PSMA Total Tumor Volume: A Simple Quantifiable Biomarker for Overall Survival Prediction—Results from the International PROMISE PET Registry

Prostate-specific membrane antigen (PSMA) PET is an accurate prognostic imaging biomarker of survival in patients with prostate cancer when assessed using Prostate Cancer Molecular Imaging Standardized Evaluation (PROMISE) criteria. Previously, PSMA PET PROMISE risk nomograms were created that surpassed clinical prediction tools. In this study, we focused on the evaluation of quantifiable biomarkers to simplify and facilitate overall survival (OS) prediction. Methods: Data from patients with histologically proven prostate cancer who underwent PSMA PET between December 2012 and April 2024 at participating imaging centers worldwide and who were included in the PROMISE PET Registry by January 31, 2026, were analyzed. Prostate-specific antigen (PSA) levels at PSMA PET, disease stage, and OS follow-up data were collected. PSMA total tumor volume (PSMA TTV) and whole-body SUVmean were assessed using predefined SUV thresholds. PSMA total lesion uptake (PSMA TL) was calculated as PSMA TTV × SUVmean. PSA level at PSMA PET adjusted for PSMA TTV was calculated as PSA × TTV. Univariate regression analysis was conducted to identify potential predictors. Prognostic accuracy of quantitative biomarkers was compared using Harrell C-indices and time-dependent concordance in the development cohort. Probabilities for 3-, 5-, and 7-y OS across PSMA TTV quartiles were derived from Kaplan–Meier curves. Subgroup analysis was conducted by cancer stage. Results: In total, 13,893 patients were included in the analysis and divided 2:1 into development (n = 9271) and validation (n = 4622) cohorts. The prognostic accuracy of PSMA TTV in the validation cohort (C-index, 0.78; 95% CI, 0.77–0.80) was superior to SUVmean (C-index, 0.62; 95% CI, 0.61–0.64) and PSA level at PET (C-index, 0.71; 95% CI, 0.69–0.72) and similar to PSMA TL (C-index, 0.78; 95% CI, 0.76–0.79) and PSA × TTV (C-index, 0.77; 95% CI, 0.75–0.78). In the entire cohort, the median OS for PSMA TTV quartile 1 (0 mL) and quartile 2 (>0–2.1 mL) was not reached. The median OS was 11.4 y (interquartile range, 10.1 y to not reached) for PSMA TTV quartile 3 (>2.1–16.2 mL) and 4.4 y (interquartile range, 4.2–4.6 y) for quartile 4 (>16.17 mL). Conclusion: Among quantifiable PET metrics, PSMA TTV had the highest prognostic accuracy for OS in patients with prostate cancer. Automated PSMA TTV assessment may facilitate fast and reproducible outcome prediction in the future.