Apalutamide (ARN-509)

ARN-509 (< 10 μM) inhibits androgen-mediated induction or repression of mRNA expression levels for 13 endogenous genes including PSA and TMPRSS2 in the LNCaP/AR prostate cancer cell line. ARN-509 (< 10 μM) inhibits the proliferative effect of R1881 (30 pM) in the LNCaP/AR prostate cancer cell line. ARN-509 (10 μM) impairs AR nuclear localization and thus reduces the concentration of AR available to bind androgen response elements (ARE) in LNCaP cells expressing AR-EYFP. ARN-509 (10 μM) is able to effectively compete with R1881 (1 nM) and prevent AR from binding to promoter regions. ARN-509 inhibits R1881-induced VP16-AR–mediated transcription with IC50 of 0.2 μM in Hep-G2 cells expressing a VP16-AR fusion protein and an ARE-driven luciferase reporter. ^[1]

ARN-509 (10 mg/kg/d, oral) inhibits tumor growth with decreased proliferative index and increased apoptotic rate in castrate male immunodeficient mice harboring LNCaP/AR-luc xenograft tumors. ARN-509 dose dependently inhibits tumor growth with highest efficacy at dose of 30 mg/kg/day in castrate male immunodeficient mice harboring LNCaP/AR-luc xenograft tumors. ARN-509 dosed at 10 mg/kg/d for 28 days results in a 3-fold reduction in prostates weight associated with lacking glandular secretory activity and 1.7-fold reduction in epididymis weight in adult male dogs. ARN-509 (10 mg/kg/d, oral) inhibits cell proliferation of prostate tissues in adult male dogs. ^[1] ARN-509 is safe and well tolerated in 24 patients with metastatic CRPC who has progressed on prior treatments and peak plasma concentrations occurred 2 to 3 hours after administration. ARN-509 results in durable PSA declines at doses ranging from 30 to 300 mg in patients with metastatic CRPC. ^[2] ARN-509 shows powerful anti-cancer activity and induces durable remissions long after therapy completion in castrate resistant prostate cancer mouse models. ^[3]

• Cell lines

  LNCaP/AR prostate cancer cell line

• Concentrations

  10 μM

• Incubation Time

  48 hours

• Method

  Cells are incubated for 48 hours, after which ARN-509 is added in a 16 μL volume to the RPMI culture medium. For the antagonist mode assay, the ARN-509 is diluted in culture medium also containing 30 pM R1881. After 7 days' incubation, 16 μL of CellTiter-Glo Luminescent Cell Viability Assay is added and Relative Luminescence Units (RLUs) measured.

• Animal Models

  Castrate male immunodeficient mice harboring LNCaP/AR-luc xenograft tumors

• Dosages

  30 mg/kg/day

• Administration

  Orally