Evolving Therapeutic Paradigms for Advanced Prostate Cancer

Improving survival in metastatic castration-resistant prostate cancer (CRPC) is no longer an elusive goal. With the expansion of knowledge regarding the biology of the disease, we are witnessing a plethora of novel therapeutics that are undergoing testing in clinical trials. Since the approval of docetaxel for metastatic CRPC in 2004, three additional agents have demonstrated improvements in overall survival in randomized phase III trials: two agents (cabazitaxel and sipuleucel-T) were approved by the FDA in 2010, and a third (abiraterone) was approved in April of 2011. A threshold has clearly been crossed in the management of advanced prostate cancer; however, the impact on survival has been relatively modest, and efforts at personalized therapy have lagged behind those for other solid tumors. Further meaningful advances are needed, and the foundation for future clinical trials must be high-quality, high-impact translational science that focuses on disease biology, the defining of relevant pathways and validated predictive biomarkers, and adequate preclinical characterization of agents and combinations that will facilitate more personalized therapy.

Introduction

Prior to 2004, major treatment options for advanced prostate cancer were limited to hormonal therapy for hormone-sensitive disease, mitoxantrone (Novantrone) and strontium-89 (Metastron) for pain palliation, and zoledronic acid (Zometa) to minimize skeletal-related events (SREs) in castration-resistant prostate cancer (CRPC).[1-4] The landmark studies demonstrating a survival improvement for patients treated with docetaxel (Taxotere) not only dramatically influenced the management of CRPC but also energized more research in this setting, leading to more FDA-approved agents available for use (Table 1).[5,6]

TABLE 1

FDA-Approved Non-Hormonal Agents for Castration-Resistant Prostate Cancer

Just in 2010, three agents were approved by the FDA: cabazitaxel (Jevtana) and sipuleucel-T (Provenge) for the treatment of metastatic CRPC based on improvements in overall survival, and denosumab (XGEVA) for the supportive management of bone disease.[7-9] In April 2011, the FDA approved abiraterone (Zytiga) for the treatment of metastatic CRPC post docetaxel. These agents work by quite distinct mechanisms; they thus reflect the complex nature of CRPC and the potential therapeutic opportunities. The expansion in the understanding of the biology of CRPC has led to a plethora of agents that are currently under clinical investigation in a variety of advanced disease settings (Tables 2 and 3). This review will discuss recently FDA-approved agents for advanced prostate cancer and those under investigation in phase III trials.

Microtubule Inhibitors

Based on cumulative scientific clinical data, particularly data on docetaxel, the microtubule is considered a validated therapeutic target in metastatic CRPC. Microtubules have numerous cellular functions, including preservation of cellular shape, intracellular transport, and formation of the mitotic spindle for movement of sister chromatids during mitosis.[10] The most widely tested microtubule inhibitors are the taxanes and the epothilones, both of which suppress microtubule activity, leading to mitotic arrest and apoptosis. The epothilones (eg, ixabepilone, patupilone) have been studied in phase II trials in patients with metastatic CRPC with variable efficacy.[11-14] The nanoparticle albumin-bound (nab) formulations of docetaxel and paclitaxel are being evaluated in CRPC.[15,16]

Cabazitaxel

Cabazitaxel is the microtubule inhibitor most recently approved by the FDA. The preclinical activity of cabazitaxel in tumor models resistant to docetaxel and paclitaxel led to clinical studies demonstrating antitumor activity in metastatic CRPC refractory to docetaxel.[10,17] This paved the way for an international, multicenter, phase III study that randomly assigned 755 men with metastatic CRPC with disease progression after docetaxel to receive prednisone plus either mitoxantrone or cabazitaxel.[18] While all patients were previously treated with docetaxel, 16% in the cabazitaxel group and 13% in the mitoxantrone group had received two or more docetaxel-containing regimens. The median time from the last docetaxel dose to disease progression was 0.8 months in the cabazitaxel group and 0.7 months in those receiving mitxantrone. Patients treated with cabazitaxel had a median overall survival of 15.1 months (95% confidence interval [CI], 14.1-16.3), compared with 12.7 months (95% CI, 11.6-13.7) in the mitoxantrone-treated patients, with a hazard ratio (HR) for death of 0.7 (95% CI, 0.59-0.83, P < .0001) for men receiving cabazitaxel. The cabazitaxel-treated patients had a median progression-free survival of 2.8 months (95% CI, 2.4-3.0) compared with 1.4 months (95% CI, 1.4-1.7) in those receiving mitoxantrone (HR, 0.74; 95% CI, 0.64-0.86; P < .0001). In patients with measurable disease, 14.4% (95% CI, 9.6-19.3) of cabazitaxel-treated patients had an objective response, compared with only 4.4% (95% CI, 1.6-7.2%) in the mitoxantrone group (P < .0005). Nearly all patients experienced some degree of myelosuppression, but more patients treated with cabazitaxel experienced grade 3 or higher neutropenia (82% vs 58%) and neutropenic fever (8% vs 1%). Grade 3 or higher anemia and diarrhea were also seen more often in patients treated with cabazitaxel (11% vs 5%, and 6% vs < 1%, respectively). In addition, more deaths occurred within 30 days of receiving the last dose of drug in cabazitaxel-treated patients (18 deaths [5%], including 7 from neutropenia and its consequences and 5 from cardiac causes) than in the mitoxantrone group (9 deaths [2%], 6 of which were due to disease progression).

Cabazitaxel was approved by the FDA in 2010 for salvage therapy after disease progression following docetaxel-based therapy.[8] However, the toxicities associated with this treatment, notably myelosuppression, warrant particular caution. Careful monitoring of blood counts is needed, and growth factor support is recommended for patients, including the elderly, who are at high risk for complications from myelosuppression. In addition, the increase in cardiac deaths seen with cabazitaxel compared with mitoxantrone warrants careful administration and monitoring in patients with underlying cardiac disease.

Immunomodulatory Agents

The immune system is heavily involved in the development and progression of cancer. Over the past several years, several strategies have been developed exploiting this concept in a multitude of malignancies, including prostate cancer.

Sipuleucel-T

Sipuleucel-T is an active cellular immunotherapy agent composed of autologous antigen-presenting cells (APCs) that have been cultured with the fusion protein PA2024, which consists of prostatic acid phosphatase and granulocyte–macrophage colony-stimulating factor, and which is designed to stimulate an immune response against prostate cancer cells.[19]

The initial phase III study using sipuleucel-T in prostate cancer, published in 2006, randomly assigned 127 patients with asymptomatic metastatic CRPC to treatment with sipuleucel-T or to a control group (in which patients received APCs cultured in the absence of PA2024). The difference in median time to disease progression (the primary endpoint) between the two groups was not statistically significant (11.7 weeks in the sipuleucel-T group vs 10.0 weeks in the control group). However, the median overall survival, a secondary endpoint, was 25.9 months in the sipuleucel-T group compared with 21.4 months in the control group (HR, 1.71 [95% CI, 1.13-2.58];P = .01). Another small phase III study of patients with asymptomatic metastatic CRPC showed a non-statistically significant trend towards increased overall survival (a secondary endpoint) with sipuleucel-T (19.7 months vs 15 months), but with no significant difference in the time to disease progression, the primary endpoint of the study.[20] A third phase III trial, with overall survival as the primary endpoint, randomly assigned patients with asymptomatic or minimally symptomatic metastatic CRPC in a 2:1 ratio to treatment with sipuleucel-T or to a control arm (in which patients received APCs cultured in the absence of PA2024).[21] Patients randomly assigned to the control arm who developed progressive disease were unblinded and offered treatment with sipuleucel-T manufactured using the patient’s cryopreserved APCs. Of the 171 patients in the control arm, a total of 109 (63.7%) received sipuleucel-T as salvage therapy, with 84 of these (49.1%) receiving it as initial therapy following disease progression. Most patients in both cohorts received additional therapy beyond sipuleucel-T. In the experimental arm, 81.8% received additional treatment and 57.2% received docetaxel after a median of 12.3 months, whereas 73.1% in the control arm received additional therapy, 50.3% of whom received docetaxel after a median 13.9 months. The results showed that sipuleucel-T–treated patients had a four-month improvement in overall survival (25.8 months vs 21.7 months; HR, 0.78 [95% CI, 0.61-0.98]; P = .03). As in the other two studies, no antitumor effect was seen, as reflected by the lack of difference in time to disease progression, symptom improvement, decrease in PSA level, or other measure of disease response.

The most common adverse reaction seen with sipuleucel-T was an infusion reaction, occurring within 24 hours in 71.2% of patients (3.5% had grade 3 reactions) and manifested by chills, fever, fatigue, nausea, tachycardia, and hypertension.[19-21] Other common side effects included headache, back pain, and joint pain. Overall, grade 3 or 4 adverse events occurred in 23.6% and 4% of patients, respectively, with the most common being back pain and chills.[7] In one trial, cerebrovascular events occurred in 7.5% of patients treated with sipuleucel-T (11 of 147) vs 2.6% of patients in the control group (2 of 76).[21]

A common concern regarding sipuleucel-T has been the lack of any demonstrable antitumor effect in any of the randomized trials as compared with results in the control groups-and therefore, the inability to assess response at the individual patient level.[22,23] It remains to be proven whether conventional response measures are appropriate with this class of agents or not. If not, then until adequate efficacy assessment measures are established, we strongly recommend that future phase III testing of such agents include an active control arm proven to be of benefit so as to allow confidence in the trial results with regard to comparable or superior outcome. This is especially important considering the per-patient cost of treatment with sipuleucel-T and the fact that it does not obviate the need for chemotherapy.[23] Proponents of this agent argue that the cost is comparable to that of other biologic agents approved by the FDA and that the price may be offset by the more favorable side-effect profile of sipuleucel-T (compared to chemotherapy).[24] However, since this agent was tested in a different patient population than that included in the docetaxel trials (which allowed accrual of patients with pain and visceral disease), and since none of the trials compared sipuleucel-T to an active control with established clinical benefit, the fact remains that thousands of patients will receive a full course of therapy without the certainty of knowing who may be benefiting.

TABLE 2

Selected Pathways, Targets, and Agents Being Evaluated in Clinical Trials in Advanced Prostate Cancer[91]

Ipilimumab

Under normal conditions, activation of cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) leads to inhibition of T-cell activation.[25] Ipilimumab (Yervoy) is a human monoclonal antibody against CTLA-4. Early work on prostate cancer has shown that this agent potentiates a sustained T-cell immune response and leads to clinical benefit.[26] Recent reports demonstrate activity in advanced prostate cancer when ipilimumab is combined with androgen ablation; 55% of patients in one study achieved undetectable PSA levels after 3 months of combined therapy compared with 38% of patients treated with androgen ablation alone.[27,28] Side effects included diarrhea (4.5%); colitis (4.5%); and cutaneous changes, such as localized vitiligo, etc (27.7%). A phase III study evaluating the effect of ipilimumab on overall survival in patients with metastatic CRPC is ongoing.[29]

Agents Targeting the Androgen Pathway

Androgen signaling is a critical and validated therapeutic target in both hormone-sensitive prostate cancer and CRPC. While the utility of androgen-deprivation therapy (ADT) is well-established in androgen-sensitive disease, targeting the androgen pathway remains important in CRPC, based on evidence that these cells continue to rely on androgen synthesis and receptor signaling.[30-34]

TABLE 3

Selected Ongoing or Recently Accrued Phase III Trials in CRPC[91]

GnRH antagonists in hormone-sensitive prostate cancer

ADT has long been the standard of care for patients with androgen-sensitive prostate cancer.[35] Bilateral orchiectomy is considered the gold standard of ADT but is not as widely used as medical therapy for a variety of reasons, including patient preference and the ability to implement intermittent ADT with medical therapy. Gonadotropin-releasing hormone (GnRH) agonists are the most widely used form of ADT. However, a downside of these agents is the initial testosterone surge that can precipitate clinical disease flare and may necessitate the concomitant use of an antiandrogen.

Degarelix (Firmagon) is a GnRH antagonist that has been shown to produce rapid and sustained testosterone suppression without causing an initial testosterone surge.[36] Degarelix was approved by the FDA in 2008 based on a phase III trial of 601 patients who required initial ADT. The results showed that over 95% of the patients treated with degarelix achieved a castration level of testosterone within three days, compared with none of the patients treated with leuprolide (Lupron). An updated analysis revealed a statistically significant decrease in the incidence of PSA recurrence (a secondary endpoint) at one year using degarelix compared with leuprolide [37]. Overall, adverse reactions with degarelix were representative of those commonly seen with ADT: 40% of treated patients experienced injection site reactions, which were overall mild.[36]

Degarelix provides another option for treating patients. It is useful in patients who have an indication for ADT but who are at high risk for prostate cancer–related flare symptoms, such as bone pain, urethral obstruction, or spinal cord compression. The currently available formulation requires an injection every 28 days, which is less convenient for patients than the available formulations of GnRH agonists that can be given less frequently (eg, every three, four, or six months).

Androgen signaling inhibition in CRPC

Despite initial success with ADT, progression to CRPC is inevitable for most patients. However, there is clear evidence that CRPC remains androgen driven through multiple different mechanisms.[30-34] These include increased expression of the androgen receptor (AR), increased activity of the AR through various gene mutations, and up-regulation of steroidogenic enzymes (such as CYP17) that lead to increased androgen production.[32]

CYP17 Inhibitors. Abiraterone is a novel inhibitor of the adrenal enzyme CYP17 (17α-hydroxylase/17,20-lyase), which is involved in the production of androgenic steroids. Results from several recently published phase I and II studies have shown abiraterone’s antitumor effects as reflected by measurable disease responses and prolonged time to PSA progression.[38-41] A recently reported phase III study randomly assigned 1195 patients with CRPC who had failed docetaxel-based therapy to treatment with prednisone plus either abiraterone or placebo.[42] The results showed that abiraterone was associated with improvements in overall survival (14.8 months vs 10.9 months; HR, 0.65 [95% CI, 0.54-0.77]; P < .0001) and time to tumor progression (10.2 months vs 6.6 months; HR, 0.58 [95% CI, 0.46-0.73]; P < .0001). Radiographic progression-free survival and PSA response were also significantly improved with abiraterone (5.6 months vs 3.6 months, and 38% vs 10%, respectively). Abiraterone was well tolerated, with the most frequent adverse events being hypertension, hyperkalemia, and fluid retention.[42] Another phase III study is evaluating abiraterone in asymptomatic or minimally symptomatic patients with CRPC who have not received cytotoxic or biologic therapy.[43] Because this agent inhibits the production of both adrenal androgens and corticosteroids, concomitant exogenous steroid administration (eg, prednisone) is required.

Abiraterone was recently approved by the FDA for patients with metastatic CRPC post docetaxel therapy.

Orteronel (TAK-700) is another inhibitor of CYP17 that has been shown to cause powerful and selective suppression of androgen production in animals.[44] Available data suggest no dose-response relationship, and because lower dose levels have no impact on adrenal corticosteroid production, orteronel presents a potential clinical advantage over abiraterone in that exogenous corticosteroids may not be needed; oreteronel may thus be better suited for long-term use. Orteronel is currently undergoing investigation in a variety of settings: a phase II trial is evaluating orteronel in patients with non-metastatic CRPC, and two phase III trials are evaluating its use in patients with metastatic CRPC who are chemotherapy-nave and who develop progressive disease after docetaxel.[45-47]

Antiandrogens. MDV3100 is an oral androgen antagonist with a higher affinity for the androgen receptor than bicalutamide (Casodex).[48] It is also a pure antagonist, whereas bicalutamide is a partial agonist. In a recently published phase I/II study of 140 patients with progressive, metastatic CRPC treated with MDV3100, 78 out of 140 (56%) experienced at least a 50% decrease in serum PSA concentration, and 13 out of 59 (22%) experienced a response in measurable soft-tissue disease. Overall, this agent was well tolerated, with fatigue being the most common toxicity. However, the most common adverse event leading to drug discontinuation was seizure, which occurred in 3 out of 53 patients who received doses of MDV3100 above the maximum tolerated dose. An ongoing phase III trial of patients with CRPC who have not been treated with chemotherapy is randomly assigning patients to treatment with MDV3100 or placebo.[49] Another phase III trial is investigating MDV3100 compared to placebo in patients with CRPC who develop progressive disease after receiving docetaxel.[50] These trials will establish the efficacy and safety of this agent.

Although the focus of research involving this class of agents and the CYP17 inhibitors has been on castration-resistant disease, clearly they may play an even more important role in the setting of hormone-sensitive disease. Trials are therefore critically needed to determine their efficacy in this latter setting.

REFERENCE GUIDE

Therapeutic Agents
Mentioned in This Article

Abiraterone (Zytiga)
Aflibercept
AT-101
Atrasentan (Xinlay)
Bamucirumab
Bevacizumab (Avastin)
Bicalutamide (Casodex)
Cabazitaxel (Jevtana)
Cabozantinib
Cixutumumab
Custirsen
Dasatinib (Sprycel)
Degarelix (Firmagon)
Denosumab (XGEVA)
Docetaxel (Taxotere)
Eribulin (Halaven)
Everolimus (Afinitor)
Ipilimumab (Yervoy)
Ixabepilone
Leuprolide (Lupron)
MDV3100
Mitoxantrone (Novantrone)
Olaratumab
Patupilone
Ramucirumab
Sunitinib (Sutent)
Tasquinimod
Temsirolimus (Torisel)
Veliparib
Vorinostat (Zolinza)

Brand names are listed in parentheses only if a drug is not available generically and is marketed as no more than two trademarked or registered products. More familiar alternative generic designations may also be included parenthetically.

Bone-Targeted Therapy

The development of bone metastases in prostate cancer is a complex process involving numerous proteins, growth factors, and pathways.[51] 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).[51] 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 bundles, and in conjunction with the osteolytic activity, account for many of the skeletal complications seen in prostate cancer, including pain and fracture.[52]

Endothelin-receptor antagonists

The endothelin pathway affects cancer progression through multiple different mechanisms, including inhibition of apoptosis and promotion of angiogenesis.[53] 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.[51]

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.[56] A phase III Southwest Oncology Group (SWOG) Intergroup study is comparing docetaxel and prednisone with atrasentan to docetaxel and prednisone without atrasentan in metastatic CRPC.[57] 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.[58] 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.[59] 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.[51] Denosumab is a monoclonal antibody against RANKL.[62] 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 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.[9] 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.[63] 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.[64] The cost-effectiveness of denosumab is also a consideration when contemplating its use.

Angiogenesis Inhibition

Angiogenesis is mediated by a variety of factors, including vascular endothelial growth factor (VEGF).[65] 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.[66]

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.[70] 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.[73] 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).[74] 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.[75] An ongoing phase III study of patients with metastatic CRPC is comparing docetaxel, prednisone, and aflibercept to docetaxel, prednisone, and placebo.[76]

Cabozantinib (XL184) is an oral inhibitor of MET and VEGF receptor 2 (VEGFR2) that has demonstrated antitumor and antiangiogenic effects in preclinical models.[77] 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.[77] 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.[83] Dasatinib (Sprycel) is a tyrosine kinase inhibitor with activity against PDGF that has also been shown to inhibit Src and the Src family kinases.[84] In a phase II study, patients with metastatic CRPC treated with dasatinib showed evidence of disease stability and decreased markers of bone turnover.[84] A phase III study evaluating overall survival using dasatinib in combination with docetaxel in CRPC is underway.[85]

Anti-apoptosis (clusterin) inhibitor

Clusterin is stress-induced protein that in part functions as an anti-apoptotic protein.[86] 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.[87] 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]

Conclusion

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).

References:

References:

1. Porter AT, McEwan AJ, Powe JE, et al. Results of a randomized phase-III trial to evaluate the efficacy of strontium-89 adjuvant to local field external beam irradiation in the management of endocrine resistant metastatic prostate cancer. Int J Radiat Oncol Biol Phys. 1993;25:805-13.

2. Kantoff PW, Halabi S, Conaway M, et al. Hydrocortisone with or without mitoxantrone in men with hormone-refractory prostate cancer: results of the cancer and leukemia group B 9182 study. J Clin Oncol. 1999;17:2506-13.

3. Tannock IF, Osoba D, Stockler MR, et al. Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points. J Clin Oncol. 1996;14:1756-64.

4. Saad F, Gleason DM, Murray R, et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst. 2002;94:1458-68.

5. 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. 2004;351:1513-20.

6. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351:1502-12.

7. Sipuleucel-T (PROVENGE). US Food and Drug Administration; [cited 2010 November 14]; Available from: http://www.fda.gov/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/ucm210012.htm.

8. Cabazitaxel (JEVTANA). US Food and Drug Administration; [cited 2010 November 14]; Available from: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails.

9. Fizazi K. A randomized phase III trial of denosumab versus zoledronic acid in patients with bone metastases from castration-resistant prostate cancer. J Clin Oncol. 2010;28:Abstract LBA4507.

10. Attard G, Greystoke A, Kaye S, De Bono J. Update on tubulin-binding agents. Pathol Biol (Paris). 2006;54:72-84.

11. Hussain A, DiPaola RS, Baron AD, et al. Phase II trial of weekly patupilone in patients with castration-resistant prostate cancer. Ann Oncol. 2009;20:492-7.

12. Rosenberg JE, Ryan CJ, Weinberg VK, et al. Phase I study of ixabepilone, mitoxantrone, and prednisone in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel-based therapy: a study of the department of defense prostate cancer clinical trials consortium. J Clin Oncol. 2009;27:2772-8.

13. Rosenberg JE, Weinberg VK, Kelly WK, et al. Activity of second-line chemotherapy in docetaxel-refractory hormone-refractory prostate cancer patients : randomized phase 2 study of ixabepilone or mitoxantrone and prednisone. Cancer. 2007;110:556-63.

14. 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. 2005;23:8724-9.

15. ABI-008 trial in patients with hormone-refractory prostate cancer. US National Institues of Health; [cited 2011 January 27]; Available from: http://www.clinicaltrials.gov/.

16. Kolevska T, Ryan CJ, Huey V, et al. Phase II trial of nab-paclitaxel as first-line therapy of hormone refractory metastatic prostate cancer (HRPC). J Clin Oncol. 2009;27:Abstract 5152.

17. Mita AC, Denis LJ, Rowinsky EK, et al. Phase I and pharmacokinetic study of XRP6258 (RPR 116258A), a novel taxane, administered as a 1-hour infusion every 3 weeks in patients with advanced solid tumors. Clin Cancer Res. 2009;15:723-30.

18. de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010;376:1147-54.

19. 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. 2006;24:3089-94.

20. Higano CS, Schellhammer PF, Small EJ, et al. Integrated data from 2 randomized, double-blind, placebo-controlled, phase 3 trials of active cellular immunotherapy with sipuleucel-T in advanced prostate cancer. Cancer. 2009;115:3670-9.

21. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-22.

22. Batchelor J. Provenge wild ride blazes trail for immunotherapy. Oncol News Intl. 2010 November 29.

23. Longo DL. New therapies for castration-resistant prostate cancer. N Engl J Med. 2010;363:479-81.

24. Nabhan C. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:1966-7; author reply 8.

25. Thompson CB, Allison JP. The emerging role of CTLA-4 as an immune attenuator. Immunity. 1997;7:445-50.

26. Small EJ, Tchekmedyian NS, Rini BI, et al. A pilot trial of CTLA-4 blockade with human anti-CTLA-4 in patients with hormone-refractory prostate cancer. Clin Cancer Res. 2007;13:1810-5.

27. Granberg CF, Karnes RJ, Tollefson MK, et al. Conversion of advanced prostate cancer to organ-confined minimal residual disease using CTLA-4 blockade (ipilimumab) immunotherapy. ASCO Genitourinary Cancers Symposium. 2010:Abstract 33.

28. Tollefson MK, Karnes RJ, Thompson RH, et al. A randomized phase II study of ipilimumab with androgen ablation compared with androgen ablation alone in patients with advanced prostate cancer. ASCO Genitourinary Cancers Symposium. 2010:Abstract 168.

29. Phase 3 study of immunotherapy to treat advanced prostate cancer. US National Institutes of Health; [cited 2010 December 19]; Available from: http://www.clinicaltrials.gov/.

30. Locke JA, Guns ES, Lubik AA, et al. Androgen levels increase by intratumoral de novo steroidogenesis during progression of castration-resistant prostate cancer. Cancer Res. 2008;68:6407-15.

31. Mohler JL, Gregory CW, Ford OH, 3rd, et al. The androgen axis in recurrent prostate cancer. Clin Cancer Res. 2004;10:440-8.

32. Montgomery RB, Mostaghel EA, Vessella R, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008;68:4447-54.

33. Debes JD, Tindall DJ. Mechanisms of androgen-refractory prostate cancer. N Engl J Med. 2004;
351:1488-90.

34. Feldman BJ, Feldman D. The development of androgen-independent prostate cancer. Nat Rev Cancer. 2001;1:34-45.

35. el-Rayes BF, Hussain MH. Hormonal therapy for prostate cancer: past, present and future. Expert Rev Anticancer Ther. 2002;2:37-47.

36. Klotz L, Boccon-Gibod L, Shore ND, et al. The efficacy and safety of degarelix: a 12-month, comparative, randomized, open-label, parallel-group phase III study in patients with prostate cancer. BJU Int. 2008;102:1531-8.

37. Tombal B, Miller K, Boccon-Gibod L, et al. Additional analysis of the secondary end point of biochemical recurrence rate in a phase 3 trial (CS21) comparing degarelix 80 mg versus leuprolide in prostate cancer patients segmented by baseline characteristics. Eur Urol. 2010;57:836-42.

38. Attard G, Reid AH, A’Hern R, et al. Selective inhibition of CYP17 with abiraterone acetate is highly active in the treatment of castration-resistant prostate cancer. J Clin Oncol. 2009;27:3742-8.

39. Danila DC, Morris MJ, de Bono JS, et al. Phase II multicenter study of abiraterone acetate plus prednisone therapy in patients with docetaxel-treated castration-resistant prostate cancer. J Clin Oncol. 2010;28:1496-501.

40. Reid AH, Attard G, Danila DC, et al. Significant and sustained antitumor activity in post-docetaxel, castration-resistant prostate cancer with the CYP17 inhibitor abiraterone acetate. J Clin Oncol. 2010;28:1489-95.

41. Ryan CJ, Smith MR, Fong L, et al. Phase I clinical trial of the CYP17 inhibitor abiraterone acetate demonstrating clinical activity in patients with castration-resistant prostate cancer who received prior ketoconazole therapy. J Clin Oncol. 2010;28:1481-8.

42. de Bono JS, Logothetis C, Fizazi K, et al. Abiraterone acetate (AA) plus low dose prednisone (P) improves overall survival (OS) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) who have progressed after docetaxel-based chemotherapy (chemo): Results of COU-AA-301, a randomized double-blind placebo-controlled phase III study. Ann Oncol. 2010;21:LBA5.

43. Abiraterone acetate in asymptomatic or mildly symptomatic patients with metastatic castration-resistant prostate cancer. US National Institutes of Health; [cited 2010 November 26]; Available from: http://www.clinicaltrials.gov/.

44. Matsunaga N, Kaku T, Ojida A, et al. C(17,20)-lyase inhibitors. Part 2: design, synthesis and structure-activity relationships of (2-naphthylmethyl)-1H-imidazoles as novel C(17,20)-lyase inhibitors. Bioorg Med Chem. 2004;12:4313-36.

45. Safety and efficacy study of TAK-700 in patients with nonmetastatic castration-resistant prostate cancer and a rising prostate-specific antigen. US National Institutes of Health; [cited 2011 January 2]; Available from: http://www.clinicaltrials.gov/.

46. Study comparing orteronel plus prednisone in patients with metastatic castration-resistant prostate cancer. US National Institutes of Health; [cited 2010 December 19]; Available from: http://www.clinicaltrials.gov/.

47. Study comparing orteronel plus prednisone in patients with chemotherapy-naive metastatic castration-resistant prostate cancer. US National Institutes of Health; [cited 2010 December 19]; Available from: http://www.clinicaltrials.gov/.

48. Scher HI, Beer TM, Higano CS, et al. Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study. Lancet. 2010;375:1437-46.

49. A safety and efficacy study of oral MDV3100 in chemotherapy-naive patients with progressive metastatic prostate cancer (PREVAIL). US National Institutes of Health; [cited 2010 November 26]; Available from: http://www.clinicaltrials.gov/.

50. Safety and efficacy study of MDV3100 in patients with castration-resistant prostate cancer who have been previously treated with docetaxel-based chemotherapy (AFFIRM). US National Institutes of Health; [cited 2010 November 26]; Available from: http://www.clinicaltrials.gov/.

51. Bradley DA, Hussain M, Dipaola RS, Kantoff P. Bone directed therapies for prostate cancer. J Urol. 2007;178:S42-8.

52. Coleman RE. Metastatic bone disease: clinical features, pathophysiology and treatment strategies. Cancer Treat Rev. 2001;27:165-76.

53. Nelson J, Bagnato A, Battistini B, Nisen P. The endothelin axis: emerging role in cancer. Nat Rev Cancer. 2003;3:110-6.

54. Carducci MA, Saad F, Abrahamsson PA, et al. A phase 3 randomized controlled trial of the efficacy and safety of atrasentan in men with metastatic hormone-refractory prostate cancer. Cancer. 2007;110:1959-66.

55. Nelson JB, Love W, Chin JL, et al. Phase 3, randomized, controlled trial of atrasentan in patients with nonmetastatic, hormone-refractory prostate cancer. Cancer. 2008;113:2478-87.

56. Banerjee S, Hussain M, Wang Z, et al. In vitro and in vivo molecular evidence for better therapeutic efficacy of ABT-627 and taxotere combination in prostate cancer. Cancer Res. 2007;67:3818-26.

57. Docetaxel and prednisone with or without atrasentan in treating patients with stage IV prostate cancer and bone metastases that did not respond to previous hormone therapy. [cited 2011 January 29]; Available from: http://www.clinicaltrials.gov/.

58. James ND, Caty A, Borre M, et al. Safety and efficacy of the specific endothelin-A receptor antagonist ZD4054 in patients with hormone-resistant prostate cancer and bone metastases who were pain free or mildly symptomatic: a double-blind, placebo-controlled, randomised, phase 2 trial. Eur Urol. 2009;55:1112-23.

59. Results of zibotentan phase III trial in castration resistant prostate cancer. Astra-Zeneca; [cited 2011 January 29]; Available from: http://www.astrazeneca.com/Media/Press-releases/Article/Results-of-Zibotentan-Phase-III-trial-in-castration-resistant-pr.

60. A phase III trial of ZD4054 (zibotentan) (endothelin A antagonist) in non-metastatic hormone resistant prostate cancer (ENTHUSE M0). US National Institutes of Health; [cited 2010 November 29]; Available from: http://www.clinicaltrials.gov/.

61. A phase III trial of ZD4054 (zibotentan) (endothelin A antagonist) and docetaxel in metastatic hormone resistant prostate cancer (ENTHUSE M1C). US National Institutes of Health; [cited 2010 November 28]; Available from: http://www.clinicaltrials.gov/.

62. Fizazi K, Lipton A, Mariette X, et al. Randomized phase II trial of denosumab in patients with bone metastases from prostate cancer, breast cancer, or other neoplasms after intravenous bisphosphonates. J Clin Oncol. 2009;27:1564-71.

63. Denosumab (XGEVA). US Food and Drug Administration; [cited 2011 January 29]; Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/125320s007lbl.pdf.

64. Hartsell WF, Scott CB, Bruner DW, et al. Randomized trial of short- versus long-course radiotherapy for palliation of painful bone metastases. J Natl Cancer Inst. 2005;97:798-804.

65. Hwang C, Heath EI. Angiogenesis inhibitors in the treatment of prostate cancer. J Hematol Oncol. 2010;3.

66. Liang WC, Wu X, Peale FV, et al. Cross-species vascular endothelial growth factor (VEGF)-blocking antibodies completely inhibit the growth of human tumor xenografts and measure the contribution of stromal VEGF. J Biol Chem. 2006;281:951-61.

67. Di Lorenzo G, Figg WD, Fossa SD, et al. Combination of bevacizumab and docetaxel in docetaxel-pretreated hormone-refractory prostate cancer: a phase 2 study. Eur Urol. 2008;54:1089-94.

68. Picus J, Halabi S, Kelly WK, et al. A phase 2 study of estramustine, docetaxel, and bevacizumab in men with castrate-resistant prostate cancer: results from Cancer and Leukemia Group B Study 90006. Cancer. 2011;117:526-33.

69. Ning YM, Gulley JL, Arlen PM, et al. Phase II trial of bevacizumab, thalidomide, docetaxel, and prednisone in patients with metastatic castration-resistant prostate cancer. J Clin Oncol. 2010;28:2070-6.

70. Kelly WK, Halabi S, Carducci MA, et al. A randomized, double-blind, placebo-controlled phase III trial comparing docetaxel, prednisone, and placebo with docetaxel, prednisone, and bevacizumab in men with metastatic castration-resistant prostate cancer (mCRPC): Survival results of CALGB 90401. J Clin Oncol 2010;28:Abstract LBA4511.

71. Dror Michaelson M, Regan MM, Oh WK, et al. Phase II study of sunitinib in men with advanced prostate cancer. Ann Oncol. 2009;20:913-20.

72. Sonpavde G, Periman PO, Bernold D, et al. Sunitinib malate for metastatic castration-resistant prostate cancer following docetaxel-based chemotherapy. Ann Oncol. 2010;21:319-24.

73. Bratt O, Haggman M, Ahlgren G, et al. Open-label, clinical phase I studies of tasquinimod in patients with castration-resistant prostate cancer. Br J Cancer. 2009;101:1233-40.

74. Pili R. A randomized, multicenter, international phase II study of tasquinimod in chemotherapy naïve patients with metastatic castrate-resistant prostate cancer (CRPC). J Clin Oncol. 2010;28:Abstract 4510.

75. Lockhart AC, Rothenberg ML, Dupont J, et al. Phase I study of intravenous vascular endothelial growth factor trap, aflibercept, in patients with advanced solid tumors. J Clin Oncol. 2010;28:207-14.

76. A multicenter, randomized, double blind study comparing the efficacy and safety of aflibercept versus placebo administered every 3 weeks in patients treated with docetaxel/ prednisone for metastatic androgen-independent prostate cancer. US National Institutes of Health; [cited 2010 November 27]; Available from: http://www.clinicaltrials.gov/.

77. Smith DC, Smith MR, Small EJ, et al. Phase II study of XL184 in a cohort of patients (pts) with castration-resistant prostate cancer (CRPC) and measurable soft tissue disease. J Clin Oncol. 2011;29:abstract 127.

78. Knudsen BS, Gmyrek GA, Inra J, et al. High expression of the Met receptor in prostate cancer metastasis to bone. Urology. 2002;60:1113-7.

79. Humphrey PA, Zhu X, Zarnegar R, et al. Hepatocyte growth factor and its receptor (c-MET) in prostatic carcinoma. Am J Pathol. 1995;147:386-96.

80. Verras M, Lee J, Xue H, et al. The androgen receptor negatively regulates the expression of c-Met: implications for a novel mechanism of prostate cancer progression. Cancer Res. 2007;67:967-75.

81. Ebos JM, Lee CR, Kerbel RS. Tumor and host-mediated pathways of resistance and disease progression in response to antiangiogenic therapy. Clin Cancer Res. 2009;15:5020-5.

82. Shojaei F, Lee JH, Simmons BH, et al. HGF/c-Met acts as an alternative angiogenic pathway in sunitinib-resistant tumors. Cancer Res. 2010;70:10090-100.

83. Fizazi K. The role of Src in prostate cancer. Ann Oncol. 2007;18:1765-73.

84. Yu EY, Wilding G, Posadas E, et al. Phase II study of dasatinib in patients with metastatic castration-resistant prostate cancer. Clin Cancer Res. 2009;15:7421-8.

85. Randomized study comparing docetaxel plus dasatinib to docetaxel plus placebo in castration-resistant prostate cancer. US National Institutes of Health; [cited 2010 November 29]; Available from: http://www.clinicaltrials.gov/.

86. Chi KN, Zoubeidi A, Gleave ME. Custirsen (OGX-011): a second-generation antisense inhibitor of clusterin for the treatment of cancer. Expert Opin Investig Drugs. 2008;17:1955-62.

87. Chi KN, Hotte SJ, Yu EY, et al. Randomized phase II study of docetaxel and prednisone with or without OGX-011 in patients with metastatic castration-resistant prostate cancer. J Clin Oncol. 2010;28:4247-54.

88. A randomized, placebo-controlled, double-blind, phase 3 study evaluating the benefit of adding custirsen to docetaxel retreatment as second-line therapy in men with castrate resistant prostate cancer. US National Institutes of Health; [cited 2010]; Available from: http://www.clinicaltrials.gov/.

89. A randomized phase 3 study comparing standard first-line docetaxel/prednisone to docetaxel/prednisone in combination with custirsen (OGX-011) in men with metastatic castrate resistant prostate cancer. US National Institutes of Health; [cited 2010 November 28]; Available from: http://www.clinicaltrials.gov/.

90. Sartor O, Reid RH, Hoskin PJ, et al. Samarium-153-lexidronam complex for treatment of painful bone metastases in hormone-refractory prostate cancer. Urology. 2004;63:940-5.

91. ClinicalTrials.gov. US National Institutes of Health; [cited 2011 January 30]; Available from: http://www.clinicaltrials.gov/.