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Enzalutamide in Metastatic Castration Resistant Prostate Cancer

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Managing Metastatic Prostate Cancer In Your Urological Oncology Practice

Abstract

Historically metastatic castration resistant prostate cancer (mCRPC), a lethal disease phenotype with disease progression despite androgen deprivation, was thought to be truly “hormonal refractory.” However, recent approval of novel of androgen receptor signaling inhibitors based on definitive survival benefit provides proof of the principle that prostate cancer growth and progression remains critically dependent on this pathway. One such therapy is enzalutamide. Formerly known as MDV3100, enzalutamide was selected for development specifically because of its ability to induce tumor death in castration resistant prostate cancer in preclinical models. After demonstrating favorable clinical efficacy and safety profiles in two large randomized phase III studies, enzalutamide is now approved for treatment of patients with mCRPC, either in docetaxel-naïve or -resistant disease. Despite its effectiveness, resistance ultimately develops for most, and several resistance mechanisms involving the androgen-signaling pathway have been identified. Moreover, the optimal use of enzalutamide therapy is yet undefined. Continued investigation of enzalutamide resistance pathways will be key in the development of novel treatments in this lethal disease.

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References

  1. Hoffman RM. Clinical practice. Screening for prostate cancer. New Engl J Med. 2011;365(21):2013–9.

    Article  CAS  PubMed  Google Scholar 

  2. Siegel R, DeSantis C, Virgo K, Stein K, Mariotto A, Smith T, et al. Cancer treatment and survivorship statistics, 2012. CA Cancer J Clin. 2012;62(4):220–41.

    Article  PubMed  Google Scholar 

  3. Huggins C, Hodges CV. Studies on prostatic cancer: I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. 1941. J Urol. 2002;168(1):9–12.

    Article  PubMed  Google Scholar 

  4. Loblaw DA, Virgo KS, Nam R, Somerfield MR, Ben-Josef E, Mendelson DS, et al. Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2006 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol. 2007;25(12):1596–605.

    Article  CAS  PubMed  Google Scholar 

  5. Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. New Engl J Med. 2013;368(2):138–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Qian SB, Shen HB, Cao QF, Zhang L, Chen YF, Qi J. Bicalutamide 150 mg as secondary hormonal therapy for castration-resistant prostate cancer. Int Urol Nephrol. 2015;47(3):479–84.

    Article  CAS  PubMed  Google Scholar 

  7. Keizman D, Huang P, Carducci MA, Eisenberger MA. Contemporary experience with ketoconazole in patients with metastatic castration-resistant prostate cancer: clinical factors associated with PSA response and disease progression. Prostate. 2012;72(4):461–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Tan MH, Li J, Xu HE, Melcher K, Yong EL. Androgen receptor: structure, role in prostate cancer and drug discovery. Acta Pharmacol Sin. 2015;36(1):3–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Linja MJ, Savinainen KJ, Saramaki OR, Tammela TL, Vessella RL, Visakorpi T. Amplification and overexpression of androgen receptor gene in hormone-refractory prostate cancer. Cancer Res. 2001;61(9):3550–5.

    CAS  PubMed  Google Scholar 

  10. Gregory CW, He B, Johnson RT, Ford OH, Mohler JL, French FS, et al. A mechanism for androgen receptor-mediated prostate cancer recurrence after androgen deprivation therapy. Cancer Res. 2001;61(11):4315–9.

    CAS  PubMed  Google Scholar 

  11. Zhang Y, Linn D, Liu Z, Melamed J, Tavora F, Young CY, et al. EBP1, an ErbB3-binding protein, is decreased in prostate cancer and implicated in hormone resistance. Mol Cancer Ther. 2008;7(10):3176–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Montgomery RB, Mostaghel EA, Vessella R, Hess DL, Kalhorn TF, Higano CS, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008;68(11):4447–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Sun S, Sprenger CC, Vessella RL, Haugk K, Soriano K, Mostaghel EA, et al. Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant. J Clin Investig. 2010;120(8):2715–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Knudsen KE, Penning TM. Partners in crime: deregulation of AR activity and androgen synthesis in prostate cancer. Trends Endocrinol Metabolism: TEM. 2010;21(5):315–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Tran C, Ouk S, Clegg NJ, Chen Y, Watson PA, Arora V, et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science. 2009;324(5928):787–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Scher HI, Beer TM, Higano CS, Anand A, Taplin ME, Efstathiou E, et al. Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study. Lancet. 2010;375(9724):1437–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. New Engl J Med. 2012;367(13):1187–97.

    Article  CAS  PubMed  Google Scholar 

  18. U.S. Food and Drug Administration [Internet] [updated 08/31/201207/11/2015].

    Google Scholar 

  19. Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, Higano CS, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. New Engl J Med. 2014;371(5):424–33.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Cookson MS, Lowrance WT, Murad MH, Kibel AS. Castration-resistant prostate cancer: AUA guideline amendment. J Urology. 2015;193(2):491–9.

    Article  PubMed  Google Scholar 

  21. Shore ND, Chowdhury S, Villers A, Klotz L, Siemens DR, Phung D, et al. Efficacy and safety of enzalutamide versus bicalutamide for patients with metastatic prostate cancer (TERRAIN): a randomised, double-blind, phase 2 study. Lancet Oncol. 2016;17(2):153–63.

    Article  CAS  PubMed  Google Scholar 

  22. Penson DF, Armstrong AJ, Concepcion R, Agarwal N, Olsson C, Karsh L, et al. Enzalutamide Versus Bicalutamide in Castration-Resistant Prostate Cancer: The STRIVE Trial. J Clin Oncol: J Am Soc Clin Oncol. 2016.

    Google Scholar 

  23. Arora VK, Schenkein E, Murali R, Subudhi SK, Wongvipat J, Balbas MD, et al. Glucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade. Cell. 2013;155(6):1309–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Claessens F, Helsen C, Prekovic S, Van den Broeck T, Spans L, Van Poppel H, et al. Emerging mechanisms of enzalutamide resistance in prostate cancer. Nat Rev Urol. 2014;11(12):712–6.

    Article  CAS  PubMed  Google Scholar 

  25. Joseph JD, Lu N, Qian J, Sensintaffar J, Shao G, Brigham D, et al. A clinically relevant androgen receptor mutation confers resistance to second-generation antiandrogens enzalutamide and ARN-509. Cancer Discov. 2013;3(9):1020–9.

    Article  CAS  PubMed  Google Scholar 

  26. Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, Roeser JC, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. New Engl J Med. 2014;371(11):1028–38.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Sweeney C, Chen Y-H, Carducci MA, Liu G, Jarrard DF, Eisenberger MA, et al. Impact on overall survival (OS) with chemohormonal therapy versus hormonal therapy for hormone-sensitive newly metastatic prostate cancer (mPrCa): an ECOG-led phase III randomized trial. ASCO Meeting Abstracts. 2014;32(15_suppl):LBA2.

    Google Scholar 

  28. James ND, Sydes MR, Mason MD, Clarke NW, Dearnaley DP, Spears MR, et al. Docetaxel and/or zoledronic acid for hormone-naive prostate cancer: First overall survival results from STAMPEDE (NCT00268476). ASCO Meeting Abstracts. 2015;33(15_suppl):5001.

    Google Scholar 

  29. Schrader AJ, Boegemann M, Ohlmann CH, Schnoeller TJ, Krabbe LM, Hajili T, et al. Enzalutamide in castration-resistant prostate cancer patients progressing after docetaxel and abiraterone. Eur Urol. 2014;65(1):30–6.

    Article  CAS  PubMed  Google Scholar 

  30. Badrising S, van der Noort V, van Oort IM, van den Berg HP, Los M, Hamberg P, et al. Clinical activity and tolerability of enzalutamide (MDV3100) in patients with metastatic, castration-resistant prostate cancer who progress after docetaxel and abiraterone treatment. Cancer. 2014;120(7):968–75.

    Article  CAS  PubMed  Google Scholar 

  31. Bianchini D, Lorente D, Rodriguez-Vida A, Omlin A, Pezaro C, Ferraldeschi R et al. Antitumour activity of enzalutamide (MDV3100) in patients with metastatic castration-resistant prostate cancer (CRPC) pre-treated with docetaxel and abiraterone. European journal of cancer (Oxford, England: 1990). 2014;50(1):78–84.

    Google Scholar 

  32. Schmid SC, Geith A, Boker A, Tauber R, Seitz AK, Kuczyk M, et al. Enzalutamide after docetaxel and abiraterone therapy in metastatic castration-resistant prostate cancer. Adv Ther. 2014;31(2):234–41.

    Article  CAS  PubMed  Google Scholar 

  33. Brasso K, Thomsen FB, Schrader AJ, Schmid SC, Lorente D, Retz M, et al. Enzalutamide antitumour activity against metastatic castration-resistant prostate cancer previously treated with docetaxel and abiraterone: a multicentre analysis. Eur Urol. 2015;68(2):317–24.

    Article  CAS  PubMed  Google Scholar 

  34. Azad AA, Eigl BJ, Murray RN, Kollmannsberger C, Chi KN. Efficacy of enzalutamide following abiraterone acetate in chemotherapy-naive metastatic castration-resistant prostate cancer patients. Eur Urol. 2015;67(1):23–9.

    Article  CAS  PubMed  Google Scholar 

  35. Suzman DL, Luber B, Schweizer MT, Nadal R, Antonarakis ES. Clinical activity of enzalutamide versus docetaxel in men with castration-resistant prostate cancer progressing after abiraterone. Prostate. 2014;74(13):1278–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Noonan KL, North S, Bitting RL, Armstrong AJ, Ellard SL, Chi KN. Clinical activity of abiraterone acetate in patients with metastatic castration-resistant prostate cancer progressing after enzalutamide. Ann Oncol: Off J Eur Soc Med Oncol/ESMO. 2013;24(7):1802–7.

    Article  CAS  Google Scholar 

  37. Loriot Y, Bianchini D, Ileana E, Sandhu S, Patrikidou A, Pezaro C, et al. Antitumour activity of abiraterone acetate against metastatic castration-resistant prostate cancer progressing after docetaxel and enzalutamide (MDV3100). Ann Oncol: Off J Eur Soc Med Oncol/ESMO. 2013;24(7):1807–12.

    Article  CAS  Google Scholar 

  38. Zhang T, Dhawan MS, Healy P, George DJ, Oldan J, Chin B, et al. Clinical benefit of docetaxel or enzalutamide after progression on first-line abiraterone acetate and prednisone in men with metastatic castration resistant prostate cancer (mCRPC). ASCO Meeting Abstracts. 2014;32(15_suppl):e16031.

    Google Scholar 

  39. Myung JK, Banuelos CA, Fernandez JG, Mawji NR, Wang J, Tien AH, et al. An androgen receptor N-terminal domain antagonist for treating prostate cancer. J Clin Investig. 2013;123(7):2948–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Montgomery RB, Antonarakis ES, Hussain M, Fizazi K, Joshua AM, Attard G et al. A phase 1/2 open-label study of safety and antitumor activity of EPI-506, a novel AR N-terminal domain inhibitor, in men with metastatic castration-resistant prostate cancer (mCRPC) with progression after enzalutamide or abiraterone. ASCO Meeting Abstracts. 2015;33(15_suppl):TPS5072.

    Google Scholar 

  41. Li J, Gregory SG, Garcia-Blanco MA, Armstrong AJ. Using circulating tumor cells to inform on prostate cancer biology and clinical utility. Crit Rev Clin Lab Sci. 2015:1–20.

    Google Scholar 

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Correspondence to William K. Oh .

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Shevach, J., Marcellino, B.K., Oh, W.K., Tsao, CK. (2016). Enzalutamide in Metastatic Castration Resistant Prostate Cancer. In: Balaji, K. (eds) Managing Metastatic Prostate Cancer In Your Urological Oncology Practice. Springer, Cham. https://doi.org/10.1007/978-3-319-31341-2_10

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  • DOI: https://doi.org/10.1007/978-3-319-31341-2_10

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