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Drugs That Offer a Survival Advantage for Men With Bone Metastases Resulting From Castration-Resistant Prostate Cancer
Bone metastases from prostate cancer are a substantial source of morbidity and mortality. Prostate cancer caused about 30,000 deaths in the U.S. in 2013, trailing only lung cancer among the leading causes of deaths attributed to cancer and accounting for 10% of all deaths from cancer in American men.1 About 90% of deaths from prostate cancer are in men 65 years of age and older.1 Most of these deaths result from invasive prostate cancer, the risk of which rises with age (
Prostate cancer is an androgen-driven disease, a characteristic that provides a therapeutic approach. Surgical or medical castration (androgen-deprivation therapy, or ADT) is commonly used in combination with radiation therapy to treat localized or locally advanced prostate cancer. ADT is a primary systemic therapy in advanced prostate cancer. Initially, ADT often results in rapid improvement in symptoms and disease markers. In patients with newly diagnosed metastatic prostate cancer, disease progression during ADT therapy can be observed in a median of 18 to 24 months after castration.2 Without treatment, median survival of men with metastatic castration-resistant prostate cancer (mCRPC) is 10 to 12 months.2 The term castration-resistant now is preferred over androgen-independent and hormone-refractory, reflecting discoveries showing that androgen signaling and overexpression of the androgen receptor drive this form of the disease, which progresses despite ADT.3
When prostate cancer metastasizes, it most commonly spreads to bone and often only to bone. Up to 90% of men with mCRPC have radiographically detectable bone metastases.4 Metastases to bone commonly result in multifocal pain, pathological fractures, and cachexia, a syndrome consisting of body wasting, anorexia, and pain that may be responsible for many deaths from prostate cancer.5
This article reviews recently approved agents and investigational agents for treating men with mCRCP that has spread to bone, with a focus on drugs for which a survival benefit has been demonstrated or is under investigation as the primary outcome (
In the late 1800s, the English surgeon Stephen Paget (1855–1926; the son of James Paget, who characterized Paget’s disease) helped to popularize the “seed-and-soil” hypothesis of metastasis, in which certain hospitable organs provide a congenial soil for tumor cells acting as the seeds of metastasis.6 Paget presented evidence from 735 necropsies of women with metastatic breast cancer showing that instead of being randomly distributed among the organs, metastases most often were found in the liver and lungs, in contrast to the kidneys and spleen. He found similarly skewed distributions in 244 necropsies after uterine cancer. He also reported the findings of other investigators who had noticed bone abnormalities, if not overt metastases, in patients with breast cancer. During the ensuing decades, clinical observations continued to suggest that some organs were more prone to metastases than others, but the seed-and-soil hypothesis didn’t gain a scientific foundation until nearly a century later, when it was shown that the nonrandom distribution of metastases depended on characteristics of tumor cells and target organs.7
What are the characteristics of prostate cancer cells and bone that facilitate the development of bone metastases?
Under normal physiological conditions, bone undergoes a continuous process of remodeling, in which osteoclasts remove old bone and osteoblasts (before becoming osteocytes) lay down new bone matrix at remodeling sites. When cancer metastasizes to bone, the remodeling process becomes dys-functional. Depending on the type of bone-remodeling cell that dominates, bone metastases can be described as osteoblastic, in which osteoblasts create excessive amounts of new bone, or osteolytic, in which osteoclasts remove bone at a rate greater than the rate at which it is replaced. In multiple myeloma, bone metastases are purely osteolytic. In about 80% of patients with breast cancer that has spread to bone, metastases are predominantly osteolytic and up to 20% of breast cancer bone metastases are predominantly osteoblastic.8 Osteoblastic metastases are characterized by an overabundance of low-quality bone that causes pain and is subject to pathological fracture.
In contrast to metastases in breast cancer, bone metastases in prostate cancer are predominantly osteoblastic. Even so, osteoclasts seem to play a key role in the establishment and maintenance of a vicious circle in mCRPC.8,9 Osteoclast activity releases cytokines from bone matrix, such as transforming growth factor-β (TFG-β), insulin-like growth factor (IGF), and fibroblast growth factor (FGF), which attract prostate cancer cells. These cancer cells, in turn, release growth factors such as IGF, endothelin-1 (ET-1), platelet-derived growth factor (PDGF), and bone morphogenic protein (MMP), which activate osteoblasts. The activated osteoblasts then secrete RANKL (receptor activator of nuclear factor-κB ligand), which binds with its receptor, RANK, on the surface of osteoclasts and activates them. RANKL also is released by prostate cancer cells.
Of the many molecules involved in this cycle, some recently have been investigated as targets for drug intervention, notably RANKL (which is blocked by denosumab [Xgeva, Amgen]) and a receptor for ET-1, ETA (blocked by atrasentan [Xinlay, Abbott] and zibotentan [AstraZeneca]). However, no benefit in overall survival (OS) has been demonstrated for any of them in phase 3 trials that enrolled men with mCRPC. Nor has an OS benefit been shown for zoledronic acid (e.g., Zometa, Novartis), which inhibits bone resorption through means not completely understood.
Since 2010, the FDA has approved five medications with indications for the treatment of patients with mCRPC (
Prior to the approval of these new therapies, the only FDA-approved drug showing an OS benefit in mCRPC was docetaxel (Taxotere, Sanofi). Docetaxel is a semisynthetic taxane that binds to tubulin, leading to dysfunctional microtubules and inhibition of mitosis. For men with symptomatic mCRPC, the National Comprehensive Cancer Network (NCCN) prefers docetaxel and prednisone as first-line chemotherapy.15
The indication for docetaxel in mCRPC was based on a phase 3 randomized study in which median OS in men receiving docetaxel every three weeks (n = 335) was 18.9 months versus 16.5 months in the group receiving mitoxantrone (Novantrone, various) every three weeks (n = 337).16 Mitoxantrone is a cytotoxic chemotherapeutic agent that relieves bone pain without conferring a survival advantage. Compared with the mitoxantrone group, docetaxel every three weeks reduced the risk of death by 24% (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.62–0.94; P = 0.009). Once-weekly docetaxel (n = 334) also was compared with mitoxantrone, but no statistically significant survival advantage was found in this docetaxel arm.
A second survival analysis conducted about 3½ years later, after the total number of deaths had increased from 557 to 867, confirmed the survival benefit seen with docetaxel every three weeks: a median OS of 19.2 months versus 16.3 months for mitoxantrone and a similar hazard ratio.17 The percentages of patients who survived at least three years were 18.6% and 13.5% in the every-three-week docetaxel and the mitoxantrone groups, respectively.
In another phase 3 study, a survival benefit of 1.9 months (17.5 vs. 15.6 months; P = 0.02) was observed in subjects with mCRPC who received docetaxel and estramustine (Emcyt, Pfizer) (n = 338) compared with those receiving mitoxantrone and prednisone (n = 336).2 In both studies, a high percentage of subjects had bone metastases. In the first study, at least 90% of subjects in each arm had bone metastases at baseline and 22% had visceral disease. In the second study, 84% to 88% had bone metastases at baseline, 10% had lung metastases, and about 9% had liver metastases.
After docetaxel fails as a first-line therapy in mCRPC, there is no consensus regarding the best second-line therapy, but the NCCN regards abiraterone acetate (with prednisone) and enzalutamide as a new standard of care in this setting.15 Both drugs interfere with androgen signaling. Other options after docetaxel failure are cabazitaxel, sipuleucel-T, and radium-223 dichloride, which also is a first-line option for men with symptomatic bone metastases but with no known visceral (liver, lung, or brain) metastases.
Like docetaxel, cabazitaxel is a semisynthetic taxane that binds to tubulin, thereby stabilizing microtubules and inhibiting mitosis. In an open-label phase 3 trial, men with mCRPC whose disease had progressed during or after docetaxel treatment were randomly assigned to cabazitaxel (n = 378) or mitoxantrone (n = 377). Each group also received daily prednisone.18 In the cabazitaxel group, the median OS was 15.1 months; in the mitoxantrone group, it was 12.7 months—a 30% relative reduction in death (HR, 0.70; 95% CI, 0.59–0.83; P < 0.001). At the time of the cutoff for the final analysis, at which point the median follow-up for both groups was 12.8 months, 63% in the cabazitaxel (234/371) and 75% in the mitoxantrone groups (279/371) had died. Of the mitoxantrone subjects, 87% had bone metastases, and of the cabazitaxel group, 80% had bone metastases; 25% of the men in each group had visceral metastases.
On the basis of this study, the FDA approved cabazitaxel in 2010 as a second-line therapy in mCRPC. The current NCCN guidelines regard cabazitaxel as a second-line option after docetaxel failure, noting that the survival benefit is relatively short (2.4 months) whereas the toxicity profile presents various challenges, notably neutropenia. However, a phase 3 trial (NCT01308567) that enrolled 1,170 chemotherapy-naive men with mCRPC is in progress, with the intention of demonstrating that cabazitaxel plus prednisone is superior to docetaxel plus prednisone in this population. The primary outcome measure is OS. The trial is expected to be completed by December 2017.
Therapies Targeting Androgen Synthesis or Signaling
Abiraterone Acetate (Zytiga)
Abiraterone acetate is a prodrug of abiraterone, which blocks cytochrome P450 17 (CYP17); CYP17 blockade prevents synthesis of androgens by the adrenal glands, testes, and the prostate tumor. Abiraterone acetate is taken orally once daily in combination with twice-daily oral prednisone to mitigate adrenocortical insufficiency. In mCRPC, the effect of abiraterone acetate on OS was evaluated in phase 3 trials in patients who previously received docetaxel19 as well as in patients who had not received docetaxel.20 These studies led to the FDA’s approval of abiraterone acetate for the treatment of mCRPC after previous therapy with docetaxel (2011) and prior to the use of docetaxel (2012).
In the trial enrolling patients who had received docetaxel, treatment with abiraterone acetate/prednisone (n = 797) reduced the risk of death by 35% compared with placebo plus prednisone (n = 398) (HR, 0.65; 95% CI, 0.54–0.77; P < 0.001).19 Median OS was 3.9 months greater in the abiraterone group (14.8 vs. 10.9 months). At the time of this primary survival analysis, death rates in the abiraterone and placebo groups were 42% (333/797) and 55% (219/398), respectively. For the final analysis, median OS was 15.8 months for abiraterone and 11.2 months for placebo (HR, 0.74; 95% CI, 0.64–0.86; P < 0.001).21 At the time of the final analysis, death rates were 63% in the abiraterone group (501/797) and 69% in the placebo group (274/398).
In the trial enrolling patients who had not received docetaxel, median OS in the group receiving placebo plus prednisone (n = 542) was 27.2 months, whereas the median OS was not reached for the group receiving abiraterone/prednisone (n = 546).20 To be eligible for this trial, patients had to be asymptomatic or minimally symptomatic; patients with visceral metastases were excluded.
Compared with placebo, abiraterone acetate reduced the risk of death by 25% (HR, 0.75; 95% CI, 0.61–0.93; P = 0.01); however, this outcome did not meet the prespecified test of statistical significance (P ≤ 0.001). In the subgroup of patients with bone metastases only at baseline, abiraterone acetate reduced the risk of death by 32% (HR, 0.68; 95% CI, 0.48–0.96).
Enzalutamide (Xtandi, MDV3100)
Enzalutamide, a once-daily oral inhibitor of androgen receptor signaling, was approved by the FDA in August 2012 for patients with mCRPC who previously received docetaxel. In a randomized pivotal phase 3 trial in which the primary endpoint was OS, median OS was 18.4 months among the patients receiving enzalutamide (n = 800) compared with 13.6 months for the placebo group (n = 399).3 The study was halted and unblinded after a planned interim analysis showed that enzalutamide reduced the risk of death by 37% compared with placebo (HR, 0.63; 95% CI, 0.53–0.75, P < 0.001). In the intent-to-treat (ITT) population, 39% of the enzalutamide patients (308/800) died, compared with 53% (212/399) of the placebo patients.
About 92% of patients in each study group had bone metastases at baseline. In the subgroup of patients with more than 20 bone lesions, the risk of death was reduced by 33% with enzalutamide compared with placebo (HR, 0.67; 95% CI, 0.52–0.87). Among patients with 20 or fewer bone lesions, the risk of death was 61% lower with enzalutamide than with placebo (HR, 0.59; 95% CI, 0.46–0.75). Enzalutamide also was superior to placebo for all secondary endpoints, including time to the first SRE (16.7 vs. 13.3 months, respectively; HR, 0.69; 95% CI, 0.57–0.84; P < 0.001).
The combination of enzalutamide plus abiraterone/prednisone versus enzalutamide alone was slated for investigation in a randomized phase 3 study (NCT01949337), which was slated to begin in December 2013 and is expected to be completed by December 2019. The primary outcome is OS in a population expected to comprise 1,224 men with mCRPC. Preliminary results for a phase 2 trial (NCT01650194), in which 41 of a planned 60 subjects with mCRPC have been enrolled, suggest that the safety profile seen with the combination of enzalutamide and abiraterone is favorable.22
Sipuleucel-T is a therapeutic cancer “vaccine” intended to induce an immune response against prostatic acid phosphatase (PAP), an antigen expressed by most prostate cancer cells. Sipuleucel-T is prepared, and tailored to each patient, by obtaining peripheral blood mononuclear cells via standard leukapheresis. Outside the body, this white blood cell fraction is cultured with a recombinant antigen consisting of PAP and granulocyte–macrophage colony-stimulating factor (GM–CSF), which activates immune cells. During culture, antigen-presenting cells (APCs) take up the PAP–GM-CSF complex and transform it into peptide fragments, displayed on the surface of APCs. Ex vivo culture allows APC activation and maturation to occur in an environment free from cancer cell immunosuppression. The activated APCs then are returned to the patient intravenously, along with the other cells obtained from leukapheresis.
The FDA approved sipuleucel-T on the basis of a randomized, double-blind, placebo-controlled phase 3 trial that enrolled 512 patients with asymptomatic or minimally symptomatic mCRPC.23 Patients with visceral (liver, lung, or brain) metastases were excluded, as were patients who reported moderate-to-severe prostate cancer-related pain and patients who used narcotics for cancer-related pain. The enrolled patients included 7% with soft-tissue disease only, 48% with bone disease only, and 44% with bone and soft-tissue disease; 43% had more than 10 bony metastases.
At the data cutoff point (median follow-up, 34 months), 62% (210/341) of patients in the sipuleucel-T group and 71% of men in the placebo group died. Median OS rates were 25.8 months for the sipuleucel-T group (n = 341) and 21.7 months for the placebo group (n = 171). Compared with placebo, sipuleucel-T reduced the risk of death by 22% (HR, 0.78; 95% CI, 0.61–0.98; P = 0.03).
The NCCN recommends sipuleucel-T for asymptomatic patients with mCRPC whose performance level is good (Eastern Cooperative Oncology Group 0–1) and whose life expectancy is six months or more, with the caveat that it is difficult to assess the benefit of sipuleucel-T in an individual patient on the basis of changes in PSA levels or bone or CT scans.15 In addition, after docetaxel failure in mCRPC, the NCCN says that sipuleucel-T could be a second-line option for systemic therapy.
Therapies Targeting Bone Metastases
Several agents that are indicated for pain relief or for the prevention of SREs in patients with prostate cancer and other diseases have not provided a survival advantage in mCRPC.
Zoledronic acid (Zometa)
Zoledronic acid is a bisphosphonate that inhibits bone resorption. It is indicated for treatment of bone metastases that have progressed following hormonal therapy, but it failed to demonstrate a survival advantage, when compared with placebo, in a phase 3 trial enrolling men with mCRPC.24 The primary outcome in this study was not OS but the proportion of patients having at least one SRE.
Denosumab, a monoclonal antibody against RANKL that is indicated for SRE prevention, also failed to show a survival advantage when compared with zoledronic acid in a phase 3 trial in mCRPC, although it did delay the time to the first on-study SRE by 18%.25 OS was an exploratory outcome in this study.
The beta particle–emitting radiopharmaceuticals strontium-89 chloride (Metastron, GE Healthcare Ltd.) and samarium-153 lexidronam pentasodium (Quadramet, EUSA Pharma) are used to relieve bone pain in mCRPC, but neither has provided a survival advantage. In a small study (N = 103), patients who responded to or remained stable after induction chemotherapy were randomly assigned to receive strontium-89 with or without doxorubicin.26 In the group receiving strontium-89 and doxorubicin (n = 36), median OS was 27.7 months versus 16.8 months in the group receiving doxorubicin alone (n = 36) (P = 0.001). However, the small sample size and a lack of balance in prognostic factors in the study arms precluded citing the results as evidence of a survival benefit.
Radium-223 Dichloride (Xofigo)
Radium-223 dichloride (formerly, Alpharadin) is a radiopharmaceutical. As a calcium mimetic, it binds to newly formed bone stroma, where its high-energy alpha particles kill cells within a very short range (less than 100 μm) by disrupting their DNA. In a phase 3 trial, median OS was extended by 2.8 months in the radium-223 group (n = 614) compared with placebo (n = 307) in men with mCRPC and bone metastases but with no known visceral metastases.27
At the planned interim analysis, median OS rates were 14.0 months with radium-223 and 11.2 months with placebo. Compared with placebo, radium-223 reduced the risk of death by 30% (HR, 0.70; 95% CI, 0.55–0.88; P = 0.002). In the updated analysis, median OS was 3.6 months longer in the radium-223 patients than in the placebo patients (14.9 vs. 11.3 months, respectively), and the 30% reduction in relative risk of death was maintained. In the ITT population, 54% of the radium-223 patients (333/614) and 64% of the placebo patients (195/307) died.
The combination of radium-223 and docetaxel, compared with docetaxel alone, is being studied in a phase 1/2 trial (NCT01106352) enrolling 60 men with mCRPC. OS is a secondary outcome in this study, which is scheduled to be completed in October 2014.
RECENT AND ONGOING CLINICAL TRIALS
Dasatinib (Sprycel, Bristol-Myers Squibb), an inhibitor of multiple tyrosine kinases, was approved by the FDA in 2006 as a second-line treatment for adults with certain forms of chronic myeloid leukemia. In a recent phase 3 trial (NCT00744497) enrolling patients with mCRPC (N = 1,522), the combination of dasatinib and docetaxel failed to provide a survival advantage compared with docetaxel and placebo.28 Median OS (the primary endpoint) was 21.5 months with dasatinib and 21.2 months with placebo.
In a phase 2 trial (NCT01685125), a different combination (dasatinib and abiraterone acetate/prednisone) is being compared with abiraterone acetate/prednisone alone. OS is a secondary outcome in this study, which is slated for completion in September 2016.
Orteronel (TAK-700, Takeda/Millennium), a CYP17 inhibitor, failed to show a survival advantage over placebo in a phase 3 trial (NCT01193257) that enrolled 1,099 men with mCRPC that had progressed during or after docetaxel-based chemotherapy.29 OS was the primary endpoint. At the planned interim analysis, the risk of death was reduced by 11% in the orteronel/prednisone group compared with the placebo group (HR, 0.89; P = 0.226).
Atrasentan and Zibotentan
Two agents that negate the effects of endothelin-1 (ET-1) by selectively blocking the endothelin-A (ETA) receptor— atrasentan and zibotentan—also have not shown a survival advantage in phase 3 trials in mCRPC. In a double-blind study in which atrasentan was evaluated as monotherapy, median OS (a secondary endpoint) was 20.5 months for atrasentan and 20.3 for placebo.30
More recently, atrasentan was studied in combination with docetaxel.31 At a planned interim analysis, the trial was halted early because of futility. In the group assigned to receive atrasentan and docetaxel (n = 498), median OS was 17.8 months compared with 17.6 months for those receiving placebo (n = 496).
The results of a double-blind, placebo-controlled phase 2 trial suggested that zibotentan might provide a survival benefit in mCRPC,32 but the ensuing phase 3 trials found no improvement in median OS when zibotentan was used as monotherapy33 or when it was used in combination with docetaxel.34 The monotherapy trial enrolled patients who were pain-free or mildly symptomatic. Median OS rates were 24.5 months for zibotentan (n = 299) and 22.5 months for placebo (n = 295), (HR, 0.87; 95% CI, 0.69–1.10; P = 0.240). In the combination trial, median OS was 20.0 months in the docetaxel/zibotentan group (n = 524) versus 19.2 months for docetaxel/placebo (n = 528). These negative results spelled the end of the investigation of zibotentan as a therapy for prostate cancer and, apparently, of the class as well. However, ETA antagonists continue to be investigated in other diseases.
Ipilimumab (Yervoy, Bristol-Myers Squibb), approved in 2011 for metastatic melanoma, is a monoclonal antibody directed against cytotoxic T-lymphocyte antigen-4 (CTLA-4). It prevents CTLA-4 from interacting with its ligands, thereby depleting regulatory T-cells and activating cytotoxic T-cells.
In a placebo-controlled phase 3 trial that enrolled men with mCRPC and bone metastases, OS was the primary endpoint.35 All patients previously had received docetaxel, and after randomization each patient received a single dose of radiotherapy. In the ITT analysis, no statistically significant survival advantage was found for the ipilimumab group (n = 399) compared with the placebo group (n = 400; HR, 0.85; 95% CI, 0.72–1.00; P = 0.053). Median OS rates were 11.2 months with ipilimumab and 10.0 months with placebo. Among the patients who received treatment, however, a statistically significant difference in OS was observed between the ipilimumab group (n = 387) and the placebo group (n = 392) in a post hoc analysis (HR, 0.84; 95% CI, 0.71–1.00; P = 0.0498).
A subset analysis suggested that patients without visceral metastases respond better to ipilimumab. A second phase 3 trial (NCT01057810) enrolling such a population (600 chemotherapy-naive patients with asymptomatic or minimally symptomatic mCRPC and no liver, lung, or brain metastases) is in progress. The primary outcome is OS. Completion of the study is expected in 2015.
Ipilimumab is also being studied in combination with abiraterone in one study (NCT01688492, phase 1/2, with primary completion anticipated in September 2014); and in combination with sipuleucel-T in two studies (NCT01804465, phase 2, with primary completion anticipated in August 2014; and NCT01832870, phase 1, with primary completion anticipated in December 2015). OS is not an outcome measure in any of these small studies, but encouraging results could spur larger trials investigating a survival benefit from these combinations.
Cabozantinib (Cometriq, formerly XL184, Exelixis) is a tyrosine kinase inhibitor with action against MET, which is the receptor for hepatocyte growth factor (HGF), and the vascular endothelial growth factor receptor 2 (VEGFR-2). These receptors are expressed by osteoblasts and osteoclasts. Blockade of these receptors may disrupt signaling important to prostate cancer cells. Cabozantinib was approved for other cancers in 2012 and was granted orphan drug status.
In a phase 2 trial, a subset of patients with mCRPC (n = 171, 87% with bone metastases) who were stable after 12 weeks of open-label lead-in treatment with cabozantinib were to receive cabozantinib or placebo.36 However, randomization was stopped after 122 patients because of resolution upon bone scan and decreased bone pain during the 12-week lead-in period. Complete resolution was observed in 12% of evaluable patients (n = 116), partial resolution in 56%, and stable disease in 33%.
A phase 3 trial of cabozantinib, COMET-1 (CabOzantinib MET Inhibition CRPC Efficacy Trial 1; NCT01605227), is in progress. It is expected to enroll 960 men with mCRPC and evidence of bone metastasis who previously were treated with docetaxel and either abiraterone or enzalutamide, with evidence of disease progression after treatment with each agent. Patients are receiving cabozantinib or an active comparator, prednisone. The primary outcome measure is OS; March 2014 is the date expected for final data collection for that measure.
OS is a secondary outcome measure in a smaller randomized phase 3 trial, COMET-2 (NCT01522443), in which 246 men with mCRPC and bone metastases who were previously treated with docetaxel and either abiraterone or enzalutamide are receiving either cabozantinib alone or an active comparator, mitoxantrone/prednisone. The primary completion date is June 2014.
Bone is the most common site of metastases in mCRPC, resulting in substantial mortality and morbidity and often manifesting as pathological fractures and bone pain. Treatment options have expanded in recent years, with the FDA’s approval of five medications that have been shown to provide a survival advantage, including one (radium-223 dichloride) with a specific indication for bone metastases in mCRPC. The other four agents have more general indications. In the pivotal studies of these drugs, however, the percentage of patients with bone metastases was so high that these agents could be regarded as de facto treatments for these patients. Although welcome, improvements in median OS gained with these therapies remain modest, and research continues to identify optimal treatment in mCRPC.
If phase 3 trials in progress are successful, even more agents soon could gain indications in mCRPC, such as ipilimumab and cabozantinib. At the same time, numerous trials are in progress to test whether various combinations of newly approved drugs provide a survival benefit beyond that offered by monotherapy. Abiraterone acetate, for example, is being studied in combination with enzalutamide, ipilimumab, dasatinib, and sipuleucel-T (and the combination of sipuleucel-T and ipilimumab is the focus of still other studies), while radium-223 is being studied in combination with docetaxel. Additional research also is needed to identify the optimal sequence for using the new agents and to discover biomarkers that would identify patient subsets most likely to benefit from each. Further research into the complex biology underlying metastatic prostate cancer is also necessary to discover molecules that could be targeted by new drugs to render the bone “soil” less fertile.
Figure and Tables
Probability of invasive prostate cancer development, by age group.
Source: American Cancer Society, 2013.
Survival Advantages in Phase 3 Trials of Agents Used or Under Investigation in Metastatic Castration-Resistant Prostate Cancer
|Docetaxel||Taxotere||1996 (May 14)||mCRPC, with prednisone (FDA approval of indication 2004)||2.9 months (19.2 vs. mitoxantrone, 16.3 months)||91% (N = 1,006) (Berthold, 2008)||Inhibits mitosis|
||Provenge||2010 (April 29)||Asymptomatic or minimally symptomatic mCRPC||4.1 months (25.8 vs. placebo, 21.7 months)||92%–93% (N = 512) (Kantoff, 2010)||Autologous cellular immunotherapy|
||Jevtana||2010 (June 17)||mCRPC with prior docetaxel-containing regimen||2.4 months (15.1 vs. mitoxantrone, 12.7 months)||80%–87% (N = 775) (de Bono, 2010)||Inhibits mitosis|
||Zytiga||2011 (April 28)||mCRPC, in combination with prednisone, after or prior to (FDA 2012) docetaxel therapy||4.6 months (15.8 vs. placebo, 11.2 months)||90% (N = 1,195) (Fizazi, 2012)||Inhibits CYP17, critical for biosynthesis of steroidal hormones; phase 3 combination study with enzalutamide to have begun December 2013|
||Xtandi||2012 (August 31)||mCRPC with prior docetaxel treatment||4.8 months (18.4 vs. placebo, 13.6 months)||92% (N = 1,199) (Scher, 2012)||AR inhibitor; phase 3 combination study with abiraterone to have begun December 2013|
|Strontium-89 chloride||Metastron||1993 (June 18)||Relief of bone pain in patients with painful skeletal metastases||No; see text (Therapies Targeting Bone Metastases)||100% (N = 72) (Tu, 2001)||Beta-particle emitter|
|Samarium-153 lexidronam pentasodium||Quadramet||1997 (March 28)||Pain relief in patients with osteoblastic metastatic lesions||Overall survival not studied in randomized clinical trial||—||Beta-particle emitter|
|Zoledronic acid||Zometa||2001 (Aug 20)||Bone metastases that have progressed after patient received one or more hormonal therapies||No benefit vs. placebo||99% (N = 643) (Saad, 2002)||Bisphosphonate that inhibits resorption|
|Denosumab||Xgeva||2010 (June 1)||SRE prevention in patients with bone metastases from solid tumors||No benefit vs. zoledronic acid||100% (N = 1901) (Fizazi, 2011)||Human monoclonal antibody against osteoclast-activating RANKL|
||Xofigo (formerly Alpharadin)||2013 (May 15)||mCRPC with bone metastases but no known visceral metastases||3.6 months (14.9 vs. placebo, 11.3 months)||99% (N = 921) (Parker, 2013)||Alpha-particle emitter|
|Dasatinib||Sprycel||2006 (June 28)||—||No benefit vs. placebo in phase 3 trial||(Araujo, 2013)||Inhibits multiple tyrosine kinases, including SRC family, c-KIT, PDGFRβ|
|Ipilimumab||Yervoy||2011 (March 25)||—||No benefit vs. placebo in phase 3 trial; see text||(Gerritsen, 2013)||Another phase 3 trial is in progress, in mCRPC population that may respond better|
|Cabozantinib (XL184)||—||—||—||COMET-1 trial in progress||Trial No. (NCT01605227)||Inhibits c-MET, VEGFR2, and other pathways|
|Orteronel (TAK-700)||—||—||—||No benefit vs. placebo in phase 3 trial||—||Inhibits CYP17, critical for biosynthesis of steroidal hormones|
|Atrasentan||—||—||—||No benefit vs. placebo||(Quinn, 2013)||ETA receptor antagonist|
|Zibotentan||—||—||—||No benefit vs. placebo in phase 3 trial||(Fizazi, 2013)||ETA receptor antagonist|
aReference appears in cell to the right.
bIf one percentage value is shown, it applies to both the study drug arm and the placebo or active comparator arm; N = total number assigned to study arms; if no percentage, not available.
AR = androgen receptor; CRPC = castration-resistant prostate cancer; CYP = cytochrome P450; ETA = endothelin-A; mCRPC = metastatic CRPC; RANKL = receptor activator of nuclear factor-κB ligand; SRE = skeletal-related event; VEGFR = vascular endothelial growth factor receptor.
Selected Characteristics of FDA-Approved Agents That Show a Survival Advantage in Metastatic Castration-Resistant Prostate Cancer
|Abiraterone acetate (Zytiga)||1,000 mg (4 250-mg tablets) orally once daily, on an empty stomach, in combination with oral prednisone 5 mg twice daily||
||Fatigue, joint swelling and discomfort, edema, hot flushes, diarrhea, constipation, cough, hypertension, dyspnea, UTI, contusion, dyspepsia||—||Abiraterone/prednisone vs. placebo: 1.5% vs. 3%||$8,200 per month (30 days of treatment)|
|Cabazitaxel (Jevtana)||After premedication, 25 mg/m2 administered as 1-hour IV infusion every 3 weeks, in combination with oral prednisone 10 mg once daily throughout treatment||
||Anemia, leukopenia, neutropenia, thrombocytopenia, diarrhea, fatigue, nausea, vomiting, constipation, asthenia, abdominal pain, hematuria, back pain, anorexia, peripheral neuropathy, pyrexia, dyspnea, dysgeusia, cough, arthralgia, alopecia||Neutropenia, leukopenia, anemia, febrile neutropenia, diarrhea, fatigue, asthenia||Cabazitaxel vs. mitoxantrone: 18% vs. 8%
Neutropenia Renal failure
|$7,500 every 3 weeks|
|Enzalutamide (Xtandi)||160 mg (4 40-mg capsules) orally once daily||
||Asthenia, back pain, diarrhea, arthralgia, hot flush, edema, musculoskeletal pain, headache, URTI||Asthenia, spinal cord compression or cauda equina syndrome, back pain||Enzalutamide vs. placebo: 16% vs. 18%
Seizure 0.9% vs 0%
|$9,500 per month (30 days of treatment)|
|Radium-223 dichloride (Xofigo)||50 kBq (1.35 microcurie) per kg of body weight; given every 4 weeks for a total of 6 doses||
||Nausea, diarrhea, vomiting, edema||—||Radium-223 vs. placebo: 17% vs. 21%||$82,800 for complete course (6 injections at 4-week intervals)|
|Sipuleucel-T (Provenge)||One dose (>50 million CD4 cells = 250 mL) given after premedication as IV infusion over about 1 hour, at approximately 2-week intervals, for a total of 3 doses||
||Chills, fatigue, fever, back pain, nausea, joint ache, headache, citrate toxicity, paresthesia, vomiting, anemia, constipation, pain, oral paresthesia, pain in extremity, dizziness, muscle aches, asthenia, diarrhea||—||Sipuleucel-T: 1.5%||$124,000 for a 3-dose course of treatment|
Source: FDA prescribing information
aGrades 1–5 adverse events (AEs) with sipuleucel-T: grade 1, mild AEs; grade 2, moderate AEs; grade 3, severe AEs; grade 4, life-threatening or disabling serious AEs (hospitalization); grade 5, death related to AEs.
bAll costs were calculated using the average wholesale price (AWP) in January 2014 from RedBook.
cBased on m2 = 1.73 (adult average).
ALT = alanine transaminase; AST = aspartate transaminase; IV = intravenous; URTI, upper respiratory tract infection; UTI, urinary tract infection.
- American Cancer Society (ACS). Cancer Facts & Figures 2013 Atlanta: American Cancer Society. 2013;
- 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;(15):1513–1520.
- Scher HI, Fizazi K, Saad F,
the AFFIRM Investigators. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012;367;(13):1187–1197.
- Lange PH, Vessella RL. Mechanisms, hypotheses and questions regarding prostate cancer micrometastases to bone. Cancer Metastasis Rev
- Saylor PJ, Lee RJ, Smith MR. Emerging therapies to prevent skeletal morbidity in men with prostate cancer. J Clin Oncol 2011;29;(27):3705–3714.
- Paget S. Distribution of secondary growths in cancer of the breast. Lancet 1889;133:571–573.
- Hart IR, Fidler IJ. Role of organ selectivity in the determination of metastatic patterns of B16 melanoma. Cancer Res 1980;40;(7):2281– 2287.
- Roodman GD. Mechanisms of bone metastasis. N Engl J Med 2004;350;(16):1655–1664.
- Ibrahim T, Flamini E, Mercatali L, et al. Pathogenesis of osteoblastic bone metastases from prostate cancer. Cancer 2010;116;(6):1406–1418.
- Provenge, prescribing information Seattle, Wash.: Dendreon Corp.. June 2011;
- Jevtana, package insert Bridgewater, N.J.: Sanofi-Aventis. May 2013;
- Zytiga (Abiraterone acetate), prescribing information Horsham, Pa.: Janssen Biotech, Inc.. September 2013;
- Xtandi (enzalutamide), prescribing information Northbrook, Ill.: Astellas Pharma US, Inc.. San Francisco: Medivation, Inc.August 2012;
- Xofigo (radium-223 dichloride), prescribing information Wayne, N.J.: Bayer. May 2013;
- National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Prostate CancerVersion 42013;Available at: www.NCCN.org.
- Tannock IF, de Wit R, Berry WR,
the TAX 327 Investigators. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004;351;(15):1502–1512.
- 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;(2):242–245.
- de Bono JS, Oudard S, Ozguroglu M,
the TROPIC Investigators. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: A randomised open-label trial. Lancet 2010;376;(9747):1147–1154.
- de Bono JS, Logothetis CJ, Molina A,
the COU-AA-301 Investigators. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 2011;364;(21):1995–2005.
- Ryan CJ, Smith MR, de Bono JS,
COU-AA-302 Investigators. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med 2013;368;(2):1381–1348.Erratum, N Engl J Med2013:368(6):584.
- Fizazi K, Scher HI, Molina A,
the COU-AA-301 Investigators. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: Final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol 2012;13;(10):983–992. Efstathiou E, Titus M, Wen AS, et al. Effects of enzalutamide (ENZA) in combination with abiraterone acetate (AA) in patients with bone metastatic castration-resistant prostate cancer (mCRPC). Abstract 2854. Presented at European Cancer Congress 2013 Brussels, Belgium September 28, 2013
- Kantoff PW, Higano CS, Shore ND,
the IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010;363;(5):411–422.
- Saad F, Gleason DM, Murray R,
Zoledronic Acid Prostate Cancer Study Group. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst 2002;94;(19):1458–1468.
- 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;(9768):813–822.
- Tu SM, Millikan RE, Mengistu B, et al. Bone-targeted therapy for advanced androgen-independent carcinoma of the prostate: A randomized phase II trial. Lancet 2001;357;(9253):336–341.Erratum,
- Parker C, Nilsson S, Heinrich D,
the ALSYMPCA Investigators. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 2013;369;(3):213–223.
- Araujo JC, Trudel GC, Saad F, et al. Overall survival (OS) and safety of dasatinib/docetaxel versus docetaxel in patients with metastatic castration-resistant prostate cancer (mCRPC): Results from the randomized phase III READY trial. Abstract LBA8. J Clin Oncol 2013;31;(Suppl 6):
- Takeda announces unblinding of phase 3 study of orteronel in patients with metastatic, castration-resistant prostate cancer that progressed post-chemotherapy based on interim analysis Cambridge, Mass.: Takeda. July
252013;Available at: www.takeda.com/news/2013/20130726_5894.html. Accessed December 6, 2013.
- Carducci MA, Saad F, Abrahamsson PA,
the Atrasentan Phase III Study Group Institutions. A phase 3 randomized controlled trial of the efficacy and safety of atrasentan in men with metastatic hormone-refractory prostate cancer. Cancer 2007;110;(9):1959–1966.
- Quinn DI, Tangen CM, Hussain M, et al. Docetaxel and atrasentan versus docetaxel and placebo for men with advanced castration-resistant prostate cancer (SWOG S0421): A randomised phase 3 trial. Lancet Oncol 2013;14;(9):893–900.
- 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;(7):966–973.
- Nelson JB, Fizazi K, Miller K, et al. Phase 3, randomized, placebo-controlled study of zibotentan (ZD4054) in patients with castration-resistant prostate cancer metastatic to bone. Cancer 2012;118;(22):5709–5718.
- Fizazi KS, Higano CS, Nelson JB, et al. Phase III, randomized, placebo-controlled study of docetaxel in combination with zibotentan in patients with metastatic castration-resistant prostate cancer. J Clin Oncol 2013;31;(14):1740–1747.
Gerritsen WR, Kwon ED, Fizazi K, et al. A randomized, multi-center, double-blind phase 3 trial comparing overall survival (OS) in patients (pts) with post-docetaxel castration-resistant prostate cancer (CRPC) and bone metastases treated with ipilimumab (ipi) vs placebo (pbo), each following single-dose radiotherapy (RT). Abstract 2850. Presented at European Cancer Congress 2013 Brussels, Belgium September 28, 2013
- Smith DC, Smith MR, Sweeney C, et al. Cabozantinib in patients with advanced prostate cancer: Results of a phase II randomized discontinuation trial. J Clin Oncol 2013;31;(4):412–419.