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Keywords:

  • prostate cancer;
  • androgen deprivation therapy;
  • LHRH agonists;
  • LHRH antagonists;
  • EAU Guidelines

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. HORMONE-THERAPY AGENTS
  5. EAU GUIDELINES ON PROSTATE CANCER
  6. INTERMITTENT ADT
  7. IMMEDIATE VS DEFERRED ADT
  8. ADT COMBINED WITH RADIOTHERAPY (RT)
  9. SIDE-EFFECTS OF HORMONE THERAPY
  10. RECENT DEVELOPMENTS IN HORMONAL THERAPY
  11. ABIRATERONE ACETATE
  12. ORTERONEL
  13. MDV3100
  14. CONCLUSIONS
  15. CONFLICT OF INTEREST
  16. REFERENCES
  • • 
    It is >70 years since the responsiveness of symptomatic metastatic prostate cancer to androgen deprivation was first demonstrated.
  • • 
    Since those pivotal studies, progress in hormonal therapy of prostate cancer has been marked by several important developments and the availability of various androgen-suppressing agents.
  • • 
    Treatment guidelines have continued to evolve with clinical and therapeutic progress, but androgen-deprivation therapy (ADT) remains the standard of care for non-localised prostate cancer.
  • • 
    Because of the long-term experience (>20 years) and wealth of evidence from the large number of clinical trials, the luteinizing hormone-releasing hormone (LHRH) agonists are currently the main forms of ADT.
  • • 
    Treatment strategies should be adapted to the individual patient in terms of timing, duration and choice of agent.
  • • 
    Prostate cancer remains the most common type of cancer in men and the development of castration-resistant disease seems inevitable, which together drive the clear and continuing need for new, effective agents for ADT to be used alongside the LHRH agonists.

Abbreviations
ADT

androgen-deprivation therapy

BMD

bone mineral density

CRPC

castration-resistant prostate cancer

(EB)RT

external beam (radiotherapy)

3D-CRT

three-dimensional conformal RT

EAU

European Association of Urology

EORTC

European Organisation for Research and Treatment of Cancer

MRC

Medical Research Council

OS

overall survival

PFS

progression-free survival

INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. HORMONE-THERAPY AGENTS
  5. EAU GUIDELINES ON PROSTATE CANCER
  6. INTERMITTENT ADT
  7. IMMEDIATE VS DEFERRED ADT
  8. ADT COMBINED WITH RADIOTHERAPY (RT)
  9. SIDE-EFFECTS OF HORMONE THERAPY
  10. RECENT DEVELOPMENTS IN HORMONAL THERAPY
  11. ABIRATERONE ACETATE
  12. ORTERONEL
  13. MDV3100
  14. CONCLUSIONS
  15. CONFLICT OF INTEREST
  16. REFERENCES

In 1941, Huggins and Hodges reported the favourable effects of surgical castration and oestrogen treatment on prostate size and symptoms of progression of metastatic prostate cancer [1]. By showing that prostatic cancers were androgen dependent, this seminal work established a rational basis for endocrine therapy of this disease and resulted in the award of the 1966 Nobel Prize in Physiology or Medicine to these researchers. Since this milestone in the history of prostate cancer, androgen ablation has been the principal therapeutic approach for patients with advanced prostate cancer.

Historically, circulating testosterone levels have been used to assess the efficacy of androgen depletion, with a target total testosterone level of <50 ng/dL (<1.74 nmol/L) [2]. This target represents the level of suppression achieved with surgical castration but was defined >40 years ago, when testosterone level testing was limited. With improved contemporary testing methods, the mean value of testosterone after surgical castration has been reported as 15 ng/dL (95% CI 12–17 ng/dL) [3]. This has led some authors to suggest <20 ng/dL to be a more appropriate definition of castration [3]. A small scale retrospective study of 73 patients with non-metastatic prostate cancer treated with androgen-deprivation therapy (ADT) suggests that 32 ng/dL might well be the lowest serum testosterone threshold with a clinical impact [4].

Androgen deprivation can be achieved by suppressing the secretion of testicular androgens by surgical or medical castration or by inhibiting the action of the circulating androgens at the level of their receptor in prostate cells using competing anti-androgens. In addition, these two methods of androgen deprivation can be combined to achieve complete (or maximal or total) androgen blockade [2].

The classical approach to suppressing testosterone production to castrate levels, the primary goal of hormonal therapy, is bilateral orchidectomy. The use of surgical castration has reduced considerably, partly because of an increasing trend towards treating earlier disease and partly because of the introduction of equally effective pharmacological methods of castration [5]. In addition, orchidectomy may have a negative psychological effect; it is irreversible and does not allow for intermittent treatment.

HORMONE-THERAPY AGENTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. HORMONE-THERAPY AGENTS
  5. EAU GUIDELINES ON PROSTATE CANCER
  6. INTERMITTENT ADT
  7. IMMEDIATE VS DEFERRED ADT
  8. ADT COMBINED WITH RADIOTHERAPY (RT)
  9. SIDE-EFFECTS OF HORMONE THERAPY
  10. RECENT DEVELOPMENTS IN HORMONAL THERAPY
  11. ABIRATERONE ACETATE
  12. ORTERONEL
  13. MDV3100
  14. CONCLUSIONS
  15. CONFLICT OF INTEREST
  16. REFERENCES

Advances in androgen endocrinology have resulted in the development of various androgen-suppressing agents for medical castration, including oestrogen agonists, LHRH agonists, LHRH antagonists, anti-androgens and ketoconazole (Table 1).

Table 1.  Hormonal agents used in the management of prostate cancer
Class of drug with examplesMechanism
Oestrogen agonists:Suppression of LHRH secretion, which inhibits LH secretion and testosterone production
 diethylstilboestrol
LHRH agonists:Suppression of LHRH secretion, which inhibits LH secretion and testosterone production
 buserelin
 goserelin
 histrelin
 leuprorelin
 triptorelin
LHRH antagonists:Direct inhibition of LHRH with no agonist properties
 abarelix
 cetrorelix
 degarelix
Antiandrogens (steroidal):Suppression of testosterone production by feedback effects at the pituitary and hypothalamus
 cyproterone acetate
 megesterol acetate
 medroxyprogesterone
Antiandrogens (nonsteroidal):Competitive inhibition of androgen binding in target tissues
 bicalutamide
 flutamide
 nilutamide
Other:Inhibition of cytochrome P450 hydroxylase for adrenal and testicular steroidogenesis
 ketoconazole

The first reversible or medical method of androgen suppression was treatment with diethylstilboestrol, a synthetic oestrogen first described in 1938. Diethylstilboestrol was shown to inhibit testosterone stimulation of dogs' prostatic cells by Huggins who with others subsequently showed the beneficial effects of diethylstilboestrol in patients with prostate cancer in the early 1940s [6].

Oestrogen therapy reduces serum testosterone by suppression of LHRH through negative feedback on the hypothalamic–pituitary axis. However, although diethylstilboestrol was highly effective in achieving castrate levels of testosterone, serious concerns were raised about the thrombogenic side-effects in patients receiving diethylstilboestrol. The Veterans Administration Cooperative Urological Research Group (VACURG) studies showed that although of efficacy comparable with orchidectomy, diethylstilboestrol 5 mg was associated with excess cardiovascular mortality [7,8]. Despite this, diethylstilboestrol remained the predominant medical alternative to orchidectomy as the standard initial treatment for symptomatic prostate cancer until the mid-1980s when a key study showed that the LHRH agonist leuprolide had similar efficacy and lacked the adverse oestrogenic side-effects of diethylstilboestrol [9]. Other LHRH agonists have been introduced and long-acting formulations of these compounds are the main forms of ADT in current use.

During long-term exposure, LHRH agonists induce down-regulation of LHRH receptors, thereby suppressing pituitary LH and FSH secretion and decreased production of testosterone by Leydig cells, achieving castration levels of testosterone within 2–4 weeks [10,11]. However, as synthetic peptide analogues of LHRH, these compounds initially stimulate pituitary LHRH receptors, inducing a transient increase in LH and FSH release [12]. This in turn elevates serum testosterone and dihydrotestosterone levels, referred to as the testosterone flare or surge, during the first 2–7 days of therapy [13]. In patients with advanced disease, short-term testosterone flare could be associated with various unwanted effects including increased bone pain and acute BOO. A review showed, that only 4–10% of patients with M1 have a potential risk of clinical flare [14].The simultaneous administration of an antiandrogen within the first 2-week period, which inhibits the action of circulating androgens at the level of the receptor, was subsequently found to neutralise the transient increase in serum androgens and reduce the potential risk of flare [13]. LHRH agonists result in equivalent oncological efficacy to orchidectomy and diethylstilboestrol [15] and with other advantages in terms of tolerability and reversibility have become the standard of care in advanced prostate cancer [16].

The LHRH antagonists represent another class of agents introduced for the hormonal treatment of prostate cancer. By binding to LHRH receptors in the pituitary gland, LHRH antagonists achieve a rapid decrease in LH, FSH and testosterone levels that, in contrast to LHRH agonists, is without the initial surge in testosterone associated with LHRH agonists. Monotherapy with abarelix has been shown to achieve medical castration without a testosterone flare [17,18]. Unlike LHRH agonists, abarelix also suppresses FSH, which may contribute to the growth of prostate cancer cells. Degarelix is another LHRH antagonist that is available as a monthly s.c. formulation, with outcome reported in a small scale Phase III study comparing degarelix (240 mg or 160 mg/month) to leuprolide (7.5 mg/month) [19]. The use of LHRH antagonists is limited by a monthly formulation, compared with 3- and 6-month depot formulations for most of the available LHRH agonists. In addition, suppression of the initial flare up with monotherapy may only clinically be relevant in a few, symptomatic, metastatic patients.

Despite the apparently more intuitive mechanism of action, the limitations of many LHRH antagonists have restricted clinical studies. Many LHRH antagonists have been associated with serious and life-threatening histamine-mediated side-effects and available formulations require administration at least monthly [2].

Another form of ADT involves the antiandrogens, which have been evaluated as monotherapy and combined with LHRH agonists. These oral compounds are classified according to their chemical structure as steroidal, e.g. cyproterone acetate, megestrol acetate and medroxyprogesterone acetate, and non-steroidal or pure, e.g. nilutamide, flutamide and bicalutamide. As monotherapy, nilutamide has been studied in patients with metastatic prostate cancer resulting in an objective response in 38.5% of patients and median progression-free survival (PFS) of 9 months and median overall survival (OS) of 23 months [20]. Promising results have been shown with nilutamide as a second-line hormonal therapy in hormone-resistant prostate cancer [21,22]. Two large scale prospective studies have compared bicalutamide with medical or surgical castration in patients with locally advanced or metastatic prostate cancer, although both studies were underpowered [23,24]. A pooled analysis revealed an improvement in OS in metastatic patients with castration compared with bicalutamide (P= 0.02) [23] but no difference between the two treatments in patients with locally advanced prostate cancer [24]. A comparative study of high-dose bicalutamide and the combination of an LHRH agonist plus antiandrogen (maximum/combined androgen blockade) showed no difference in OS [25]. The European Association of Urology (EAU) Guidelines on Prostate Cancer state that non-steroidal antiandrogen monotherapy (e.g. bicalutamide) is an alternative to castration in patients with locally advanced disease. However, the guidelines go on to state the expected benefit of bicalutamide for health-related quality of life compared with castration is far from being proven.

EAU GUIDELINES ON PROSTATE CANCER

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. HORMONE-THERAPY AGENTS
  5. EAU GUIDELINES ON PROSTATE CANCER
  6. INTERMITTENT ADT
  7. IMMEDIATE VS DEFERRED ADT
  8. ADT COMBINED WITH RADIOTHERAPY (RT)
  9. SIDE-EFFECTS OF HORMONE THERAPY
  10. RECENT DEVELOPMENTS IN HORMONAL THERAPY
  11. ABIRATERONE ACETATE
  12. ORTERONEL
  13. MDV3100
  14. CONCLUSIONS
  15. CONFLICT OF INTEREST
  16. REFERENCES

The latest version of the EAU Guidelines on Prostate Cancer, published in 2011, confirm that ADT with the LHRH agonists is one of the main treatment options for advanced, relapsing and castration-resistant prostate cancer (CRPC) [2,26]. The EAU Guidelines recommend a risk adapted approach to the use of ADT in patients with locally advanced disease and in those with PSA relapse after radical prostatectomy. Patient care should thus be individualised, balancing the risks and benefits of different management strategies. ADT may be administered immediately, intermittently, after a delay, and combined with radiation therapy, aspects of ADT that are reviewed briefly here.

INTERMITTENT ADT

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. HORMONE-THERAPY AGENTS
  5. EAU GUIDELINES ON PROSTATE CANCER
  6. INTERMITTENT ADT
  7. IMMEDIATE VS DEFERRED ADT
  8. ADT COMBINED WITH RADIOTHERAPY (RT)
  9. SIDE-EFFECTS OF HORMONE THERAPY
  10. RECENT DEVELOPMENTS IN HORMONAL THERAPY
  11. ABIRATERONE ACETATE
  12. ORTERONEL
  13. MDV3100
  14. CONCLUSIONS
  15. CONFLICT OF INTEREST
  16. REFERENCES

Normal prostate cells are physiologically dependent on androgens and are unable to grow, function and proliferate in the absence of androgen, even over several decades of androgen ablation. Testosterone, although not tumorigenic, is similarly essential for the growth and perpetuation of tumour cells [27]. However, prostate cancer cells can become androgen-independent [28]. In patients with metastatic prostate cancer receiving continuous ADT, disease progression is probable within 2–3 years [29].

Progression to a hormone-refractory state appears due to the fact that apoptosis induced by androgen ablation is not able to eradicate all malignant cells, the remaining cells losing their apoptotic potential [30]. The emergence of androgen-independent prostate cancer cells may arise from the selection of pre-existing clones of androgen-independent cells resistant to apoptosis generated randomly by genetic instability of tumours (clonal selection hypothesis) or from the upregulation of androgen-repressed adaptive mechanisms and growth factors (adaptation hypothesis) [31].

Experimental and preclinical models of prostate cancer [32,33] have provided compelling evidence that allowing testosterone recovery after a period of androgen deprivation would help prevent the development of resistance by lessening the selection pressure for tumour growth in low-androgen conditions. By cycling of reversible androgen suppression, there appears to be recovery of apoptosis and subsequent slower progression to an androgen-independent state, thereby providing the rationale for intermittent ADT [34,35]. The potential advantages of intermittent ADT over continuous ADT are a prolonged period of androgen dependence, a decrease in the cost of care and improved health-related quality of life through a reduction in ADT-associated adverse effects during off-treatment phases.

Clinical use of intermittent ADT was first reported in 1986 [36]; Klotz et al. reported that withdrawal of diethylstilboestrol from patients with metastatic prostate cancer after initial clinical response led to a reduction in the side-effects experienced by the patients, without any obvious adverse outcome. After re-emergence of symptoms, treatment was reinitiated and all patients had a rapid clinical response to treatment. Subsequent studies showed that normal testosterone levels recovered in most patients, who had a high chance of a second hormone response [1,37–39].The first large scale published trial on intermittent ADT was by Da Silva et al. [40]. The study involved 766 patients with locally advanced or metastatic prostate cancer who underwent a 3-month induction phase on an LHRH agonist plus cyproterone acetate. Those patients whose PSA level decreased to <4 ng/mL or to 80% below their initial value were randomised to intermittent treatment (n= 127) or continuous ADT (n= 107). The median follow-up was 51 months; maximum 12 years. Survival in the two arms of the study was comparable (170 and 169 in the intermittent and continuous arms, respectively). The number of cancer deaths in the intermittent treatment arm was greater at 106 vs 84, but this could be balanced by a greater number of cardiovascular deaths in the continuous arm (52 vs 41). Side-effects were more pronounced in the continuous arm and in addition, patients treated with intermittent therapy reported better sexual function. It was reported in a recent review of Phase II and Phase III clinical studies that intermittent ADT generally provided similar efficacy to continuous ADT in regard to a number of outcomes, including PFS, OS and biochemical progression [41].

IMMEDIATE VS DEFERRED ADT

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. HORMONE-THERAPY AGENTS
  5. EAU GUIDELINES ON PROSTATE CANCER
  6. INTERMITTENT ADT
  7. IMMEDIATE VS DEFERRED ADT
  8. ADT COMBINED WITH RADIOTHERAPY (RT)
  9. SIDE-EFFECTS OF HORMONE THERAPY
  10. RECENT DEVELOPMENTS IN HORMONAL THERAPY
  11. ABIRATERONE ACETATE
  12. ORTERONEL
  13. MDV3100
  14. CONCLUSIONS
  15. CONFLICT OF INTEREST
  16. REFERENCES

Important factors to be considered when initiating ADT are the side-effects of treatment and the potential for developing CRPC. Hormonal therapy may be deferred, for example, in men with prostate cancer considered putatively curable by definitive therapy in which PSA levels subsequently rise, i.e. who have biochemical relapse or progression, or in men with localised disease who were unwilling or unfit due to comorbidities or age to undergo local therapy with curative intent.

In locally advanced prostate cancer, the risk of delaying hormone therapy until disease progression has occurred appears to be modest. Overall, it seems that hormonal therapy should be withheld until there is definitive proof of disease activity (progression). There are conflicting data whether there might be some benefit in starting hormone therapy before the patient develops more advanced disease. Shorter cancer-specific survival times have been reported after deferred therapy compared with immediate hormone therapy in presumed locally advanced prostate cancer (not using PSA for staging) after 15 years of follow-up [42]. In contrast, the Casodex Early Prostate Cancer Trialists' Group programme showed a higher mortality in a group of men with localised prostate cancer managed conservatively who were treated with bicalutamide 150 mg than in those who received placebo [43].

The timing of ADT in locally advanced prostate cancer has been researched in prospective, randomised, controlled trials: the European Organisation for Research and Treatment of Cancer (EORTC) 30846 trial [44], the EORTC 30891 trial [45] and a Medical Research Council (MRC) study [46]. The EORTC 30846 study showed that there was no benefit of immediate ADT compared with delayed ADT for OS, cancer-specific or cancer-independent survival [47]. The median OS favoured immediate treatment (7.4 vs 6.5 years for deferred treatment) in the EORTC 30891 trial. However, no significant difference between treatments in prostate cancer mortality or symptom-free survival was reported [46]. In the MRC study, early treatment produced more favourable outcomes primarily on M0 patients [46]. In addition, Messing et al. [48] examined the role of immediate ADT vs observation in patients with positive lymph nodes at the time of initial surgery and showed a significant improvement in OS with immediate therapy at a median follow-up of 11.9 years.

The conflicting data from the trials on immediate vs deferred ADT provide no clear advice for patient management. For this reason, the decision about early or delayed treatment in asymptomatic men with locally advanced or metastatic prostate cancer should be individualised after a careful discussion with the patient about the pros and cons based on the available clinical trial data.

ADT COMBINED WITH RADIOTHERAPY (RT)

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. HORMONE-THERAPY AGENTS
  5. EAU GUIDELINES ON PROSTATE CANCER
  6. INTERMITTENT ADT
  7. IMMEDIATE VS DEFERRED ADT
  8. ADT COMBINED WITH RADIOTHERAPY (RT)
  9. SIDE-EFFECTS OF HORMONE THERAPY
  10. RECENT DEVELOPMENTS IN HORMONAL THERAPY
  11. ABIRATERONE ACETATE
  12. ORTERONEL
  13. MDV3100
  14. CONCLUSIONS
  15. CONFLICT OF INTEREST
  16. REFERENCES

The combination of ADT and RT has been has been studied with varying durations of ADT applied and with a benefit for combined therapy reported. It should be noted that some of the earlier trials involved radiation dosages that are not used today. The first Phase III study to show a significant benefit for OS for RT combined with ADT was the EORTC study 22863. Immediate androgen suppression with an LHRH analogue given during and for 3 years after external beam RT (EBRT) improved 10-year disease-free survival and OS for patients with locally advanced prostate cancer [49]. The benefits of long-term adjuvant ADT with RT were subsequently shown in Radiation Therapy Oncology Group (RTOG) protocols 85-31 [50] and 92-02 [1]. With technological progress, three-dimensional conformal RT (3D-CRT) with or without intensity-modulated RT has replaced conventional irradiation, allowing dose escalation with improvement of loco-regional control without increasing serious toxicity. The results of the EORTC study 22961 showed clearly that 6 months of androgen suppression combined with 3D-CRT resulted in inferior survival compared with RT and 3-years ADT in the treatment of locally advanced prostate cancer. While further trials are in progress, 3D-CRT plus concomitant and adjuvant 3-year ADT can be recommended for locally advanced prostate cancer [49].

SIDE-EFFECTS OF HORMONE THERAPY

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. HORMONE-THERAPY AGENTS
  5. EAU GUIDELINES ON PROSTATE CANCER
  6. INTERMITTENT ADT
  7. IMMEDIATE VS DEFERRED ADT
  8. ADT COMBINED WITH RADIOTHERAPY (RT)
  9. SIDE-EFFECTS OF HORMONE THERAPY
  10. RECENT DEVELOPMENTS IN HORMONAL THERAPY
  11. ABIRATERONE ACETATE
  12. ORTERONEL
  13. MDV3100
  14. CONCLUSIONS
  15. CONFLICT OF INTEREST
  16. REFERENCES

The side-effects of long-term ADT are well established and include loss of libido, erectile dysfunction, bone problems, obesity, sarcopenia, lipid alterations, insulin resistance, metabolic syndrome, diabetes and cardiovascular disease [51,52]. Androgens mediate osteoblast proliferation and bone development [53]; androgen deprivation causes a 3–5% annual decrease in bone mineral density (BMD) [53] and up to a six-fold increase per year in fracture risk from the induced osteoporosis [54]. To alleviate these effects, bisphosphonates, e.g. pamidronate, alendronate or zoledronic acid, have been shown to increase BMD in hip and spine by up to 7% in 1 year [55,56]. One study on denusomab also indicated an increase in BMD in the lumbar spine of 5.6% after 24 months of treatment compared with a loss of 1% in placebo-treated patients [57]. Differences between the placebo and denusomab arms of the study were reported from 1 month and were sustained through to 3 years. The rate of new vertebral fractures at 3 years was also decreased (1.5% vs 3.6% with placebo). ADT has been associated with an increased risk of diabetes mellitus and cardiovascular disease, but not cardiovascular death [58,59]. Preventative measures include non-specific actions such as weight loss, increased exercise, better nutrition and the cessation of smoking.

RECENT DEVELOPMENTS IN HORMONAL THERAPY

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. HORMONE-THERAPY AGENTS
  5. EAU GUIDELINES ON PROSTATE CANCER
  6. INTERMITTENT ADT
  7. IMMEDIATE VS DEFERRED ADT
  8. ADT COMBINED WITH RADIOTHERAPY (RT)
  9. SIDE-EFFECTS OF HORMONE THERAPY
  10. RECENT DEVELOPMENTS IN HORMONAL THERAPY
  11. ABIRATERONE ACETATE
  12. ORTERONEL
  13. MDV3100
  14. CONCLUSIONS
  15. CONFLICT OF INTEREST
  16. REFERENCES

Recent preclinical and clinical studies have identified intracellular signalling pathways and other characteristics of prostate cancer pathophysiology as important components and potential treatment targets in CRPC. CRPC commonly remains dependent on ligand-activated androgen receptor signalling. This improved understanding has driven the development of several new agents, including novel androgen biosynthesis inhibitors (CYP17 inhibitors: abiraterone acetate [inhibition of 17-hydroxylase], orteronel [inhibiton of 17,20-lyase]) and a second-generation androgen-receptor inhibitors (MDV3100). The CYP17 inhibitors give rise to increased pituitary release of adrenocorticotrophic hormone and excessive mineralocorticoid production. Patients can suffer from hypokalaemia, arterial hypertension, fluid overload and rennin suppression; however, these can be managed successfully using low-dose glucocorticoid supplements [60]. It is considered that these agents represent a strong opportunity for the future treatment of CRPC.

ABIRATERONE ACETATE

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. HORMONE-THERAPY AGENTS
  5. EAU GUIDELINES ON PROSTATE CANCER
  6. INTERMITTENT ADT
  7. IMMEDIATE VS DEFERRED ADT
  8. ADT COMBINED WITH RADIOTHERAPY (RT)
  9. SIDE-EFFECTS OF HORMONE THERAPY
  10. RECENT DEVELOPMENTS IN HORMONAL THERAPY
  11. ABIRATERONE ACETATE
  12. ORTERONEL
  13. MDV3100
  14. CONCLUSIONS
  15. CONFLICT OF INTEREST
  16. REFERENCES

Abiraterone acetate is an irreversible, highly selective inhibitor of CYP17A1 (17α-hydroxylase/C17,20-lyase), which is a key enzyme in androgen biosynthesis. The conversion of pregnenolone to dehydroepiandrosterone in the testes and adrenal glands is blocked when the enzyme is inhibited, which reduces serum testosterone levels to <1 ng/dL [61]. Phase II studies have shown its efficacy in chemotherapy and ketoconazole-naïve patients with CRPC [62,63]. Phase III studies have been initiated in both the chemotherapy naïve and post-docetaxel setting. In the post-docetaxel study, there was a reported improvement in OS compared with placebo (14.8 vs 10.9 months); P < 0.001) and in PFS (5.6 vs 3.6 months; P < 0.001) [64]. Abiraterone acetate has been approved in several countries for the treatment of metastatic CRPC post-docetaxel-based chemotherapy.

ORTERONEL

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. HORMONE-THERAPY AGENTS
  5. EAU GUIDELINES ON PROSTATE CANCER
  6. INTERMITTENT ADT
  7. IMMEDIATE VS DEFERRED ADT
  8. ADT COMBINED WITH RADIOTHERAPY (RT)
  9. SIDE-EFFECTS OF HORMONE THERAPY
  10. RECENT DEVELOPMENTS IN HORMONAL THERAPY
  11. ABIRATERONE ACETATE
  12. ORTERONEL
  13. MDV3100
  14. CONCLUSIONS
  15. CONFLICT OF INTEREST
  16. REFERENCES

Orteronel (TAK-700) is a non-steroidal imidazol that is a potent and highly selective inhibitor of CYP17A1 (17α-hydroxylase/C17,20-lyase) [65]. At doses of ≥400 mg (twice a day), orteronel reduced median serum testosterone levels to <0.6 ng/dL while PSA levels were reduced by >50% in 70% of patients treated with the ≥300 mg (twice a day) [66]. A Phase II study has been conducted in patients with nonmetastatic CRPC and a rising PSA level. Orteronel monotherapy at a dose of 300 mg (twice a day) was shown to reduce the PSA level by ≥50% in 76% of patients and by ≥90% in 32% of patients at 3 months; toxicity was manageable [67]. Two Phase III studies known as the ELM-PC (Evaluation of Lyase inhibitor in Metastatic Prostate Cancer) are on-going. One of the trials (C21004) is a randomised, double-blind and multicentre trial of prednisone plus orteronel or placebo in patients with chemotherapy-naïve metastatic CRPC. The primary endpoints are OS and radiographic PFS. The second (C21005) is a randomised, double-blind and multicentre trial of prednisone plus orteronel or placebo in patients with metastatic CRPC who have progressed during or after docetaxel-based therapy.

MDV3100

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. HORMONE-THERAPY AGENTS
  5. EAU GUIDELINES ON PROSTATE CANCER
  6. INTERMITTENT ADT
  7. IMMEDIATE VS DEFERRED ADT
  8. ADT COMBINED WITH RADIOTHERAPY (RT)
  9. SIDE-EFFECTS OF HORMONE THERAPY
  10. RECENT DEVELOPMENTS IN HORMONAL THERAPY
  11. ABIRATERONE ACETATE
  12. ORTERONEL
  13. MDV3100
  14. CONCLUSIONS
  15. CONFLICT OF INTEREST
  16. REFERENCES

MDV3100 is a nonsteroidal androgen receptor antagonist that has a strong androgen receptor binding affinity that blocks testosterone binding and also impairs nuclear translocation of the receptor–hormone complex from the cytoplasm into the nucleus [68]. A Phase I/II study showed antitumour activity through decrease in serum PSA levels of >50% in over 56% of patients with CRPC as well as tumour regression in soft tissues and bone [69]. Four global studies have been initiated in chemotherapy-naïve patients in the post-docetaxel setting, in comparison with bicalutamide and in hormone therapy-naïve patients. In November 2011, the Data Monitoring Committee recommended to close the post-docetaxel trial due to improved survival and offer MDV3100 to all patients in the placebo arm. The estimated median survival for men treated with MDV3100 was 18.4 months compared with 13.6 months for men treated with placebo [70].

CONCLUSIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. HORMONE-THERAPY AGENTS
  5. EAU GUIDELINES ON PROSTATE CANCER
  6. INTERMITTENT ADT
  7. IMMEDIATE VS DEFERRED ADT
  8. ADT COMBINED WITH RADIOTHERAPY (RT)
  9. SIDE-EFFECTS OF HORMONE THERAPY
  10. RECENT DEVELOPMENTS IN HORMONAL THERAPY
  11. ABIRATERONE ACETATE
  12. ORTERONEL
  13. MDV3100
  14. CONCLUSIONS
  15. CONFLICT OF INTEREST
  16. REFERENCES

The current EAU Guidelines for Prostate Cancer confirm that ADT remains the standard of care for non-localised prostate cancer. Because of the long-term experience (>20 years) and the wealth of evidence from the large number of clinical trials, the LHRH agonists are currently the main forms of ADT. Intermittent ADT can be considered for selected patients, while the use of immediate vs deferred ADT in locally advanced disease remains controversial. As understanding of the pathophysiology and clinical management of prostate cancer improves, the development of new agents heralds the availability of new therapeutic options for patients with advanced, metastatic and CRPC.

CONFLICT OF INTEREST

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. HORMONE-THERAPY AGENTS
  5. EAU GUIDELINES ON PROSTATE CANCER
  6. INTERMITTENT ADT
  7. IMMEDIATE VS DEFERRED ADT
  8. ADT COMBINED WITH RADIOTHERAPY (RT)
  9. SIDE-EFFECTS OF HORMONE THERAPY
  10. RECENT DEVELOPMENTS IN HORMONAL THERAPY
  11. ABIRATERONE ACETATE
  12. ORTERONEL
  13. MDV3100
  14. CONCLUSIONS
  15. CONFLICT OF INTEREST
  16. REFERENCES

P.H. is an investigator for clinical trials abiraterone, MDV 3100, TAK 700 (orteronel), abarelix and degarelix. Lecturer and Member of advisory board for Millenium, Cougar, Takeda, Ferring and SAP for TAK 700 and abiraterone

S.M. is a lecturer and member of advisory boards for Takeda, Ferring and Astellas.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. HORMONE-THERAPY AGENTS
  5. EAU GUIDELINES ON PROSTATE CANCER
  6. INTERMITTENT ADT
  7. IMMEDIATE VS DEFERRED ADT
  8. ADT COMBINED WITH RADIOTHERAPY (RT)
  9. SIDE-EFFECTS OF HORMONE THERAPY
  10. RECENT DEVELOPMENTS IN HORMONAL THERAPY
  11. ABIRATERONE ACETATE
  12. ORTERONEL
  13. MDV3100
  14. CONCLUSIONS
  15. CONFLICT OF INTEREST
  16. REFERENCES
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