PSMA-targeted radioligand therapy with [177Lu]Lu-PSMA-I&T in metastatic castration-resistant prostate cancer: a prospective, multicentre, Swiss registry study

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Background Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy is the leading theranostic strategy for metastatic castration-resistant prostate cancer (mCRPC). Randomised trials have shown survival benefit with [ 177 Lu]Lu-PSMA-617, but prospective multicentre real-world data for the widely used alternative ligand [ 177 Lu]Lu-PSMA-I&T remain scarce. In this study, we evaluated the safety and clinical activity of [ 177 Lu]Lu-PSMA-I&T in routine practice. Methods This prospective, multicentre, Swiss registry enrolled consecutive men older than 18 years with histologically confirmed prostate adenocarcinoma undergoing intravenous [ 177 Lu]Lu-PSMA-I&T therapy (7 GBq every 6 weeks for up to six cycles). Eligible patients had Eastern Cooperative Oncology Group performance status of 2 or less and PSMA-positive mCRPC with progressive disease after androgen receptor pathway inhibitor therapy or chemotherapy, or both, unless deemed unfit. The primary outcome was safety, assessed by treatment-emergent adverse events graded according to Common Terminology Criteria for Adverse Events (version 5.0). Assessments were performed at predefined timepoints before each treatment cycle and during the post-therapy follow-up. Secondary outcomes included the best prostate-specific antigen (PSA) response and PSA decline of 50% or more (PSA50) response according to the Prostate Cancer Working Group 3 criteria. All patients who underwent at least one treatment cycle were included in the final analysis of the observational registry. This study is registered at ClinicalTrials.gov, NCT06830408. Findings Between May 25, 2020, and June 4, 2024, 333 patients with mCRPC received [ 177 Lu]Lu-PSMA-I&T therapy and were included in the analysis. The median follow-up was 12·0 months (IQR 6·5–20·0). Grade 3 treatment-emergent haematological toxicities included anaemia in 26 (8·8%; 95% CI 5·8–12·6) of 295, thrombocytopenia in nine (3·1%; 1·4–5·7) of 295, leukopenia in five (1·7%; 0·6–3·9) of 295, lymphopenia in 54 (21·1%; 16·3–26·6) of 256, and neutropenia in one (0·4%; 0·0–2·2) of 256. No grade 3 or worse renal toxicity or grade 4–5 treatment-emergent adverse events were observed. Best PSA response was achieved in 198 (64·3%; 95% CI 58·7–69·6) of 308 patients and PSA50 in 137 (44·5%; 38·8–50·2). Interpretation [ 177 Lu]Lu-PSMA-I&T showed clinically meaningful activity with a favourable safety profile in heavily pretreated mCRPC. These findings provide prospective evidence supporting the safety and activity of PSMA-targeted radioligand therapy with [ 177 Lu]Lu-PSMA-I&T in routine clinical practice.