Optimization of Response Dynamics Assessment for Targeted ¹⁷⁷Lu-PSMA Radioligand Therapy Using PET/CT, PSA, and SPECT/CT

Purpose : To optimize the evaluation of response dynamics during PSMA-targeted radioligand therapy (RLT) ¹⁷⁷Lu-PSMA based on a comprehensive analysis of prostate-specific antigen (PSA), post-therapeutic single-photon emission computed tomography/ computed tomography (SPECT/CT), and positron emission tomography/computed tomography (PET/CT) with ¹⁸F-PSMA-1007 in patients with metastatic castration-resistant prostate cancer (mCRPC). Material and methods : A retrospective single-center study was conducted, including 78 patients with mCRPC who received 2 to 6 cycles of ¹⁷⁷Lu-PSMA-617 therapy. Monitoring included three levels: PSA dynamics (before each cycle), post-therapeutic SPECT/ CT (24 hours after each administration), and PET/CT with ¹⁸F-PSMA-1007 (baseline and after 2, 4, and 6 cycles). The dynamics of radiopharmaceutical uptake, SUV max values, and concordance between methods were assessed. The primary endpoint was progression-free survival (PFS) assessed by PET/CT. Results : The median PFS by PET/CT in the overall cohort was 9 months. Stratified by PET/CT dynamics after 2 cycles, median PFS was: positive dynamics — 14 months, divergent — 8 months, negative — 5 months (p30 % reduction in SUV max in bone lesions on SPECT/CT after the 1st cycle was associated with longer PFS (13.5 months vs. 5.5 months; p < 0.001). Concordance between PSA and PET/ CT was moderate (κ=0.44), with discordance observed in 17.9 % of cases. The highest concordance was between SPECT/CT and PET/ CT (κ=0.68-0.70). PSMA-negative progression was detected in 5 patients (6.4 %), with 4 of them showing decreasing or stable PSA levels. A >30 % reduction in SUV max in bone lesions on SPECT/CT after the 1st cycle was associated with longer PFS (13.5 months vs. 5.5 months; p < 0.001). No grade ≥3 adverse events were recorded. Conclusion : Combined monitoring (PSA + SPECT/CT after each cycle + PET/CT with ¹⁸F-PSMA-1007 every 2 cycles) is optimal for response assessment during ¹⁷⁷Lu-PSMA therapy. Isolated PSA assessment is insufficient due to high discordance with imaging methods. Post-therapeutic SPECT/CT allows outcome prediction, while PET/CT is essential for detecting PSMA-negative progression and making decisions on therapy continuation or cessation. The proposed three-level approach enables timely treatment individualization.