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BackgroundMetastatic cancer remains one of the leading causes of cancer-related mortality worldwide. Yet, the prediction of survivability in this population remains limited by heterogeneous clinical presentations and high-dimensional molecular features. Advances in machine learning (ML) provide an opportunity to integrate diverse patient- and tumor-level factors into explainable predictive ML models. Leveraging large real-world datasets and modern ML techniques can enable improved risk stratification and precision oncology. ObjectiveThis study aimed to develop and interpret ML models for predicting overall survival in patients with metastatic cancer using the Memorial Sloan Kettering-Metastatic (MSK-MET) dataset and to identify key prognostic biomarkers through explainable artificial intelligence techniques. MethodsWe performed a retrospective analysis of the MSK-MET cohort, comprising 25,775 patients across 27 tumor types. After data cleaning and balancing, 20,338 patients were included. Overall survival was defined as deceased versus living at last follow-up. Five classifiers (extreme gradient boosting [XGBoost], logistic regression, random forest, decision tree, and naive Bayes) were trained using an 80/20 stratified split and optimized via grid search with 5-fold cross-validation. Model performance was assessed using accuracy, area under the curve (AUC), precision, recall, and F1-score. Model explainability was achieved using Shapley additive explanations (SHAP). Survival analyses included Kaplan-Meier estimates, Cox proportional hazards models, and an XGBoost-Cox model for time-to-event prediction. The positive predictive value and negative predictive value were calculated at the Youden index–optimal threshold. ResultsXGBoost achieved the highest performance (accuracy=0.74; AUC=0.82), outperforming other classifiers. In survival analyses, the XGBoost-Cox model with a concordance index (C-index) of 0.70 exceeded the traditional Cox model (C-index=0.66). SHAP analysis and Cox models consistently identified metastatic site count, tumor mutational burden, fraction of genome altered, and the presence of distant liver and bone metastases as among the strongest prognostic factors, a pattern that held at both the pan-cancer level and recurrently across cancer-specific models. At the cancer-specific level, performance varied; prostate cancer achieved the highest predictive accuracy (AUC=0.88), while pancreatic cancer was notably more challenging (AUC=0.68). Kaplan-Meier analyses demonstrated marked survival separation between patients with and without metastases (80-month survival: approximately 0.80 vs 0.30). At the Youden-optimal threshold, positive predictive value and negative predictive value were approximately 70% and 80%, respectively, supporting clinical use for risk stratification. ConclusionsExplainable ML models, particularly XGBoost combined with SHAP, can strongly predict survivability in metastatic cancers while highlighting clinically meaningful features. These findings support the use of ML-based tools for patient counseling, treatment planning, and integration into precision oncology workflows. Future work should include external validation on independent cohorts, integration with electronic health records via Fast Healthcare Interoperability Resources–based dashboards, and prospective clinician-in-the-loop evaluation to assess real-world use.