Outcome Prediction After [ ¹⁷⁷ Lu]Lu-PSMA I&T in Metastatic Castration-Resistant Prostate Cancer: External Validation of a [ ⁶⁸ Ga]Ga-PSMA-11 PET–Based Model with [ ¹⁸ F]F-Flotufolastat

¹⁷⁷Lu-prostate-specific membrane antigen (PSMA)–targeted radiopharmaceutical therapy is an established treatment for metastatic castration-resistant prostate cancer, though responses vary. A prognostic model using [⁶⁸Ga]Ga-PSMA-11 PET–derived parameters was developed to predict therapy outcomes. This retrospective analysis validates the model in an independent cohort imaged with [¹⁸F]F-flotufolastat ([¹⁸F]rhPSMA-7.3 PET) before [¹⁷⁷Lu]Lu-PSMA I&amp;T. <b>Methods:</b> In total, 174 consecutive patients treated with [¹⁷⁷Lu]Lu-PSMA I&amp;T at a single center were included in this analysis. The Cox proportional hazards models for overall survival (OS) and prostate-specific antigen (PSA) progression-free survival (PFS) and the logistic regression model for PSA response, as proposed in the prognostic model, were applied to our validation data. Model performance was evaluated using the Harrell concordance index (C-index) and calibration plots. OS, PSA-PFS, and PSA response were reported with median values and 95% CI, as well as stratified by published cutoff values into low- and high-risk groups.<b> Results:</b> The estimated OS probabilities were 60% (95% CI, 53%–68%) at 12 mo and 40% (95% CI, 33%–49%) at 18 mo. Our validation yielded a C-index of 0.71 (95% CI, 0.67–0.76) for OS prediction compared with a C-index of 0.72 (95% CI, 0.68–0.76) in the validation cohort. For PSA-PFS, the estimated probabilities were 56% (95% CI, 49%–65%) at 3 mo and 34% (95% CI, 27%–42%) at 6 mo, with a C-index of 0.62 (95% CI, 0.57–0.67) compared with a C-index of 0.71 (95% CI, 0.68–0.74) in the validation data. Low-risk patients had significantly longer OS (21.8 vs. 11.6 mo, <i>P</i> &lt; 0.0001) and PSA-PFS (6.9 vs. 2.9 mo, <i>P</i> = 0.003) than did high-risk patients. The prognostic PSA response model showed slightly worse discrimination in our cohort (area under the receiver operating characteristic curve, 0.71; 95% CI, 0.63–0.79) than with the validation data (area under the receiver operating characteristic curve; 95% CI, 0.78, 0.68–0.88). <b>Conclusion:</b> Our results indicate accuracy similar to that of the prognostic model for prediction of OS and PSA-PFS and for PSA response in an independent patient population undergoing [¹⁷⁷Lu]Lu-PSMA I&amp;T radiopharmaceutical therapy with [¹⁸F]F-flotufolastat instead of [⁶⁸Ga]Ga-PSMA-11.