[¹⁷⁷Lu]Lu-PSMA-617 as first-line systemic therapy in patients with metastatic castration-resistant prostate cancer: a real-world study

Purpose The use of [Lu-177]Lu-PSMA-617 radioligand therapy has become increasingly recognized as a viable therapeutic approach for patients in the advanced stages of metastatic castration-resistant prostate cancer (mCRPC). However, there is limited data regarding its effectiveness and safety in earlier lines. This study aims to present our institution's experience with [Lu-177]Lu-PSMA-617 as a first-line systemic therapy for mCRPC. Methods We collected and analyzed data from consecutive mCRPC patients who underwent first-line treatment with [Lu-177]Lu-PSMA-617 at our center from 2015 to 2023. The various outcome measures included best prostate-specific antigen-response rate (PSA-RR) (proportion of patients achieving a >= 50% decline in PSA); objective radiographic response rate (ORR) (proportion of patients achieving complete or partial radiographic responses); radiographic progression-free survival (rPFS) (measured from treatment initiation until radiographic progression or death from any cause); overall survival (OS) (measured from treatment initiation until death from any cause); and adverse events. Results Forty treatment-na & iuml;ve mCRPC patients with PSMA-positive disease on [Ga-68]Ga-PSMA-11 PET/CT were included (median age: 68.5 years, range: 45-78; median PSA: 41 ng/mL, range: 1-3028). These patients received a median cumulative activity of 22.2 GBq (range: 5.55-44.4) [Lu-177]Lu-PSMA-617 over 1-6 cycles at 8-12 week intervals. A >= 50% decline in PSA was observed in 25/40 (62.5%) patients (best PSA-RR). Radiographic responses were evaluated for thirty-eight patients, with thirteen showing partial responses (ORR 34.2%). Over a median follow-up of 36 months, the median rPFS was 12 months (95% confidence interval, CI: 9-15), and the median OS was 17 months (95% CI: 12-22). Treatment-emergent grade >= 3 anemia, leucopenia, and thrombocytopenia were noted in 4/40 (10%), 1/40 (2.5%), and 3/40 (7.5%) patients, respectively. Conclusion The findings suggest that [Lu-177]Lu-PSMA-617 is a safe and effective option as a first-line treatment in mCRPC. Further trials are needed to definitively establish its role as an upfront treatment modality in this setting.