This multicenter retrospective study evaluated the safety and efficacy of extended [177Lu]Lu-PSMA radiopharmaceutical therapy in patients with metastatic castration-resistant prostate cancer (mCRPC) who received more than 6 cycles of treatment. The study included 111 patients, with 43 receiving continuous treatment and 68 undergoing rechallenge treatment after a therapy break. The median cumulative doses were 57.4 GBq and 60.8 GBq for continuous and rechallenge treatments, respectively. Overall survival, 50% prostate-specific antigen (PSA) decline, PSMA PET response, and adverse events were assessed. The median overall survival was 31.3 months from the first administration, with a significantly higher rate of 50% PSA decline in the rechallenge group (90.4% vs. 61.9%). The rate of grades 3-4 toxicity was comparable between continuous and rechallenge treatments. The study concluded that extended [177Lu]Lu-PSMA therapy is safe and effective, with favorable median survival and preserved efficacy after a treatment break.This multicenter retrospective study evaluated the safety and efficacy of extended [177Lu]Lu-PSMA radiopharmaceutical therapy in patients with metastatic castration-resistant prostate cancer (mCRPC) who received more than 6 cycles of treatment. The study included 111 patients, with 43 receiving continuous treatment and 68 undergoing rechallenge treatment after a therapy break. The median cumulative doses were 57.4 GBq and 60.8 GBq for continuous and rechallenge treatments, respectively. Overall survival, 50% prostate-specific antigen (PSA) decline, PSMA PET response, and adverse events were assessed. The median overall survival was 31.3 months from the first administration, with a significantly higher rate of 50% PSA decline in the rechallenge group (90.4% vs. 61.9%). The rate of grades 3-4 toxicity was comparable between continuous and rechallenge treatments. The study concluded that extended [177Lu]Lu-PSMA therapy is safe and effective, with favorable median survival and preserved efficacy after a treatment break.