Androgen receptor directed therapies in castration-resistant metastatic prostate cancer

Current Treatment Options in Oncology

Volumn 13, Issue 2, 2012, Pages 189-200

  Kim, Won ^a   Ryan, Charles J ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

Abiraterone; Androgen receptor antagonists; ARN 509; CYP17 inhibitors; Galeterone; MDV3100; Metastatic castration resistant prostate cancer; Orteronel

Indexed keywords

4 [3 [4 CYANO 3 (TRIFLUOROMETHYL)PHENYL] 5,5 DIMETHYL 4 OXO 2 THIOXO 1 IMIDAZOLIDINYL] 2 FLUORO N METHYLBENZAMIDE; ABIRATERONE; ABIRATERONE ACETATE; ANDROGEN; ANDROGEN RECEPTOR; ANTIANDROGEN; ARN 509; BICALUTAMIDE; CABAZITAXEL; DOCETAXEL; FLUTAMIDE; GALETERONE; GONADORELIN AGONIST; GONADORELIN ANTAGONIST; KETOCONAZOLE; MITOXANTRONE; NILUTAMIDE; ORTERONEL; PLACEBO; PREDNISONE; PROSTATE SPECIFIC ANTIGEN; SIPULEUCEL T; TESTOSTERONE; UNCLASSIFIED DRUG;

ADVANCED CANCER; ANDROGEN SYNTHESIS; ARTICLE; CANCER COMBINATION CHEMOTHERAPY; CANCER CONTROL; CANCER GROWTH; CANCER PALLIATIVE THERAPY; CANCER PATIENT; CANCER RADIOTHERAPY; CANCER REGRESSION; CANCER SURVIVAL; CASTRATION RESISTANT PROSTATE CANCER; DIARRHEA; DRUG DOSE ESCALATION; DRUG DOSE REDUCTION; DRUG MECHANISM; DRUG MEGADOSE; FATIGUE; HUMAN; HYPERTENSION; HYPOKALEMIA; METASTASIS POTENTIAL; MONOTHERAPY; NONHUMAN; OVERALL SURVIVAL; SEIZURE; SIGNAL TRANSDUCTION; TREATMENT RESPONSE;

ANDROGEN RECEPTOR ANTAGONISTS; ANDROSTENOLS; ANTINEOPLASTIC AGENTS; ANTINEOPLASTIC AGENTS, HORMONAL; DRUG RESISTANCE, NEOPLASM; HUMANS; KETOCONAZOLE; MALE; ORCHIECTOMY; PHENYLTHIOHYDANTOIN; PROSTATIC NEOPLASMS; RECEPTORS, ANDROGEN; STEROID 17-ALPHA-HYDROXYLASE; TAXOIDS; THIOHYDANTOINS;

EID: 84863727226     PISSN: 15272729     EISSN: 15346277     Source Type: Journal    
DOI: 10.1007/s11864-012-0188-2     Document Type: Article

References (41)

1. Huggins C, Hodges CV. Studies on prostatic cancer, effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res. 1941;1: 293-7.
2. Crawford ED, Eisenberger MA, McLoed DG, et al. A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N Engl J Med. 1989;321:419-24.
3. Dijkman GA, Janknegt RA, De Reijke THM, et al. Long-Term efficacy and safety of nilutamide plus castration in advanced stage prostate cancer, and the significance of early prostate specific antigen normalization. J Urol. 1997;158:160-3.
4. Eisenberger MA, Blumenstein BA, Crawford ED, et al. Bilateral orchiectomy with or without flutamide for metastatic prostate cancer. N Engl J Med. 1998;339:1036-42.
5. Edwards J, Krishna NS, Grigor KM, et al. Androgen receptor gene amplification and protein expression in hormone refractory prostate cancer. Br J Cancer. 2003;89:552-6.
6. Holzbeierlein J, Lal P, LaTulippe E, et al. Gene expression analysis of human prostate carcinoma during hormonal therapy identifies androgen-responsive genes and mechanisms of therapy resistance. Am J Pathol. 2004;164:217-27.
7. Stanbrough M, Bubley GJ, Ross K, et al. Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Res. 2006;66:2815-25.
8. Taplin ME, Bubley GJ, Ko YJ, et al. Selection for androgen receptor mutations in prostate cancers treated with androgen antagonist. Cancer Res. 1999;59:2511-5.
9. Sun S, Sprenger CC, Vessella RL, et al. Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant. J Clin Invest. 2010;120:2715-30.
10. Guo Z, Yang X, Sun F, et al. A novel androgen receptor splice variant is up-regulated during prostate cancer progression and promotes androgen depletion-resistant growth. Cancer Res. 2009;69:2305-13.
11. Taylor CD, Elson P, Trump DL. Importance of continued testicular suppression in hormone-refractory prostate cancer. J Clin Oncol. 1993;11:2167-72.
12. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351:1502-12.
13. Kantoff PW, Higano CS, Shore ND, et al: Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 363:411-22
14. de Bono JS, Oudard S, Ozguroglu M, et al: Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: A randomised open-label trial. Lancet. 376:1147-54
15. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364:1995-2005. First phase III trial showing survival advantage in men with mCRPC treated with AR-directed therapy.
16. Cai C, Chen S, Ng P, et al. Intratumoral de novo steroid synthesis activates androgen receptor in castration-resistant prostate cancer and is upregulated by treatmentwith CYP17A1 inhibitors. Cancer Res. 2011;71:6503-13. AR-dependent intratumoral steroid synthesis was shown to be upregulated after treatment with abiraterone in this study, providing a mechanism for the development of resistance to abiraterone (and other CYP17 inhibitors).
17. Pont A, Williams PL, Azhar S, et al. Ketoconazole blocks testosterone synthesis. Arch Intern Med. 1982;142:2137-40.
18. De Coster R, Caers I, Coene MC, et al. Effects of high dose ketoconazole therapy on the main plasma testicular and adrenal steroids in previously untreated prostatic cancer patients. Clin Endocrinol (Oxf). 1986;24:657-64.
19. Haidar S, Ehmer PB, Barassin S, et al. Effects of novel 17alpha-hydroxylase/C17, 20-lyase (P450 17, CYP 17) inhibitors on androgen biosynthesis in vitro and in vivo. J Steroid Biochem Mol Biol. 2003;84:555-62.
20. Small EJ, Baron AD, Fippin L, et al. Ketoconazole retains activity in advanced prostate cancer patients with progression despite flutamide withdrawal. J Urol. 1997;157:1204-7.
21. Small E, Halabi S, Dawson NA, et al. Antiandrogen withdrawal alone or in combination with ketoconazole in androgen-independent prostate cancer patients: A phase III trial (CALGB 9583). J Clin Oncol. 2004;22:1025-33.
22. Barrie SE, Potter GA, Goddard PM, et al. Pharmacology of novel steroidal inhibitors of cytochrome P450(17) alpha (17 alpha-hydroxylase/C17-20 lyase). J Steroid Biochem Mol Biol. 1994;50:267-73.
23. Potter GA, Barrie SE, Jarman M, et al. Novel steroidal inhibitors of human cytochrome P45017 alpha (17 alpha-hydroxylase-C17,20-lyase): Potential agents for the treatment of prostatic cancer. J Med Chem. 1995;38:2463-71.
24. Attard G, Reid AH, Yap TA, et al. Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. J Clin Oncol. 2008;26:4563-71.
25. Ryan CJ, Smith MR, Fong L, et al. Phase I clinical trial of the CYP17 inhibitor abiraterone acetate demonstrating clinical activity in patients with castration-resistant prostate cancer who received prior ketoconazole therapy. J Clin Oncol. 2010;28:1481-8. These early phase studies demonstrated 1) the clinical efficacy of abiraterone, even in patients who had been pretreated with ketoconazole, proof that the greater potency of abiraterone over ketoconazole shown in the preclinical setting has clinical relevance; 2) the necessity of concomitant steroid administration.
26. Attard G, Reid AH, A'Hern R, et al. Selective inhibition of CYP17with abiraterone acetate is highly active in the treatment of castration-resistant prostate cancer. J Clin Oncol. 2009;27:3742-8. References 25,26: These early phase studies demonstrated 1) the clinical efficacy of abiraterone, even in patients who had been pretreated with ketoconazole, proof that the greater potency of abiraterone over ketoconazole shown in the preclinical setting has clinical relevance; 2) the necessity of concomitant steroid administration.
27. Matsunaga N, Kaku T, Itoh F, et al. C17,20-lyase inhibitors I. Structure-based de novo design and SAR study of C17,20-lyase inhibitors. Bioorg Med Chem. 2004;12:2251-73.
28. Dreicer R, Agus DB, MacVicar GR, et al. Safety, pharmacokinetics, and efficacy of TAK-700 in metastatic castration-resistant prostrate cancer: A phase I/II, open-label study. J Clin Oncol. 2010;28:15s. Phase I/II study demonstrating the clinical efficacy of orteronel, including in a group of patients who did not receive prednisone. The rate of adverse events related to secondary mineralocorticoid excess was low, lending support to the hypothesis that orteronel may be administered without steroids. This remains to be seen.
29. Agus DB, Stadler WM, Shevrin D, et al. Safety, efficacy, and pharmacodynamics of the investigational agent TAK-700 in metastatic castration-resistant prostate cancer (mCRPC): Updated data froma phase 1/2 study. Chicago: American Society of ClinicalOncology; 2011. Phase I/II study demonstrating the clinical efficacy of orteronel, including in a group of patients who did not receive prednisone. The rate of adverse events related to secondarymineralocorticoid excesswas low, lending support to the hypothesis that orteronel may be administered without steroids. This remains to be seen.
30. Vasaitis T, Belosay A, Schayowitz A, et al. Androgen receptor inactivation contributes to antitumor efficacy of 17{alpha}-hydroxylase/17,20- lyase inhibitor 3beta-hydroxy-17-(1H-benzimidazole-1-yl)androsta-5,16-diene in prostate cancer. Mol Cancer Ther. 2008;7:2348-57.
31. Fowler JE, Pandey P, Seaver LE, et al. Prostate specific antigen after gonadal androgen withdrawal and deferred flutamide treatment. J Urol. 1995;154:448-53.
32. Small EJ, Srinivas S. The antiandrogen withdrawal syndrome: Experience in a large cohort of unselected patients with advanced prostate cancer. Cancer. 1995;76:1428-34.
33. Chen CD, Welsbie DS, Tran C, et al. Molecular determinants of resistance to antiandrogen therapy. Nat Med. 2004;10:33-9.
34. Tran C, Ouk S, Clegg NJ, et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science. 2009;324:787-90. Characterization of MDV3100, including rationale for its selection for clinical development.
35. ScherHI, Beer TM,HiganoCS, et al. Antitumour activity of MDV3100 in castration-resistant prostate cancer: A phase 1-2 study. Lancet. 2010;375:1437-46. The clinical efficacy of MDV3100 was demonstrated in this early phase study of 140 men with mCRPC. Concern were raised regarding the risk of seizures with MDV3100, as 3 seizure events (2 witnessed and 1 possible) were reported.
36. Scher, HI: Effect of MDV3100 an androgen receptor signaling inhibitor (ARSI), on overal survival in patient with prostate cancer postdocetaxel: Results from the phase III AFFIRMstudy. J ClinOncol. 2012;30(suppl 5, abstr LBA1). After planned interim analysis at 520 deaths, the study was unblinded and patient on placebo were offered treatment with MDV3100 based on the significant im-provement in overall survival in patient treated with MDV3100.
37. Sawyers CL: New Insights into the Prostate Cancer Genome and Therapeutic Implications, State of the Science Report. Presented at the 17th Annual Prostate Cancer Foundation Scientific Retreat, Washington D.C., 2010
38. Hu R, Dunn TA, Wei S, et al. Ligand-independent androgen receptor variants derived from splicing of cryptic exons signify hormone-refractory prostate cancer. Cancer Res. 2009;69:16-22.
39. Taylor BS, Schultz N, Hieronymus H, et al. Integrative genomic profiling of human prostate cancer. Cancer Cell. 2010;18:11-22.
40. Carver BS, Chapinski C, Wongvipat J, et al. Reciprocal Feedback Regulation of PI3K and Androgen Receptor Signaling in PTEN-Deficient Prostate Cancer. Cancer Cell. 2011;19:575-86. This study implicates other signaling pathways (such as PI3K) in resistance to AR-directed therapies, suggesting that the interaction of these pathways with the AR signaling pathway must be an area of ongoing preclinical and clinical research.
41. Darshan MS, Loftus MS, Thadani-Mulero M, et al. Taxane-induced blockade to nuclear accumulation of the androgen receptor predicts clinical responses in metastatic prostate cancer. Cancer Res. 2011;71:6019-29.