Metastatic hormone-resistant prostate cancer has proven largely resistant to cytotoxic therapy. Since 2004, docetaxel (Taxotere)/prednisone has become the standard chemotherapy used to treat advanced hormone-resistant prostate cancer. However, the survival advantage is modest and a significant number of patients do not respond to chemotherapy. It is hoped that an increased understanding of the mechanisms underlying the progression of prostate cancer will lead to new treatment modalities. With the growing number of biologic and targeted agents under development, the potential armamentarium of prostate cancer treatments is steadily growing. However, none of the new treatment modalities has yet been shown to be more effective than standard treatments. This article will provide an overview of targeted or innovative therapies in the treatment of prostate cancer.
In 2004, the US Food and Drug Administration (FDA) approved the use of docetaxel (Taxotere) in advanced prostate cancer based on the publication of two large randomized clinical trials, namely the TAX 327 trial and Southwest Oncology Group (SWOG) 9916 trial. The TAX 327 study involved 1,006 patients, randomized into three equivalent arms comparing mitoxantrone (Novantrone), weekly docetaxel, or 3-weekly docetaxel, each with prednisone. The survival advantage in the 3-weekly docetaxel arm was 2.5 months over the mitoxantrone arm. Similar results were obtained in the SWOG 9916 study. These were the first studies to demonstrate a survival benefit in hormone-resistant disease with the use of docetaxel. The prostate-specific antigen (PSA) response rate was approximately 50% and the median survival was 18 months. An effective second-line chemotherapy regimen has not yet been established. Therefore, new approaches are highly desirable.[3-6]
With the recent discovery of new pathways involved in prostate cancer progression, progress has been made in the understanding of the biology of the disease. Also, a variety of new molecules—for example, tyrosine-kinase inhibitors, antiangiogenic agents, and differentiation therapies—have entered clinical testing. This article will discuss the novel agents in clinical trials for prostate cancer (Table 1).
Prostate Cancer Growth
Normal and neoplastic prostate tissue responds to androgenic stimulation through the androgen receptor. The androgen receptor plays a crucial role in prostate cancer progression. Overexpression of the androgen receptor has been associated with higher Gleason scores and earlier relapse. Significant attempts have been made to determine androgen receptor expression reliably, for use as a biomarker. Recent progress has been made in quantification of the androgen receptors in pathologic specimens.[8,9]
Hormone-Independent Prostate Cancer
The progression of prostate cancer despite androgen ablation has several causes. In fact, in most prostate cancers, the androgen receptor is still functioning and frequently overexpressed in order to counteract the low levels of androgens during androgen-deprivation therapies. However, other mechanisms such as mutation of the androgen receptor or a response to other ligands have been described. Further, there are a number of androgen receptor-interacting proteins, which have been characterized from a biochemical point of view but less from a functional perspective. Some of these cofactors might be overexpressed, and therefore, there is a reduced need for androgenic steroids to activate the androgen receptor.
Apart from the androgen receptor-related progression models, other relevant pathways can promote prostate cancer growth. Growth factors such as HER2, insulin-like growth factor, kerationcyte growth factor, and epidermal growth factor, as well as interleukin (IL)-6, can activate the androgen receptor.[11-13] Other mechanisms are represented by the reduction of HER-kinase inhibitors. In fact, a large percentage of prostate cancer cells have reduced levels of PTEN, which leads to an increased activation of AKT and, further down the signaling cascade, to the activation of mammalian target of rapamycin (mTOR)—another crucial cellular checkpoint for tumor growth and protein synthesis.
There is a fine balance between the various promoters and control mechanisms of cell proliferation and apoptosis. Many of these potential targets are reduced in their function by molecules we are able to synthesize.
The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
1. Tannock IF, de Wit R, Berry WR, et al: Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 351:1502-1512, 2004.
2. Petrylak DP, Tangen CM, Hussain MH, et al: Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 351:1513-1520, 2004.
3. Armstrong AJ, Carducci MA: New drugs in prostate cancer. Curr Opin Urol 16:138-145, 2006.
4. Dawson NA: New molecular targets in advanced prostate cancer. Expert Rev Anticancer Ther 6:993-1002, 2006.
5. Berthold DR, Moore MJ: Novel targets in prostate cancer. Expert Opin Ther Targets 10:777-780, 2006.
6. Sonpavde G, Hutson TE: New approaches in hormone refractory prostate cancer. Am J Clin Oncol 29:196-201, 2006.
7. Scher HI, Sawyers CL: Biology of progressive, castration-resistant prostate cancer: directed therapies targeting the androgen-receptor signaling axis. J Clin Oncol 23:8253-8261, 2005.
8. Donovan MJ, Scher H, Scardino P, et al: Systems pathology for building predictive models: The androgen receptor as a prototype biomarker in prostate cancer progression and targeted therapeutic response assessment (abstract 4504). J Clin Oncol 24(18S):218s, 2006.
9. Gaston KE, Ford IO, Singh S, et al: A novel method for the analysis of the androgen receptor. Curr Urol Rep 3:67-74, 2002.
10. Culig Z, Steiner H, Bartsch G, et al: Mechanisms of endocrine therapy-responsive and -unresponsive prostate tumours. Endocr Relat Cancer 12:229-244, 2005.
11. Krueckl SL, Sikes RA, Edlund NM, et al: Increased insulin-like growth factor I receptor expression and signaling are components of androgen-independent progression in a lineage-derived prostate cancer progression model. Cancer Res 64:8620-8629, 2004.
12. Wen Y, Hu MC, Makino K, et al: HER-2/neu promotes androgen-independent survival and growth of prostate cancer cells through the Akt pathway. Cancer Res 60:6841-6845, 2000.
13. Lee SO, Lou W, Hou M, et al: Interleukin-6 promotes androgen-independent growth in LNCaP human prostate cancer cells. Clin Cancer Res 9:370-376, 2003.
14. Majumder PK, Sellers WR: Akt-regulated pathways in prostate cancer. Oncogene 24:7465-7474, 2005.
15. Canil CM, Moore MJ, Winquist E, et al: Randomized phase II study of two doses of gefitinib in hormone-refractory prostate cancer: A trial of the National Cancer Institute of Canada-Clinical Trials Group. J Clin Oncol 23:455-460, 2005.
16. Ziada A, Barqawi A, Glode LM, et al: The use of trastuzumab in the treatment of hormone refractory prostate cancer; phase II trial. Prostate 60:332-337, 2004.
17. Delongchamps NB, Peyromaure M, Dinh-Xuan AT: Role of vascular endothelial growth factor in prostate cancer. Urology 68:244-248, 2006.
18. Figg WD, Dahut W, Duray P, et al: A randomized phase II trial of thalidomide, an angiogenesis inhibitor, in patients with androgen-independent prostate cancer. Clin Cancer Res 7:1888-1893, 2001.
19. Dahut WL, Gulley JL, Arlen PM, et al: Randomized phase II trial of docetaxel plus thalidomide in androgen-independent prostate cancer. J Clin Oncol 22:2532-2539, 2004.
20. Ning YM, Arlen PM, Gulley J, et al: A phase II trial of docetaxel, thalidomide, bevacizumab, and prednisone in patients (pts) with metastatic androgen-independent prostate cancer (AIPC) (abstract 13037). J Clin Oncol 24:605s, 2006.
21. Dahut WL, Scripture CD, Posadas EM, et al: Bony metastatic disease responses to sorafenib (BAY 43-9006) independent of PSA in patients with metastatic androgen independent prostate cancer (abstract 4506). J Clin Oncol 24:218s, 2006.
22. Small EJ, Schellhammer PF, Higano CS, et al: Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol 24:3089-3094, 2006.
23. Simons JW, Sacks N: Granulocyte-macrophage colony-stimulating factor-transduced allogeneic cancer cellular immunotherapy: The GVAX(R) vaccine for prostate cancer. Urol Oncol 24:419-424, 2006.
24. Beer TM, Ryan CW, Venner PM, et al: Interim results from ASCENT: A double-blinded randomized study of DN-101 (high-dose calcitriol) plus docetaxel vs. placebo plus docetaxel in androgen-independent prostate cancer (AIPC) (abstract 4516). J Clin Oncol 23(16S):382s, 2005.
25. Venner PM, Ryan C, Petrylak DP, et al: Reduced thromboembolic events with DN-101 (high-dose calcitriol) treatment of androgen-independent prostate cancer: Hypothesis for a new class of anticoagulants (abstract 4505). J Clin Oncol 24(18S):218s, 2006.
26. Nelson JB, Hedican SP, George DJ, et al: Identification of endothelin-1 in the pathophysiology of metastatic adenocarcinoma of the prostate. Nat Med 1:944-949, 1995.
27. Zonnenberg BA, Groenewegen G, Janus TJ, et al: Phase I dose-escalation study of the safety and pharmacokinetics of atrasentan: An endothelin receptor antagonist for refractory prostate cancer. Clin Cancer Res 9:2965-2972, 2003.
28. Carducci MA, Padley RJ, Breul J, et al: Effect of endothelin-A receptor blockade with atrasentan on tumor progression in men with hormone-refractory prostate cancer: A randomized, phase II, placebo-controlled trial. J Clin Oncol 21:679-689, 2003.
29. Vogelzang NJ, Nelson JB, Schulman CC, et al: Meta-analysis of clinical trials of atrasentan 10 mg in metastatic hormone-refractory prostate cancer (abstract 4563). J Clin Oncol 23(16S):393s, 2005.
30. Milowsky MI, Nanus DM, Kostakoglu L, et al: Phase I trial of yttrium-90-labeled anti-prostate-specific membrane antigen monoclonal antibody J591 for androgen-independent prostate cancer. J Clin Oncol 22:2522-2531, 2004.
31. Morris MJ, Divgi CR, Pandit-Taskar N, et al: Pilot trial of unlabeled and indium-111-labeled anti-prostate-specific membrane antigen antibody J591 for castrate metastatic prostate cancer. Clin Cancer Res 11:7454-7461, 2005.
32. Miyake H, Hara I, Fujisawa M, et al: The potential of clusterin inhibiting antisense oligodeoxynucleotide therapy for prostate cancer. Expert Opin Investig Drugs 15:507-517, 2006.
33. Chi KN, Eisenhauer E, Fazli L, et al: A phase I pharmacokinetic and pharmacodynamic study of OGX-011, a 2'-methoxyethyl antisense oligonucleotide to clusterin, in patients with localized prostate cancer. J Natl Cancer Inst 97:1287-1296, 2005.
34. Carbone GM, McGuffie EM, Collier A, et al: Selective inhibition of transcription of the Ets2 gene in prostate cancer cells by a triplex-forming oligonucleotide. Nucleic Acids Res 31:833-843, 2003.
35. Goodin S, Kane MP, Rubin EH: Epothilones: Mechanism of action and biologic activity. J Clin Oncol 22:2015-2025, 2004.
36. Lee D: Activity of epothilone B analogues ixabepilone and patupilone in hormone-refractory prostate cancer. Clin Prostate Cancer 3:80-82, 2004.
37. Lin AM, Rosenberg JE, Weinberg VK, et al: Clinical outcome of taxane-resistant (TR) hormone refractory prostate cancer (HRPC) patients (pts) treated with subsequent chemotherapy (ixabepilone (Ix) or mitoxantrone/prednisone (MP) (abstract 4558). J Clin Oncol 24(18S):231s, 2006.
38. O'Reilly T, McSheehy PM, Wenger F, et al: Patupilone (epothilone B, EPO906) inhibits growth and metastasis of experimental prostate tumors in vivo. Prostate 65:231-240, 2005.
39. Rubin EH, Rothermel J, Tesfaye F, et al: Phase I dose-finding study of weekly single-agent patupilone in patients with advanced solid tumors. J Clin Oncol 23:9120-9129, 2005.
40. Hussain A, Dipaola RS, Baron AD, et al: A Phase IIa trial of weekly EPO906 in patients with hormone-refractory prostate cancer (HPRC) (abstract 4563). Proc Am Soc Clin Oncol 23:396, 2004.
41. Sternberg CN: Satraplatin in the treatment of hormone-refractory prostate cancer. BJU Int 96:990-994, 2005.
42. Sternberg CN, Whelan P, Hetherington J, et al: Phase III trial of satraplatin, an oral platinum plus prednisone vs. prednisone alone in patients with hormone-refractory prostate cancer. Oncology 68:2-9, 2005.