Multimodal Evaluation of [225Ac]Ac-PSMA-617 Therapy in mCRPC: PET Based Total Tumor Volume, PSA Kinetics, and Blood Biomarkers

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 SUVpeak-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 (SUVmax −63.7%; SUVmean −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.