Background177Lu 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. MethodsThis retrospective, multicenter study evaluated 233 mCRPC patients treated with 177Lu PSMA at five 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. ResultsPatients 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=0.001). Platelet counts were significantly lower in the progressive group compared to the responsive group (p=0.01). Multivariate regression confirmed lower platelet levels as a predictor of poor response (p=0.029). 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=0.003). ECOG performance status (p=0.004) and ALP levels (p=0.030) were significant predictors of mortality, while CRP showed a trend towards significance (p=0.064). 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). Conclusions177Lu 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. Micro-abstractEven in a real-world setting, 177Lu PSMA remains an effective treatment for mCRPC, achieving response rates up to 54% even in patients previously treated with 223Ra. Our findings indicate that 177Lu PSMA is well-tolerated after 223Ra, with no significant increase in adverse events. However, higher mortality rates were observed in the 223Ra cohort, suggesting a potentially poorer prognosis for patients who received 223Ra as an initial treatment.