Tuesday, September 24, 2013

How Does AR Antagonist ARN-509 Work

Mechanism of Action Series: ARN 509

ARN-509 is an androgen receptor signaling inhibitor currently in phase 2 clinical trial for castration-resistant prostate cancer (CRPC).  How does ARN-509 work to block prostate cancer cells is described below.

Prostate cancer cells during the early phase are often androgen-dependent, ie, they require the male hormone testosterone for growth. Testosterone (a fat-soluble hormone) diffuses across the cell membrane. Once inside, it is converted to dihydrotestosterone (DHT) by an enzyme called 5α-reductase which is present in prostate, testes, hair follicles, and adrenal glands. 

DHT binds the androgen receptor (AR) which then translocates into the nucleus and binds specific sites on the DNA called androgen-response elements (AREs) activating the gene transcription of these ARE-containing genes. Many of these ARE-containing genes are involved in cancer cell growth. 

Androgen receptors can also be activated by other signaling pathways, including JAK/Stat, Ras/Raf/Mek/Erk and PI3K/Akt. Thus, a wide variety of cytokines and growth factors can also feed into the AR signaling pathway. In other words, these cancer cells can easily learn to bypass traditional androgen deprivation therapies.  Therefore, the key is to target AR itself. And that's where new drugs, such as ARN-509 and MDV-3100 come in.

(Image: Pelekanou et al, Hormones 2013, LINK) 

ARN-509 is a competitive inhibitor of AR (ie, an AR antagonist or a blocker.) It has a very strong binding affinity for AR compared to DHT. The binding of ARN-509 to AR also prevents AR localization into the nucleus as well as binding of AR to the androgen-response elements in DNA.

ARN-509, at least in the preclinical models, appears to be more effective or has better desirable properties than the other drug in its class, enzalutamide (Trade name: XTANDI; Medivation, San Francisco, Calif.). The maximum tolerated dose of ARN-509 is 100 mg/kg/day compared to 30 mg/kg/day for enuzalutamide. 

(Image from Clegg et al. Cancer Res. 2012, LINK)

Unlike enzalutamide, ARN-509 is less effective in crossing blood-brain barrier and thus, may avoid seizures, an off-target effect seen with enzalutamide due to its presumed inhibitory effects on γ-aminobutyric acid type A.

Currently ARN-509 is in Phase I/II trials in patients with metastatic or nonmetastatic castration-resistant prostate cancer (CRPC). The Phase I data was released at ASCO last year [link]. In the Phase I dose-finding study, PSA marker declined in 14 of 29 patients (48.3%) during the 12 week study period.

Future development of ARN-509

Three months ago, J&J agreed to pay $1 billion to Aragon Pharmaceuticals to acquire rights to this drug for prostate cancer. The deal does not include Selective ER inhibitors for use in breast cancer which are now being developed by the newly launched Seragon Pharmaceuticals. J&J already has a very successful prostate cancer drug Zytiga in the market, and is looking forward to trials combining both ARN-509 and Zytiga for better response. 


  • Pelekanou, et al. Androgen receptors in early and castration resistant prostate cancer: friend or foe? Hormones. 2013;12(2):224-235 [Full Text
  • Ryan CJ, Tindall DJ. Androgen Receptor Rediscovered: The New Biology and Targeting the Androgen Receptor Therapeutically. J Clin Oncol. 2011;29(27):3651-3658 [Full Text
  • Schweizer, MT, Antonarakis, ES. Abiraterone and Other Novel Androgen-Directed Strategies for the Treatment of Prostate Cancer. A New Era of Hormonal Therapies Is Born. Ther Adv Urol. 2012;4(4):167-178. [Full Text]
    ABOUT ARN-509
    • Clegg NJ, et al. ARN-509: a novel antiandrogen for prostate cancer treatment. Cancer Res. 2012;72(6):1494-503. [Full Text]
    • Rathkopf DE, et al. A Phase I Study of the Androgen Signaling Inhibitor ARN-509 in Patients with Metastatic Castration-Resistant Prostate Cancer (mCRPC). J Clin Oncol, Vol. 30 (suppl; abstr 4548) (2012) [Abstract]
    • Rathkopf DE, et al. A phase II study of the androgen signaling inhibitor ARN-509 in patients with castration-resistant prostate cancer (CRPC). J Clin Oncol 30, 2012 (suppl; abstr TPS4697) [Abstract]

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