Patterns of Progression on Posttreatment Imaging During [¹⁷⁷Lu]Lu-PSMA Radiopharmaceutical Therapy

We characterized patterns of treatment response and progression during [¹⁷⁷Lu]Lu-PSMA radiopharmaceutical therapy (RPT) using serial posttreatment SPECT/CT and prostate-specific membrane antigen (PSMA) PET imaging and evaluated cycle-by-cycle prostate-specific antigen (PSA)-imaging concordance. Methods: We retrospectively analyzed 361 patients from 2 academic centers who received at least 2 cycles of [¹⁷⁷Lu]Lu-PSMA RPT between May 2017 and March 2025. Posttreatment SPECT/CT scans were qualitatively evaluated to determine the site and pattern of response and progression, including PSMA low-avidity and PSMA-negative disease. Progression was defined by the appearance of new lesions or at least a 2-fold growth in preexisting lesions on SPECT/CT. PSA response was defined per Prostate Cancer Clinical Trials Working Group 3 criteria as at least a 50% decline from baseline. For cycle-by-cycle concordance analysis, PSA change was classified directionally as rising or falling relative to the prior cycle. In patients who paused or completed RPT after response, progression imaging was compared with the final on-treatment SPECT/CT scan. Results: Overall, 290 of 361 (80%) patients demonstrated a decrease in lesion size or number on posttreatment imaging. Of 312 patients with baseline bone disease, 81% demonstrated a response on posttreatment imaging. In total, 156 of 361 patients (43%) demonstrated progression during treatment. New osseous lesions developed in 132 patients, of whom 89 (67%) had PSMA low-avidity disease. At cycle 2, 64% of new lesions were osseous, increasing to at least 90% by cycles 4-6. PSMA-negative progression occurred in 22 patients (6%), predominantly in the liver (n = 11) and lymph nodes (n = 8), with 59% detected at cycle 2. Among 81 patients with imaging available at PSA progression after treatment completion or pause, 74 (91%) had imaging progression; of these, 69 (93%) demonstrated osseous and 13 (18%) nodal progression. PSA and imaging were discordant in 25%-43% of patients across cycles, with discordance increasing from cycle 2 to cycle 6. Conclusion: Progression during [¹⁷⁷Lu]Lu-PSMA RPT occurs most frequently in bone, with 67% of patients with new osseous lesions demonstrating a PSMA low-avidity disease component. PSMA-negative progression is uncommon and tends to emerge early. PSA-imaging discordance is frequent, underscoring the need for integrated imaging assessment throughout treatment.