Evolution of Treatment Options for Patients With CRPC and Bone Metastases: Bone-Targeted Agents That Go Beyond Palliation of Symptoms to Improve Overall Survival

Metastasis to bone represents an all-too-frequent complication of advanced-stage prostate cancer (PCa): 50% to 70% of these patients will ultimately develop this devastating complication. PCa preferentially metastasizes to bone, and the skeletal complications increase mortality and decrease quality of life. The clinical consequences of skeletal metastasis also include pain, skeletal-related events (SREs), and increased costs of therapy. Recent advances in our understanding of the mechanisms of metastasis and the physiologic changes that occur with it, together with the introduction of new treatments, are furthering our ability to combat this problem. In this review, we examine bone-targeted palliative agents, nontargeted systemic cytotoxic therapies, and bone-targeted agents that go beyond palliation to also potentially improve progression-free and overall survival. We specifically focus on post-treatment outcomes-including pain relief, decreased opioid use, improvement in quality of life, freedom from SREs or new bony metastases, and increases in overall survival-in men with symptomatic, metastatic PCa. Treatments discussed include varied drug classes, such as bisphosphonates and human monoclonal antibodies; beta-emitting radiopharmaceuticals; external beam radiotherapy; systemic chemotherapies; Src inhibitors; endothelin-A receptor antagonists; clusterin inhibitors; and alpha-emitting radiopharmaceuticals.

Introduction

Metastasis to bone represents a frequent complication of advanced-stage prostate cancer (PCa). The exact prevalence of bony metastasis is generally unknown, but some estimate that 50% to 70% of patients with advanced-stage PCa will ultimately develop this devastating complication.[1,2] PCa preferentially metastasizes to the axial skeleton, including the vertebrae, pelvis, proximal ends of long bones, and skull.[3] The resulting skeletal complications are widely recognized to increase mortality and decrease quality of life, since affected patients suffer loss of independence, mobility, and social functioning (Figure 1). The clinical consequences of skeletal metastasis also include pain, skeletal-related events (SREs), and increased costs of therapy. Recent advances in our understanding of the mechanisms of metastasis and of the physiologic changes that occur along with it, along with the introduction of new treatments, are improving our ability to combat this problem.

FIGURE 1

The Negative Impact of Bone Complications

There are several important characteristics of bone that implicate it as the preferential site for metastasis of visceral cancers. In 1889, Stephen Paget first noted in his “seed and soil” hypothesis that the complementary characteristics of target organs and circulating tumor cells would determine where tumors metastasize.[4] Bone has high blood flow to marrow, where many important growth factors and cytokines reside and are involved in the constant remodeling of bone; these factors include transforming growth factor β, endothelin-1, interleukin (IL)-1 and IL-6, prostaglandins, insulin-like growth factors, fibroblast growth factors, and platelet-derived growth factors.[5] The final necessary step in metastasis involves tumor cell expression of adhesive molecules. The bone microenvironment milieu provides the perfect environment for tumor cell deposition and clonal expansion.

Skeletal pain from metastasis manifests as a deep nonspecific ache that worsens with movement and that can be quite severe; it progresses as metastatic disease progresses. Patients usually start on nonsteroidal anti-inflammatory drugs (NSAIDs), move to opioids, and then require more advanced, systemic palliation therapies, which will be reviewed here. Some early studies mentioned in the sections below measured the palliative effects of an intervention using pain scale questionnaires or diaries, opioid usage (either prescribed or patient-reported usage), patient-reported sleep patterns, or even doctor-reported pain scores. As the reader may realize, some of these measures are highly subjective and vary from patient to patient, making the comparison of different studies more difficult.

TABLE

Trials of Treatments for Castration-Resistant Prostrate Cancer Mentioned in This Review

Unfortunately, few treatments specifically target tumor cells that reside in bone, and those that are available have drawbacks related to dose-limiting toxicities and may have only small therapeutic benefit. Further, patients who have exhausted chemotherapeutic options or who do not tolerate their side effects find themselves with a limited number of treatment options after the diagnosis of skeletal metastasis. This review will examine agents with potential activity in the palliation and treatment of skeletal metastases of PCa, and will weigh the clinical-outcomes evidence for and against their broad use (Table).

Targeted Treatments for Symptom Palliation

Bisphosphonates

Bisphosphonates target the osteoclastic feedback loop that develops between a metastatic lesion and bone, thereby preventing or delaying the onset of SREs.[6,7] These drugs bind to the active site of bone resorption and turnover, enter osteoclasts, disrupt cellular signaling pathways, induce apoptosis, and prevent further resorption.[8] The goals of bisphosphonate therapy include increasing bone mineral density (BMD), preventing new and recurrent SREs, palliating bone pain, reducing the need for other therapies, and mitigating further morbidity. The efficacy of this class of drug in attaining these clinical goals has been investigated in multiple placebo-controlled randomized trials, which have shown significant improvements in clinical outcomes with these agents.[9-11] Zoledronic acid (Zometa) is a bisphosphonate approved for the prevention of SREs in men with metastatic castration-resistant prostate cancer (CRPC). Its role was established by a study of men with metastatic CRPC by Saad et al, in which 4 mg of zoledronic acid was given every 3 weeks; the incidence of SREs was reduced from 44% in the placebo arm to 33% in the zoledronic acid arm.[12] Follow-up phase II trials have examined other dosing regimens, such as 4 mg every 3 months-or even yearly-and have demonstrated preservation of BMD in men receiving androgen-deprivation therapy (ADT), but these studies did not specifically examine outcomes involving SREs.[13,14]

Bisphosphonates, when used for the treatment of debilitating bone pain, reduce the need for NSAIDs and opioid analgesics, which can have unintended consequences for patients with advanced cancer. Zoledronic acid is administered intravenously. Despite its systemic activity, it lacks the myelosuppressive side effects of chemotherapy or radiation, and it can be used as an adjunct to such therapies. Bisphosphonates have never been shown to prevent metastasis, but they do offer prevention of their deleterious effects and mitigation of SREs and bone pain. Some studies have demonstrated in vitro synergistic cytotoxic effects between bisphosphonates and chemotherapies, but these have never been borne out in clinical studies.[15,16]

FIGURE 2

The Vicious Cycle of Bone Destruction From Metastases: the Role of RANK Ligand-

Human monoclonal antibodies

Denosumab (Xgeva) is a fully human monoclonal antibody against receptor activator of nuclear factor-κB ligand (RANKL); it disrupts the normal homeostatic messaging that occurs between osteoblasts and osteoclasts in bone, and its administration causes a decrease in bone turnover and resorption (Figure 2). Denosumab has been well studied in several clinical areas that involve bone loss, including in postmenopausal women and in men with CRPC. It is currently FDA-approved for use in both postmenopausal women and men with advanced prostate cancer and bone metastase, to prevent bone loss and subsequent fracture.[17,18] The latter group presents a particular challenge with respect to potential loss in BMD and subsequent SREs for several reasons, including prolonged use of ADT and/or development of skeletal metastasis. Below we highlight several of the key studies of denosumab that have been published to date.

In a phase II trial of denosumab in patients with bone metastases from prostate, breast, and other cancers who were noted to have persistently elevated bone turnover markers (urinary N-telopeptide [uNTx]) while receiving intravenous (IV) bisphosphonate treatment, patients were randomly assigned to receive subcutaneous denosumab or continuation of the IV bisphosphonate. This study noted that more patients achieved normal levels of urinary bone turnover markers (about 64% vs 37%; P = .01) and that patients experienced fewer SREs (8% vs 17%; odds ratio [OR], 0.31; 95% confidence interval [CI], 0.08-1.18) with denosumab than with bisphosphonate treatment. Similar numbers of patients suffered adverse events in the two arms.[19]

In 2009, Smith et al published the results of a phase III randomized controlled trial comparing denosumab to placebo in patients with nonmetastatic PCa who were receiving ADT. The key endpoints were percent change in BMD in the lumbar spine, total hip, and femoral neck at 24 and 36 months, and incidence of new vertebral fractures.[20] Lumbar spine BMD increased by 5.6% in the treatment group as opposed to a BMD decrease of 1.0% in the placebo arm (P < .001). Patients who received denosumab also experienced a decreased incidence of new vertebral fractures at 36 months (1.5% vs 3.9% with placebo) (relative risk, 0.38; 95% CI, 0.19 to 0.78; P = .006). Subsequent analyses noted that patients with high baseline levels of turnover markers (serum C-telopeptide and tartrate-resistant alkaline phosphatase 5b) had the greatest increases in BMD.[21]

Phase III studies comparing denosumab to the bisphosphonate zoledronic acid with respect to time to development of a first SRE in patients with CRPC and at least one bone metastasis were published in 2010.[22,23] Denosumab improved the median time to development of a first SRE (20.7 months vs 17.1 months for zoledronic acid, a difference of 3.6 months). Rates of osteonecrosis of the jaw were not significantly different between the two study arms, at 2.3% and 1.3%, respectively (P = .09), but hypocalcemia was observed more frequently with denosumab than with zoledronic acid (13% vs 6%). This report showed no difference in overall survival between the two groups.

Recently, results were presented regarding the ability of denosumab to prevent the development of bone metastasis.[24] Some have hypothesized that, by limiting bone turnover and resorption, denosumab may make bone an environment that is less amenable to circulating tumor cells remaining and clonally expanding. In this report by Saad et al, denosumab increased the time to development of first bone metastasis by a median of 4.2 months compared with placebo, in a population of men deemed to be at high risk for development of metastatic disease. No difference in overall survival was noted, however.

In summary, denosumab is a fully human monoclonal antibody against RANKL; it inhibits osteoclast activity, limiting bone turnover and resorption. It is approved for the prevention of SREs in high-risk postmenopausal women and men with advanced prostate cancer and bone metastasis. Denosumab does not have any direct antitumor activity, and while there is some recent evidence that denosumab prevents development of bone metastasis, it has not yet been approved for this use. Studies published to date have demonstrated its ability to help prevent and reduce SREs in men with and without bone metastasis, compared with bisphosphonates and placebo, to increase BMD over placebo, and to improve the time to development of a first SRE compared with zoledronic acid. Clinicians will ultimately have to grapple with cost-benefit issues, since denosumab is more expensive than zoledronic acid. Clinicians will also have to weigh the convenience of a subcutaneous injection of denosumab against the intravenous administration of zoledronic acid and fewer cases of renal toxicity with denosumab. As mentioned, in a head-to-head study, denosumab delayed SREs by 3.6 months compared with zoledronic acid.

Beta-emitting radionuclides

Patients with multifocal metastases from visceral cancers, primarily breast and prostate, have long had their symptoms palliated with radiopharmaceuticals. These patients typically suffer marked decreases in quality of life as a result of pain, which has been described as "deep nonspecific ache rising in intensity as the disease progresses, incident pain on movement (allodynia), which renders patients virtually immobile, and spontaneous pain that can be severe."[25] Patients generally progress from NSAIDs to opioids, and then to more advanced, systemic palliation therapies.

Mechanism of action, side effects, range, and safety considerations. While discrete sites of metastasis can be amenable to external beam radiotherapy for the palliation of pain, diffuse bony metastatic disease requires agents that preferably localize to bone, have limited toxicity but long enough half-lives to kill tumor cells, have favorable pharmacokinetic properties, and are safe to handle. To date, phosphorus-32, strontium-89 (Metastron), samarium-153 (Quadramet), rhenium-186, and rhenium-188 have all been used in this setting. ³²P was noted early on to cause marked bone marrow suppression and thus is not used or approved for clinical use.[26] The beta particles (which consist of electrons) emitted by these radioisotopes cause the destruction of malignant cells through DNA damage and the induction of apoptosis. They have a relatively low, linear energy transfer (LET) radiation that tracks 2.5 to 11 mm.[25] The limited range of these particles minimizes danger to healthcare personnel, but the deceleration of beta particles as they pass through shielding (eg, lead) can result in the formation of more dangerous, high-energy x-rays. In addition to emitting beta particles, ¹⁵³Sm, ¹⁸⁶Re, and ¹⁸⁸Re also decay to gamma photons, allowing for external monitoring of radionuclide biodistribution after administration. Bone marrow suppression, primarily in the form of thrombocytopenia and leukopenia, is the most common side effect seen with clinical use. ⁸⁹Sr and ¹⁵³Sm are FDA-approved for the palliation of bone pain associated with metastasis, while ¹⁸⁶Re and ¹⁸⁸Re are still considered experimental.

Strontium-89. The therapeutic benefit of ⁸⁹Sr was first established in 1942 by Pecher, who administered 3 doses over 5 months to a patient with advanced prostate cancer metastasized to bone.[27] The patient was noted to have an excellent clinical and radiographic response. Since that time, many observational and randomized controlled trials examining the use of ⁸⁹Sr have been published. Strontium sits below calcium in the periodic table, and it thus follows the path of calcium in the human body and localizes to areas of bone where calcium turnover is the greatest. In general, although subjective pain scales and definitions of responders differ between many of these studies, published reports have largely demonstrated that the palliative effect of ⁸⁹Sr is substantial (absolute risk reduction for achieving pain relief, 0.321; 95% CI, −0.035 to 0.678) and not secondary to a placebo effect.[28] Comparison of ⁸⁹Sr and local external beam radiation showed similar response rates but no difference in overall survival.[29]

Samarium-153.¹⁵³Sm was approved by the FDA in 1997 for palliation of pain from cancer metastasized to bone. The radioactive element is chelated to ethylenediaminetetramethylene phosphonic acid to form ¹⁵³Sm-EDTMP. This compound is cleared renally within 6 hours of intravenous administration. The element itself has a half-life of 1.9 days, but it is cleared from the blood with a t_1/2 of 5.5 minutes. Although its mechanisms of targeting bone are not completely understood, ¹⁵³Sm preferentially accumulates and associates with hydroxyapatite crystals in areas of high bone turnover. Examinations of metastatic lesions have noted concentrations of ¹⁵³Sm that are five times those seen in normal tissue, thus exposing these tumors to greater amounts of radiation and protecting healthy tissues. The range of emitted beta particles from ¹⁵³Sm is only 0.5 to 3 mm, shorter than that for beta particles from ⁸⁹Sr.

Multiple observational studies have reported improvements in pain scores for patients with bony metastases from CRPC. Phase II randomized controlled trials have demonstrated that higher doses of ¹⁵³Sm-EDTMP (37 megabecquerel/kg) were more effective than lower doses (18.5 megabecquerel/kg) or placebo at lowering pain scores and reducing analgesic use.[30,31] A phase III randomized controlled trial randomly assigned patients to receive either radioactive ¹⁵³Sm-EDTMP or nonradioactive 152

Sm-EDTMP. The investigators noted significant reductions in analgesic use in the active treatment group at 4 weeks, 9% of complete responders had a greater than 50% reduction in serum prostate-specific antigen (PSA), and myelosuppression accounted for the majority of side effects.[32] Sartor et al also demonstrated that ¹⁵³Sm-EDTMP can be safely redosed in patients after loss of analgesic effect.[33]

Comparisons of various beta emitters. Multiple studies have performed head-to-head comparisons of different beta particle–emitting radionuclides reviewed here.[25] No clinically significant differences in pain, analgesic usage, or performance status have been noted. Recommendations to date have maintained that clinician or patient preference, ease and safety of handling, pharmacokinetics, and cost remain the primary determinants of which therapy should be used. There have been shortages in supplies of radionuclides in recent years, and this may pose some limitations on the choice of radiopharmaceutical.

Beta emitters in combination with chemotherapy and bisphosphonates. Although beta particle–emitting compounds have shown mixed data with regard to PSA response rates after therapy, researchers have investigated combinations of these radioactive, bone-targeted therapies with chemotherapeutic drugs and/or bisphosphonates to determine whether any synergistic effects might be seen. Several have hypothesized that the radiation might sensitize tumor cells to further damage by chemotherapeutic agents. A phase II trial randomly assigned patients to chemotherapy either with or without ⁸⁹Sr. Overall survival improved considerably in the combination arm compared with chemotherapy alone (28 vs 17 months).[34] Another phase II trial examined the combination of docetaxel and ¹⁵³Sm-EDTMP in men with bone metastases from CRPC: PSA response was seen in 77%, pain response was seen in 69%, and the combination was well tolerated.[35] The primary endpoint was PSA progression–free survival, which was 6.4 months, with all patients ultimately relapsing. Median survival was 29 months.

In summary, these agents offer palliation of pain and can reduce opioid use. While the radiation produced by these compounds is cytotoxic, PSA response is not the primary indicator of effect, and no study has shown these compounds by themselves to affect overall survival. They are relatively well tolerated, with the most common side effect being myelosuppression that is reversible. These drugs may be re-dosed for continued effect, and combinations with other accepted treatments for metastatic CRPC may provide synergistic effects. Given the concerns regarding radiation safety of clinical personnel and patients, they should always be administered in special facilities by qualified personnel.

External beam radiation therapy

Bony metastasis of primary cancers results in considerable morbidity for patients, primarily causing pain, neurologic and functional sequalae, and hypercalcemia.[36] External beam radiotherapy has been a mainstay of palliation and treatment for these lesions, but the exact mechanism of action is not well defined. The doses required to provide pain relief are far less than those required to destroy tumorous lesions, implying effects on bone homeostasis and alteration of signaling pathways involved in bone turnover. Palliative goals of external beam radiotherapy include improvement in quality of life through pain reduction, prevention of further bone destruction, maintenance of the functional capacity of the patient, and prevention of neurologic sequalae, particularly in metastases to the spinal column.

Most studies report complete or partial pain relief in 70%, with 40% to 60% of those reporting partial relief. Onset of relief is variable, ranging from as soon as 48 hours after therapy to 4 weeks. Focal therapy can treat single lesions confirmed by imaging and correlated with patient symptoms. Considerations of site, surrounding tissues, margin, performance status, and current hematologic parameters should be taken into account when making decisions regarding treatment volume and dosing. Hemibody radiation should be considered in patients with multiple metastases. One trial compared local radiation to local radiation plus hemibody radiation. Development of new, symptomatic lesions was similar between the two groups, but time to progression was significantly longer in the combination group (12.6 vs 6.3 months).[37]

The optimum dose and timing of delivery has been a hotly contested issue, but a meta-analysis showed no significant differences between the different schedules.[38] A review of 12 randomized trials on the duration of pain relief and median overall survival by Ratanatharathorn et al largely concluded that no patients had durable responses that lasted the remainder of the life of the patient and that higher doses trended to the greatest pain relief.[39] With respect to the cost-benefit ratio of a single-fraction dose (4 to 8 Gy) vs multifraction higher doses of radiotherapy (30 to 45 Gy total), this meta-analysis concluded that while the former does provide some relief in a large percentage of patients, the higher-dose fractionated regimens were much better. In the United States, a survey of radiation oncologists showed that most employ 30 Gy in 10 fractions.[40]

Nontargeting Treatments That Improve Survival and/or Palliate Symptoms

Systemic chemotherapy

The development and use of cytotoxic chemotherapies for the treatment of advanced PCa has lagged behind parallel advances in other common cancers. In the 1990s, mitoxantrone (Novantrone) in combination with prednisone was approved for the treatment of advanced prostate cancer, based on improvement in palliative and quality of life measures.[41] The paper by Tannock et al, on which the approval was based, noted that at the time, chemotherapy for these patients was controversial given the frequently seen unwanted secondary effects offsetting pain relief. Prior to this study, the coadministration of corticosteroids muddled cause and effect, since their use alone had also been shown to offer palliation of symptoms from metastatic disease. The Tannock study, however, proved that chemotherapy (mitoxantrone) plus prednisone provides better palliation than prednisone alone.

Since that time, however, several cytotoxic agents have been or are being considered for approved use in patients with CRPC with and without metastasis. In general, this class of agents acts systemically, and their direct cytotoxic activity is not specific to metastatic sites and affects healthy tissues. Chemotherapeutic toxicities and natural and acquired drug resistance remain unresolved issues. Furthermore, objective measurement of response to therapy at metastatic sites remains difficult; although it can be performed radiologically, the classification of response requires radiologist knowledge of the criteria (eg, RECIST [Response Evaluation Criteria In Solid Tumors]). Many of the studies simultaneously report on palliation, but as with the beta particle–emitting radionuclide class of compounds, measures of palliation are more subjective and highly variable between studies. Moreover, these symptomatic outcomes do not reliably indicate tumor regression or reduction in overall disease burden.

To date, most clinicians and study investigators have used serum PSA as a marker of outcome; however, there have been numerous reports of the deficiencies of this marker in the case of cancer immunotherapy.[42,43] Namely, although some prostate cancer immunotherapies have been shown to improve overall survival, they have had little or no impact on PSA kinetics, sometimes even increasing PSA levels despite positive therapeutic effect. Some groups have advocated the use of circulating tumor cells (CTCs) as a marker, where a count of ≥ 5 CTCs/7.5 mL of blood has been shown to correlate with worse outcome compared with < 5 CTCs/7.5 mL of blood.[44]

Despite these hurdles with respect to determining outcomes in patients with metastatic disease, the data clearly show that chemotherapies such as docetaxel and cabazitaxel (Jevtana), and immunotherapy with sipuleucel-T (Provenge), improve overall survival-largely the best measure of cytotoxic effect. To date, there has been relatively little focus on responses in patients with bone metastasis or on survival as a function of extent of bony disease. We are, however, beginning to understand which compounds work best as first-, second-, and third-line agents. After the approval of docetaxel, there had been no clear standard of care in the second-line chemotherapy setting. Mitoxantrone was used, but its activity after progression on docetaxel is modest.[45] The development of newer agents that are examined in different patient classes-such as those who are chemotherapy-naive or chemotherapy-resistant-promises to open up advanced PCa to many new forms of treatment.[46]

Docetaxel. In 2004, docetaxel plus estramustine (Emcyt) was reported to yield an improvement in survival compared with mitoxantrone and prednisone, in men with metastatic, advanced CRPC.[47] Median time to progression, defined as two consecutive increases in PSA level over baseline or an interval increase in a bidimensionally-measured lesion, was 6.3 months in those receiving docetaxel and estramustine and 3.2 months in the group given mitoxantrone and prednisone (P < .001). Despite an improvement in overall survival (17.5 months vs 15.6 months, P = .02), no significant differences were noted in measurable disease or pain between the two groups.

Tannock et al compared docetaxel and prednisone, given every week or every 3 weeks, to mitoxantrone and prednisone administered every 3 weeks.[48] This study showed a statistically significant improvement in survival (of approximately 3 months), and it demonstrated improvements in reported pain levels. No efficacy with respect to disease progression was reported in this study. Mature follow-up data comparing mitoxantrone to docetaxel given every 3 weeks confirmed the 3-month survival advantage of the earlier study.[49] On the basis of these data, docetaxel chemotherapy has become the standard first-line chemotherapy treatment for advanced CRPC.

Cabazitaxel. This microtubule inhibitor with a mechanism of action similar to that of docetaxel was approved by the FDA in June 2010 for the treatment of metastatic CRPC after the use of docetaxel chemotherapy.[50] In a recently reported, randomized phase III trial, cabazitaxel given every 3 weeks with prednisone improved median overall survival by 2.4 months (15.1 vs 12.7 months) compared with mitoxantrone and prednisone.[51,52] The investigator-assessed tumor response rate was 14.4% for patients in the cabazitaxel group compared with 4.4% in the mitoxantrone group, and median progression-free survival was 2.8 months in the cabazitaxel group vs 1.4 months in the mitoxantrone group (hazard ratio [HR], 0.74; 95% CI, 0.64–0.86; P < .0001). The patients in this study were required to have chemotherapy-resistant, very advanced disease, thus establishing a new standard, second-line therapy for metastatic CRPC. About 80% of patients had bony metastasis, 50% had measurable soft-tissue disease, and 25% had visceral lesions. The authors did not break out results with respect to palliation of bone pain or disease progression as a function of bone metastasis, which would likely have been difficult in this patient population with mixed bony, visceral, and soft-tissue disease; interpretation of the results with respect to specific treatment of bony disease is thus difficult.

Bone marrow suppression was observed in those treated with cabazitaxel, who experienced a 7.5% incidence of febrile neutropenia compared with 1.3% in those treated with mitoxantrone. There was an increased risk of death within 30 days of last dose in the cabazitaxel-treated patients (5%) compared with the risk in the mitoxantrone-treated patients (2%). Bone marrow suppression can be minimized by granulocyte colony–stimulating factor support. Study investigators recommend close monitoring of patients and future investigation into possible single-nucleotide polymorphisms in genes such as CYP3A4 and CYP3A5, which are responsible for the metabolism of cabazitaxel and which may contribute to such toxicities.

Immunotherapies

Sipuleucel-T. In the late 1990s, researchers began to investigate the concept of tumor-specific immunity, whereby an immune response is stimulated in order to target tumor cells for destruction.[53] This idea was central to the development of sipuleucel-T. In the course of treatment with sipuleucel-T, a patient’s antigen-presenting cells (APCs; specifically dendritic cells) are collected via leukapheresis and then loaded ex vivo with a fusion protein consisting of prostatic acid phosphatase (PAP) and granulocyte-macrophage colony–stimulating factor (GM-CSF). After culturing this fusion protein with the dendritic cells, the product is then reinfused into the patient, activating T-cells via class I and class II HLA molecules and resulting in a beneficial immune response against PAP.

Initial studies found PSA level to be a poor marker of clinical response in the case of sipuleucel-T.[54] To address this potential inadequacy of PSA levels, investigators altered the definition of “progression” from a biochemical change (in PSA level), to objective enlargement of soft tissue disease or the appearance of two or more new lesions on radionuclide bone scan. Using this new definition, median time to progression in a phase II study was 118 days.[55]

A phase III trial enrolled 127 asymptomatic men with metastatic CRPC randomized in a 2:1 ratio to receive either sipuleucel-T or placebo.[56] Interestingly, there was no significant difference in time to progression between the two treatment arms, but there was a 4.5-month improvement (P = .01) in overall survival in the sipuleucel-T arm. However, this study was not originally designed to detect an increase in overall survival.

To bolster proof of clinical efficacy, investigators proceeded with a second phase III, double-blind, placebo-controlled, multicenter trial of sipuleucel-T that was designed to measure its effect on overall survival.[57] In this trial, 512 patients were randomized in a 2:1 ratio to receive either sipuleucel-T or placebo. The study detected a 4.1-month improvement in overall survival compared with placebo, despite allowing 109 of 171 patients in the placebo group to cross over and receive salvage sipuleucel-T (prepared and cryopreserved at the time of placebo preparation). Adverse events in the treated group were primarily limited to fever, chills, and headache at or near the time of the infusion. Similar to previous studies, there were no differences in the time to disease progression (measured radiographically at 6, 14, 26, and 34 weeks, and every 12 weeks thereafter) between the two groups.

Investigators attributed the discordance between the observed survival benefit and the lack of effect on disease progression to a possible class effect, since a similar phenomenon has been reported in a study on poxviral-based PSA-targeted immunotherapy (PROSTVAC-VF).[43] Other studies of metastatic CRPC have also shown a lack of correlation between disease progression and overall survival.[56,58] Sipuleucel-T was approved by the FDA in April 2010 for the treatment of metastatic CRPC that is asymptomatic or minimally symptomatic. Because the focus of this review is palliative treatment of metastatic disease, we point out that there is currently no evidence to support the use of sipuleucel-T in symptomatic patients.

Emerging Bone-Targeted Agents That Go Beyond Palliation and May Improve Survival

Src inhibitors

Src is a member of the largest family of protein tyrosine kinases, the Src family kinases (SFKs). Src has been widely implicated through increased expression and/or activity in many visceral cancers, including prostate cancer. In addition, Src has been implicated in proliferation, invasion, and migration of prostate cancer cell lines in vitro, and may be involved in the transition from the castrate-sensitive to the castrate-resistant state.[59,60] Of further interest, Src is implicated in osteoblast differentiation and osteoclast activation, and inhibitors have demonstrated induced apoptosis of osteoclasts, reduced bone resorption, but enhanced bone-forming activity through osteoblast activity.[61,62] For an excellent overview of Src and its implications in prostate cancer, see the 2007 article by Karim Fizazi in the Annals of Oncology.[63]

A phase II study of dasatinib (Sprycel) monotherapy in 47 patients with chemotherapy-naive CRPC reported lack of progression in 43% of patients at week 12 and in 19% at week 24, reductions in uNTx and bone-specific alkaline phosphatase (ALP) levels in a majority of patients, and achievement of a PSA decline of ≥ 50% in three patients.[64-66] Dasatinib and other Src inhibitors are interesting in that this class of pharmaceuticals theoretically has both direct anti-tumor effects (evidenced by lack of progression, regression, and/or PSA declines) and bone-targeted mitigation of the deleterious effects of metastases. Although this phase II study demonstrated both these effects, only changes in bone-turnover markers were reported, not clinical outcomes such as SREs or overall survival. Other studies, however, have shown a positive correlation of these markers with clinical outcomes.

A phase I/II study combining dasatinib with docetaxel in patients with metastatic CRPC showed a PSA response in 41% and an objective tumor response in 57% of patients with measurable disease.[67] One third of patients experienced an improvement of disease on bone scan, and two thirds had stable disease in bone for ≥ 6 weeks. A randomized phase III trial of docetaxel and prednisone with or without dasatinib (NCT00744497) is ongoing, with a primary endpoint of overall survival.[68]

In summary, Src kinase inhibitors offer the potential for direct antitumor activity and bone-targeted therapy, although clinical outcomes with respect to SREs have yet to be reported. This class of drugs has been evaluated as monotherapy in chemotherapy-naive patients and is undergoing further study in combination with docetaxel. While there are other Src inhibitors in development, only saracatinib (previously referred to as AZD0530) is currently being studied in prostate cancer.[69,70] Phase II trials of this drug are currently in the recruitment phase.

Endothelin-A receptor antagonists

The endothelin pathway has been implicated in the development and progression of PCa. Endothelins modulate vasomotor tone, nociception, cell proliferation, and angiogenesis; in addition, endothelins bind two receptors, endothelin-A and endothelin-B. Patients with metastatic CRPC have been noted to have elevated levels of endothelin-1 in plasma compared with patients with nonmetastatic disease. In addition to their involvement with PCa tumor cells, there is evidence that endothelins are involved in osteoblastic bone turnover activity.[71,72] Inhibitors of the endothelin receptors have thus been studied clinically in the setting of nonmetastatic and metastatic CRPC.

Atrasentan. Atrasentan (Xinlay) is primarily an endothelin-A antagonist. Initial, phase II study data comparing a 10-mg oral daily dose of atrasentan to placebo in 288 patients with asymptomatic, metastatic CRPC found encouraging results: there was a statistically significant longer median time to progression with atrasentan (196 vs 129 days; P = .021).[73] Median time to PSA progression was also longer with atrasentan than with placebo (155 vs 71 days; P = .002). At 180 days, only 35% of placebo-treated patients were free from progression of disease, but 54% of atrasentan-treated patients were still free from progression. Serum markers (lactate dehydrogenase and alkaline phosphatase) were not significantly different between the two groups.

Based on these promising data, phase III trials were conducted in patients with nonmetastatic CRPC and in patients with metastatic CRPC.[74,75] Neither trial demonstrated any difference in time to progression between the atrasentan and placebo groups, but there were significant differences in serum bone turnover markers and PSA levels. In the nonmetastatic CRPC trial, there was a trend towards prevention of progression to skeletal metastasis, but this did not reach significance. Bone pain was not significantly different between the two groups in the metastatic CRPC trial, but a subset analysis of patients with bone metastases at baseline (59%) suggested a greater delay in time to progression. Thus, it has been suggested that this drug class may provide more benefit in patients with bone disease.[72]

Zibotentan. Another endothelin-A receptor antagonist, zibotentan (or ZD4054), has undergone testing in phase I and II studies. A phase II study randomly assigned patients with metastatic CRPC to receive placebo or zibotentan; study investigators found that time to progression was not different between the two groups, but overall survival was significantly different (23.5 months vs 17.3 months; HR, 0.65 [80% CI, 0.49–0.86]; P = .052). Final analysis demonstrated that there were fewer new metastases to bone with 10 mg zibotentan than with placebo (treatment ratio, 0.83; 80% CI, 0.70–0.98; P = .155), but this was not seen with 15-mg dosing (although the latter cohort did have a slightly higher number of baseline bony metastases).[76]

Currently, there are multiple phase III trials underway for both atrasentan and zibotentan as combination therapy with docetaxel in patients with metastatic CRPC; primary outcomes are progression-free survival and overall survival.[77-79] Some survival advantage with this class of drugs and trends towards increased efficacy in patients with metastatic lesions to bone have been seen; we await the final results of the combination trials for final assessment of these drugs with respect to treatment of bony disease, pain, and progression of disease.

Antisense therapies

Clusterin functions as a cytoprotective chaperone protein that is upregulated with therapy-induced cell stress; clusterin has been identified as a potential therapeutic target in CRPC.[80] OGX-011 (Custersin) is complementary to the clusterin mRNA translation initiation site, thereby inhibiting its translation into function product. A randomized controlled trial comparing docetaxel plus prednisone with or without OGX-011 in the treatment of patients with metastatic CRPC demonstrated promising results. Overall survival was 23.8 with OGX-011 vs 16.9 months without OGX-011 (HR, 0.50; 95% CI, 0.29-0.87).[81] A second randomized controlled trial examined OGX-011 in combination with docetaxel or mitoxantrone as second-line therapy in patients with metastatic CRPC after progression on docetaxel therapy.[82] Overall survival was 15.8 months in the docetaxel plus OGX-011 arm vs 11.5 months in the mitoxantrone plus OGX-011 arm, comparing favorably to cabazitaxel. Phase III studies of OGX-011 are underway, with one exploring survival as a primary endpoint and another examining pain palliation.[83,84]

Alpha-particle emitters

Alpha particles consist of two protons and two neutrons, similar to a helium nucleus. They are highly ionizing and have low penetration depth, affecting only nearby tissues and limiting toxicity. There is currently only one alpha-emitting radionuclide under investigation, radium-223 (²²³Ra; Alpharadin).

Initial phase I data, published in 2005, included 15 PCa and 10 breast cancer patients.[85] Each patient received a single dose of ²²³Ra, with the doses ranging in intensity from 46 to 250 kBq/kg. Grade 3 neutropenia and leucopenia occurred in two and three patients, respectively. Ten of the 25 patients experienced transient diarrhea. Nausea and vomiting were more frequently observed in the highest dosage group. Notably, pain relief was reported by 52%, 60%, and 56% of the patients after 7 days, 4 weeks, and 8 weeks, respectively. ²²³Ra was noted to clear rapidly from blood and was below 1% of initial level at 24 hours. Excretion was primarily gastrointestinal (GI), accounting for the GI-related side effects.

Another phase I dose-escalation study involved 10 men with progressive CRPC with more than two bone metastases; the patients were treated in three cohorts, with dose levels of 50, 100, and 200 kBq/kg.[86] Patients received one treatment at the cohort-defined dose, followed by one optional treatment 6 weeks later at 50 kBq/kg. This study demonstrated no dose-related toxicities. ²²³Ra accumulated in bone metastases within the first 10 minutes of injection. Three patients suffered grade 3 hematologic toxicities, which were not related to dose level. ²²³Ra was well tolerated at doses up to 200 kBq/kg.

Another study examined dosimetry and biodistribution of ²²³Ra in six patients with CRPC and bone metastases.[87] Doses of absorbed radiation were calculated for various tissues: red marrow, 0.23 Gy/MBq; and lower large intestine wall, 0.05 Gy/MBq. As decaying alpha particles are released from ²²³Ra, their short range (< 100 µm) affects only a small volume of red marrow, likely accounting for a favorable safety profile even in patients with extensive skeletal metastatic disease.

Phase II data from a larger cohort of patients were published in Lancet Oncology in 2007.[88] Thirty-three patients were randomly assigned to receive 4 IV injections of ²²³Ra (50 kBq/kg), and 31 were randomly assigned to receive placebo. Primary endpoints included changes in bone ALP and time to an SRE. Secondary endpoints consisted of side-effect profile, time to PSA progression, and overall survival. ALP declined 66% relative to baseline in the ²²³Ra-treated patients, whereas it increased 9% in the patients who received placebo (P < .0001). Hazard ratio for time to SRE was 1.75, but significance was not achieved (95% CI, 0.96-3.19; P = .065). Time to PSA progression was 26 weeks for ²²³Ra vs 9 weeks for placebo. Overall survival was 65 weeks for the treatment group vs 46 weeks for the control group (P = .066), but after adjusting for baseline patient characteristics, this became significant (P = .020). The bone-targeted effects were significant, yet there was minimum myelotoxicity (no difference was noted between the two groups).

On the basis of these results, a phase III randomized controlled trial with 922 patients was started. Investigators randomly assigned the patients in a 2:1 ratio to receive ²²³Ra or placebo, in addition to standard care. Each patient randomized to ²²³Ra received injections every 4 weeks for 6 total doses. The primary endpoint was overall survival. Results have not yet been published, but very recently, investigators announced that the trial was going to halt early after a planned interim analysis.[89] The data safety monitoring board noted a 30% reduction in the odds of dying during follow-up in the ²²³Ra treatment arm, and a median increase in overall survival of 3 months. Four percent of patients were noted to have suffered hematologic toxicity (2% grade 3/4), and 8% suffered thrombocytopenia (4% grade 3/4).

Perspectives

Cytotoxic therapies such as docetaxel and cabazitaxel have been shown to have proven benefit and potential. They are, however, limited by the development of resistance and systemic toxicities. Treatment with other agents after the development of resistance is not well defined, although some of the other drugs discussed in this review may ultimately be of use for patients with chemotherapy-resistant CRPC. In a future article, we will deal with the important challenges of sequencing the many new therapies for CRPC.

REFERENCE GUIDE

Therapeutic Agents
Mentioned in This Article

Atrasentan (Xinlay)
Cabazitaxel (Jevtana)
Dasatinib (Sprycel)
Denosumab (Xgeva)
Docetaxel
Estramustine (Emcyt)
Mitoxantrone (Novantrone)
OGX-011(Custersin)
Phosphorus-32
Prednisone
PROSTVAC-VF
Radium-223 (Alpharadin)
Rhenium-186
Rhenium-188
Samarium-153 (Quadramet)
Saracatinib
Sipuleucel-T (Provenge)
Strontium-89 (Metastron)
Zibotentan
Zoledronic acid (Zometa)

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.

Despite an explosion in the number of agents under investigation for the treatment of CRPC, very few offer direct efficacy against metastatic disease spread to the bone. As stated, bony metastasis accounts for a great deal of morbidity and mortality. Palliation is an important aspect of treatment, and some interventions have also shown success in mitigating SREs. Systemic chemotherapy is likely to remain the mainstay of treatment for CRPC in the years to come, with therapies such as those discussed here used as adjunctive treatments to achieve specific clinical aims.

Endothelin-A receptor antagonists may have some activity against tumor in bone, but single-agent studies do not show any evidence of benefit, and it remains unclear whether endpoints other than those reported might be associated with positive results. Nevertheless, these agents are currently under study in combination with other proven therapies for CPRC in the hope of realizing synergistic outcomes. We await these results.

Among agents that specifically target bone, alpha pharmaceuticals offer particular promise for activity and safety in men with bony metastasis. Investigators have finished phase I and II studies, and recently ended phase III study early after the safety monitoring board found a significant increase in overall survival in patients receiving ²²³Ra compared with those receiving placebo. In a future article, we hope to review in detail the development and clinical activity of this agent. There are ongoing studies examining ²²³Ra in combination with docetaxel. If approved for use, it remains to be seen in which patient population and following which other therapies alpha pharmaceuticals might be most appropriate. Given the plethora of agents now available to clinicians, the choice will likely depend largely on the comfort of the physician with the administration of a given therapy (radiopharmaceuticals require extra safety and training) and on discussion with the patient.

Conclusions

For many years, docetaxel chemotherapy was the only treatment that showed a true survival advantage for men with CRPC. Now, entire new classes of drugs aim to treat and target disease, palliate symptomatic pain, and prevent SREs. These represent dramatic new advances in the field of urologic oncology and promise a real therapeutic advantage in the treatment of CRPC and bony metastases. Treating physicians will be faced with significant challenges in determining the sequencing of these new agents.

Financial Disclosure: Dr. Crawford serves on advisory boards for Ferring, sanofi aventis, Bayer, Amgen, and Dendreon; also, a member of his family is an employee of Ferring. Dr. Rove has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

REFERENCES

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

2. Mundy GR. Metastasis: Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer. 2002;2:584-93.

3. Galasko C. The anatomy and pathways of skeletal metastases. In: Bone metastasis. Weiss I, Gilbert A, editors. Boston: GK Hall Medical Publishers; 1981.

4. Paget S. The distribution of secondary growths in cancer of the breast. Lancet. 1989;1:571-2.

5. Hauschka P, Mavrakos A, Iafrati M, et al. Growth factors in bone matrix. Isolation of multiple types by affinity chromatography on heparin-Sepharose. J Biol Chem. 1986;261:12665-75.

6. Rosen LS, Gordon D, Kaminski M, et al. Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter, comparative trial. Cancer. 2003;98:1735-44.

7. Mohammad KS, Fournier PG, Guise TA, et al. Agents targeting prostate cancer bone metastasis. Anti-Cancer Agents Med Chem. 2009;9:1079-88.

8. Licata AA. Discovery, clinical development, and therapeutic uses of bisphosphonates. Ann Pharmacother. 2005;39:668-77.

9. Smith MR, Eastham J, Gleason DM, et al. Randomized controlled trial of zoledronic acid to prevent bone loss in men receiving androgen deprivation therapy for nonmetastatic prostate cancer. J Urol. 2003;169:2008-12.

10. Saad F, Gleason DM, Murray R, et al. Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst. 2004;96:879-82.

11. Weinfurt KP, Anstrom KJ, Castel LD, et al. Effect of zoledronic acid on pain associated with bone metastasis in patients with prostate cancer. Ann Oncol. 2006;17:986-9.

12. Saad F, Gleason D, 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.

13. Campbell S, Bhoopalam N, Moritz T, et al. The use of zoledronic acid in men receiving androgen deprivation therapy for prostate cancer with severe osteopenia or osteoporosis. Urology. 2010;75:1138-43.

14. Bhoopalam N, Campbell S, Moritz T, et al. Intravenous zoledronic acid to prevent osteoporosis in a veteran population with multiple risk factors for bone loss on androgen deprivation therapy. J Urol. 2009;182:2257-64.

15. Ozturk OH, Bozcuk H, Burgucu D, et al. Cisplatin cytotoxicity is enhanced with zoledronic acid in A549 lung cancer cell line: preliminary results of an in vitro study. Cell Biol Int. 2007;31:1069-71.

16. Bertelli G, Heouaine A, Arena G, et al. Weekly docetaxel and zoledronic acid every 4 weeks in hormone-refractory prostate cancer patients. Cancer Chemother Pharmacol. 2006;57:46-51.

17. Cummings S, Martin J, Mcclung M, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361:756.

18. Approved drug label: Denosumab. US Food and Drug Administration; 2011. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/125320s007lbl.pdf.

19. 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.

20. Smith MR, Egerdie B, Hernández Toriz N, et al. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med. 2009; 361: 745-55.

21. Smith MR, Saad F, Egerdie B, et al. Effects of denosumab on bone mineral density in men receiving androgen deprivation therapy for prostate cancer. J Urol. 2009;182:2670-75.

22. Fizazi K, Carducci MA, Smith MR, et al. 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.

23. Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet. 2011;377:813-22.

24. Saad F, Smith MR, Coleman R, et al. Denosumab treatment for prolonging bone metastasis-free survival in men with castrate-resistant prostate cancer. South Central Section of the American Urological Association. 2011. San Antonio, TX.

25. Finlay IG, Mason MD, Shelley M. Radioisotopes for the palliation of metastatic bone cancer: a systematic review. Lancet Oncol. 2005;6:392-400.

26. Winston M. Radioisotope therapy in bone and joint disease. Semin Nucl Med. 1979;9:114-20.

27. Pecher C. Biological investigations with radioactive calcium and strontium: preliminary report on the use of radioactive strontium in treatment of metastatic bone cancer. Berkeley, CA: University of California Press. 1942;117.

28. Lewington V, McEwan A, Ackery D, et al. A prospective, randomised double-blind crossover study to examine the efficacy of strontium-89 in pain palliation in patients with advanced prostate cancer metastatic to bone. Eur J Cancer. 1991;27:954-8.

29. Quilty PM, Kirk D, Bolger JJ, et al. A comparison of the palliative effects of strontium-89 and external beam radiotherapy in metastatic prostate cancer. Radiother Oncol. 1994;31:33-40.

30. Resche I, Chatal JF, Pecking A, et al. A dose-controlled study of153Sm-ethylenediaminetetramethylenephosphonate (EDTMP) in the treatment of patients with painful bone metastases. Eur J Cancer. 1997;33:1583-91.

31. Serafini AN, Houston SJ, Resche I, et al. Palliation of pain associated with metastatic bone cancer using samarium-153 lexidronam: a double-blind placebo-controlled clinical trial. J Clin Oncol. 1998;16:1574-81.

32. 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.

33. Sartor O, Reid RH, Bushnell DL, et al. Safety and efficacy of repeat administration of samarium Sm-153 lexidronam to patients with metastatic bone pain. Cancer. 2007;109:637-43.

34. Tu SM, Millikan RE, Mengistu B, et al. Bone-targeted therapy for advanced androgen-independent carcinoma of the prostate: a randomised phase II trial. Lancet. 2001;357:336-41.

35. Fizazi K, Beuzeboc P, Lumbroso J, et al. Phase II trial of consolidation docetaxel and samarium-153 in patients with bone metastases from castration-resistant prostate cancer. J Clin Oncol. 2009;27:2429-35.

36. Frassica DA. General principles of external beam radiation therapy for skeletal metastases. Clin Orthop Relat Res. 2003;415:S158-64.

37. Poulter CA, Cosmatos D, Rubin P, et al. A report of RTOG 8206: a phase III study of whether the addition of single dose hemibody irradiation to standard fractionated local field irradiation is more effective than local field irradiation alone in the treatment of symptomatic osseous metastases. Int J Radiat Oncol Biol Phys. 1992;23:207-14.

38. Wu JS-Y, Wong R, Johnston M, et al. Meta-analysis of dose-fractionation radiotherapy trials for the palliation of painful bone metastases. Int J Radiat Oncol Biol Phys. 2003;55:594-605.

39. Ratanatharathorn V, Powers WE, Moss WT, et al. Bone metastasis: review and critical analysis of random allocation trials of local field treatment. Int J Radiat Oncol Biol Phys. 1999;44:1-18.

40. Chow E, Danjoux C, Connolly R, et al. Bone metastasis: review and critical analysis of random allocation trial of local field treatment: regarding Ratanatharathorn et al. IJROB. 1999;44(1):1-18. Int J Radiat Oncol Biol Phys. 2000;46:517-18.

41. Tannock IF, Osoba D, Stockler M, 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.

42. Sidana A, Chowdhury W, Fuchs E, et al. Cryoimmunotherapy in urologic oncology. Urology. 2010;75:1009-14.

43. Kantoff PW, Schuetz TJ, Blumenstein BA, et al. Overall survival analysis of a phase II randomized controlled trial of a Poxviral-based PSA-targeted immunotherapy in metastatic castration-resistant prostate cancer. J Clin Oncol. 2010;28:1099-1105.

44. de Bono JS, Scher HI, Montgomery RB, et al. Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer. Clin Cancer Res. 2008;14:6302-09.

45. Rosenberg J, Weinberg V, Kelly WK, et al. Activity of second‐line chemotherapy in docetaxel‐refractory hormone‐refractory prostate cancer patients. Cancer. 2007;110:556-63.

46. Rove KO, Flaig TW. A renaissance in the medical treatment of advanced prostate cancer. Oncology (Williston Park, NY). 2010;24:1308-13, 1318.

47. Petrylak DP, Tangen C, Hussain M, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004;351:1513.

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

49. Berthold DR, Pond GR, Soban F, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study. J Clin Oncol. 2008;26:242-5.

50. Galsky M, Dritselis A, Kirkpatrick P, et al. Cabazitaxel. Nat Rev Drug Discov. 2010;9:677-8.

51. Sartor A, Oudard S, Ozguroglu M, et al. Cabazitaxel or mitoxantrone with prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel: final results of a multinational phase III trial (TROPIC). ASCO Genitourinary Cancers Symposium. 2010; abstract 9.

52. 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.

53. Celluzzi CM, Mayordomo JI, Storkus WJ, et al. Peptide-pulsed dendritic cells induce antigen-specific CTL-mediated protective tumor immunity. J Exp Med. 1996;183:283-7.

54. Small EJ, Fratesi P, Reese D, et al. Immunotherapy of hormone-refractory prostate cancer with antigen-loaded dendritic cells. J Clin Oncol. 2000;18:3894.

55. Burch PA, Croghan GA, Gastineau DA, et al. Immunotherapy (APC8015, Provenge) targeting prostatic acid phosphatase can induce durable remission of metastatic androgen-independent prostate cancer: a Phase 2 trial. Prostate. 2004;
60:197-204.

56. Small EJ, Schellhammer P, Higano C, 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.

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

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. Unni E, Sun S, Nan B, et al. Changes in androgen receptor nongenotropic signaling correlate with transition of LNCaP cells to androgen independence. Cancer Res. 2004;64:7156-68.

60. Saad F. SRC kinase inhibition: targeting bone metastases and tumor growth in prostate and breast cancer. Cancer Treat Rev. 2010;36:177-84.

61. Recchia I, Rucci N, Funari A, et al. Reduction of c-Src activity by substituted 5,7-diphenyl-pyrrolo[2,3-d]-pyrimidines induces osteoclast apoptosis in vivo and in vitro. Involvement of ERK1/2 pathway. Bone 2004;34:65-79.

62. Marzia M, Sims NA, Voit S, et al. Decreased c-Src expression enhances osteoblast differentiation and bone formation. J Cell Biol. 2000;151:311-20.

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

64. Yu E, Wilding G, Posadas E, et al. Dasatinib in patients with hormone-refractory progressive prostate cancer: a phase II study. J Clin Oncol. 2008;
26: 88s.

65. 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.

66. Yu EY, Massard C, Gross ME, et al. Once-daily dasatinib: expansion of phase II study evaluating safety and efficacy of dasatinib in patients with metastatic castration-resistant prostate cancer. Urology. 2011;77:1166-71.

67. Araujo J, Armstrong A, Braud E, et al. Dasatinib and docetaxel combination treatment for patients with castration-resistant progressive prostate cancer: a phase I/II study (CA180086). J Clin Oncol. 2009;27:249s.

68. Clinical Trial NCT00744497: Randomized study comparing docetaxel plus dasatinib to docetaxel plus placebo in castration-resistant prostate cancer. US National Institutes of Health. Available at: http://clinicaltrials.gov/ct2/show/NCT00744497. Accessed November 6, 2011.

69. Tabernero J, Cervantes A. Phase I study of AZD0530, an oral potent inhibitor of Src kinase: first demonstration of inhibition of Src activity in human cancers. J Clin Oncol. 2007;25(suppl):23s.

70. Lara PN Jr, Longmate J, Evans CP, et al. A phase II trial of the Src-kinase inhibitor AZD0530 in patients with advanced castration-resistant prostate cancer: a California Cancer Consortium study. Anti-Cancer Drugs. 2009;20:179-84.

71. Akhavan A, McHugh KH, Guruli G, et al. Endothelin receptor A blockade enhances taxane effects in prostate cancer. Neoplasia. 2006;8:725-32.

72. Carducci MA, Jimeno A. Targeting bone metastasis in prostate cancer with endothelin receptor antagonists. Clin Cancer Res. 2006;12:6296s-6300s.

73. Carducci MA, Padley RJ, Breul J, et al. Effect of endothelin-A receptor blockade with atrasentan on tumor progression in men with hormone-refractory prostate cancer: a randomized, phase II, placebo-controlled trial. J Clin Oncol. 2003;21:679-89.

74. Carducci MA, Saad F, Abrahamsson P-A, 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.

75. 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.

76. James ND, Caty A, Payne H, et al. Final safety and efficacy analysis of the specific endothelin A receptor antagonist zibotentan (ZD4054) in patients with metastatic castration-resistant prostate cancer and bone metastases who were pain-free or mildly symptomatic for pain: a double-blind, placebo-controlled, randomized phase II trial. BJU Int. 2010;106:966–73.

77. Clinical Trial NCT00134056: 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. US National Institutes of Health. Available at: http://clinicaltrials.gov/ct2/show/NCT00134056. Accessed October 15, 2011.

78. Clinical Trial NCT00617669: A phase III trial of ZD4054 (zibotentan) (endothelin A antagonist) and docetaxel in metastatic hormone resistant prostate cancer. US National Institutes of Health. Available at: http://clinicaltrials.gov/ct2/show/NCT00617669. Accessed November 6, 2011.

79. Clinical Trial NCT00554229: A phase III trial of ZD4054 (zibotentan) (endothelin A antagonist) in hormone resistant prostate cancer with bone metastases. US National Institutes of Health. Available at: http://clinicaltrials.gov/ct2/show/NCT00554229. Accessed October 30, 2011.

80. July LV, Akbari M, Zellweger T, et al. Clusterin expression is significantly enhanced in prostate cancer cells following androgen withdrawal therapy. Prostate. 2002;50:179-88.

81. 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.

82. Saad F, Hotte S, North S, et al. Randomized phase II trial of Custirsen (OGX-011) in combination with docetaxel or mitoxantrone as second-line therapy in patients with metastatic castrate-resistant prostate cancer progressing after first-line docetaxel: CUOG trial P-06c. Clin Cancer Res. 2011;17:5765-73.

83. Clinical Trial NCT01188187: Comparison of docetaxel/prednisone to docetaxel/prednisone in combination with OGX-011 in men with prostate cancer. US National Institutes of Health. Available at: http://clinicaltrials.gov/ct2/show/NCT01188187. Accessed November 1, 2011.

84. Clinical Trial NCT01083615: A study evaluating the pain palliation benefit of adding custirsen to docetaxel retreatment or cabazitaxel as second line therapy in men with metastatic castrate resistant prostate cancer (mCRPC). US National Institutes of Health. Available at: http://clinicaltrials.gov/ct2/show/NCT01083615. Accessed November 6, 2011.

85. Nilsson S, Larsen R, Fosså S, et al. First clinical experience with α-emitting radium-223 in the treatment of skeletal metastases. Clin Cancer Res. 2005;11:4451-9.

86. Morris M, Carrasquillo J, O’Donoghue J, et al. Phase I pharmacokinetic (PK) and biodistribution study with escalating doses of radium-223 in men with castration-resistant metastatic prostate cancer (CRMPC). ASCO Genitourinary Cancers Symposium. 2010; abstract 211.

87. Lewington V, Parker C, Hindorf C, et al. Alpharadin: a novel, targeted approach for treatment of bone metastases from CRPC-calculated alpha-particle dosimetry compared to a favorable clinical safety profile. ASCO Genitourinary Cancers Symposium. 2010; abstract 216.

88. Nilsson S, Franzén L, Parker C, et al. Bone-targeted radium-223 in symptomatic, hormone-refractory prostate cancer: a randomised, multicentre, placebo-controlled phase II study. Lancet Oncol. 2007;8:587-94.

89. Bankhead C. Radium-223 Improves prostate cancer survival. Medpage Today. 2011. Available at: http://www.medpagetoday.com/MeetingCoverage/ECCO-ESMO/28706. Accessed October 2, 2011.

90. Clinical Trial NCT00699751: Phase III study of Alpharadin (radium-223) in patients with symptomatic hormone refractory prostate cancer with skeletal metastases. US National Institutes of Health. Available at: http://clinicaltrials.gov/ct2/show/NCT00699751. Accessed November 6, 2011.

91. Groot MTZ, Boeken Kruger CG, Pelger RC, Uyl-de Groot CA. Costs of prostate cancer, metastatic to the bone, in the Netherlands. Eur Urol. 2003;43:226-32.

92. Weinfurt KP, Li Y, Castel LD. The impact of skeletal-related events on health-related quality of life of patients with metastatic prostate cancer. Ann Oncol. 2002;13(suppl 5): abstract 662P.

93. Weinfurt KP, Castel LD, Li Y, et al. Health-related quality of life among patients with breast cancer receiving zoledronic acid or pamidronate disodium for metastatic bone lesions. Med Care. 2004;42:
164-75.

94. Saad F, Olsson C, Schulman CC. Skeletal morbidity in men with prostate cancer: quality-of-life considerations throughout the continuum of care. Eur Urol. 2004;46:731-39; discussion 739-40.

95. Oefelein MG, Ricchiuti V, Conrad W, Resnick MI. Skeletal fractures negatively correlate with overall survival in men with prostate cancer. J Urol. 2002;
168:1005-7.

96. Riggs BL, Melton LJ 3rd. The worldwide problem of osteoporosis: insights afforded by epidemiology. Bone. 1995;17(Suppl 5):505S-511S.

97. Roodman GD. Mechanisms of bone metastasis. N Engl J Med. 2004;350:1655-64.