Background/Objectives: The aim of this study was to demonstrate the importance of ⁶⁸Gallium (⁶⁸Ga)–prostate specific membrane antigen (PSMA)–positron emissions tomography (PET)/computed tomography (CT)(PET/CT) in prostate cancer patients for therapy management with individual analyses regarding the Gleason score, prostate specific antigen (PSA) value, and the risk groups defined by D’Amico. Methods: We retrospectively analyzed 562 ⁶⁸Ga-PSMA-11-PET/CT examinations performed from January 2015 to March 2023 at University Hospital Marburg. We assessed treatment changes post ⁶⁸Ga-PSMA-11-PET/CT and categorized the cases based on PSA values, Gleason scores, and D’Amico risk groups. Results: In 415/562 (73.8%) of ⁶⁸Ga-PSMA-11-PET/CT examinations, a modification in the therapy concept was recorded. Patients categorized as high risk or patients with Gleason scores of 7 through 10 or with PSA levels above 0.5 ng/mL (particularly within the ranges of 1.01–2 ng/mL, 3.01–5 ng/mL, and values exceeding 10 ng/mL) demonstrated a statistically significant association with treatment change. While no evidence of the disease was found most frequently in 38% of cases in the “Therapy continued without explicit reference” group, in the group with the adapted therapy, there was a considerable higher proportion of local tumors (19.2%) compared to the other groups (4.4% and 1.4%). Conclusions: Our results show the high impact of ⁶⁸Ga-PSMA-PET/CT for patients with prostate cancer regarding therapy management planning, which is even more important for some patient groups.

This retrospective analysis interrogates the value of a multimodal biomarker paradigm to characterize molecular and clinical responses to [²²⁵Ac]Ac-PSMA-617-targeted α-therapy (TAT) in cohorts of heavily pretreated metastatic castration-resistant prostate cancer patients who had shown limited benefit from prior [¹⁷⁷Lu]Lu-PSMA-617. By integrating quantitative PSMA-PET/CT metrics—notably total tumor volume (TTV) and lesion SUV indices—with longitudinal PSA kinetics, routine hematologic and biochemical markers, and semiquantitative assessment of salivary gland uptake, we sought to delineate treatment effect, organ-specific off-target impact, and prognostic biomarker signatures. In twelve patients receiving 2–6 cycles of therapy (median activity 8 MBq), biochemical responses were frequent: 8/12 experienced PSA declines and 5/12 achieved ≥50% reduction. Concordant molecular responses were observed on PSMA-PET, with SUV_peak-based partial response in 7/12, stable disease in 3/12, and progressive disease in 2/12 of the target lesions. Qualitative concordance between TTV and PSA response was observed in four illustrative patients; no formal cohort-level concordance analysis was performed. Notably, salivary gland tracer uptake on [⁶⁸Ga]Ga-PSMA-11 PET/CT decreased after two cycles of [²²⁵Ac]Ac-PSMA-617 compared with baseline (SUV_max −63.7%; SUV_mean −45.5%). In this exploratory cohort, elevations in PSA, alkaline phosphatase, and LDH measured after two cycles of therapy, along with low hemoglobin, platelet count, and creatinine, were associated with shorter overall survival. Median progression-free survival and overall survival were 27 and 53 weeks, respectively. Collectively, these findings suggest that a combined PSMA-PET TTV–PSA–blood biomarker framework may offer complementary insight alongside PSA alone for characterizing therapeutic response, although its incremental value over PSA was not formally tested in this exploratory cohort; blood-based biomarkers (PSA, ALP) showed the most consistent prognostic association with survival, providing objective measures of both tumor response and collateral tissue impact. Prospective validation in larger, controlled cohorts is warranted to refine biomarker thresholds and guide personalized TAT strategies.