Enzalutamide as a second generation antiandrogen for treatment of advanced prostate cancer

Abstract

Prostate cancer (PCa) is the most common malignancy, and the third leading cancer-related cause of death among men of the Western world. Upon PCa progression into metastatic disease, androgen deprivation therapy is applied as the first-line treatment, and has been shown to be effective in most patients, leading to a decrease in serum prostate-specific antigen and relief of disease-related symptoms. However, advanced PCa almost inevitably progresses to a castration-resistant state, and is currently regarded as incurable. The large body of evidence indicates that PCa cells remain dependent on androgen receptor (AR) signaling even in an androgen-deprived environment. As such, development of drugs that target AR and AR signaling pathways have become one of the major milestones in treatment of castration-resistant PCa (CRPC). Nevertheless, currently available therapies that target AR signaling are still regarded as palliative and more potent therapies are in great need. Over the past few years, a wide range of novel therapies has entered clinical trial for treatment of CRPC, including androgen synthesis inhibitors (abiraterone acetate), chemotherapeutic agents (docetaxel and cabazitaxel), and immunotherapies (sipuleucel-T). In this context, enzalutamide (previously referred to as MDV3100) is a novel second generation antiandrogen that has been demonstrated to significantly improve survival in men with metastatic CRPC in several clinical trials. In this paper we summarize recently completed and ongoing clinical trials of enzalutamide, and briefly discuss the efficacy of the novel antiandrogen therapy and its limitations for treatment of CRPC.

Keywords: castration resistant prostate cancer; clinical trials; drug resistance.

Figure 1

Molecular structure of enzalutamide.

Figure 2

Kaplan–Meier estimates of primary and secondary outcome measures in Phase I–II clinical trial of enzalutamide (ClinicalTrials.gov identifier: NCT00510718). (A) PSA progression defined as ≥25% increase in PSA from baseline. (B) PSA progression defined by Prostate Cancer Working Group criteria as ≥25% increase from nadir. (C) Progression-free survival defined by radiological imaging in chemotherapy-naïve and chemotherapy-treated patients. Reprinted from Scher HI, Beer TM, Higano CS, et al, Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1–2 study. Lancet. 375:1437–1446. Copyright 2010, with permission from Elsevier. Abbreviation: PSA, prostate-specific antigen.

Figure 3

Kaplan–Meier estimates of primary and secondary outcome measures in Phase III clinical trial of enzalutamide (ClinicalTrials.gov identifier: NCT00974311). (A) Overall survival. (B) Progression-free survival defined by prostate-specific antigen progression. (C) Progression-free survival defined by radiological imaging. From N Engl J Med, Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. 367;1187–1197. Copyright © 2012 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. Abbreviations: CI, confidence interval; PSA, prostate-specific antigen.