Purpose <p>This study examines patients with metastatic castration-resistant prostate cancer who had durable responses to radioligand therapy (RLT) with [177Lu]Lu-PSMA-617, remaining asymptomatic with prostate-specific antigen (PSA) levels persistently under 1 ng/mL. We also discuss ongoing research to extend therapeutic responses in prostate cancer with [177Lu]Lu-PSMA-617 RLT.</p> Methods <p>We retrospectively reviewed data from 168 mCRPC patients referred for [177Lu]Lu-PSMA-617 RLT at our center between December 2017 and December 2024. We identified three patients who achieved a durable complete PSA response, defined as PSA &lt; 1 ng/mL for at least 24 months. We analyzed their clinical characteristics, treatment details, and follow-up data.</p> Results <p>Three patients (median age: 73 years, range 62–85) with mCRPC achieved durable complete PSA responses following frontline [177Lu]Lu-PSMA-617 RLT. Two patients received four cycles and one patient received three cycles of therapy. The duration of complete PSA response was 25, 67, and 70 months, respectively. All three patients remained alive and asymptomatic at the last follow-up. All patients continued on maintenance androgen deprivation therapy (ADT).</p> Conclusion <p>In conclusion, our cases indicate that [177Lu]Lu-PSMA may be an effective treatment approach as first-line treatment patients with metastatic castration-resistant prostate cancer. While the role of nuclear medicine is expanding rapidly, its full potential will be realized through comparative studies with established therapies. Commitment to evidence-based research is essential for advancing patient care in patients with metastatic castration-resistant prostate cancer.</p>