Prostate-Specific Membrane Antigen PET/CT Complements MRI for Focal Therapy Selection in Prostate Cancer: A Whole-Mount Histopathologic Study

The incremental value of prostate-specific membrane antigen (PSMA) PET/CT over multiparametric MRI (mpMRI) for selecting patients for prostate cancer focal therapy is undefined. Unlike lesion-detection studies, we evaluated whether PSMA PET/CT, mpMRI, and their combination correctly determine focal therapy eligibility when validated against whole-mount histopathology (WMHP). Methods: We retrospectively analyzed patients undergoing radical prostatectomy (RP) at UCLA (2017-2024) with preoperative PSMA PET/CT and mpMRI, a biopsy grade group (GG) of 3 or less, unilateral disease, and a prostate-specific antigen level of less than 20 ng/mL. Two blinded readers per modality assessed extraprostatic extension (EPE), seminal vesicle invasion (SVI), bilateral disease, and multifocality; a third adjudicated discordances. Eligibility required the absence of all 4. On WMHP, ineligibility was EPE, SVI, multifocal or bilateral disease with a contralateral or secondary GG of at least 2 nodules, or any GG greater than 3 focus at RP. Modalities were compared by McNemar tests. Results: Of 112 patients, 77 (69%) were ineligible on WMHP, including 19 (17%) with a GG greater than 3 focus at RP. Sensitivity and specificity were 53% and 54% for PET and 70% and 49% for mpMRI. Combined imaging improved sensitivity to 83% (P < 0.001 vs. PET; P = 0.002 vs. MRI) but reduced specificity to 26%. Per 100 patients at this prevalence, this would correctly identify approximately 9 additional ineligible patients while falsely excluding approximately 7 true candidates. mpMRI was more sensitive than PET for EPE (77% vs. 32%, P < 0.001), whereas PET was more specific (90% vs. 58%, P < 0.001). Combined imaging improved detection of multifocal (44% vs. 23%, P = 0.001) and bilateral disease (45% vs. 23%, P = 0.002) versus MRI alone. Conclusion: Adding PSMA PET/CT to mpMRI significantly improves sensitivity for exclusionary features, reflecting complementary molecular and anatomic information. However, combined imaging still misses a substantial proportion of adverse pathology, so imaging alone should not determine eligibility.