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Enzalutamide: looking back at its preclinical discovery

Introduction: In patients with metastatic prostate cancer (PCa), castration is the standard first-line therapy. However, all patients eventually develop castration-recurrent PCa (CRPC). In these patients who fail the first-line therapy, enzalutamide has emerged as a viable alternative. Enzalutamide is a second-generation small molecule androgen receptor (AR) antagonist that blocks the AR nuclear translocation and DNA binding without any known AR agonist activity. Areas covered: This review provides an overview of the history of the oral selective AR modulator, enzalutamide, and discusses its discovery and current preclinical experimental results including resistance mechanisms. The article illustrates the history of discovery based on enzalutamide’s mechanism of action. Furthermore, the authors highlight the drug’s clinical development and post-launch developments. Expert opinion: The landscape of CRPC has changed dramatically over the last few years, as new agents with proven benefit in overall survival have been approved. Compared to the average time of 10 – 15 years for a new drug to go from pre-clinical discovery to registration, enzalutamide obtained FDA approval in < 6 years after its initial characterization. Enzalutamide, a targeted agent of the androgen-AR axis, has shown promising results in CRPC and is generally well tolerated. However, drug resistance inevitably emerges is a severe limitation. The authors believe that further clinical studies that look at its use as either a combinational or sequential therapy could help to address these concerns.