Prognostic Value of Early Follow-Up PSMA PET/CT After 2 Cycles of [<sup>177</sup>Lu]Lu-PSMA RPT in Patients with mCRPC: Comparison with PSA Dynamics.

Abstract

Prostate-specific membrane antigen (PSMA) PET/CT is recommended for response evaluation during [177Lu]Lu-PSMA radiopharmaceutical therapy (RPT) in patients with metastatic castration-resistant prostate cancer (mCRPC). Evidence supporting the predictive value of such a follow-up PSMA PET/CT relative to changes in prostate-specific antigen (PSA) monitoring is limited. Methods: This retrospective study evaluated 109 patients with mCRPC receiving [177Lu]Lu-PSMA RPT. Patients underwent [18F]F-PSMA-1007 PET/CT at baseline and after 2 cycles of RPT. We compared baseline and follow-up scans to assess relative changes in PSMA tumor volume (PSMA-TV), SUVmean, and total lesion PSMA (TL-PSMA, defined as PSMA-TV × SUVmean). PSA change was also defined as the change from baseline to follow-up after the second cycle. The prognostic performance of laboratory and image-based changes for overall survival (OS) were then tested using univariate Cox regression. We also performed Kaplan-Meier analysis, applying a 25% threshold for increases in PSA level and PET-based parameters. Finally, direct comparison of the predictive value was tested in multivariate Cox regression, applying the same cutoff. Results: Relative changes in volumetric PET-based parameters after 2 cycles of RPT correlated significantly with the change in PSA level (P ≤ 0.006 for each), validating the reliability of PET quantification of changes for response evaluation. In a univariate analysis, changes in PSMA-TV (P = 0.012) and TL-PSMA (P = 0.014) were predictive for OS, with PSA change providing comparable significance (P = 0.012). Applying the established 25% threshold for increase, TL-PSMA change best identified patients at risk for shorter OS (hazard ratio [HR], 2.298; P = 0.004), outperforming both PSA change (HR, 1.292; P = 0.369) and PSMA-TV change (HR, 1.798; P = 0.024). Further, TL-PSMA change emerged as the sole independent predictor of OS in multivariate analysis (P = 0.016). Conclusion: During RPT, relative changes in volumetric PET metrics from baseline to follow-up PSMA PET/CT demonstrated superior predictive value over PSA monitoring. These results highlight the clinical utility of repeat PSMA PET/CT in patients with mCRPC and indicate that follow-up scans during treatment should not be omitted.