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

Enzalutamide, a second-generation androgen receptor (AR) inhibitor, has significantly improved outcomes for patients with metastatic castration-resistant prostate cancer (mCRPC). However, resistance to enzalutamide remains a significant clinical hurdle, driven by diverse mechanisms, including AR amplification, point mutations, and splice variants such as AR-V7, which sustain signaling despite AR inhibition. In parallel, bypass pathways, including glucocorticoid receptor activation, PI3K/Akt/mTOR signaling, noncanonical Wnt activation, and lineage plasticity, contribute to AR-independent resistance. Nonetheless, the tumor microenvironment also plays a vital role in fostering immune evasion and suppressing cytotoxic immune responses. This review summarizes the current understanding of these resistance mechanisms and highlights emerging strategies to overcome them, including combination therapies targeting DNA repair (e.g., PARP inhibitors), epigenetic reprogramming (e.g., EZH2 inhibitors), and immune escape (e.g., checkpoint blockade or fulvestrant). Ongoing clinical trials and drug repurposing efforts, such as the use of artesunate or masofaniten, offer promising avenues for combating resistance. Ultimately, a precision medicine framework that integrates molecular diagnostics, biomarker-guided interventions, and rational drug combinations is essential to improve outcomes for patients with enzalutamide-resistant metastatic castration-resistant prostate cancer (mCRPC).