Sifting Through the Multitude of Novel Therapies for Prostate Cancer

December 1, 2006

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.

Prostate cancer is the third most common cause of death from cancer in males, associated with an estimated 27,350 deaths and 234,460 new cases in 2006. In 2004, two landmark trials—TAX 327 and Southwest Onology Group (SWOG) 9916[1,2]—led to the US Food and Drug Administration (FDA) approval of docetaxel (Taxotere) and prednisone as first-line therapy for patients with metastatic, progressive prostate cancer. However, treatment continues to be palliative, and survival benefits are modest. Therefore, there is great interest in novel therapies for this disease. Our ever more detailed understanding of pathways involved in the development and progression of cancer has resulted in the identification of a number of new targets for drug development. Fortunately, several different classes of drugs are in simultaneous development, a result of varied approaches to different parts of the tumor-progression cascade.

Berthold and Moore[3] provide an excellent overview of the major classes of agents currently being evaluated in clinical trials, including inhibitors of the epidermal growth factor receptor, antiangiogenic therapies (bevacizumab [Avastin] and others), vaccines, agents promoting cell differentiation and inhibiting cell proliferation (DN-101, or high-dose calcitriol), endothelin-receptor antagonists (atrasentan [Xinlay]), monoclonal antibodies, antisense oligonucleotides, and novel cytotoxic agents such as epothilones and satraplatin. The most promising phase III trials are evaluating docetaxel plus prednisone in combination with atrasentan, bevacizumab, DN-101, and a variety of vaccine strategies, to address the important question of whether these therapies will result in improved survival or time to progression compared with the current standard of care.

Areas of Investigation

The primary and most significant site of metastases in prostate cancer is bone. Therefore, agents targeting both primary prostate cancer and its bone metastases would be optimal. Endothelins and their receptors are expressed in endothelial cells and are overexpressed in prostate cancer cells and in bone metastases.[4,5] Receptor activation leads to tumor proliferation, migration, angiogenesis, and osteogenesis.[6-9] As Berthold and Moore note, trials of the endothelin inhibitor atrasentan have shown promise, although we are still waiting for the results of the phase III trial of atrasentan in combination with docetaxel and prednisone.

Agents inhibiting angiogenesis and the angiogenic cascade are also under active investigation. Thalidomide (Thalomid) has shown significant activity in combination with docetaxel in a phase II trial,[10] and the combination of thalidomide, bevacizumab, and docetaxel also appears promising.[11] The monoclonal antibody bevacizumab targets and inactivates vascular endothelial growth factor (VEGF)-A. The Cancer and Leukemia Group B (CALGB) 90006 trial evaluated bevacizumab together with estramustine (Emcyt) and docetaxel in 79 patients with androgen-independent prostate cancer (AIPC). In this trial, 53 of those with measurable disease experienced a partial response, with 65% of 20 evalauble patients showing a > 50% decline in prostate-specific antigen (PSA) levels.[12] CALGB 90401 is a randomized, phase III trial evaluating bevacizumab with docetaxel and prednisone vs docetaxel/prednisone in patients with AIPC. Overall survival is the primary endpoint in this trial.[13]

The fact that VEGF and its receptor have also been found to be expressed in prostate cancer cells[14] provides an additional rationale for using these agents in prostate cancer. In this regard, receptor tyrosine kinase (RTK) inhibitors such as sorafenib (Nexavar), sunitinib (Sutent), and AZD2171—all in phase II development—could prove to be especially efficacious. Other kinase inhibitors, including those with activity against MEK and Src/Abl, are also in development for the treatment of solid tumors. Our concern with some of these agents is the discord between PSA change and tumor burden.

Multiple Targets

Novel combination therapies aimed at inhibiting multiple targets in a single pathway or separate signaling pathways, with or without docetaxel and/or prednisone, are also worth investigating. Considering that downstream signaling of RTKs acts through the Ras/MEK/ERK pathway, a combination consisting of docetaxel, an RTK, and a MEK inhibitor may be reasonable. In addition, the endothelin receptor is downstream of the Ras/MEK/ERK cascade, and a MEK inhibitor has been found to be active against the endothelin receptor.[15]

Histone deacetylase inhibitors (HDACi) inhibit proliferation and induce apoptosis in a variety of cell types. In addition, these compounds have antiangiogenic properties.[16] A combination of inhibitors of histone deacetylase and RTKs with and without docetaxel and/or prednisone may be active in this setting. The HDACi suberoylanilide hydroxamic acid (SAHA) has been shown to be active in preclinical studies of prostate cancer.[17] In a murine xenograft model of prostate cancer, the combination of inhibitors against peroxisome proliferator-activated receptor gamma (PPARgamma) and valproic acid (an HDACi) were active.[18]

Immunotherapy

Another active area of research involves immunotherapies for prostate cancer. GVAX is a GM-CSF-transduced tumor cell vaccine for patients with AIPC. The GM-CSF serves to recruit dendritic cells to the vaccine site. Two phase II trials in patients with metastatic AIPC enrolled 96 and 80 patients. In the larger trial, one patient had a complete response with PSA normalization and lesion regression on bone scan. Among the hormone-refractory patients with metastatic bone disease at baseline, investigators observed a trend toward longer median time to disease progression as measured by bone scan in patients who received the higher dose of vaccine compared to comparable patients who received a lower dose (140 vs 85 days, P = .095).[19] Phase III trials are currently underway.[20]

Sipuleucel-T (APC8015 [Provenge]) consists of autologous peripheral blood mononuclear cells cultured with a recombinant fusion protein composed of prostatic acid phosphatase and GM-CSF. A phase II study enrolled 22 patients receiving bevacizumab and sipuleucel-T until disease progression (defined as doubling of baseline or nadir PSA) or toxicity. Median pretreatment PSA doubling time was 6.7 vs 12.7 months on treatment, resulting in an approximately 90% increase in doubling time (P = .004). No patient had objective disease progression, and four patients stopped therapy secondary to toxicity.[21] A randomized, phase III trial enrolled 127 patients with asymptomatic AIPC. Although the primary endpoint—time to progression—was not met, intent-to-treat analysis revealed an overall survival of 25.9 vs 21.4 months in the sipuleucel-T vs placebo groups (hazard ratio [HR] = 1.771, log rank P = .010), with 36-month survival rates of 33% vs 11% favoring sipuleucel-T.[22] Further studies are ongoing.

The PSA-TRICOM vaccine strategy utilizes poxviruses as delivery vehicles for tumor-associated antigens in combination with a triad of costimulatory molecules.[23] A phase I trial is investigating intraprostatic administration,[24] while a phase II trial is evaluating the safety and immune response to sequential vaccinations in patients with metastatic AIPC.[25]

Other Agents

Satraplatin is an oral platinum analog with significant activity in platinum-resistant tumor models. Phase II and III studies[26] evaluating satraplatin with or without prednisone have shown promise. A two-arm trial being conducted through the European Organisation for Research and Treatment of Cancer (EORTC), known as SPARC (Satraplatin and Prednisone Against Refractory Cancer), is comparing satraplatin and prednisone vs placebo and prednisone. The trial has enrolled 950 patients with AIPC. Preliminary results show a highly significant (P < .00001) increase in progression-free survival in the satraplatin arm, with a 40% reduction in the risk of progression (HR = 0.6, 95% confidence interval = 0.5-0.7).[27]

Epothilones inhibit microtubulin and are a new class of agents active in taxane-resistant animal models.[28] Ixabepilone (BMS-247550), a novel synthetic epothilone B analog, has shown promise in combination with estramustine[29] and in first-line single-agent treatment.[30]

Immunomodulatory drugs are a novel class of structural and functional analogs of thalidomide designed to have more potent immunomodulatory and anticancer properties while possessing a superior safety profile compared to the parent compound.[31] CC-5013 (lenalidomide [Revlimid]), a nonteratogenic 4-amino-glutaramide analog of thalidomide, is an immunomodulatory drug that has shown excellent activity in myelodysplastic syndromes and multiple myeloma,[32,33] and is being evalutated in prostate cancer.[34,35]

In summary, a wide variety of novel therapies are in development for patients who have progressed after docetaxel therapy. The comparison of these drugs with docetaxel in the clinical trial setting is ongoing. The timely review by Berhtold and Moore is an important update on the status of these much needed new agents.

—Christoph M. Ahlers, MD
—William D. Figg, PHARMD

Disclosures:

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.

References:

1. 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.

2. 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.

3. Berthold DR, Moore MJ: Novel targets in metastatic prostate cancer: The search for innovative systemic therapies. Oncology (Williston Park) 20:000-000, 2006.

4. Guise TA, Yin JJ, Mohammad KS: Role of endothelin-1 in osteoblastic bone metastases. Cancer 97(3 suppl):779-784, 2003.

5. 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.

6. Godara G, Cannon GW, Cannon GM Jr, et al: Role of endothelin axis in progression to aggressive phenotype of prostate adenocarcinoma. Prostate 65:27-34, 2005.

7. Nelson JB, Chan-Tack K, Hedican SP,
et al: Endothelin-1 production and decreased endothelin B receptor expression in advanced prostate cancer. Cancer Res 56:663-668, 1996.

8. Nelson JB, Nguyen SH, Wu-Wong JR, et al: New bone formation in an osteoblastic tumor model is increased by endothelin-1 overexpression and decreased by endothelin A receptor blockade. Urology 53:1063-1069, 1999.

9. Nelson JB, Udan MS, Guruli G, et al: Endothelin-1 inhibits apoptosis in prostate cancer. Neoplasia 7:631-637, 2005.

10. 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.

11. Ning YM, Arlen PM, Gulley JL, 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(18S), 2006.

12. Picus J, Halabi S, Rini B, et al: The use of bevacizumab (B) with docetaxel (D) and estramustine (E) in hormone refractory prostate cancer (HRPC): Initial results of CALGB 90006 (abstract 1578). Proc Am Soc Clin Oncol 22:393, 2003.

13. Clinical trial details for study CALBG 90401. Greenebaum Cancer Center, Baltimore, Md, 2005.

14. Pallares J, Rojo F, Iriarte J, et al: Study of microvessel density and the expression of the angiogenic factors VEGF, bFGF and the receptors Flt-1 and FLK-1 in benign, premalignant and malignant prostate tissues. Histol Histopathol 21:857-865, 2006.

15. Henriksson M, Stenman E, Vikman P,
et al: MEK1/2 inhibition attenuates vascular ET(A) and ET (B) receptor alterations after cerebral ischaemia. Exp Brain Res November 8, 2006 (Epub ahead of print).

16. Qian DZ, Kato Y, Shabbeer S, et al: Targeting tumor angiogenesis with histone deacetylase inhibitors: The hydroxamic acid derivative LBH589. Clin Cancer Res 12:634-642, 2006.

17. Kulp SK, Chen CS, Wang DS, et al: Antitumor effects of a novel phenylbutyrate-based histone deacetylase inhibitor, (S)-HDAC-42, in prostate cancer. Clin Cancer Res 12:5199-5206, 2006.

18. Annicotte JS, Iankova I, Miard S, et al: Peroxisome proliferator-activated receptor gamma regulates E-cadherin expression and inhibits growth and invasion of prostate cancer. Mol Cell Biol 26:7561-7574, 2006.

19. Simons JW, Small EJ, Nelson W, et al: Phase II trials of GM-CSF gene-transduced prostate cancer cell line vaccine (GVAX) demonstrate anti-tumor activity (abstract 1073). Proc Am Soc Clin Oncol 20:269a, 2001.

20. Simons JW, Sacks N: Granulocyte-macrophage colony-stimulating factor-transduced allogeneic cancer cellular immunotherapy: The GVAX vaccine for prostate cancer. Urol Oncol 24:419-424, 2006.

21. Rini BI, Weinberg V, Fong L, et al: Combination immunotherapy with prostatic acid phosphatase pulsed antigen-presenting cells (provenge) plus bevacizumab in patients with serologic progression of prostate cancer after definitive local therapy. Cancer 107:67-74, 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. Garnett CT, Greiner JW, Tsang KY, et al: TRICOM vector based cancer vaccines. Curr Pharm Des 12:351-361, 2006.

24. Protocol 05-C-0017: A phase I feasibility study of an intraprostatic PSA-based vaccine in men with prostate cancer and local failure following radiotherapy or cryotherapy or clinical progression on androgen deprivation therapy in the absence of local definitive therapy, 2004. Available at http://clinicalstudies.info.nih.gov/detail/A_2005-C-0017.html. Accessed November 29, 2006.

25. A Phase I/II Pilot Study of Sequential Vaccinations with rFowlpox-PSA (L155)-TRICOM (prostvac-F/TRICOM) Alone, or in Combination with rVaccinia-PSA (L155)-TRICOM (PROSTVAC-V/TRICOM), and the Role of GM-CSF, in Patients with Prostate Cancer, 2004. Available at http://clinicalstudies.info.nih.gov/cgi/wais/bold032001.pl?B_03-C-0176.html@prostvac-F. Accessed December 4, 2006.

26. 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(1):2-9, 2005.

27. Spectrum Pharmaceuticals: Spectrum Pharmaceuticals announces positive results of satraplatin pivotal phase 3 trial in patients with hormone-refractory prostate cancer (press release). September 24, 2006. Available at http://phx.corporate-ir.net/phoenix.zhtml?c =83249&p=irolnewsArticle&ID=908453
&highlight. Accessed November 30, 2006.

28. Goodin S, Kane MP, Rubin EH: Epothilones: Mechanism of action and biologic activity. J Clin Oncol 22:2015-2025, 2004.

29. Galsky MD, Small EJ, Oh WK, et al: Multi-institutional randomized phase II trial of the epothilone B analog ixabepilone (BMS-247550) with or without estramustine phosphate in patients with progressive castrate metastatic prostate cancer. J Clin Oncol 23:1439-1446, 2005.

30. Hussain M, Tangen CM, Lara PN Jr, et al: Ixabepilone (epothilone B analogue BMS-247550) is active in chemotherapy-naive patients with hormone-refractory prostate cancer: A Southwest Oncology Group trial S0111. J Clin Oncol 23:8724-8729, 2005.

31. Bartlett JB, Dredge K, Dalgleish AG: The evolution of thalidomide and its IMiD derivatives as anticancer agents. Nat Rev Cancer 4:314-322, 2004.

32. Kale V, List AF: Immunomodulatory drugs (IMiDs): A new treatment option for myelodysplastic syndromes. Curr Pharm Biotechnol 7:339-342, 2006.

33. Maier SK, Hammond JM: Role of lenalidomide in the treatment of multiple myeloma and myelodysplastic syndrome. Ann Pharmacother 40:286-829, 2006.

34. Figg WD, Kruger EA, Price DK, et al: Inhibition of angiogenesis: Treatment options for patients with metastatic prostate cancer. Invest New Drugs 20:183-194, 2002.

35. Tohnya TM, Ng SS, Dahut WL, et al:
A phase I study of oral CC-5013 (lenalidomide, Revlimid), a thalidomide derivative, in patients with refractory metastatic cancer. Clin Prostate Cancer 2:241-243, 2004.