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This study evaluates the efficacy and safety of [²²⁵Ac]Ac-PSMA-617 targeted alpha therapy (TAT) in patients with metastatic castration-resistant prostate cancer (mCRPC) who demonstrated Prostate-Specific Antigen (PSA) based non-responsiveness to prior [¹⁷⁷Lu]Lu-PSMA-617 therapy. Moving beyond traditional PSA-level assessments, we integrate blood biomarkers, PSMA-PET based total tumor volume (TTV) and salivary glands uptake. This retrospective analysis provides a comprehensive framework for evaluating treatment efficacy. Twelve patients underwent 2–6 cycles of [²²⁵Ac]Ac-PSMA-617, with a median activity of 8 MBq. PSA decline was observed in 8/12 patients, with 5/12 achieving a > 50% reduction. TTV results showed partial response in 7/12, stable disease in 3/12, and progression in 2/12, correlating strongly with PSA trends. Salivary glands showed significantly lower post-TAT PSMA-PET SUVmax and SUVmean (-63.7% and -45.5%, respectively). Moreover, elevated PSA, ALP, and LDH, along with low hemoglobin, platelet count, and creatinine, were associated with reduced overall survival (OS). Median progression-free survival (PFS) and OS were 27 and 53 weeks, respectively. The Barthel Index remained stable indicating preserved functional independence. These findings suggest that combining PSA, TTV, and blood biomarkers enhances the predictive accuracy and supports a more holistic evaluation of treatment efficacy. Validation in larger cohorts is warranted.