Real-World Outcomes of [¹⁷⁷Lu]Lu-PSMA-617 in the French Early-Access Program for Patients with Metastatic Castration-Resistant Prostate Cancer.

Abstract

Metastatic castration-resistant prostate cancer (mCRPC) remains challenging to treat, especially after failure of standard therapies, such as androgen receptor pathway inhibitors and taxane-based chemotherapy. Radiopharmaceutical therapy with [177Lu]Lu-PSMA-617 targets prostate-specific membrane antigen (PSMA)-positive tumor cells. In the VISION trial, [177Lu]Lu-PSMA-617 has demonstrated significant benefits in terms of median overall survival and a significant improvement of median radiographic progression-free survival (PFS) versus standard of care. Recent guidelines support its use in PSMA-positive mCRPC. In France, [177Lu]Lu-PSMA-617 was available via an early-access program from December 1, 2021, to April 29, 2025. This analysis reports the largest real-world cohort of patients with mCRPC treated with [177Lu]Lu-PSMA-617, evaluating its use, safety, and effectiveness in routine clinical practice. Methods: This multicenter descriptive cohort included adult patients with mCRPC who had progressive disease after at least 1 androgen receptor pathway inhibitor and 1 taxane-based treatment, and 1 positive PSMA PET scan. Patients received up to 6 cycles of intravenous [177Lu]Lu-PSMA-617 every 6 wk. Clinical evaluation, prostate-specific antigen (PSA) status, imaging assessments, and treatment-related adverse events were prospectively collected during regular follow-up. PFS was analyzed using Kaplan-Meier methods. Outcomes were compared descriptively to the VISION trial. Results: From December 2021 to April 2025, 3709 patients from 46 centers received at least 1 dose and 2476 had more than 8 mo of follow-up for efficacy analysis. Compared with VISION, patients were older, more heavily pretreated, and had more lymph node metastases but lower baseline PSA. Median imaging PFS was 7.6 mo versus 8.7 mo in VISION. Disease control was achieved in 82% according to PSA criteria. Some patients with early PSA progression after the first cycle subsequently showed a response, suggesting a flare-up effect. The safety profile was manageable, with treatment discontinuations mainly due to progression. No new safety signals were identified. Subgroup analyses confirmed efficacy in elderly patients (aged >75 y) and more favorable outcomes in patients less heavily pretreated with taxane-based chemotherapy. Conclusion: The French early-access program confirms a favorable benefit-risk profile for [177Lu]Lu-PSMA-617 in a real-world mCRPC population. Use trends suggest earlier use of the treatment after 1 taxane-based treatment, with patients being less pretreated and characterized by fewer metastases.