Prognostic Value of Baseline High-Uptake PSMA Tumor Volume Fraction in Metastatic Castration-Resistant Prostate Cancer Patients Treated with [177Lu]Lu-PSMA Radioligand Therapy

Background/Objectives: Lutetium-177 prostate-specific membrane antigen radioligand therapy ([177Lu]Lu-PSMA-RLT) is an effective treatment for patients with metastatic castration-resistant prostate cancer (mCRPC), but no validated PSMA-PET/CT-based biomarker currently identifies patients at risk of early treatment failure. The aim of this study was to assess whether semi-quantitative PSMA-PET/CT parameters, in particular the fraction of PSMA-positive tumor volume with high uptake, are associated with early biochemical progression (EBP) and PSA50 response and secondarily with PSA-PFS and OS. Methods: Semiquantitative PSMA-PET parameters comprised reference lesion SUVmax (RL-SUVmax), SUVmean, total PSMA tumor volume (tPSMA-TV), tPSMA-TV above a fixed SUV threshold of 20 (tPSMA-TV20), the percentage of tPSMA-TV20 within tPSMA-TV (tPSMA-TV%), total lesion quotient (TLQ), TLQ20, and rTLQ%. The co-primary endpoints were EBP, defined as PSA progression according to the PCWG3 criteria within 4 months of the start of treatment, and PSA50 response, defined as a reduction in PSA of at least 50% compared with baseline. PSA-PFS (PCWG3-defined PSA progression or death from any cause) and OS were secondary endpoints. Results: 63 patients were retrospectively included (median follow-up, 20.9 months). In univariable analyses, higher baseline tPSMA-TV% was significantly associated with lower odds of EBP (OR per 10% increase, 0.71; 95% CI, 0.57–0.87; p = 0.001) and higher odds of PSA50 response (OR, 1.31; 95% CI, 1.07–1.61; p = 0.009). It was associated with longer PSA-PFS (HR, 0.75; 95% CI, 0.67–0.84; p < 0.001) and longer OS (HR, 0.81; 95% CI, 0.72–0.91; p < 0.001). Exploratory ROC analysis identified a tPSMA-TV% cut-off of 47.54% for EBP (AUC, 0.73 [95% CI, 0.57–0.86]; sensitivity, 0.61; specificity, 0.93), although this threshold requires external validation. In exploratory models including tPSMA-TV and SUVmean, tPSMA-TV% remained associated with PSA-PFS and OS but not with EBP or PSA50 response. Conclusions: Baseline tPSMA-TV% was associated with EBP, PSA50 response, PSA-PFS and OS in mCRPC patients undergoing [177Lu]Lu-PSMA-RLT, and these associations remained after adjustment for baseline PSA and metastatic presentation. tPSMA-TV% is a candidate prognostic imaging biomarker that requires external validation.