Predictive biomarkers of response in metastatic prostate cancer: paving the way for a new era of precision medicine

INTRODUCTION: The therapeutic landscape for metastatic prostate cancer has expanded substantially over the last decade, yet treatment selection remains predominantly driven by clinical parameters rather than validated molecular predictors. This review addresses the urgent need to refine patient stratification by critically examining emerging and established predictive biomarkers that may enable a precision medicine approach in advanced disease. AREAS COVERED: This review provides a comprehensive overview of predictive biomarkers in metastatic prostate cancer, including androgen receptor aberrations, mismatch repair deficiency, SPOP mutations, TMPRSS2/ERG fusions, PTEN/PI3K/AKT pathway alterations, and novel therapeutic targets such as STEAP1, DLL3, TROP-2, and Nectin-4. We discuss their biological underpinnings, mechanistic relevance, and clinical evidence supporting their potential predictive role across treatment settings. A structured literature search was conducted using PubMed/MEDLINE and major international oncology congress databases, focusing on peer-reviewed publications and clinical trial reports published up to February 2026, with particular emphasis on prospective and biomarker-driven studies. EXPERT OPINION: While several molecular alterations show compelling biological rationale and encouraging clinical signals, few biomarkers have achieved prospective validation sufficient for routine implementation. The next phase of progress will depend on biomarker-enriched trial designs, harmonized testing strategies, and integration of multi-omic profiling to overcome biological heterogeneity and therapeutic resistance.