Purpose <p>Metastatic castration-resistant prostate cancer (mCRPC) remains a therapeutic challenge. Radioligand therapy (RLT) with ¹⁷⁷Lu-PSMA-617 has shown promising efficacy. This study reports the first Italian prospective trial evaluating efficacy and safety at 5.5 GBq per cycle in mCRPC.</p> Methods <p>This prospective, single arm, monocentre, Phase-II study enrolled PSMA-avid mCRPC patients (April 2017–October 2022). Patients received 5.5 GBq of ¹⁷⁷Lu-PSMA-617 per cycle for four cycles at 8 ± 2 weeks; up to two additional cycles were allowed. Mannitol and polyglutamate tablets were given to limit renal and salivary uptake. Primary endpoint was PSA response, assessed as best response; secondary endpoints were safety, progression-free survival (PFS) according to PCWG3 criteria, and overall survival (OS). Adverse events were assessed using the Common Terminology Criteria for Adverse Events (CTCAE) v5.0.</p> Results <p>Forty-eight patients were assessed for safety; 44 were evaluable for efficacy. A ≥ 50% PSA decline occurred in 22 patients (50%). At 12 months, PFS was 22.7% (95% CI: 11.8–35.9) and OS 87.9% (95% CI: 73.4–94.8); median OS was 18.8 months. Treatment was generally well tolerated, with mostly Grade 1–2 events. Grade 3 toxicities were rare (6.3%), and no Grade 4 events occurred. One Grade 3 hyponatraemia led to discontinuation.</p> Conclusions <p>¹⁷⁷Lu-PSMA-617 at 5.5 GBq per cycle was safe and effective, achieving survival comparable to studies using 7.4 GBq with fewer severe toxicities. Tailored regimens may benefit patients at higher toxicity risk. These data support further studies to optimize dosage, timing, sequencing and combinations of RLT.</p>