Abstract
BACKGROUND AND OBJECTIVE: Genomic characterization of metastatic prostate cancer (mPCa) plays a pivotal role in guiding precision oncology. This study aimed to evaluate the feasibility of combining radiomics and clinical data within a machine learning (ML) framework to non-invasively predict key genomic mutations in patients with mPCa undergoing PSMA PET imaging. METHODS: A retrospective cohort of 14 mPCa patients who underwent [(18) F]PSMA-1007 PET/CT was analysed. Prostate and metastatic lesions were segmented, and radiomics features were extracted. Somatic genomic alterations were obtained from formalin-fixed paraffin-embedded tissue samples using FoundationOne CDx testing. Six ML algorithms - Discriminant Analysis, Support Vector Machines, K-Nearest Neighbours, Neural Networks, Random Forest, and Boosting - were trained using a 5-times repeated pipeline with 80/20 train/test split, LASSO feature selection, and 5-fold cross-validation. Model performance was assessed using accuracy, AUC, sensitivity, specificity, precision, and F-score. KEY FINDINGS: Fourteen patients with mPCa were included, and 46 lesions were analysed. Genomic alterations included mutations in TP53, TMPRSS2, PTEN, BRCA1/2, ATM, and others. Owing to data limitations, mutations other than TP53, TMPRSS2, and PTEN were grouped into a composite "OTHER" category. The best-performing clinical-radiomics ML models achieved AUCs of 91.11% (TP53), 84.44% (TMPRSS2), 80.00% (PTEN), and 77.78% (OTHER). Selected feature stability was consistent across repeated runs. CONCLUSIONS AND CLINICAL IMPLICATIONS: Clinical-radiomics ML models based on PSMA PET imaging show promising accuracy in predicting actionable genomic alterations in mPCa. These findings support further investigation into radiogenomics modelling as a complementary, non-invasive tool to inform molecular profiling and treatment stratification.