The HGF/MET Axis in Advanced Prostate Cancer: From Context-Dependent Biology to Biomarker-Driven Therapeutic Strategies

Background/Objectives: Advanced prostate cancer (PCa) evolves through adaptive mechanisms that sustain tumor growth despite the suppression of androgen receptor (AR) signaling. Accumulating evidence identifies activation of the hepatocyte growth factor (HGF)/MET pathway as a potential driver of PCa progression in advanced disease states characterized by AR-independence and therapeutic resistance. We review the biological and clinical evidence supporting MET as a context-dependent therapeutic target and discuss its implications for patient selection and combination strategies. Methods: A comprehensive narrative review of preclinical, translational, and clinical studies evaluating MET-directed therapies for PCa was performed. Results: Aberrant activation of the HGF–MET axis is frequently driven by autonomous paracrine and autocrine loops that sustain pathway activation during disease progression. MET overexpression is associated with adverse pathological features, increased tumor aggressiveness, bone metastasis, lineage plasticity, and resistance to AR-targeted treatments. Preclinical studies have demonstrated that AR suppression, tumor hypoxia and tumor–microenvironment interactions promote MET upregulation, supporting AR-independent growth and epithelial-to-mesenchymal transition. Clinical trials of MET inhibitors have shown modest activity as monotherapies, with the most consistent biological effects observed in bone-dominant disease. Recent studies indicate greater therapeutic potential when MET inhibition is incorporated into rational combination strategies targeting complementary molecular pathways. Emerging data further indicate that MET activation characterizes a biologically aggressive, AR-low or neuroendocrine-like disease state. These findings support a transition from empiric use of MET inhibitors toward precision, context-driven therapeutic development. Conclusions: MET is not a universal therapeutic target but defines a clinically relevant subset of aggressive, AR-indifferent PCa. Future development should focus on biomarker-guided patient selection and rational combination strategies. Integration of molecular profiling, imaging, and liquid biopsy approaches will be essential to identify patients most likely to benefit from MET-directed interventions.