Development of a Second-Generation Antiandrogen for Treatment of Advanced Prostate Cancer

TLDR

Metastatic prostate cancer is treated with androgen antagonists, yet most patients progress to castration‑resistant disease driven by elevated androgen receptor expression. The study aims to characterize the diarylthiohydantoin compounds RD162 and MDV3100, nonsteroidal antiandrogens optimized to remain active when androgen receptor levels are high. Both compounds bind the androgen receptor with higher affinity than bicalutamide, inhibit its nuclear translocation, and block DNA binding to androgen response elements and coactivator recruitment. RD162 and MDV3100 are orally available, induce tumor regression in castration‑resistant prostate cancer mouse models, and in a Phase I/II trial 43 % of 30 patients achieved >50 % PSA decline, indicating promise for advanced prostate cancer treatment.

Abstract

Metastatic prostate cancer is treated with drugs that antagonize androgen action, but most patients progress to a more aggressive form of the disease called castration-resistant prostate cancer, driven by elevated expression of the androgen receptor. Here we characterize the diarylthiohydantoins RD162 and MDV3100, two compounds optimized from a screen for nonsteroidal antiandrogens that retain activity in the setting of increased androgen receptor expression. Both compounds bind to the androgen receptor with greater relative affinity than the clinically used antiandrogen bicalutamide, reduce the efficiency of its nuclear translocation, and impair both DNA binding to androgen response elements and recruitment of coactivators. RD162 and MDV3100 are orally available and induce tumor regression in mouse models of castration-resistant human prostate cancer. Of the first 30 patients treated with MDV3100 in a Phase I/II clinical trial, 13 of 30 (43%) showed sustained declines (by >50%) in serum concentrations of prostate-specific antigen, a biomarker of prostate cancer. These compounds thus appear to be promising candidates for treatment of advanced prostate cancer.