Development and Validation of a Multimodal Artificial Intelligence-derived Digital Pathology-based Biomarker Predicting Metastasis Among Patients with Biochemical Recurrence After Radical Prostatectomy in NRG/RTOG Trials.

Morgan, Todd M; Ren, Yi; Tang, Siyi; Zwerink, Wouter; Chen, Emmalyn; Mitani, Akinori; Huang, Huei-Chung; Simko, Jeffry P et al. · Eur Urol · 2025

retrospective_cohort · Level III

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Abstract

Biochemical recurrence (BCR) after radical prostatectomy (RP) is a heterogeneous disease state in prostate cancer with multiple treatment options. Improved risk stratification could enable more personalized decision-making. We developed and validated a digital pathology-based multimodal artificial intelligence (MMAI) model to predict outcomes in post-RP BCR patients undergoing salvage therapy. An MMAI model was trained to predict distant metastasis (DM) using prostate histopathology image features and clinical variables (pathologic grade group, pathologic T stage, prostate-specific antigen level before salvage radiotherapy [SRT], age, and surgical margin). The locked model was validated in 533 patients from NRG/RTOG 9601 and 0534 treated with SRT ± hormone therapy (HT), using Cox regression and time-dependent area under the receiver operating characteristic curve. With a median follow-up of 9.3 yrs, MMAI score was significantly associated with DM (subdistribution hazard ratio = 2.17 per standard deviation [95% confidence interval 1.65-2.85]; p < 0.001) and remained independently prognostic after adjusting for clinical variables and treatment. The 10-yr time-dependent area under the receiver operating characteristic curve for MMAI was 0.74 compared with 0.68 for a clinical nomogram. Binary risk categorization demonstrated higher 10-yr DM incidence in the MMAI high-risk (25%) than in the low-risk (8.8%) group. The absolute reduction in 10-yr DM incidence with HT plus SRT versus SRT alone was 21% in the high-risk group versus 2.5% in the low-risk group. Limitations include the use of archived trial cohorts. The post-RP MMAI model provides individualized risk estimates after SRT ± HT and may support shared decision-making about salvage treatment. External and prospective validation are ongoing.