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Enzalutamide for the treatment of metastatic castration-resistant prostate cancer.

Rodriguez-Vida A, Galazi M, Rudman S, Chowdhury S, Sternberg CN - Drug Des Devel Ther (2015)

Bottom Line: The incorporation of these agents has revolutionized the treatment of CRPC but has also raised the question of what is the ideal sequence of administering them.Enzalutamide is a nonsteroidal second-generation antiandrogen that has been approved for the treatment of metastatic CRPC both in the post-docetaxel and chemotherapy-naïve settings.This article reviews the pharmacological characteristics of enzalutamide, the efficacy studies which led to its approval, its safety profile, and quality of life-related parameters as well as its place in the sequential treatment and management of metastatic prostate cancer.

View Article: PubMed Central - PubMed

Affiliation: Medical Oncology Department, Guy's and St Thomas' NHS Foundation Trust, London, UK.

ABSTRACT
In recent years, several nonhormonal and hormonal agents, including enzalutamide, have been approved for the treatment of metastatic castration-resistant prostate cancer (CRPC) on the basis of improved overall survival in prospective clinical trials. The incorporation of these agents has revolutionized the treatment of CRPC but has also raised the question of what is the ideal sequence of administering them. Enzalutamide is a nonsteroidal second-generation antiandrogen that has been approved for the treatment of metastatic CRPC both in the post-docetaxel and chemotherapy-naïve settings. This article reviews the pharmacological characteristics of enzalutamide, the efficacy studies which led to its approval, its safety profile, and quality of life-related parameters as well as its place in the sequential treatment and management of metastatic prostate cancer.

No MeSH data available.


Related in: MedlinePlus

Mechanism of action of enzalutamide in the androgen receptor signaling pathway.Abbreviations: AR, androgen receptor; T, testosterone; C, coactivators.
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f1-dddt-9-3325: Mechanism of action of enzalutamide in the androgen receptor signaling pathway.Abbreviations: AR, androgen receptor; T, testosterone; C, coactivators.

Mentions: Enzalutamide (formerly MDV3100) is a nonsteroidal second-generation antiandrogen that acts on different steps in the AR signaling pathway. It competitively inhibits androgen binding to AR, but unlike first-generation antiandrogen, it also inhibits nuclear translocation of the AR, DNA binding, and coactivator recruitment (Figure 1). Enzalutamide was first identified in a drug development study that was looking for nonsteroidal antiandrogens that retain activity in the setting of increased AR expression as a model of castration resistance.12 A library of 200 thiohydantoin derivatives was evaluated, and enzalutamide was selected in view of its favorable drug properties,12 its inhibitory effect on CRPC cell models, its high AR-binding affinity, and its lack of agonistic activity.13 A competition assay was used to compare the relative AR-binding affinity of bicalutamide and enzalutamide in a model of hormone-sensitive cells overexpressing AR (LNCaP/AR human prostate cancer cells), where bicalutamide has an antagonist effect. Importantly, enzalutamide bound to AR with five- to eightfold greater affinity than bicalutamide.13 In order to assess the potential agonistic activity, the authors compared the effects of enzalutamide vs bicalutamide on androgen-dependent gene expression in LNCaP/AR cells. Expression of the AR target genes prostate-specific antigen (PSA) and transmembrane protease serine 2 (TMPRSS2) was induced by bicalutamide but not by enzalutamide indicating that the latter does not have agonistic activity in a castration-resistant setting.13


Enzalutamide for the treatment of metastatic castration-resistant prostate cancer.

Rodriguez-Vida A, Galazi M, Rudman S, Chowdhury S, Sternberg CN - Drug Des Devel Ther (2015)

Mechanism of action of enzalutamide in the androgen receptor signaling pathway.Abbreviations: AR, androgen receptor; T, testosterone; C, coactivators.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492664&req=5

f1-dddt-9-3325: Mechanism of action of enzalutamide in the androgen receptor signaling pathway.Abbreviations: AR, androgen receptor; T, testosterone; C, coactivators.
Mentions: Enzalutamide (formerly MDV3100) is a nonsteroidal second-generation antiandrogen that acts on different steps in the AR signaling pathway. It competitively inhibits androgen binding to AR, but unlike first-generation antiandrogen, it also inhibits nuclear translocation of the AR, DNA binding, and coactivator recruitment (Figure 1). Enzalutamide was first identified in a drug development study that was looking for nonsteroidal antiandrogens that retain activity in the setting of increased AR expression as a model of castration resistance.12 A library of 200 thiohydantoin derivatives was evaluated, and enzalutamide was selected in view of its favorable drug properties,12 its inhibitory effect on CRPC cell models, its high AR-binding affinity, and its lack of agonistic activity.13 A competition assay was used to compare the relative AR-binding affinity of bicalutamide and enzalutamide in a model of hormone-sensitive cells overexpressing AR (LNCaP/AR human prostate cancer cells), where bicalutamide has an antagonist effect. Importantly, enzalutamide bound to AR with five- to eightfold greater affinity than bicalutamide.13 In order to assess the potential agonistic activity, the authors compared the effects of enzalutamide vs bicalutamide on androgen-dependent gene expression in LNCaP/AR cells. Expression of the AR target genes prostate-specific antigen (PSA) and transmembrane protease serine 2 (TMPRSS2) was induced by bicalutamide but not by enzalutamide indicating that the latter does not have agonistic activity in a castration-resistant setting.13

Bottom Line: The incorporation of these agents has revolutionized the treatment of CRPC but has also raised the question of what is the ideal sequence of administering them.Enzalutamide is a nonsteroidal second-generation antiandrogen that has been approved for the treatment of metastatic CRPC both in the post-docetaxel and chemotherapy-naïve settings.This article reviews the pharmacological characteristics of enzalutamide, the efficacy studies which led to its approval, its safety profile, and quality of life-related parameters as well as its place in the sequential treatment and management of metastatic prostate cancer.

View Article: PubMed Central - PubMed

Affiliation: Medical Oncology Department, Guy's and St Thomas' NHS Foundation Trust, London, UK.

ABSTRACT
In recent years, several nonhormonal and hormonal agents, including enzalutamide, have been approved for the treatment of metastatic castration-resistant prostate cancer (CRPC) on the basis of improved overall survival in prospective clinical trials. The incorporation of these agents has revolutionized the treatment of CRPC but has also raised the question of what is the ideal sequence of administering them. Enzalutamide is a nonsteroidal second-generation antiandrogen that has been approved for the treatment of metastatic CRPC both in the post-docetaxel and chemotherapy-naïve settings. This article reviews the pharmacological characteristics of enzalutamide, the efficacy studies which led to its approval, its safety profile, and quality of life-related parameters as well as its place in the sequential treatment and management of metastatic prostate cancer.

No MeSH data available.


Related in: MedlinePlus