From Imaging Guidance to Dosimetric and Staging Superiority: Impact of 68Ga-PSMA PET/CT and mpMRI on Target Delineation, Organs at Risk Sparing, and Biochemical Response in Prostate Cancer Radiotherapy—A Single-Center Experience

Purpose: To evaluate inter-modality agreement and differences in detection rates between 68Ga-PSMA PET/CT and mpMRI for primary staging in prostate cancer, and to assess their impact on radiotherapy (RT) target-volume personalization, organ-at-risk (OAR) sparing, and post-RT prostate-specific antigen (PSA) dynamics. Methods: We retrospectively analyzed 98 patients with biopsy-proven prostate adenocarcinoma who underwent pretreatment 68Ga-PSMA PET/CT and definitive intensity-modulated or volumetric-modulated arc RT; baseline mpMRI was available in 75 patients. Treatment plans were classified into six categories according to fractionation (conventional vs. moderate hypofractionation), pelvic nodal coverage, and focal boost to dominant intraprostatic lesions (DILs). Inter-modality agreement was assessed using Cohen’s kappa. DVH parameters for target volumes and OARs, including physical dose, EQD2, and BED, were compared between fractionation regimens. Post-RT PSA levels were evaluated at 1 week–1 month, 3–6 months, 12 months, and 24 months. Results: For primary T-stage (n = 70), overall agreement between mpMRI and 68Ga-PSMA PET/CT was 32.9% (23/70), with slight agreement (Cohen’s κ = 0.19; 95% CI, 0.04–0.34; p = 0.008). Among 47 patients classified as having organ-confined disease (T2a–T2c) on mpMRI, 7 (14.9%) were upstaged to T3–T4 by 68Ga-PSMA PET/CT. For pelvic nodal disease (n = 74), 68Ga-PSMA PET/CT detected N1 disease more frequently than mpMRI (25.7% [19/74] vs. 10.8% [8/74]; p = 0.012, McNemar test), with fair agreement (κ = 0.26; 95% CI, 0.05–0.47; overall percent agreement, 77.0%). For seminal vesicle invasion (n = 73), agreement was moderate (κ = 0.47; 95% CI, 0.24–0.70; p < 0.001; overall percent agreement, 82.2%). Compared with conventional RT, moderately hypofractionated RT provided significantly lower absolute OAR exposure: mean rectal dose (21.57 ± 3.58 vs. 28.46 ± 6.55 Gy; p < 0.001), mean rectal BED3 (39.54 ± 6.56 vs. 47.67 ± 10.96 Gy3; p < 0.001), rectal V50Gy (11.32 ± 3.65% vs. 14.39 ± 5.17%; p < 0.001), mean bladder dose (24.17 ± 8.63 vs. 31.02 ± 8.84 Gy; p < 0.001), and maximum femoral-head dose (35.12 ± 7.46 vs. 47.20 ± 7.99 Gy; p < 0.001). Target coverage, when normalized to the prescription dose, was comparable between fractionation groups. The median PSA decreased from 0.96 ng/mL before RT to 0.18 ng/mL at 1 week–1 month, 0.06 ng/mL at 3–6 months, and 0.04 ng/mL at 12 months. In exploratory subgroup analyses, baseline clinicopathological variables, mpMRI PI-RADS category, and 68Ga-PSMA PET/CT parameters were not significantly associated with the magnitude of post-RT PSA decline (all p > 0.05). Conclusions: In this retrospective cohort, 68Ga-PSMA PET/CT provided complementary staging information to mpMRI, particularly by identifying additional pelvic nodal disease and selected local upstaging, thereby supporting individualized target-volume delineation. Moderately hypofractionated image-guided RT achieved comparable relative target coverage with lower absolute OAR doses. Early and sustained PSA suppression likely reflects the combined effect of precise RT and risk-adapted androgen deprivation therapy. Owing to the retrospective design, absence of histopathological validation, and limited long-term follow-up, these findings require confirmation in larger prospective cohorts.