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 trialsTAX 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 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, and the combination of thalidomide, bevacizumab, and docetaxel also appears promising. 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. 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.
The fact that VEGF and its receptor have also been found to be expressed in prostate cancer cells 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 AZD2171all in phase II developmentcould 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.
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.
Histone deacetylase inhibitors (HDACi) inhibit proliferation and induce apoptosis in a variety of cell types. In addition, these compounds have antiangiogenic properties. 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. 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.
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). Phase III trials are currently underway.
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. A randomized, phase III trial enrolled 127 patients with asymptomatic AIPC. Although the primary endpointtime to progressionwas 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. 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. A phase I trial is investigating intraprostatic administration, while a phase II trial is evaluating the safety and immune response to sequential vaccinations in patients with metastatic AIPC.
Satraplatin is an oral platinum analog with significant activity in platinum-resistant tumor models. Phase II and III studies 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).
Epothilones inhibit microtubulin and are a new class of agents active in taxane-resistant animal models. Ixabepilone (BMS-247550), a novel synthetic epothilone B analog, has shown promise in combination with estramustine and in first-line single-agent treatment.
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. 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
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.
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