Targeting Metastatic Prostate Cancer: The Search for Innovative Systemic Therapies

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[1] and Southwest Oncology Group (SWOG) 9916 trial.[2] 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.[7] 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.[10]

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.[14]

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.

Targeted Therapies

EGFR Inhibitors

The epidermal growth factor receptor (EGFR) family is associated with tumor progression in a number of solid cancers. Inhibition of EGFR has shown benefit in the treatment of colon, lung, and breast cancers. That said, EGFR is not frequently overexpressed in prostate cancer, and single-agent strategies targeting EGFR have been disappointing. Gefitinib (Iressa),[15] erlotinib (Tarceva), and trastuzumab (Herceptin)[16] have shown negative results in terms of PSA response in hormone-refractory disease. Other EGFR inhibitors, such as lapatinib (a dual kinase inhibitor) and pertuzumab (Omnitarg), are still under investigation. If EGFR inhibitors are to prove beneficial in this setting, it will be in combination therapies with other agents or modalities.

Antiangiogenic Therapies

As with any other cancer, prostate cancer progression depends on the formation of new vessels. Vascular endothelial growth factor (VEGF) and its receptor is crucial for the development of new blood vessels. Therapies that target VEGF are thought to be effective in preventing tumor-associated neoangiogenesis as well as normalizing existing tumor vessels. Tumor-associated angiogenesis is known to be chaotic, leading frequently to increased osmotic pressure, thereby preventing or reducing the penetration of drugs into the tissue.[17]

Thalidomide (Thalomid) was prescribed from 1957 to 1961 to pregnant women, as an antiemetic and sedative. Due to the drug's antiangiogenic properties (which were unknown in that period), catastrophic deformities resulted for children of women who had taken thalidomide during their pregnancies. Since the renaissance of thalidomide, this agent has been tested in many solid and hematologic tumors. Single-agent thalidomide has shown some activity in prostate cancer, with expected toxicities including constipation, dizziness, fatigue, and peripheral neuropathy.[18] The combination with docetaxel demonstrated significant antitumor activity in a recent phase II trial,[19] but at the price of increased toxicity, most notably thromboembolic events and neuropathy. Thalidomide has also been studied in combination with docetaxel and the anti-VEGF monoclonal antibody bevacizumab (Avastin), with promising preliminary results.[20] Other agents with similar properties to thalidomide, such as lenalidomide (Revlimid), are currently being investigated.

In addition, bevacizumab has shown relevant activity when combined with docetaxel and estramustine (Emcyt) in a phase II study. PSA responses greater than 50% from baseline have been seen in 65% of patients. Bevacizumab is currently being evaluated in a large phase III trial. The Cancer and Leukemia Group B (CALGB) 90401 study is meant to accrue 1,020 patients, who will be randomized between standard docetaxel vs docetaxel plus bevacizumab.

Another group of antiandrogenic therapies are the multitargeted tyrosine kinase inhibitors. After the impressive results obtained in advanced kidney cancer, sorafenib (Nexavar) and sunitinib (Sutent) have been investigated in phase II trials in prostate cancer. Unfortunately, none of these trials produced positive results. The study of sorafenib, presented at this year's American Society for Clinical Oncology (ASCO) annual meeting,[21] enrolled 22 patients, none of whom had a PSA decline of more than 50%. On closer look, however, two patients presented with impressive bone scan improvements. At ASCO, the discussion arose as to which endpoint might be appropriate for evaluation of these agents. In fact, these agents might be responsible for at least a transitory increase in PSA values. PSA may not be an adequate biomarker for monitoring the clinical activity of multitargeted tyrosine kinase inhibitors.

Vaccines

The search for effective cancer vaccines has a long history. Early observations of spontaneous tumor regression in the 19th century and the development of preventive vaccines for infective agents have encouraged investigators to explore therapeutic vaccines against cancer. Many of the initial trials focused on melanoma or kidney cancer. Prostate cancer vaccines have been studied more recently, and presently there are multiple phase III trials investigating the efficacy of cancer vaccines-more than in any other solid tumor.

Sipuleucel-T (APC8015, Provenge) is a vaccine consisting of dendritic cells collected from the patient's peripheral blood by leukapheresis and then pulsed in the laboratory with the fusion protein PA2024, which consists of a prostate-specific antigen and granulocyte-macrophage colony-stimulating factor (GM-CSF). A total of 120 patients with asymptomatic and metastatic hormone-resistant prostate cancer were randomized to receive sipuleucel-T or placebo in a phase II trial.[22] The primary endpoint of the trial, progression-free survival, was not met. However, subsequent analysis showed a significant survival advantage for men undergoing the active treatment. To rule out the potential bias of a statistical artifact, this trial is currently being repeated at over 90 centers and extended to patients with all Gleason scores and to patients who are asymptomatic or minimally symptomatic. It should be noted that the strategy is rather cost-intensive and complicated, considering the need for a leukapheresis center, as well as a specifically equipped laboratory.

GVAX is another vaccine approach, which explores the possibility of using allogeneic prostate cancer cell lines [23]. These are prostate cancer cells that have been genetically modified to secrete GM-CSF and are then injected subcutaneously into the recipient. This product is currently being investigated in a phase III trial comparing GVAX vs chemotherapy with docetaxel. Another randomized phase III trial is exploring the possibility of combining the vaccine strategy with docetaxel.

A phase II study of vaccine therapy comprising Vaccinia-PSA-TRICOM vaccine and Fowlpox-PSA-TRICOM vaccine combined with GM-CSF in patients with prostate-specific antigen progression after local therapy for early prostate cancer is underway.

Differentiation Agents

Vitamin D is not only a key vitamin for bone metabolism and calcium homeostasis but also plays a crucial role as differentiation agent. Calcitriol, a metabolite of vitamin D, is a potent natural agonist of the vitamin D receptor (VDR). Activation of the VDR is responsible for the promotion of cell differentiation and inhibition of cell proliferation. Calcitriol has shown potent antineoplastic activity via the vitamin D receptor gene transcription. DN-101 is a high-dose (15 mg) formulation of calcitriol.

The DN-101 ASCENT trial (AIPC [androgen-independent prostate cancer] Study of Calcitriol Enhancing Taxotere) was a placebo-controlled, double-blind trial randomizing 250 patients to either weekly docetaxel or weekly docetaxel plus DN-101.[24] The trial's primary endpoint, PSA response (≥ 50% reduction from baseline), was not met. However, on subsequent analysis, it was found that patients in the investigational arm lived longer.

Furthermore, adverse events were recorded during the ASCENT trial, and it was found that thromboembolic events were detected in only 1.6% of patients treated with DN-101, compared to 8.8% in the docetaxel arm.[25] Patients had been stratified by baseline characteristics, so the reduction of thromboembolic complications in the DN-101 arm was not due to an imbalance in these data. Therefore, DN-101 may also have an anticoagulant effect. The hypothesis is that superphysiologic concentrations of calcitriol may reduce the procoagulant effects of docetaxel. Interestingly enough, a low level of vitamin D is a common problem in medical patients, and mouse and cell models underline the importance of the VDR pathway for maintaining coagulation balance. These hypotheses need to be confirmed, and thus, a large randomized phase III trial is underway to further explore the benefits of high-dose vitamin D.

Endothelial Receptor Antagonists

Considering bone as the most frequent and often only site of metastasis of advanced prostate cancer, the idea of targeting the endothelin receptor ET-1 is logical. ET-1 plays a critical role in the pathogenesis of osteoblastic bone metastasis, activating mitogenic changes in osteoblasts. ET‑1 is frequently secreted from metastatic prostate cancer cells.[26]

Atrasentan (Xinlay) is an oral bioavailable potent inhibitor of ET-1. In a phase I toxicity trial, the most common adverse events were rhinitis, headache, and peripheral edema. No maximum tolerated dose was found in the dose range studied.[27] The drug was further evaluated in a double-blind, randomized, placebo-controlled phase II trial. A total of 288 asymptomatic patients with hormone-resistant prostate cancer and evidence of metastatic disease were randomly assigned to 2.5 or 10 mg of atrasentan, or placebo. The primary endpoint was time to progression; median time to progression in intent-to-treat patients (n = 288) was longer in the 10-mg atrasentan group compared with the placebo group (183 vs 137 days, respectively; P =.13). Median time to progression in evaluable patients (n = 244) was significantly prolonged, from 129 days (placebo group) to 196 days (10-mg atrasentan group; P = .021). The clinical evaluation is currently ongoing in large phase III trials.[28,29]

Monoclonal Antibodies

J591 is a prostate-specific membrane antibody that has been labeled with yttrium. Phase I trials have been concluded.[30] In one study, antitumor activity was seen, with two patients experiencing 85% and 70% declines in PSA levels lasting 8 and 8.6 months, respectively. Another phase I trial enrolled patients with progressive metastatic hormone-refractory prostate cancer. Fourteen patients were treated, each receiving 10, 25, 50, or 100 mg of J591, and treatment was well tolerated. The study revealed selective targeting of indium-111-labeled J591 to tumor. One patient showed a > 50% prostate-specific antigen decline. Phase II studies using J591 as a radioconjugate are underway.[31]

Antisense Oligonucleotides

Antisense oligonucleotides are short sequences of nucleic acid that are designed to complement a selected gene's mRNA and thereby specifically inhibit the synthesis of the targeted protein. The antisense approach continues to hold promise as a therapeutic modality to target genes involved in cancer progression, especially those in which the gene products are not amenable to small-molecule inhibition or antibodies. Several approaches are currently being investigated in prostate cancer.

OGX-011 is an antisense oligonucleotide that is complementary to clusterin mRNA and has been reported to inhibit clusterin expression and enhance drug efficacy in xenograft models. Clusterin is a cytoprotective chaperone protein that promotes cell survival and confers broad-spectrum treatment resistance.[32] A phase I trial has found OGX-011 to be safe, and an optimal biologic dose has been established.[33] A randomized phase II trial of docetaxel with or without OGX-011 is underway.

Other targets have been identified. The transcription factor Ets2 has a role in cancer development and represents an attractive therapeutic target. A triplex-forming oligonucleotide has been designed, directed to the homopyrimidine sequence in the Ets2 promoter. This antitranscriptional approach may be useful for examining the effects of selective downregulation of Ets2 expression and may have therapeutic applications.[34]

Novel Cytotoxics

The survival benefit seen with docetaxel has lead to increased interest in the development of novel cytotoxic agents.

Epothilones are a class of cytotoxics with mechanisms of action similar to that of the taxanes, in that they induce microtubulin binding, formation of multipolar spindles, and mitotic arrest; however, their chemical structures differ from the taxanes.[35] Ixabepilone is the most studied compound and is thought to be capable of overcoming the resistance to taxanes.[36] Unfortunately, in a recent randomized phase II trial, ixabepilone was not superior to mitoxantrone in the second-line setting.[37]

Patupilone is a more potent epothilone, stabilizing the microtubule bundle and arresting the cell cycle. The toxicity profile differs from that of the taxanes. Animal models have shown impaired primary tumor growth, abrogated metastases, and enhanced survival.[38] The most common events are gastrointestinal, including diarrhea, nausea, and vomiting.[39] A phase II trial showed a PSA partial response rate of 22% in patients who had received one previous line of chemotherapy.[40] Further studies are planned to explore the potential role of patupilone in the treatment of advanced prostate cancer.

Satraplatin is a new platinum analog with oral bioavailability. Oral drugs will be particularly desirable in the advanced prostate cancer patient population considering their age and frequent inability to travel. Considering the encouraging results of a recent trial comparing satraplatin plus prednisone vs prednisone (10 mg) alone,[41,42] a large randomized phase III trial (SPARC) was conducted. Early results were released very recently, and the combination of satraplatin with prednisone proved superior to prednisone alone in terms of progression-free survival (P < .00001). Patients in the SPARC trial who received satraplatin plus prednisone had a 40% reduction in the risk of disease progression (hazard ratio = 0.6; 95% confidence interval = 0.5-0.7) compared with patients who received prednisone plus placebo.

Conclusions

The development of prostate cancer therapeutics is currently characterized by a long list of unmet endpoints in phase II and phase III trials. At the end of 2006, hormonal therapy followed by docetaxel and prednisone remains the preferred option in the management of advanced prostate cancer. However, a broad range of novel approaches are in advanced stages of development, and we look forward to new options to treat advanced prostate cancer in the near future.

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.

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