Safety and Efficacy of ¹⁷⁷Lu-PSMA Therapy Following ²²³Radium Treatment: A Retrospective Multinational Real-World Analysis

Background: ¹⁷⁷Lu PSMA therapy is increasingly used for metastatic castration-resistant prostate cancer (mCRPC) treatment. However, data on its efficacy and safety in patients previously treated with ²²³Ra remain limited.

Methods: This retrospective, multicenter study evaluated 233 mCRPC patients treated with ¹⁷⁷Lu PSMA at 5 European centers. The cohort included 27 patients previously treated with ²²³Ra and 206 Radium-naive patients. Statistical analyses, including Chi-squared, Mann-Whitney U tests, and multivariate logistic regression, were used to assess response and mortality. Predictors of response and mortality were identified using multivariate models.

Results: Patients who experienced a longer interval between castration resistance and the initiation of ¹⁷⁷Lu PSMA therapy demonstrated better responses (median 17 months in responders vs. 8.5 months in progressors, P = .001). Platelet counts were significantly lower in the progressive group compared to the responsive group (P = .01). Multivariate regression confirmed lower platelet levels as a predictor of poor response (P = .029). The overall response rate to ¹⁷⁷Lu PSMA was 54%, similar between the ²²³Ra-pretreated and Radium-naive groups. However, mortality was significantly higher in the ²²³Ra-pretreated group (86%) compared to the Radium-naive group (51%, P = .003). ECOG performance status (P = .004) and ALP levels (P = .030) were significant predictors of mortality, while CRP showed a trend towards significance (P = .064). Tolerability of ¹⁷⁷Lu PSMA was comparable to the safety profile reported in the literature, with 44% of ²²³Ra-pretreated patients experiencing AEs and 22% experiencing severe AEs (Grade ≥ 3).

Conclusions: ¹⁷⁷Lu PSMA therapy is effective and well-tolerated in mCRPC patients pretreated with ²²³Ra. However, higher mortality was observed in the ²²³Ra-pretreated group. ECOG PS, ALP, and platelet counts were significant predictors of response and mortality, and a longer interval between therapies was associated with better outcomes. These findings underscore the importance of treatment sequencing and monitoring prognostic markers.