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  1. Important Information • This promotional, educational activity is brought to you by Janssen Biotech, Inc., and is not certified for continuing medical education. This is presented on behalf of Janssen Biotech, Inc., and must present information in compliance with FDA requirements applicable to Janssen Biotech, Inc. In accordance with FDA Disease Awareness Communications Guidelines, this program is disease-focused and may not discuss a particular product/drug.

  2. Myth or Fact? Myth: In metastatic hormone-resistant/refractory prostate cancer, tumor growth is no longer sensitive to androgen.Fact: Metastatic castration-resistant prostate cancer remains androgen-sensitive despite castrate levels of testosterone.

  3. Three Sites of Androgen Biosynthesis Dehydroepiandrostenedione Androstenedione Dehydroepiandrostenedione Androstenedione Testosterone Dihydrotestosterone Adrenal Gland Testes Prostate Cancer Cells • Denmeade SR, et al. Nat Rev Cancer. 2002;2:389-396. • Mostaghel E, et al. Best Pract Res Clin Endocrinol Metab. 2008;22:243-258.

  4. mCRPC Remains Dependent on Androgen Production Benign Prostate Primary Prostate Cancer CRPC Metastasis mCRPC tumor and stromal cells demonstrate increased expression of androgen biosynthesis resulting in heightened levels of testosterone and DHT mCRPC=metastatic castration-resistant prostate cancer; DHT=dihydrotestosterone. Stanbrough M, et al. Cancer Res. 2006;66:2815-2825.

  5. Over Time, mCRPC Tumor Cells May Develop the Ability to Proliferate Despite Castrate Levels of Androgen Pienta KJ, et al. Clin Cancer Res. 2006;12:1665-1671.

  6. How Does the Tumor Survive Despite Castrate Levels of Androgen? • Tumors may produce their own androgens to fuel their progression through an intracrine process1 • Levels of androgen in the tumor (tissue) are sufficient to activate androgen receptor signaling2,3 • In the setting of overexpressed AR the tumors may become hypersensitive to low levels of androgens3 • Androgen remains the primary driver of tumor progression—and even a slight amount will result in tumor growth4 • Reducing the production of androgen to the lowest level possible is critical in the management of mCRPC4,5 • Stanbrough M, et al. Cancer Res. 2006;66:2815-2825. • Montgomery RB, et al. Cancer Res. 2008;68:4447-4454. • Chen CD, et al. Nat Med. 2004;10:33-39. • Pienta KJ, et al. Clin Cancer Res. 2006;12:1665-1671. • Chen Y, et al. Lancet Oncol. 2009;10:981-991.

  7. Genetic Alterations in Androgen Receptor (AR) May Fuel Adaptive Processes • Up to 50% of mCRPC tumors harbor AR mutations1 • AR mutations are rare in untreated tumors • Most AR mutations are gain-of-function1 • Increase the AR expression level • Sensitize it to lower concentrations of androgen • Some point mutations may result in “promiscuous” AR activity1,2 • Koochekpour S. Asian J Androl. 2010;12:639-657. • Taplin M. Expert Rev Anticancer Ther. 2008;8:1495-1508.

  8. Reducing the Production of Androgen Is Critical to the Management of mCRPC • In prostate tumors that are sensitive to androgen, small amounts of androgen may help fuel tumor growth1 • Reducing the production of androgen to the lowest level possible is critical in the management of mCRPC2 • Chen CD, et al. Nat Med. 2004;10:33-39. • Chen Y, et al. Lancet Oncol. 2009;10:981-991.

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