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26-04-2016 | Genitourinary cancers | Book chapter | Article

10. Enzalutamide in Metastatic Castration Resistant Prostate Cancer

Authors: Jeffrey Shevach, Bridget K. Marcellino, William K. Oh, Che-Kai Tsao

Publisher: Springer International Publishing

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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.
Literature
1.
Hoffman RM. Clinical practice. Screening for prostate cancer. New Engl J Med. 2011;365(21):2013–9.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMed
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMedPubMedCentral
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.PubMed
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.PubMed
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMed
18.
U.S. Food and Drug Administration [Internet] [updated 08/31/201207/11/2015].
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.CrossRefPubMedPubMedCentral
20.
Cookson MS, Lowrance WT, Murad MH, Kibel AS. Castration-resistant prostate cancer: AUA guideline amendment. J Urology. 2015;193(2):491–9.CrossRefPubMed
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.CrossRefPubMed
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.
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMedPubMedCentral
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.
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.
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.CrossRefPubMed
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.CrossRefPubMed
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.
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMedPubMedCentral
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.CrossRef
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.CrossRef
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.
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.CrossRefPubMedPubMedCentral
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.
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.
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