Updated prostate cancer risk groups by PSMA-PET PROMISE (PPP2): Results from an international multi-centre registry study.

5045 Background: We previously established prognostic two-tier risk nomograms based on PSMA-PET and Prostate Cancer Molecular Imaging Standardized Evaluation (PROMISE) criteria in a large single-centre cohort. Here, we validate three-tier risk stratification by PSMA-PET PROMISE (PPP2) in a large international multi-centre registry study for prostate cancer survival. Methods: We included prostate cancer patients who underwent PSMA-PET at 20 hospitals in EU, USA or Australia between 2013 and 2022. PSMA-PET was standardized by PROMISE version 2 (V2). Total lesion count, total tumour volume, PSMA expression score, and overall survival follow-up were obtained. Investigator sites were split 2:1 into development and validation cohorts, considering site characteristics. In the development cohort we assessed PPP predictors and created version 2 for visual and quantitative PPP nomograms (PPP2) based on Cox regression models with least absolute shrinkage and selection operator penalty for overall survival. Performance of both nomograms was measured in the validation cohort using Harrell´s C-index and calibration plots. Head-to-head comparison to the National Comprehensive Cancer Network (NCCN) risk score was examined by ROC-curves. Results: We analyzed 6128 male patients (4044 development and 2084 validation cohorts) across all disease stages with 1915 (31·2%) reported deaths and median follow-up of 4·8 years (IQR 3·4-6·4). Predictors in the visual PPP2 nomogram were presence of distant metastases (extrapelvic nodal metastases [M1a], bone metastases [M1b; oligometastatic, disseminated or diffuse marrow involvement], and visceral metastases [M1c]), PSMA expression score, and total lesion count. Predictors in the reassessed quantitative PPP2 nomogram were distant metastases (M1a, M1b, and M1c), total tumour volume, and PSMA expression score. C-indices (95% CI) in the validation cohort were 0·80 (0·78-0·82) for the visual and 0·80 (0·79-0·82) for the quantitative nomogram, respectively. In the validation cohort for three-tier stratification (high, intermediate, low risk), accuracy of both PPP2 nomograms was superior when compared to the NCCN risk score (n=1034, AUC 0·84 vs. 0·76; p<0·0001, respectively). Performance of both PPP2 nomograms was independent from radiopharmaceutical (68Ga vs. 18F) or PROMISE version (V1 vs. V2; n=2084, visual: both AUC 0·79, respectively, p=0·11; quantitative: both AUC 0·79, respectively, p=0·56). Conclusions: PSMA-PET PROMISE nomograms were improved in an international multi-centre study to accurately stratify high vs. intermediate vs. low risk for overall survival across all stages of prostate cancer. PPP2 yields superior accuracy compared to the NCCN risk score. Follow-up continues in the PROMISE Registry (NCT06320223, promise-pet.org).