A new phase III, randomized, controlled trial was carried out to assess the efficacy of 177Lu-PSMA-617 in patients with taxane-naive metastatic castration-resistant prostate cancer (mCRPC). A total of 468 patients with PSMA+ mCRPC who experienced disease progression after receiving an androgen receptor pathway inhibitor (ARPI) were randomly allocated to receive 177Lu-PSMA-617 or a different ARPI. Treatment with 177Lu-PSMA-617 resulted in improved median radiographic progression-free survival (PFS) compared with a change of ARPI (11.60 months (95% CI 9.30–14.19) versus 5.59 months (95% CI 4.21–5.95)), with a good safety profile. These results showed that 177Lu-PSMA-617 prolonged radiographic PFS and could be a valid therapeutic alternative for patients considered for a change of ARPI.