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Keywords:

  • prostate cancer;
  • treatment;
  • survival;
  • chemotherapy;
  • immunotherapy;
  • castration-resistant prostate cancer

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. NON-HORMONAL PHARMACOLOGICAL THERAPIES
  5. CHEMOTHERAPY
  6. IMMUNOTHERAPIES
  7. BONE-TARGETING DRUGS
  8. STROMALLY DIRECTED THERAPIES: ENDOTHELIN RECEPTOR ANTAGONISTS
  9. MOLECULAR-TARGETING AGENTS
  10. CONCLUSION
  11. CONFLICT OF INTEREST
  12. REFERENCES
  • • 
    The treatment of metastatic and castration-resistant prostate cancer (CRPC) has advanced considerably from the era where it was considered that the disease was resistant to chemotherapy.
  • • 
    Cytotoxic chemotherapy involving docetaxel is now used routinely as a first-line therapy after failed first- and second-line androgen deprivation in advanced disease, improving quality of life and to a limited extent, survival in patients with advanced prostate cancer.
  • • 
    The cytotoxic taxane, cabazitaxel has also become a second-line treatment option for patients with CRPC failing previous docetaxel therapy.
  • • 
    Additionally, a broad range of agents are now available or under development including immune-based therapies (cellular therapies and vaccines), bone-targeting agents (anti-osteolytic and anti-tumour therapies) and molecular-based agents targeting cellular control mechanisms.
  • • 
    Most of these remain experimental but on-going pharmacological development will inevitably provide urologists and urological oncologists with a broader range of therapeutic options for better cancer management in the future.

Abbreviations
CRPC

castration-resistant prostate cancer

CTLA4

cytotoxic-T-lymphocyte antigen-4

EAU

European Association of Urology

ET-1

endothelin-1

GM-CSF

granulocyte-macrophage colony-stimulating factor

HRQL

health-related quality of life

Hsp

heat-shock protein

PFS

progression-free survival

SRE

skeletal-related event

uNTx

urinary N-telopeptide

VEGF(R)

vascular endothelial growth factor (receptor)

INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. NON-HORMONAL PHARMACOLOGICAL THERAPIES
  5. CHEMOTHERAPY
  6. IMMUNOTHERAPIES
  7. BONE-TARGETING DRUGS
  8. STROMALLY DIRECTED THERAPIES: ENDOTHELIN RECEPTOR ANTAGONISTS
  9. MOLECULAR-TARGETING AGENTS
  10. CONCLUSION
  11. CONFLICT OF INTEREST
  12. REFERENCES

The complexity of managing prostate cancer has increased with improved understanding of the biology of the disease and the evolution of research and development leading to new therapies for locally advanced and metastatic disease. The urologist and urological cancer physician now have a range of options for the different manifestations of the disease in relation to an individual's clinical stage, risk group and co-morbidity. Optimal treatment of individuals in this setting requires interdisciplinary collaboration between urology, medical and clinical oncology, with additional input from other supportive and palliative treatment groups to provide the best individualised cancer management. The manifold options for treatment can be demonstrated by the numerous published review articles and guidelines, such as the European Association of Urology (EAU) guidelines on the treatment of prostate cancer (Table 1) [1]. This complexity goes further when we examine other developmental areas exploring the treatment of advanced and metastatic disease. This review will explore some aspects of current non-hormone related research for these patient groups.

Table 1.  Primary treatment of prostate cancer [1]
StageTreatmentComment
  1. PSADT, PSA doubling time.

T1aWatchful waitingStandard treatment for Gleason score ≤6 and 7 adenocarcinomas and <10-year life expectancy
Active surveillanceIn patients with <10-year life expectancy, re-staging with TRUS and biopsy is recommended
Radical prostatectomyOptional in younger patients with a long life expectancy, especially for Gleason score ≤7 adenocarcinomas
RadiotherapyOptional in younger patients with a long life expectancy, in particular in poorly differentiated tumours. Higher complication risks after TURP, especially with interstitial radiation
HormonalNot an option
CombinationNot an option
T1b–T2bActive surveillanceTreatment option in patients with cT1c–cT2a, PSA < 10 ng/mL, biopsy Gleason score ≤6, ≤2 biopsies positive, ≤50% cancer involvement of each biopsy
Patients with a life expectancy <10 years
Patients with a life expectancy >10 years once they are informed about lack of survival data beyond 10 years
Patients who do not accept treatment-related complications
T1a–T2cRadical prostatectomyStandard treatment for patients with a life expectancy >10 years who accept treatment-related complications
RadiotherapyPatients with a life expectancy >10 years who accept treatment-related complications
Patients with contraindications for surgery
Unfit patients with 5–10 years of life expectancy and poorly differentiated tumours (combined therapy is recommended: see below)
BrachytherapyLow-dose rate brachytherapy can be considered for low-risk patients with prostate cancer with a prostate volume ≤50 mL and an IPSS ≤ 12
HormonalSymptomatic patients, who need palliation of symptoms, unfit for curative treatment
Anti-androgens are associated with a poorer outcome compared to ‘active surveillance’ and are not recommended
CombinationFor high-risk patients, neoadjuvant hormonal treatment and concomitant hormonal therapy plus radiotherapy results in increased OS
T3–T4Watchful waitingOption in asymptomatic patients with T3, well-differentiated and moderately-differentiated tumours, and a life expectancy <10 years who are unfit for local treatment
Radical prostatectomyOptional for selected patients with T3a, PSA level of <20 ng/mL, biopsy Gleason score ≤8 and a life expectancy >10 years
Patients have to be informed that radical prostatectomy is associated with an increased risk of positive surgical margins, unfavourable histology and positive lymph nodes and that, therefore, adjuvant or salvage therapy, e.g. radiation therapy or androgen deprivation might be indicated
RadiotherapyT3 with >5–10 years of life expectancy. Dose escalation of >74 Gy seems to be of benefit. A combination with hormonal therapy can be recommended (see below)
HormonalSymptomatic patients, extensive T3–T4, high PSA level (>25–50 ng/mL), PSADT < 1 year
Patient driven, unfit patients
Hormone monotherapy is not an option for patients who are fit enough for radiotherapy
CombinationOS is improved by concomitant and adjuvant hormonal therapy (3 years) combined with external beam radiation
Neoadjuvant hormonal treatment plus radical prostatectomy: no indication
N+, M0Watchful waitingAsymptomatic patients. Patient-driven (PSA < 20–50 ng/mL), PSADT > 12 months. Requires very close follow-up
Radical prostatectomyOptional for selected patients with a life expectancy of >10 years a part of a multimodal treatment approach
RadiotherapyOptional in selected patients with a life expectancy of >10 years, combined therapy with adjuvant androgen deprivation for 3 years is mandatory
HormonalStandard adjuvant therapy in more than one positive node to radiation therapy or radical prostatectomy as primary local therapy. Hormonal therapy should only be used as monotherapy in patients who are unfit for any type of local therapy
CombinationNo standard option
Patient-driven
M+Watchful waitingNo standard option. May have worse survival/more complications than with immediate hormonal therapy. Requires very close follow-up
Radical prostatectomyNot an option
RadiotherapyNot an option for curative intent; therapeutic option combined with androgen deprivation for treatment of local cancer-derived symptoms
HormonalStandard option. Mandatory in symptomatic patients

NON-HORMONAL PHARMACOLOGICAL THERAPIES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. NON-HORMONAL PHARMACOLOGICAL THERAPIES
  5. CHEMOTHERAPY
  6. IMMUNOTHERAPIES
  7. BONE-TARGETING DRUGS
  8. STROMALLY DIRECTED THERAPIES: ENDOTHELIN RECEPTOR ANTAGONISTS
  9. MOLECULAR-TARGETING AGENTS
  10. CONCLUSION
  11. CONFLICT OF INTEREST
  12. REFERENCES

There are a range of therapeutic options currently being studied that target different disease stages in prostate cancer. They address the spectrum of castration-resistant prostate cancer (CRPC), including patients with locally advanced and/or metastatic disease. Such therapies encompass approaches using cytotoxic chemotherapy but in addition, several other options have been investigated successfully, including immune-based, bone-targeted, molecular and radiotherapeutic techniques alone or in combination. This innovative and multi-layered approach continues in this disease area, offering new avenues for treatment on the one hand, whilst on the other, generating questions about dosage, combinations, drug sequencing and toxicity.

CHEMOTHERAPY

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. NON-HORMONAL PHARMACOLOGICAL THERAPIES
  5. CHEMOTHERAPY
  6. IMMUNOTHERAPIES
  7. BONE-TARGETING DRUGS
  8. STROMALLY DIRECTED THERAPIES: ENDOTHELIN RECEPTOR ANTAGONISTS
  9. MOLECULAR-TARGETING AGENTS
  10. CONCLUSION
  11. CONFLICT OF INTEREST
  12. REFERENCES

The use of cytotoxic chemotherapy in advanced prostate cancer has changed dramatically since the publication of landmark studies using mitoxantrone [2], docetaxel [3,4] and cabazitaxel [5]. This has reversed the previously held view that prostate cancer is a chemo-refractory disease [6]. Cytotoxic chemotherapy is now used routinely in advanced disease, improving health-related quality of life (HRQL) and to a limited extent, survival in patients with advanced prostate cancer. Studies have generally been conducted in patients with CRPC and a summary of the key trials is shown in Table 2[4,7–12]. The primary first-line agent is the taxane, docetaxel, usually given with steroid support according to the dosing schedule set out in the TAX 327 study (75 mg/m2 at 3-week intervals), although there are variations on this regimen [3]. The 4-month augmented survival reported using this dosing regimen was an improvement on results following the use of mitoxantrone monotherapy, which was previously shown to improve the HRQL of patients with CRPC without affecting their survival [13]. The side-effect profile of the taxane was higher but overall there was general added value for patients receiving this treatment [4]. In patients who have responded to docetaxel during initial therapy, a proportion will also respond when re-challenged with the drug after evidence of further relapse [14].

Table 2.  Survival rates reported in Phase II/III studies of chemotherapy in hormone resistant prostate cancer
StudyRegimenNo patientsOS, months
  1. G-CSF, granulocyte-colony-stimulating factor; OS, overall survival.

Dahut et al. [7]Docetaxel2414.7
Docetaxel + thalidomide4728.9
Ning et al. [8]Docetaxel + thalidomide + bevacizumab5828.2
Scher et al. [9]Docetaxel47620.2
Docetaxel + calcitrol47717.8
Oh et al. [10]Docetaxel + estramustine + carboplatin + G-CSF3419
Picus et al. [11]Docetaxel + estramustine + bevacizumab7724
Berthold et al. [12]Docetaxel 30 mg/m233417.4
Docetaxel 75 mg/m235518.9
Mitoxantrone33716.5
Petrylak et al. [4]Docetaxel + estramustine33815.6
Mitoxantrone33617.5

This therapeutic regimen is now recommended by various urological/oncological guidelines, such as those from the EAU [1] and the European Society for Medical Oncology [15], and it has now become part of routine practice in patients with CRPC failing initial and (usually) secondary hormone therapy. Similar overall survival (OS) rates have been reported when docetaxel is combined with thalidomide [7]; thalidomide plus bevacizumab [8]; estramustine plus carboplatin [16] or bevacizumab [11]; epirubicin [17]; and calcitriol [18] but none of these supplementary treatments has provided extra benefit. However, they have added to the side-effects of treatment and in circumstances where they have produced additive effects, these have been of only marginal benefit and this, usually at considerable financial cost.

Recent data about the use of second-line chemotherapy with the taxane cabazitaxel have now been published [5]. Results of a large open label Phase III randomised trial (TROPIC trial) showed an additional improvement in OS in patients who had already received treatment with docetaxel and had relapsed. The study reported a median progression-free survival (PFS) of 2.8 months with cabazitaxel compared with 1.4 months using mitoxantrone and prednisone (P < 0.001) [5]. The neutropenic sepsis rate using cabazitaxel was higher than that with other cytotoxic agents, but in experienced high-volume treatment centres this was managed safely and effectively. It should also be borne in mind that the patients receiving this therapy were further down the treatment path, having already received and failed first-line docetaxel-based treatment. They were, therefore, likely to have been a less fit study population, a fact which may in part reflect the higher toxicity rates. This therapy is now a recommended treatment option in commonly used clinical guidelines [1,15] for patients with CRPC failing previous docetaxel therapy.

IMMUNOTHERAPIES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. NON-HORMONAL PHARMACOLOGICAL THERAPIES
  5. CHEMOTHERAPY
  6. IMMUNOTHERAPIES
  7. BONE-TARGETING DRUGS
  8. STROMALLY DIRECTED THERAPIES: ENDOTHELIN RECEPTOR ANTAGONISTS
  9. MOLECULAR-TARGETING AGENTS
  10. CONCLUSION
  11. CONFLICT OF INTEREST
  12. REFERENCES

Several approaches have been taken in the development of vaccine-based treatments for prostate cancer. These largely comprise boosted immune cellular therapies e.g. sipuleucil T (formerly known as Provenge®) and GVAX, stimulatory treatments to improve the immunological effect of cellular immunity (ipilimumab), or booster therapies aimed at enhancing directed immune targeting towards prostate cancer cells (Prostvac®).

IMMUNE CELLULAR THERAPIES

Sipuleucel-T

Sipuleucel-T uses the principle of harvesting dendritic cells by leucopheresis from individual patients and boosting them with the immunostimulant, granulocyte-macrophage colony-stimulating factor (GM-CSF) combined with a fusion protein incorporating prostatic acid phosphatase. The activated cells are then re-injected back into the patient. The process, originally developed under the name of Provenge® (APC8015) [19] is repeated twice more after the initial infusion to complete the course of treatment. An analysis of Phase III studies using sipuleucel-T in men with CRPC (IMPACT Study) showed a reduction in overall mortality of 26.5% and an increase in OS by 3.9 months [19–21]. Sipuleucel-T has been approved by the USA Food and Drug Administration (FDA) in men with metastatic CRPC who have minimal symptoms and no visceral metastases.

GVAX

Another cellular approach has been the use of GVAX, whereby activated prostate cancer cells originally from prostate cancer cell lines are immune boosted and injected into individual patients. The therapy involves injection of two whole cellular components derived from two of the most common prostate cancer cell lines, PC-3 and LNCaP, which have been modified so that they secrete GM-CSF. Two Phase II studies were conducted in which OS was between 20 and 29.1 months [22,23]. A dose-response was reported and toxicities were minimal, being reported as ‘not dose-limiting’. On the basis of this, two large scale multi-centre randomised Phase III studies were initiated. Unfortunately, these had to be terminated early due to a lack of efficacy in one and in the other because there was a higher death rate in the trial arm containing the active drug than in the standard control arm [24,25]. No further studies of this treatment are planned.

Ipilumumab

The cytotoxic-T-lymphocyte antigen-4 (CTLA4) is a co-stimulatory molecule expressed on activated T cells that delivers an inhibitory signal to these T cells. CTLA4 blockade with antibody treatment has been shown to augment anti-tumour immunity in animal models and is being developed as a treatment for patients with cancer. In studies in malignant melanoma, this therapeutic approach has, for the first time, shown improvements in survival [26]. Ipilimumab is an anti-CTLA-4 antibody that disrupts the immune tolerance towards antigens located on tumour cells. A Phase I study has examined a combination of increasing doses of ipilumumab with a fixed dose of GM-CSF in patients with metastatic CRPC [27]. Of the patients treated at the highest dose level, 50% had reduction in PSA level of >50%, including one patient who had a partial response in visceral metastases. Another Phase I study involving a combination of ipilimumab plus radiotherapy also resulted in >50% reduction in PSA level in 23% of patients with metastatic CRPC [28]. A large scale Phase III trial of radiotherapy to metastatic sites followed by randomisation to placebo or ipilimumab (CA184-043 Cancertrials.gov) is currently under way.

IMMUNOSTIMULATORY VACCINES

PROSTVAC

Vaccines have also been developed based on PSA recombinant vaccinia vectors (rV-PSA) together with a boosting agent of rFowlpox-PSA (rF-PSA). This approach has been developed further with the addition of a collection of immune stimulatory molecules (LFA-3, ICAM-1 and B7-1) to the poxviral vectors, resulting in an augmented activation of the immune system [29]. The resulting vaccine, PROSTVAC-VF has been studied in a randomised, controlled Phase II study in minimally symptomatic patients with CRPC [30]. PFS was similar in the active treatment group and the vector control. However, at 3 years the PROSTVAC-VF-treated patients had an improved OS compared with controls (30% vs 17%), as well as longer median survival (25.1 vs 16.6 months; P= 0.006). These promising results have spawned a large scale international Phase III study of PROSTVAC alone or combined with GM-CSF vs placebo (PROSPECT Trial), the results of which are awaited.

BONE-TARGETING DRUGS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. NON-HORMONAL PHARMACOLOGICAL THERAPIES
  5. CHEMOTHERAPY
  6. IMMUNOTHERAPIES
  7. BONE-TARGETING DRUGS
  8. STROMALLY DIRECTED THERAPIES: ENDOTHELIN RECEPTOR ANTAGONISTS
  9. MOLECULAR-TARGETING AGENTS
  10. CONCLUSION
  11. CONFLICT OF INTEREST
  12. REFERENCES

Most patients with metastatic prostate cancer develop bone metastases [31]. Prostate cancer spreads to the red bone marrow and usually targets the axial skeleton, including the vertebrae, pelvis and ribs and is the main cause of disability and death among men with CRPC. Thus, targeting bone metastases is an important aspect of treatment of this disease and it has been an area of clinical research actively pursued in recent years.

ANTI-OSTEOLYTIC THERAPIES

Bisphosphonates

The bisphosphonate class of drugs is active in reducing osteoclast mediated bone resorption in prostate cancer [32]. Zoledronic acid is the most potent of these and it has been shown to reduce the incidence and time to occurrence of skeletal-related events (SREs) in men with CRPC after treatment for up to 24 months. Compared with placebo, 4 mg of zoledronic acid significantly reduced the percentage of patients with ≥1 SREs by 11% (P= 0.028) [33]. The median time to the first SRE was 488 days for the zoledronic acid group vs 321 days for the placebo group (P= 0.009). The current recommendation in the EAU guidelines is that bisphosphonates may be offered to patients with skeletal masses to prevent osseous complications. However, the benefits must be balanced against the toxicity of these agents. In particular, zoledronic acid cannot be used in patients with renal impairment and caution needs to be used in relation to the induction of hypocalcaemia (by contrast with breast cancer, most patients with prostate cancer with bone metastases have mildly lowered serum calcium and are mildly hyper-parathyroid). A further small but significant risk is osteonecrosis of the jaw [1]. This is a relatively uncommon problem but the risks are greater in patients who have poor dental hygiene, prolonged exposure to bisphosphonate drugs and who have been exposed heavily to drugs with adverse skeletal effects (e.g. steroids) [34].

Denosumab

Denosumab is a fully human monoclonal antibody that specifically inhibits the receptor activator of NF-κB (nuclear factor κ-light-chain-enhancer of activated B cells) ligand (RANKL) resulting in inhibition of osteoclast-mediated bone destruction [35]. This drug is an extremely potent inhibitor of bone resorption and it is much more active than the most potent bisphosphonate in reducing markers of bone turnover in patients with advanced cancer [36]. A randomised Phase II study was conducted using denosumab in patients with bone metastases from prostate, breast and other cancers after i.v. bisphosphonate treatment [36]. Patients had elevated levels of urinary N-telopeptide (uNTx), representing excessive bone resorption. The primary end point of normalisation of uNTx levels was achieved in 71% of patients in the denosumab arms compared with 29% patients treated with bisphosphonates (P < 0.001). A subsequent large scale trial involving >1900 patients has now been conducted in advanced prostate cancer; the results show that denosumab was 11% better than the most potent biphosphonate, zoledronic acid, in reducing SREs. It also produced a significant reduction in the time to first and subsequent SREs on study. The drug is well tolerated, is administered s.c. once a month and can be used in patients with renal impairment. However, there is a slightly higher risk of osteonecrosis of the jaw (2% vs 1% in zoledronic acid-treated patients) [37]. In a further recent study, this compound has been given to men with high-risk prostate cancer but without metastases. Results show that this drug significantly reduced the time to first bone metastasis compared with placebo [38]. It remains to be determined whether the cost benefit analysis of the use of this compound for this indication will be justified, although targeting of the drug to the highest risk cases may be of importance.

RADIONUCLIDE THERAPY

Radiotherapy to bone metastases has been a longstanding and effective therapy for palliation of bone pain [39,40]. Systemically injected radionuclides have been developed over the last 30 years on the basis that many metastatic lesions are radiosensitive and radionuclides are potentially effective in multifocal lesions, where focally directed external beam radiotherapy is ineffective. Radionuclides are bone-seeking radioisotopes that are assimilated in skeletal areas where the bone turnover is rapid, i.e. in metastatic deposits. After a single injection, the active agent is taken up selectively in areas of skeletal metastatic activity and the radiotherapy emitted is effective locally against the tumour deposit. Most are γ-emitters (strontium, rhenium, samarium), but more recently, the α-emitter radium-223 (Alpharidin®) has been used with significant benefit.

Strontium

Strontium-89 is an effective therapy for relief of pain from bone metastases in several cancers. Rates of pain palliation range from 46% [41] to 88% [42]. In prostate cancer, it has been shown to be of significant benefit in the relief of multi-site bone pain [43] and it is at least as effective as external beam radiotherapy in pain control in many settings [44]. It has even been shown in some studies to prolong survival in metastatic prostate cancer [45]. Other γ-emitting isotopes, e.g. rhenium and in particular, samarium-153, have also been shown to have benefit. In studies comparing the latter to placebo, there was significantly better pain control for patients with painful bone metastases than with the use of standard pain relieving therapies [46,47].

The principal advantage of α radiation is that the energy dissipation of the α particles occurs over a much shorter distance (<100 µm) than that seen with β or γ radiation. This, theoretically, means greater radiation dose to the local tumour and less damage to surrounding tissue, especially the bone marrow. In a study by Nilsson et al. [48], the α-emitter radium-233 (Alpharadin®) improved OS of patients with CRPC and symptomatic bone metastases by 44%. In a large scale Phase III study (ALSYMPCA Trial) by Parker et al. [49] involving >900 men with metastatic disease, this therapeutic advantage was confirmed, with improved median OS (14.0 months in patients receiving Alpharadin® vs 11.2 months for placebo). There was also an extension in median time to first SRE (13.6 vs. 8.4 months). The side-effect profile was low and it is likely that this therapy will be used more widely in the future in men with this disease.

RADIONUCLIDE AND CHEMOTHERAPY COMBINATIONS

Strontium plus chemotherapy

This therapeutic approach is under test after the publication of an innovative study in patients with advanced CRPC using induction chemotherapy with doxorubicin/estramustine plus vinblastine followed by additional strontium-89 (vs placebo) for 6 weeks in patients who responded to the chemotherapy [50]. Results showed a ≥50% reduction in PSA level in 60% of patients and a ≥80% reduction in 42% of patients. Of patients with bone pain before treatment, 52% had a complete resolution of pain. The median (range) survival reported with doxorubicin plus strontium was 27.7 (4.9–37.7) months compared with 16.8 (4.4–34.2) months for doxorubicin alone. This principle is now under test in a large scale multicentre trial of docetaxel ± strontium ± zoledronic acid (TRAPEZE trial) [51]. Results of this study will hopefully yield new information about the true benefit of this combination.

STROMALLY DIRECTED THERAPIES: ENDOTHELIN RECEPTOR ANTAGONISTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. NON-HORMONAL PHARMACOLOGICAL THERAPIES
  5. CHEMOTHERAPY
  6. IMMUNOTHERAPIES
  7. BONE-TARGETING DRUGS
  8. STROMALLY DIRECTED THERAPIES: ENDOTHELIN RECEPTOR ANTAGONISTS
  9. MOLECULAR-TARGETING AGENTS
  10. CONCLUSION
  11. CONFLICT OF INTEREST
  12. REFERENCES

The activation of the endothelin-A receptor by endothelin-1 (ET-1) is thought to promote several processes involved in tumour progression, including inhibition of apoptosis, promotion of angiogenesis and invasion, and changes in skeletal biology associated with bone metastasis [52]. By contrast, endothelin-B receptor signalling may promote apoptosis and thus inhibit tumour progression [53]. Several endothelin-A receptor antagonists have been studied in patients with CRPC including atrasentan and zibotentan (ZD4054) but unfortunately, the results in Phase III testing have been disappointing, despite early promise.

ATRASENTAN

The first ET-1 antagonist atrasentan was tested in Phase III placebo-controlled trials in patients with non-metastatic CRPC, where it failed to show a significant advantage on PFS [54]. Similarly in metastatic CRPC, no advantage was found in a Phase III study for time to delay disease progression or PSA progression, OS or mean change in bone scan index [55]. A Phase III study (Southwest Oncology Group [SWOG] 0421) was set up to examine the effect of a docetaxel/prednisone plus atrasentan combination. However, the study was closed early due to the lack of benefit with atrasentan.

ZIBOTENTAN

Further studies have been carried out using the selective ET-1 antagonist zibotentan based on a highly promising result from a double-blind placebo-controlled Phase II study using two dose levels (10 and 15 mg). Results reported a median time to progression of 3.6, 4.0 and 3.8 months in the placebo, zibotentan 10 mg and zibotentan 15 mg groups, respectively, with no statistically significant difference between zibotentan groups and placebo [56]. However, a benefit in OS was shown; the median OS was 17.3, 24.5 and 23.5 months in the placebo group, the zibotentan 10 mg and 15 mg groups, respectively. Based on this a large Phase III testing programme (ENTHUSE Trial) [57] was set up studying use of the drug in CRPC without metastases and in CRPC with metastases, with and without docetaxel. Unfortunately, the interim analysis of results of these studies was disappointing and consequently, this trial programme has now been discontinued. However, there are two Phase III studies continuing to explore zibotentan in different settings. One is comparing zibotentan plus chemotherapy with chemotherapy alone in men with metastatic CRPC; the other is comparing zibotentan with placebo in men with non-metastatic CRPC.

MOLECULAR-TARGETING AGENTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. NON-HORMONAL PHARMACOLOGICAL THERAPIES
  5. CHEMOTHERAPY
  6. IMMUNOTHERAPIES
  7. BONE-TARGETING DRUGS
  8. STROMALLY DIRECTED THERAPIES: ENDOTHELIN RECEPTOR ANTAGONISTS
  9. MOLECULAR-TARGETING AGENTS
  10. CONCLUSION
  11. CONFLICT OF INTEREST
  12. REFERENCES

VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR (VEGFR)-DIRECTED THERAPIES

Sunitinib

VEGFR signalling is noted as being involved in prostate cancer growth [58], giving rise to targeted therapeutic research in this area. One agent with selectivity for the VEGFR axis is the tyrosine kinase inhibitor, sunitinib. A Phase II study of this drug in men with CRPC showed a >50% drop in PSA levels and a 30% decline in measurable disease was reported in 11% based on the RECIST criteria [59]. Drug toxicity was problematic and >50% of men had to withdraw from the study due to severe drug reactions. However, a Phase III trial assessing the potential of sunitinib combined with prednisone for men with advanced CRPC who had progressed despite docetaxel treatment was stopped due to a lack of effect on OS.

Bevacizumab

Bevacizumab, a humanised monoclonal antibody directed against VEGF, has been evaluated in prostate cancer in several clinical trials. In a Phase II trial involving 15 patients with CRPC, 12 weeks of therapy with bevacizumab dosed (10 mg/kg every 2 weeks) resulted in no patients having an objective response or PSA decline of >50% [60]. In a randomised, double-blind, placebo-controlled Phase III trial involving docetaxel plus prednisone with or without bevacizumab in 1050 men with chemotherapy-naïve CRPC, the median OS was not significantly longer with the addition of bevacizumab. However, the median PFS interval was longer at 7.5 months in the control arm and 9.9 months in the bevacizumab-containing arm (P < 0.001) [61]. Patients receiving bevacizumab had more adverse effects, with patients having more fatigue, febrile neutropenia, hypertension, and more gastrointestinal complications including gastrointestinal perforation and haemorrhage.

Cabazantinib (XL184-306)

Cabazantinib is a multi-targeted tyrosine kinase inhibitor with specific activity against the proto-oncogene cMET and its ligand, hepatocyte growth factor [62]. A Phase II study has examined the safety and efficacy on patients with progressive measurable disease [63]. Patients received cabazantinib after a 12-week lead-in stage before randomisation: the median follow-up was 4 months in 100 evaluable patients. There were dramatic improvements on bone scans in some patients and there was associated RECIST measurable tumour shrinkage (in 84% of patients) and reduction in markers of bone destruction. The 12-week disease control rate was 71% and the median PFS has not yet been reached. Dose reductions due to adverse events occurred in 51% of patients and discontinuations in 10%. Further consolidated Phase III results are awaited eagerly.

Src KINASE INHIBITION: DASATINIB

Inhibitors of the Src kinase family help suppress cell adhesion, migration and invasion of cancer cells. One such inhibitor, dasatinib, has demonstrated a reduction in tumour progression in 43% of patients with CRPC after 12 weeks of treatment in a Phase II study [64]. Current research is examining combinations of dasatinib with docetaxel [65].

CLUSTERIN ANTISENSE INHIBITION

Clusterin is expressed in various human cancers including prostate cancer, particularly CRPC [66]. In cancer models, over-expression of clusterin confers resistance to radio-, hormone- and chemotherapy because of its inter-relationship with the stabilising heat-shock protein (Hsp)90, which confers resistance to apoptotic cell death [67,68]. OGX-011, an antisense inhibitor of clusterin, has been studied combined with docetaxel/prednisone in patients with metastatic CRPC. The median PFS and OS were 7.3 and 23.8 months, respectively, in the arm containing OGX-011 and 6.1 and 16.9 months, respectively, with chemotherapy alone [69]. Large Phase III trials of this compound are now on-going and are likely to complete recruitment in the near future.

Hsp INHIBITION

Resistance to apoptosis is associated with high expression of Hsps and the use of inhibitors of a variety of these in tumour models can induce apoptosis [70]. Hsp27 can protect cells against cytotoxic chemotherapy and other cytotoxic conditions [71]. In prostate cancer, Hsp27 inhibits apoptosis and is thought to play a critical role in the development of androgen independence [72]. OGX-427 is a 2′-methoxyethyl modified phosphorothioate antisense oligonucleotide that inhibits Hsp27 expression and has been shown to cause a 40–76% inhibition of cell growth in LNCaP and PC-3 cells [73]. Preliminary results from a Phase II study in chemotherapy-naïve patients with metastatic CRPC showed a higher number of patients without disease progression at 12 weeks, and greater declines in PSA levels and circulating tumour cells with OGX-427 plus prednisone treatment compared with prednisone alone [74]. It is too early, at this stage, to say whether these agents will be of use in clinical practice but they are promising.

CONCLUSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. NON-HORMONAL PHARMACOLOGICAL THERAPIES
  5. CHEMOTHERAPY
  6. IMMUNOTHERAPIES
  7. BONE-TARGETING DRUGS
  8. STROMALLY DIRECTED THERAPIES: ENDOTHELIN RECEPTOR ANTAGONISTS
  9. MOLECULAR-TARGETING AGENTS
  10. CONCLUSION
  11. CONFLICT OF INTEREST
  12. REFERENCES

The non-hormonal management of prostate cancer has become a rapidly evolving area for new therapy. Cytotoxic chemotherapy is effective for both palliation and improved survival in a proportion of patients and a range of new therapies are becoming available, which will either supplement this efficacy or change the scheme of management completely. In most circumstances, clinicians need to ‘road test’ these new therapies in general populations of patients with CRPC to ascertain their true efficacy and toxicity. Furthermore, many questions relating to drug combinations, drug dose, treatment sequencing and individual patient selection remain unanswered. It is therefore of fundamental importance for clinicians to continue to work together in a multi-disciplinary way with translational scientists and major pharmaceutical companies to acquire additional clinical trial-based data. In this way, patients with CRPC will have a better chance of having their treatment optimised and delivered in an evidence-based manner, and with a better chance of improved survival and HRQL.

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  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. NON-HORMONAL PHARMACOLOGICAL THERAPIES
  5. CHEMOTHERAPY
  6. IMMUNOTHERAPIES
  7. BONE-TARGETING DRUGS
  8. STROMALLY DIRECTED THERAPIES: ENDOTHELIN RECEPTOR ANTAGONISTS
  9. MOLECULAR-TARGETING AGENTS
  10. CONCLUSION
  11. CONFLICT OF INTEREST
  12. REFERENCES
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