PSMA-RECAP: [177Lu]Lu-PSMA-617 retreatment in metastatic castration-resistant prostate cancer.

PURPOSE: Radioligand therapy (RLT) with [177Lu] Lu-PSMA-617 has shown significant benefits in metastatic castration-resistant prostate cancer (mCRPC), including prolonged overall survival (OS) and progression-free survival (PFS), as well as improved quality of life. For patients previously treated with [177Lu]Lu-PSMA-617 who subsequently experience disease progression, retreatment with [177Lu] Lu-PSMA-617 has emerged as a potential approach, yet data on the outcomes of RLT retreatment remains limited. This study aimed to assess the efficacy and safety of retreatment RLT in mCRPC. METHODS: Clinical and imaging data of patients who underwent at least two cycles of [177Lu] Lu-PSMA-617, followed by a second course of treatment with [177Lu] Lu-PSMA-617 between March 2018 and December 2024, were retrospectively reviewed. Endpoints included biochemical response, imaging response, toxicity, PSA-PFS, rPFS, and OS. Radiologic and biochemical responses were evaluated using RECIST 1.1 criteria and PSA levels, respectively. RESULTS: A total of 589 patients underwent [177Lu] Lu-PSMA-617 RLT, of whom 20 (3.4%, 20/589) received RLT retreatment. The median age was 71.3 years (range: 63.7-95.2), and the median follow-up was 73.3 months (95% CI, 35.7-77.2 months) after the initial treatment and 21.7 months (95% CI, 16.9-26.0 months) after retreatment. The initial treatment involved a median of 4.5 cycles (range: 2-6). Following the first course of RLT, 15 patients (75%, 15/20) had exhibited a >50% decline in PSA levels, including 9 who achieved a >90% decrease. Additionally, 12 patients (60%, 12/20) had demonstrated a complete or partial imaging response, while 3 (15%, 3/20) patients had stable disease, and 5 (25%, 5/20) patients had progressive radiologic disease. Patients received a median of 4 retreatment cycles (range, 1-6), and the median interval between initial RLT and retreatment RLT was 33.1 months (IQR, 16.2-48.9 months; range, 10.7-58.8 months). A PSA decline of ≥50% was observed in 9 out of 20 patients (45%, 9/20). An imaging response was observed in 10 patients (50%, 10/20), with 4 achieving a complete response and 6 achieving a partial response, whereas 10 patients (50%, 10/20) showed progression. The median PSA-PFS was 9.8 months (95% CI, 4.1-17.9 months), and the median rPFS was 8.2 months (95% CI, 3.3-17.9 months). Eight deaths occurred during follow-up. The estimated Kaplan Meier OS rates were 83.6% at 12 months (95% CI, 57.3%-94.4%) and 53.7% at 24 months (95% CI, 28.3%-73.7%). Grade 2 renal toxicity was observed in one patient (5%, 1/20). Three patients (15%, 3/20) developed Grade 2 anemia. Notably, no grade 3 or grade 4 adverse events were observed during either treatment period. CONCLUSION: In our cohort, retreatment with [¹77Lu]Lu-PSMA-617 RLT was associated with biochemical and imaging responses in some patients, with observed survival outcomes that support further investigation. However, given the retrospective single-arm design and small sample size, large prospective studies are needed to more rigorously evaluate the safety, efficacy, and optimal patient selection for retreatment RLT.