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Published on: December 9, 2015
Enzalutamide: Development from bench to bedside
1Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Abstract:
Prostate tissue, whether benign or malignant, is heavily dependent on androgen receptor (AR) signaling for growth and proliferation. Androgen deprivation therapy has been standard of care for management of metastatic prostate cancer for the past 70 years. AR antagonists were developed to further abrogate signaling through this pathway by competitive inhibition of the receptor. First-generation compounds such as bicalutamide had modest efficacy, and in the setting of AR overexpression or specific mutations in the AR ligand-binding domain, these early compounds had partial agonist properties that could stimulate tumor growth. Enzalutamide was developed to overcome these deficiencies, and here, we present the story of its preclinical discovery, clinical development, and ultimate approval as a standard-of-care therapy for castration-resistant prostate cancer. Also discussed are ongoing efforts to elucidate mechanisms of resistance to this agent as well as studies that are investigating its role in other prostate cancer disease states and other cancer types.
Insights
Enzalutamide offers improved efficacy over older drugs for prostate cancer by targeting androgen receptor (AR) signaling. Research continues on resistance mechanisms and broader applications of this AR antagonist.
Area of Science:
- Oncology
- Pharmacology
- Urology
Background:
- Prostate cancer growth relies on androgen receptor (AR) signaling.
- Androgen deprivation therapy is a long-standing treatment for metastatic prostate cancer.
- First-generation AR antagonists like bicalutamide have limitations, including partial agonist activity in certain cases.
Purpose of the Study:
- To detail the preclinical discovery and clinical development of enzalutamide.
- To highlight enzalutamide's approval as a standard therapy for castration-resistant prostate cancer.
- To discuss ongoing research into resistance mechanisms and new applications for enzalutamide.
Main Methods:
- Preclinical studies evaluating AR antagonist efficacy.
- Clinical trials assessing safety and effectiveness in prostate cancer patients.
- Mechanistic studies investigating resistance pathways to AR-targeted therapies.
Main Results:
- Enzalutamide demonstrates superior efficacy compared to first-generation AR antagonists.
- Enzalutamide is approved for castration-resistant prostate cancer treatment.
- Understanding resistance mechanisms is crucial for optimizing AR-targeted therapy.
Conclusions:
- Enzalutamide represents a significant advancement in prostate cancer treatment by effectively inhibiting AR signaling.
- Further research is needed to overcome resistance and expand the use of enzalutamide in various prostate cancer settings and other malignancies.
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