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

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.

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.

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.

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.