data System (PI-RADS) score of 4 or greater on multiparametric MRI (mpMRI) indicate a high likelihood of prostate cancer (PCa), and guidelines recommend a targeted biopsy. We aimed to compare the diagnostic performance of robotic arm–assisted [⁶⁸Ga]Ga-PSMA-11 PET/CT–guided prostate biopsy (PGPB) with mpMRI-directed cognitive-fusion transrectal ultrasound–guided biopsy (MCFB) in biopsy-naïve men with clinical findings suggestive of PCa. <b>Methods:</b> This prospective, single-center, randomized clinical trial (NCT05137561) enrolled biopsy-naïve men age 50–90 y with elevated levels of prostate-specific antigen (≥4 ng/mL) and abnormal digital rectal examination findings. All participants underwent mpMRI, and those with a PI-RADS score of 4 or greater were randomized into 2 arms. In arm 1, participants underwent PGPB for a [⁶⁸Ga]Ga-PSMA–avid lesion, and participants in arm 2 underwent MCFB. Participants in arm 1 with PET-negative findings subsequently underwent MCFB, and participants with negative biopsy results underwent PET and PGPB. The primary outcome was the detection of PCa. Secondary outcomes included complication rates and participant-reported pain. <b>Result:</b> Of the 267 participants enrolled, 81.3% (217) had lesions with a PI-RADS score of 4 or greater and were randomized to either PGPB (<i>n</i> = 112) or MCFB (<i>n</i> = 105). PCa was detected in 97.1% of participants (101/104) in arm 1 and 81.0% (85/105) in arm 2 (<i>P</i> &lt; 0.05). PGPB showed higher diagnostic accuracy for PI-RADS 5 lesions (100% vs. 95.1%, <i>P</i> = 0.09). Major complications were observed in arm 2 only (<i>n</i> = 5). Arm 1 had significantly fewer complications (10.8% vs. 51.4%, <i>P</i> &lt; 0.01), a lower median visual analog scale score for pain (3 vs. 5), and shorter procedure times. The core positivity rate was higher in arm 1 (60% ± 20%), despite obtaining fewer cores. <b>Conclusion:</b> [⁶⁸Ga]Ga-PSMA-11 PCPB demonstrated higher diagnostic performance, fewer complications, and better tolerability compared with MCFB. This approach enables integrated diagnosis and staging, offering a promising alternative for efficient, safe, and accurate evaluation of prostate cancer.