The development of bone metastases in prostate cancer is a complex process involving numerous proteins, growth factors, and pathways. The four major players are the cancer cells, osteoblasts, osteoclasts, and mineralized bone matrix (the latter a major source of immobilized growth factors). Skeletal metastases in prostate cancer result in both osteoblastic and osteolytic lesions. Factors released by cancer cells stimulate the osteoblast to grow, differentiate, and secrete growth factors into the bony microenvironment. The enriched microenvironment in turn supports the tumor cells. On the other hand, metastatic cancer cells in the bone activate osteoclasts, leading to bone resorption. The ensuing breakdown of the bone leads to release of a variety of growth factors that stimulate osteoblastic activity; these include endothelin, insulin-like growth factor, and platelet-derived growth factor (PDGF). The end result is osteoblast-mediated bone mineralization, which overcomes the osteoclast-mediated bone resorption, resulting in the formation of osteoblastic metastases. These lesions are composed of loosely packed collagen(Drug information on collagen) bundles, and in conjunction with the osteolytic activity, account for many of the skeletal complications seen in prostate cancer, including pain and fracture.
The endothelin pathway affects cancer progression through multiple different mechanisms, including inhibition of apoptosis and promotion of angiogenesis. As discussed above, the endothelin pathway appears to be highly involved in the development of bone metastasis, making it an attractive target in metastatic prostate cancer.
Atrasentan (Xinlay). This was the first endothelin-A receptor antagonist to be tested in prostate cancer. Two phase III studies (one in metastatic CRPC and the other in non-metastatic CRPC) showed no significant difference in the time to progression (the primary endpoint in both studies), but statistically significant differences in PSA and bony alkaline phosphatase values were observed that favored atrasentan over placebo.[54,55] Preclinical work has suggested enhanced antitumor effects when atrasentan is combined with docetaxel. A phase III Southwest Oncology Group (SWOG) Intergroup study is comparing docetaxel and prednisone(Drug information on prednisone) with atrasentan to docetaxel(Drug information on docetaxel) and prednisone without atrasentan in metastatic CRPC. This trial has completed accrual and the results are expected soon.
Zibotentan. This is another endothelin-A receptor antagonist being evaluated in advanced prostate cancer. In a phase II trial, asymptomatic or mildly symptomatic patients with metastatic CRPC were randomly assigned to receive one of two doses of zibotentan or placebo. The results showed no difference in time to disease progression (the primary endpoint), but overall survival was 24.5 months with the 10-mg dose of zibotentan compared with 17.3 months in the placebo group. A phase III trial evaluating this agent in patients with metastatic CRPC recently showed no improvement over placebo in overall survival. Additional phase III studies are underway evaluating the efficacy of zibotentan in patients with CRPC without evidence of metastases (ENTHUSE M0) and in combination with docetaxel in patients with bone metastases (ENTHUSE M1c).[60,61]
Osteoclast (RANKL) inhibitor
The interaction between receptor activator of nuclear factor kappa B (RANK) and its associated ligand (RANKL) lead to osteoclast differentiation, activation, and survival. Denosumab is a monoclonal antibody against RANKL. Early studies using this agent in patients with skeletal metastases showed improvement in markers of bony turnover (urinary N-telopeptide), as well as a reduction in SREs, including pathologic fracture and spinal cord compression.
Results from a phase III study comparing denosumab and zoledronic acid(Drug information on zoledronic acid) for the prevention or delaying of SREs (defined as a pathologic fracture, radiation or surgery to bone, or spinal cord compression) in patients with CRPC and bone metastasis showed non-inferiority with denosumab, which significantly increased the time to the first on-study SRE (HR, 0.82 [95% CI, 0.71-0.95]; P = .008), with a median time of 20.7 months, compared with 17.1 months with zoledronic acid. Overall survival and time to disease progression were similar in the two groups. There was a non-significant increase in the incidence of osteonecrosis of the jaw with denosumab (2.3% vs 1.3%) as well as more frequent hypocalcemia (12.8% vs 5.8%).
Currently, denosumab is FDA-approved for preventing SREs in patients with bone metastases from a variety of malignancies, including prostate cancer. Although it provides another treatment option, the observed effects represent a modest clinical advantage, considering that it is no better than zoledronic acid with regard to progression-free survival or overall survival. The landscape of effective therapeutics is changing, and radiation therapy, if needed, can now be achieved with as little as one fraction. The cost-effectiveness of denosumab is also a consideration when contemplating its use.
Angiogenesis is mediated by a variety of factors, including vascular endothelial growth factor (VEGF). VEGF, which is produced by both tumor cells and tumor-associated stroma in response to hypoxic conditions, binds to the VEGF receptor, leading to downstream signaling that results in new blood vessel formation.
Agents targeting the VEGF pathway
Several agents targeting the VEGF pathway have been developed and are currently being investigated in clinical trials. Bevacizumab (Avastin) is a recombinant humanized monoclonal antibody that targets VEGF. Promising data from phase II trials[67-69] led to a phase III study conducted by Cancer and Leukemia Group B (CALGB). This recently reported trial compared docetaxel and prednisone plus bevacizumab to docetaxel and prednisone plus placebo in men with CRPC. The results showed no improvement in overall survival (the primary endpoint) as well as a significant increase in serious adverse events and treatment-related deaths with bevacizumab.
Sunitinib (Sutent) is a tyrosine kinase inhibitor that inhibits angiogenesis by targeting the VEGF and PDGF pathways. Phase II studies in CRPC have shown only modest activity for sunitinib when used as upfront therapy with docetaxel or as salvage therapy following docetaxel, and a recent phase III trial failed to demonstrate an advantage to the combination over docetaxel alone.[71,72]
The lack of a survival benefit with these two agents could be a function of the lack of efficacy of the specific agent in this disease or a reflection of the relative importance of VEGF targeting at this late stage of the disease. However, early data from other trials provide support for the potential value of targeting angiogenesis. Tasquinimod is a novel angiogenesis inhibitor that acts independently of VEGF inhibition, although its mechanism of action is unknown. A randomized phase II study comparing tasquinimod to placebo in patients with metastatic CRPC showed an improvement in progression-free survival with tasquinimod (24.7 weeks vs 12.9 weeks). A phase III study evaluating the effect of tasquinimod is planned.
Aflibercept (VEGF-trap) is a circulating VEGF antagonist that prevents VEGF receptor binding. Phase I studies showed activity of this agent in a variety of solid tumors. An ongoing phase III study of patients with metastatic CRPC is comparing docetaxel, prednisone, and aflibercept to docetaxel, prednisone, and placebo.
Cabozantinib (XL184) is an oral inhibitor of MET and VEGF receptor 2 (VEGFR2) that has demonstrated antitumor and antiangiogenic effects in preclinical models. MET and VEGFR2 synergize to induce angiogenesis. Expression of MET and/or its ligand (hepatocyte growth factor [HGF]) increases with prostate cancer progression and metastasis.[78,79] Preclinical studies indicate that MET expression increases with androgen deprivation.[79,80] Upregulation of MET and the emergence of an invasive phenotype have been associated with the ability of tumors to evade antiangiogenic therapy.[81,82] A phase II trial evaluated cabozantinib in patients with a variety of cancers, including a cohort of patients with progressive CRPC who had or had not received prior docetaxel. Preliminary data reported at the recent American Society of Clinical Oncology (ASCO) genitourinary symposium indicated that cabozantinib has unique antitumor activity, as reflected by resolution of bone scans (complete or partial) in 85% of patients, reduction in bone pain, and reduction in narcotic use. The overall disease control rate at 12 weeks (partial response plus stable disease) was 74%.
Other Targeted Therapies
Src/Src family kinase inhibitor
In addition to affecting prostate cancer proliferation and metastasis, Src and Src family kinases are involved in bone turnover through their induction of osteoclast activity and inhibition of osteoblast activity. Dasatinib (Sprycel) is a tyrosine kinase inhibitor with activity against PDGF that has also been shown to inhibit Src and the Src family kinases. In a phase II study, patients with metastatic CRPC treated with dasatinib showed evidence of disease stability and decreased markers of bone turnover. A phase III study evaluating overall survival using dasatinib in combination with docetaxel in CRPC is underway.
Anti-apoptosis (clusterin) inhibitor
Clusterin is stress-induced protein that in part functions as an anti-apoptotic protein. It is upregulated in a variety of cancer cells, including prostate cancer, and leads to resistance to radiation therapy, chemotherapy, and hormonal therapy. Custirsen is an antisense inhibitor of clusterin. A recent phase II study randomly assigned patients with metastatic CRPC to treatment with either docetaxel and prednisone plus custirsen or docetaxel and prednisone without custirsen. Although the primary endpoint of a PSA decline of more than 50% in 60% of patients was not achieved, patients who received custirsen had improvements in both progression-free survival (7.3 months [95% CI, 5.3-8.8] vs 6.1 months [95% CI, 3.7-8.6]) and overall survival (23.8 months [95% CI, 16.2-not reached] vs 16.9 months [95% CI, 12.8-25.8]). Two phase III studies evaluating the benefit of custirsen added to docetaxel retreatment as second-line therapy in CRPC and in combination with docetaxel and prednisone as first-line therapy in CRPC are ongoing.[88,89]
Prostate cancer is a heterogeneous disease marked by a complex molecular profile. The identification and elucidation of numerous signaling pathways involved in disease progression and treatment resistance has paved the way for the development of new therapeutic agents, some of which are now available for clinical use. With the advent of these new drugs comes the opportunity for more personalization of therapy, thus enhancing the benefit-to-risk ratio and cost-effectiveness of treatment. Now that it has been demonstrated that survival can be improved with a diverse group of agents, further advances will rely on ongoing improvements in the understanding of prostate cancer biology, along with prompt, rigorous testing of promising agents in well-designed and well-conducted trials.
Financial Disclosure: Dr. Ruch has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article. Dr. Hussain serves as a consultant to Bristol-Myers Squibb, Merck, and Lilly/Imclone (in areas unrelated to the subject matter of this paper), and she has received an honorarium from Ferring Pharmaceuticals (also for work in areas unrelated to the subject matter of this paper).