Emerging novel therapies for advanced prostate cancer

Abstract

This review examines the development and efficacy of novel treatment options for advanced prostate cancer and discusses novel therapies that are on the horizon. Since the introduction of docetaxel as the standard treatment for patients with metastatic castration-resistant prostate cancer (CRPC), a number of different agents have been tested but failed to demonstrate improvement in overall survival (OS). Recently, three novel compounds have demonstrated OS benefit and one other showed reduction in skeletal-related events (SREs). Sipuleucel-T, a novel vaccine, was approved by the US regulatory authorities in April 2010 for patients with early advanced prostate cancer. A new taxane, cabazitaxel, and abiraterone acetate, an androgen biosynthesis inhibitor, have shown an OS benefit in advanced CRPC after docetaxel, leading to drug approval. A new bone-targeting agent, denosumab, a receptor activator of nuclear factor κB ligand (RANKL) antagonist, showed a modest reduction in SREs in comparison to zoledronic acid in patients with bone metastases. Other promising novel agents are currently being tested in the clinical setting of advanced CRPC. These include, androgen receptor inhibitors (MDV3100), androgen biosynthesis inhibitors, angiogenesis inhibitors (thalidomide, lenalidomine, aflibercept, tasquinimod), a novel form of radiotherapy (radium-223), and immune-modulating compounds (PROSTVAC-VF). Improvements in progression-free survival and OS rates, observed with novel agents, in metastatic prostate cancer have led to a shift in treatment paradigm. The challenge will be to position the current established and expected novel treatments in the new landscape of metastatic prostate cancer and to determine at what point and time in the disease course they can best be administered.

Introduction

Prostate cancer is the most common cancer in men in northern European countries and the USA, and the second leading cause of cancer-related death in men in most western countries. In 2008, the projected number of new cases worldwide was 914,000, with an estimated 258,000 deaths [Ferlay et al. 2010; Jemal et al. 2010, 2011]. Advanced prostate cancer, in the first instance sensitive to androgen deprivation therapy, usually progresses into a state of castration resistance. The vast majority of men with castration-resistant prostate cancer (CRPC) have radiological evidence of bone metastases.

Years ago three drugs were given US Food and Drug Administration (FDA) approval for first-line chemotherapy. Estramustine and mitoxantrone plus prednisone had a palliative effect on bone pain, but did not improve survival. Docetaxel was the first drug with proven survival benefit, although small, in men with metastatic CRPC. Data from two large randomized phase III trials, TAX327 and Southwest Oncology Group (SWOG) 9916, demonstrated a significant improvement in overall survival (OS) with docetaxel given every 3 weeks, although the difference was small. In the SWOG 9916 and TAX327 trials the median survival was 17.5 and 18.9 months in the group receiving docetaxel every 3 weeks, while the median survival was 15.6 and 16.5 months in the mitoxantrone group [Petrylak et al. 2004; Tannock et al. 2004]. Weekly docetaxel did not improve survival but was better tolerated. Patients treated with docetaxel every 3 weeks experienced improved pain relief and quality of life compared with mitoxantrone plus prednisone. The regimen of docetaxel plus estramustine every 3 weeks in the SWOG 9916 trial was associated with increased toxicity and did not appear to improve efficacy compared with docetaxel plus prednisone in the TAX327 study. Thus, the regimen of docetaxel plus prednisone every 3 weeks became the standard of care in patients with CRPC. Following docetaxel, patients often received docetaxel again because crossing over to mitoxantrone seemed of little benefit second line [Berthold et al. 2008].

Since 2004, various trials using different drugs and approaches failed to demonstrate improvement in OS and therefore docetaxel remained the only standard treatment for CRPC. Now, the landscape is changing rapidly. Results from phase III trials have become available, resulting in the introduction of various new approaches pre- and post- docetaxel. These efforts have led to new drugs being approved by the US FDA and the European Medicines Evaluation Agency (EMEA). In April 2010, the FDA approved an autologous cellular vaccine, sipuleucel-T (Provenge) for the treatment of metastatic CRPC based on demonstrated OS benefit. In the same year, a third-generation taxane, cabazitaxel (Jevtana), was approved for the treatment of metastatic CRPC based on improvement in OS, and denosumab (XGEVA) was approved for the supportive management of bone disease. In April 2011, abiraterone (Zytiga) was approved for the treatment of patients with metastatic CRPC post docetaxel.

A large number of agents are currently under investigation for various stages of CRPC. Based on the currently approved treatments, the paradigm of metastatic prostate cancer is rapidly changing whereas more studies are expected to demonstrate OS benefit of treatment with novel compounds. This review discusses the recently approved agents and other drugs in the pipeline and treatment strategies for advanced prostate cancer.

Immunotherapeutic strategies

Sipuleucel-T

Sipuleucel-T is an autologous vaccine consisting of patients’ autologous peripheral blood mononuclear cells (PBMCs) stimulated ex vivo with PSA-GM-CSF, a recombinant protein consisting of the target antigen prostatic acid phosphatase (PAP) fused to granulocyte macrophage colony-stimulating factor (GM-CSF). After reinfusion, this strategy aims at stimulating an effective immune response against human PAP, an antigen highly expressed in prostate cancer tissue.

Three randomized, double-blind, controlled, multicenter phase III studies (D9901, D9902A and D9902B) enrolled a total of 737 patients [Small et al. 2006; Higano et al. 2009; Kantoff et al. 2010a]. The efficacy of sipuleucel-T was compared with that of control infusions and the primary outcome of the studies was OS. Control infusional products were prepared by culturing leukapheresis PBMCs stored at 2–8°C, in the absence of PAP-GM-CSF. Patients needed to stop corticosteroids 4 weeks prior to entry into the study. Two studies enrolled 225 patients with asymptomatic metastatic CRPC [Small et al. 2006; Higano et al. 2009] and the Immunotherapy for Prostate Adenocarcinoma Treatment (IMPACT) study enrolled 512 patients with asymptomatic or minimally symptomatic metastatic CRPC [Kantoff et al. 2010a] (Table 1). The majority of patients in the IMPACT trial were chemotherapy naïve; approximately 20% had received prior chemotherapy.

Table 1.

Randomized phase III clinical studies in castration-resistant prostate cancer.

Study/agent	Study design/patients	Patients (n)	Overall survival/TTP	PSA response	Safety/QOL	Reference
IMPACT Sipuleucel-T	Double-blind RCT (IMPACT, D9902B) Median FU: 34.1 months Asymptomatic or minimally symptomatic chemotherapy-naïve mCRPC Sipuleucel-T arm–control arm	512	Primary endpoint: OS Median OS: 25.8 versus 21.7 months (HR 0.78, 95% CI 0.62–0.98, p = 0.032) OS advantage: 4.1 months Extended 3-year survival rate: 31.7% versus 23%	≥50% decrease in PSA: 8/311 (2.6%) versus 2/153 (1.3%)	Well tolerated. Most common AEs: chills, pyrexia, headache, asthenia. Within 1 day after infusion, grade 1–2: chills, fever, fatigue, nausea, headache; grade ≥3: 6.8% versus 1.8%. One grade 4: IV catheter-associated bacteraemia. CVEs: 2.4% versus1.8%	[Kantoff et al. 2010b]
TROPIC trial Cabazitaxel	RCT (1:1) Median FU: 12.8 months Symptomatic post docetaxel mCRPC Cabazitaxel + prednisone−mitoxantrone + prednisone	755	Primary endpoint: OS Median OS: 15.1 versus 12.7 months. OS advantage 2.4 months (HR death 0.70, 95% CI 0.59–0.83, p < 0.0001). Secondary endpoints: PFS and safety. Median PFS: 2.8 versus 1.4 months (HR 0.74, 0.64–0.86, p < 0.0001)	PSA response rate 39.2% versus 17.8%, p = 0·0002	Most common AEs: neutropenia (cabazitaxel 82% versus mitoxantrone 58%) and diarrhoea (6% versus <1%). Cabazitaxel: 5% deaths due to AEs versus mitoxantrone: 2% deaths (all associated with myelosuppression)	[De Bono et al. 2010]
COU-AA-301 Abiraterone	Double-blind RCT (2:1) Median FU: 12.8 months Symptomatic post docetaxel mCRPC Abiraterone arm–control arm	1195	Primary endpoint: OS Median OS: 14.8 versus 10.9 months (HR 0.65, 95% CI 0.54–0.77; p < 0.001) OS advantage: 2.9 months Secondary endpoint: PFS and time to PSA progression. PFS 5.6 versus 3.6 months (p < 0.001)	Time to PSA progression (10.2 versus 6.6 months; p < 0.001). PSA response rate (29% versus 6%, p < 0.001)	Mineralocorticosteroid-excess related side effects (fluid retention, oedema, hypokalaemia, hypertension): 55% versus 43%, p < 0.001. Fluid retention and oedema: 31% versus 22%, p = 0.04. Hypokalaemia: 17% versus 8%, p < 0.001	[De Bono et al. 2011]
ALSYMPCA Alpharadin	Double-blind, placebo-controlled RCT (2:1) Symptomatic, bone mCRPC. Alpharadin arm–placebo arm	922	Primary endpoint: OS Median OS: 14.0 versus 11.2 months (HR 0.695; 95% CI 0.552–0.875, p = 0.0018) OS benefit: 2.8 months	Time to PSA progression: HR 0.67, 95% CI 0.546–0.826, p = 0.00015	All grade, grade 3 or 4, and serious AEs were less frequent in the radium-223 group with 88%, 51%, 43% versus 94%, 59%, 55% in the placebo group	[Parker et al. 2011] ECCO–ESMO

AE, adverse event; ALSYMPCA, Alphardin in Symptomatic Prostate Cancer; ECCO, European Cancer Organization; ESMO, European Society for Medical Oncology; FU, follow up; HR, hazard ratio; IMPACT, Immunotherapy for Prostate Adenocarcinoma Treatment; IV, intravenous; mCRPC, metastatic castration-resistant prostate cancer; OS, overall survival; PFS, progression-free survival; PSA, prostate-specific antigen; QOL, quality of life; RCT, randomized controlled trial; TTP, time to progression.

Side effects were mild and were mainly chills, fever and flu-like syndrome. A combined analysis of the two smaller studies showed a median survival benefit of 4.3 months [23.2 versus 18.9 months for controls; hazard ratio (HR) 1.50, 95% confidence interval (CI) 1.10–2.05, p = 0.011]. The median survival benefit in IMPACT was 4.1 months for patients treated with sipuleucel-T compared with controls (25.8 versus 21.7 months, HR for death 0.78, 95% CI 0.61–0.98, p = 0.032). The 3-year survival probability also improved significantly (31.7% versus 23.0% for controls).

Prostate-specific antigen (PSA) responses were rarely observed. In the IMPACT study, reductions in PSA ≥ 50% were observed in eight of 311 patients (2.6%) in the sipuleucel-T group and two of 153 patients (1.3%) in the control group. T-cell responses to the immunizing antigen were measured in the sipuleucel-T and control groups (73% versus 12.1%).

The favourable outcome of the pivotal IMPACT trial demonstrating an OS benefit of approximately 4 months with sipuleucel-T in a largely chemo-naïve cohort of patients with CRPC led to approval by the US FDA.

Other novel forms of immunotherapy being tested in patients with CRPC include the use of anti-CTLA4 blockade with ipilimumab and immunization with PROSTVAC-VF, a poxviral-based PSA-targeted vaccine [Kantoff et al. 2010b]. A recently published, randomized, controlled, double-blind, phase II study of PROSTVAC-VF including 125 patients with chemotherapy-naïve minimally symptomatic metastatic CRPC and Gleason score of ≤7 showed promising results [Kantoff et al. 2010b]. There was no improvement in progression-free survival (PFS), the primary endpoint of the study, but patients receiving PROSTVAC-VF experienced a median survival benefit of 8.5 months (25.1 versus 16.6 months for controls, HR 0.56, 95% CI 0.37–0.85, p = 0.006) and an extended 3-year survival (30% versus 17%). Similar results in median OS were found in the much smaller of the two phase II studies using PROSTVAC-VF [Gulley et al. 2010]. These encouraging phase II results ask for a formal phase III trial to demonstrate whether this novel approach can indeed extend OS when compared with the standard of care.

Novel chemotherapeutic agent

Cabazitaxel

Cabazitaxel is a novel semisynthetic tubulin-binding taxane which showed activity in docetaxel-resistant tumour cell lines. After phase I and II studies in other malignancies, the phase III trial comparing cabazitaxel plus prednisone with mitoxantrone plus prednisone in patients with docetaxel-refractory prostate cancer was designed (TROPIC). No information on the efficacy of cabazitaxel in prostate cancer was available when the study was launched.

In the TROPIC trial, progression was defined by Response Evaluation Criteria in Solid Tumors (RECIST) in patients with measureable disease, or by two consecutive PSA increases (at least 1 week apart) in patients with nonmeasurable disease [De Bono et al. 2010] (Table 1). Prior androgen deprivation therapy was mandatory, and patients on luteinizing hormone releasing hormone (LHRH) agonists continued with this treatment during participation in the study. A total of 755 men were randomized 1:1 to receive cabazitaxel plus prednisone (n = 378) or mitoxantrone plus prednisone (n = 377) in a total of 26 countries. The study was amended to exclude patients who had received a cumulative docetaxel dose of less than 225 mg/m². The mean docetaxel dose in the cabazitaxel arm was 576.6 mg/m² compared with 529.2 mg/m² in the control arm. The mean time from the last docetaxel dose to disease progression was 0.8 months in the cabazitaxel arm and 0.9 months in the mitoxantrone arm. The majority of patients had bone metastases (84%), whereas 25% had visceral metastases.

Men were randomized to receive either 12 mg/m² mitoxantrone intravenously or 25 mg/m² cabazitaxel intravenously every 3 weeks. Both groups received 10 mg oral prednisone daily. The primary endpoint was OS and the secondary endpoint was PFS.

The median survival was 15.1 months (95% CI 14.1–16.3) in the cabazitaxel group and 12.7 months (11.6–13.7) in the mitoxantrone group (median survival benefit was 2.4 months). The HR for death of men treated with cabazitaxel compared with those taking mitoxantrone was 0.70 (95% CI 0.59–0.83, p < 0.0001). Interestingly, patients who progressed during docetaxel also benefited from cabazitaxel treatment.

Median PFS was 2.8 months (95% CI 2.4–3.0) in the cabazitaxel group and 1.4 months (1.4–1.7) in the mitoxantrone group (HR 0.74, 95% CI 0.64–0.86, p < 0.0001). The most common clinically significant grade 3 or higher adverse events were neutropenia, which was more frequently observed in the cabazitaxel group (82% versus 58%), and diarrhoea (6% versus <1%). Febrile neutropenia occurred in 28 (8%) patients in the cabazitaxel group and 5 (1%) in the mitoxantrone group. Importantly, in the cabazitaxel arm 5% of patients died due to adverse events compared with 2% in the mitoxantrone arm and deaths were associated with myelosuppression.

Thus, treatment with cabazitaxel plus prednisone improved OS in patients with metastatic CRPC whose disease had progressed during or after docetaxel-based therapy. This pivotal TROPIC trial subsequently led to the approval of cabazitaxel in patients with metastatic prostate cancer whose condition had failed to respond to docetaxel.

Novel endocrine treatments

Prostate cancer is sensitive to androgen deprivation therapy, although the disease eventually progresses to CRPC. After medical or surgical castration, persistent low levels of androgens are produced from nongonadal sources, such as the adrenal glands. Some CRPCs acquire the ability to convert adrenal steroids to androgens, maintaining levels sufficient to activate the androgen receptor. Extragonadal synthesis of androgens, including intratumoural biosynthesis of androgens, may contribute to progression of CRPC. Recent evidence has shown that CRPC remains hormone driven with intratumoural steroid synthesis driving tumour growth. Thus, androgen receptor signalling remains essential for many prostate cancers that have progressed despite androgen deprivation therapy. Therefore, androgen receptor targeting may still contribute to disease control at the time of CRPC development. Both inhibition of persistent (nongonadal) androgen production and androgen-receptor-mediated signalling are relevant therapeutic strategies for CRPC.

CYP17 is an enzyme that catalyzes two key serial reactions (17α-hydroxylase and 17, 20 lyase) in androgen and oestrogen biosynthesis. An important therapeutic pathway for CRPC is the selective inhibition of cytochrome p450 17. New investigational agents for CRPC, specifically selective cytochrome p450 17 inhibitors and second-generation anti-androgens, are being evaluated in clinical trials. These include the novel androgen biosynthesis inhibitors (abiraterone, TAK-700 and TOK-001).

Abiraterone

Abiraterone acetate, a potent, selective, and orally bioavailable small molecule inhibitor of CYP17 that is key to androgen and oestrogen, showed promising activity and tolerability in phase I–II trials. This led to the design of phase III trials in men with progression after docetaxel-based chemotherapy and those with chemotherapy-naïve CRPC.

In the pivotal phase III trial, 1195 patients with CRPC were randomized in a 2:1 ratio between abiraterone acetate 1000 mg daily (n = 797) and placebo (n = 398) [De Bono et al. 2011] (Table 1). Both groups of men received prednisone 5 mg twice daily to prevent adrenal suppression symptoms.

The primary endpoint of the study was OS. The secondary endpoint was time to PSA progression, PFS according to radiological findings and the PSA response rate. After a median follow up of 12.8 months, OS was longer in the abiraterone acetate–prednisone group than in the placebo–prednisone group (14.8 versus 10.9 months; HR 0.65, 95% CI 0.54–0.77, p < 0.001).

All secondary endpoints, including time to PSA progression (10.2 versus 6.6 months; p < 0.001), PFS (5.6 versus 3.6 months; p < 0.001) and PSA response rate (29% versus 6%; p < 0.001), favoured the treatment group, indicating that advanced CRPC indeed remains hormone driven.

Mineralocorticoid-related adverse events, including fluid retention, hypertension and hypokalaemia, were more frequently observed in the abiraterone acetate–prednisone group.

The outcome of this pivotal trial led to FDA approval of the compound in April 2011. Another phase III trial is testing abiraterone acetate plus prednisone versus placebo plus prednisone in patients with asymptomatic or mildly symptomatic chemo-naïve advanced CRPC.

MDV3100

MDV3100 is a rationally designed novel antagonist of androgen receptor and second-generation anti-androgen that blocks androgen receptor signalling by inhibiting nuclear translocation of the ligand–receptor complex. MDV3100 binds DNA and induces apoptosis, and has no agonist activity when androgen receptors are overexpressed. In a phase I–II trial, 140 patients were treated with doses varying between 30 and 600 mg daily. Positron emission tomography imaging showed androgen blockade and diminished 18- fluorodihydrotestosterone binding at dosages of 60 mg/day and higher [Scher et al. 2010]. Antitumor effects were observed at all dosages, including declines in serum PSA of 50% or more in 56% of patients, responses in soft tissue and stabilized bone disease. Antitumor effects were observed in patients with CRPC who were chemotherapy naïve or had received chemotherapy.

Following this phase I–II trial, two placebo- controlled phase III trials evaluating MDV3100 in the pre and post docetaxel setting were initiated: PREVAIL is testing patients who are chemo naïve, whereas the phase III AFFIRM trial is testing patients with progressive disease post docetaxel. Androgen receptor blockade is an exciting approach and the trial outcome is expected to be favourable. If confirmed in phase III trials, MDV3100 will be an important additional tool for the clinician, providing more options for patients, and will certainly induce treatment paradigm dilemmas in terms of positioning of these novel compounds.

Several other agents targeting the androgen receptor axis are undergoing evaluation in early clinical studies.

Combination with angiogenesis inhibitors

Angiogenesis inhibitors (aflibercept, tasquinimod) are being investigated in the clinical setting. Aflibercept (ZALTRAP) is a fusion protein which binds all forms of vascular endothelial growth factor-A (VEGF-A), VEGF-B and placental growth factor, with higher affinity than their native receptors. Aflibercept is being investigated in a randomized phase III, placebo-controlled study in combination with docetaxel and prednisone in patients with CRPC (the VENICE study).

A phase III randomized, double-blind, placebo- controlled study of tasquinimod, an oral second-generation quinoline-3-carboxamide anti- angiogenic drug, in asymptomatic to mildly symptomatic patients with metastatic CRPC, is investigating whether tasquinimod delays disease progression compared with placebo.

Bevacizumab

Bevacizumab (Avastin), a monoclonal antibody targeting the human VEGF ligand, specifically the major isoform VEGF-A, was considered an important compound with expected efficacy in CRPC.

The results of the phase II Cancer and Leukemia Group B (CALGB) trial of 79 patients with metastatic CRPC treated with bevacizumab combined with chemotherapeutic agents docetaxel and estramustine seem promising [Picus et al. 2011]. However, a substantial number of patients stopped protocol treatment because of disease progression, or a physician or patient decision, and 15 patients stopped treatment due to toxicity. The primary endpoint of PFS in this study was not met, but encouraging antitumor activity and OS were observed. A randomized phase III trial (CALGB 90401) of 1050 patients with metastatic CRPC who were chemotherapy naïve with evidence of progressive disease despite castrate testosterone levels and anti-androgen withdrawal compared the combined use of docetaxel, prednisone (DP), and bevacizumab (Bev) with docetaxel and prednisone alone [Kelly et al. 2010]. Despite an improvement in PFS, measurable disease response and post-therapy PSA decline, the addition of bevacizumab to docetaxel and prednisone did not improve OS in men with metastatic CRPC, and was associated with greater morbidity and mortality.

Thalidomide

The efficacy of docetaxel compared with docetaxel plus thalidomide, another anti-angiogenic agent with demonstrated activity in CRPC, was investigated in 75 patients with metastatic CRPC who were chemotherapy naïve. Patients received either docetaxel 30 mg/m² intravenously every week for 3 consecutive weeks, followed by a 1-week rest period (n = 25), or docetaxel at the same dose and schedule plus thalidomide 200 mg orally each day (n = 50) [Dahut et al. 2004]. The percentage of patients with a decline of more than 50% in PSA was higher in the docetaxel plus thalidomide group (53% in the combined group, 37% in the docetaxel-alone arm). At 18 months, OS was 42.9% in the docetaxel group and 68.2% in the combined group.

A phase II trial in 60 patients with metastatic CRPC who were chemo-naïve investigated the efficacy of bevacizumab in combination with standard chemotherapy with docetaxel and prednisone as well as thalidomide. The findings showed a PSA decline rate of more than 50% occurring in 90% of patients [Ning et al. 2010]. The median OS was 28.2 months in this group with a Halabi-predicted survival of 14 months. Toxicities of bevacizumab and thalidomide added to docetaxel were manageable. The estimated median survival is encouraging.

These results suggest that definitive clinical trials combining an anti-angiogenic agent (e.g. with lenalidomide, the presumably less toxic thalidomide derivative) with docetaxel are warranted to assess whether treatment outcome for patients with metastatic CRPC can be improved.

Novel bone-targeting agents

The bone is an important target in advanced metastatic prostate cancer since most patients will develop bone metastases during the course of their disease, and most disease-related symptoms are directly related to bone metastases. Bone metastases are the main cause of significant morbidity and poor quality of life, and may hasten death. Bisphosphonates such as zoledronic acid have demonstrated utility at preventing skeletal complications in patients with CRPC with bone metastases [Saad et al. 2004]. Zoledronic acid (4 mg via a 15 min infusion every 3 weeks for 15 months) reduced the incidence of skeletal-related events (SREs) in men with hormone-refractory metastatic prostate cancer. The median time to the first SRE was 488 days for the 4 mg zoledronic acid group versus 321 days for the placebo group (p = 0.009). Compared with placebo, 4 mg of zoledronic acid reduced the ongoing risk of SREs by 36% (risk ratio 0.64, 95% CI 0.485–0.845, p = 0.002). Patients in the 4 mg zoledronic acid group had a lower incidence of SREs than patients in the placebo group, regardless of whether they had an SRE prior to entry in the study.

Denosumab

The nuclear factor κB ligand (RANKL) inhibitor, denosumab, has been developed for the treatment of bone metastases. RANKL is involved in the regulation of bone metabolism and is overexpressed in osteoblasts. A phase III, randomized noninferiority trial in men with bone metastases from CRPC compared denosumab and zoledronic acid with endpoint time to first SRE [Fizazi et al. 2011]. Men with CRPC and no previous exposure to intravenous bisphosphonate were enrolled from 342 centres in 39 countries.

In this double-blind study, 1904 patients were randomized 1:1 to receive 120 mg subcutaneous denosumab plus intravenous placebo or 4 mg intravenous zoledronic acid plus subcutaneous placebo every 4 weeks until the primary analysis cutoff date. Randomization was stratified by previous SRE, PSA concentration and chemotherapy for prostate cancer within 6 weeks of randomization. Supplementary use of calcium and vitamin D was strongly recommended.

The primary endpoint was time to first on-study SRE (pathological fracture, radiation therapy, surgery to bone or spinal cord compression).

Median time to first on-study SRE was 20.7 months (95% CI 18.8–24.9) with denosumab compared with 17.1 months (15.0–19.4) with zoledronic acid (HR 0.82, 95% CI 0.71–0.95, p = 0.0002 for noninferiority, p = 0.008 for superiority). Adverse effects were noted in the majority of patients in both arms, namely in 916 patients (97%) on denosumab and 918 patients (97%) on zoledronic acid. Serious adverse events were recorded in 594 patients (63%) on denosumab and 568 patients (60%) on zoledronic acid. Hypocalcaemia occurred more frequently in the denosumab group (121 patients, 13%) than in the zoledronic acid group (55 patients, 6%; p < 0.0001). At the time of analysis, osteonecrosis of the jaw had occurred in 22 patients (2%) on denosumab versus 12 patients (1%) on zoledronic acid (p = 0.09).

Thus, denosumab (120 mg subcutaneously every 4 weeks) has been shown to significantly reduce and delay SREs in comparison to zoledronic acid. The outcome of this trial led to licensing of the drug for this indication by the FDA. Importantly, longer follow-up data on the frequency of osteonecrosis of the jaw during treatment with denosumab, a major adverse event related to bone targeting treatment, are essential.

The placebo-controlled phase III Hormone Ablation Bone Loss (HALT) trial investigated the clinical benefit of denosumab at a dose of 60 mg every 6 months in 1468 patients undergoing androgen deprivation therapy and showed significantly increased bone mineral density of the lumbar spine at 24 months (5.6% versus –1%, p < 0.001) and significantly reduced incidence of new vertebral fractures (1.5% versus 3.9, p = 0.006) compared with placebo [Smith et al. 2009]. Another large placebo-controlled trial studying whether denosumab can prolong bone-metastasis-free survival in 1432 men with CRPC is ongoing.

The licensing of the drug by the EMEA for patients with androgen-deprived prostate cancer is pending.

Alpharadin

Alpharadin (radium-223 chloride) is an investigational pharmaceutical containing an alpha-particle-emitting nuclide [Nilsson et al. 2007]. The ALSYMPCA (Alpharadin in Symptomatic Prostate Cancer) trial is a phase III, randomized (2:1), double-blind, placebo-controlled international study of Alpharadin plus current standard of care compared with placebo plus current standard of care in patients with symptomatic bone metastatic CRPC. The primary endpoint of the trial is OS. Secondary endpoints included time to occurrence of SREs, changes and time to progression in PSA, quality of life and health economics. The phase III trial was presented at the European Society for Medical Oncology–European Cancer Organization (ESMO-ECCO) 2011 conference and Alpharadin was shown to significantly improve OS in men according to a preplanned interim analysis of the trial (Table 1). The safety and tolerability of Alpharadin were similar to those observed in previous phase I and II trials. Thus, based on the OS benefit and its favourable safety profile, Alpharadin may become an important treatment in the current armamentarium against CRPC.

New treatment paradigm in metastatic prostate cancer

Previously, docetaxel was the only drug with proven survival benefit, although small, in the CRPC setting. Mitoxantrone plus prednisone resulted in palliation but no demonstrable survival advantage. Therefore, new therapies were urgently needed to improve the outcome in patients with metastatic prostate cancer and extend their survival. Various strategies have been explored in the pre- and post-docetaxel setting. Clinical trials explored whether novel chemotherapeutic agents may be of benefit in patients whose condition fails to respond to docetaxel; other approaches included immunotherapeutic strategies or novel hormonal manipulations.

The conventional paradigm in advanced prostate cancer until 2010 was LHRH agonists and anti-androgens followed by docetaxel. The current paradigm is LHRH antagonists/anti-androgens, followed by sipuleucel-T, docetaxel, and after docetaxel failure, the option of cabazitaxel or abiraterone.

Current data suggest that a significant proportion of CRPC remains dependent on the androgen receptor axis, and therefore, novel strategies for targeting androgen receptor signalling may still be able to induce clinical benefit. Novel endocrine therapies for CRPC that target persistent androgen production (abiraterone) and androgen-receptor-mediated signalling (MDV3100) have demonstrated promising activity in many men with CRPC and may substantially redefine the clinical management of these patients. The outcomes of other phase III trials investigating abiraterone and MD3100 in the pre-docetaxel setting are awaited and if positive will lead to their use prior to conventional chemotherapy.

Various trials testing combinations of docetaxel with angiogenesis inhibitors are awaited. The development of novel active agents is expected to substantially improve the prognosis for patients with CRPC with the potential to substantially prolong survival.

Conclusion

A myriad of novel agents are currently entering the field of CRPC treatment, spanning the early metastatic phase of CRPC to the more advanced stage post-chemotherapy in patients with higher tumour burden. The challenges of the coming years will include optimal spacing of novel treatment strategies in this area by identifying and optimizing the most appropriate sequence of administration of these new agents and combinations of agents. Clinical studies are needed to study optimal timing of drug initiation and the value of discontinuation beyond progression and after commencement of subsequent therapies.

Development of molecular biomarkers to better identify the patients who are likely to benefit from a particular agent is essential. Exploration of the utility of imaging techniques as predictive markers of efficacy will be crucial to minimize the time on treatment for patients whose condition does not respond to a particular agent.

Future perspectives

Currently two new drugs, abiraterone and cabazitaxel, are approved for patients with metastatic prostate cancer post docetaxel. Both drugs seem equally effective in the post-docetaxel setting in terms of median survival benefit and HR for death, with similar 95% CIs. Whether cabazitaxel or abiraterone will be chosen as the first treatment option in the post-docetaxel setting may be determined by the expertise of the physician, the ease of oral drug administration, health economic considerations, and different reimbursement systems for inpatient and outpatient treatment. As soon as a head-to-head comparison of docetaxel and cabazitaxel has been performed and the superiority of cabazitaxel has been shown, cabazitaxel may replace docetaxel as the first choice for treating CRPC.

Sipuleucel-T has been tested in the setting of asymptomatic, chemotherapy-naïve metastatic CRPC. Therefore, this patient-individualized cellular product should only be considered in this particular patient population. The logistics for preparation and shipment of three cellular product infusions for an individual patient are at present only effectively implemented and operational in the USA. Although the costs of production of this personalized medicine are considerable, the current costs of the product (three cell infusions) may affect the prescription of this novel treatment in the presence of other available novel treatment options. The use of sipuleucel-T in Europe has not yet been approved by the EMEA, precluding its current use in Europe.

Phase III trials testing abiraterone, MDV 3100 and related compounds in patients who are chemo naïve patients are underway. Extrapolating the results of phase II trials in the pre-docetaxel setting suggests that several hormonal treatment agents will be effective immediately after assessment of castration resistance. More treatment options are expected to become available for patients after the initial diagnosis of metastatic disease and before first-line chemotherapy. In addition, the total period from first hormonal manipulation to first-line chemotherapy may be considerably prolonged.

Whether MDV3100 or abiraterone would be the first choice after failure of first-line hormonal treatment with LHRH analogues cannot be determined as yet. The OS and PFS advantage of one drug over the other, toxicity profiles, costs and restraints in healthcare budgets may determine the preference for one oral compound over the other. Studies comparing the novel agents head to head or testing the superiority of one sequential treatment over the other will be needed in the future.

With escalating healthcare costs and more limited resources, healthcare systems may become unsustainable in the future, even in the richest and most capitalistic economies in the world. Improved methods to select patients will become important to restrict treatment to those who may benefit and/or stop ineffective treatment early on.