Mechanisms and Therapeutic Strategies to Overcome Enzalutamide Resistance in Advanced Prostate Cancer.

Enzalutamide, a second-generation androgen receptor (AR) inhibitor, has significantly improved survival outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC). However, resistance to enzalutamide emerges in nearly all patients, posing a major clinical challenge. This review comprehensively examines the multifaceted mechanisms underlying enzalutamide resistance, including AR amplification, point mutations, splice variants such as AR-V7, and the activation of bypass signaling pathways, including glucocorticoid receptor signaling, PI3K/Akt/mTOR, and Wnt signaling. Additionally, the tumor microenvironment, lineage plasticity, and neuroendocrine differentiation contribute to therapy resistance through immune evasion and epigenetic reprogramming. We further discuss promising therapeutic strategies aimed at overcoming resistance, including combination treatments with PARP inhibitors, epigenetic modulators, and next-generation androgen receptor (AR) inhibitors. Biomarkers and personalized medicine approaches increasingly guide ongoing clinical trials to optimize treatment efficacy. This review also highlights drug repurposing as a practical avenue for targeting noncanonical vulnerabilities in resistant prostate cancer. Together, these insights provide a foundation for developing more durable and individualized treatment strategies for patients with enzalutamide-resistant metastatic castration-resistant prostate cancer (mCRPC).