Data for this Review were identified by searches of PubMed, ASCO abstracts, and references from relevant articles using the search terms: “androgen receptor, “abiraterone”, “prostate cancer”, “ketoconazole”, “bicalutamide”, “CYP17A”, “flutamide”, and “nilutamide”. Only articles published in English were included. Abstracts and reports were included only when they related directly to previously published work.
ReviewAnti-androgens and androgen-depleting therapies in prostate cancer: new agents for an established target
Introduction
Prostate cancer is an androgen-dependent malignant disease (figure 1). This was first proven in 1941 by the Nobel Prize-winning research of Huggins and Hodges,1 which showed that reducing serum androgen concentrations by orchiectomy or exogenous oestrogen administration induced tumour regressions and palliation of symptoms.
The prostate-cancer disease continuum can be described as a series of states (figure 2), defined by the presence or absence of detectable metastases and whether testosterone concentrations are in the castrate or non-castrate range.2 Each state represents a clinically significant milestone in the illness that forms the basis for clinical research and for medical decision-making in the context of routine clinical practice. Current treatment for localised, early stage prostate cancer involves either surgery (radical prostatectomy) or radiation, although in some cases active surveillance is appropriate. The standard treatment for patients with hormone-sensitive metastatic disease is to deplete testosterone concentrations with a gonadotropin-releasing hormone (GnRH) analogue or surgical orchiectomy, either alone or in combination with an anti-androgen. The results are predictable: an initial decline in serum prostate-specific antigen (PSA), the secreted protein product of an androgen-receptor-regulated gene, followed by tumour regression. After a period of quiescence, PSA concentrations rise, indicating androgen-receptor reactivation, followed by radiographic progression and the development of disease-related symptoms. This phase of the illness represents a transition to the lethal phenotype of the disease. We refer to this state of the disease as castration-resistant prostate cancer (CRPC). Because most of these tumours still depend on androgen-receptor signalling for growth, the terms androgen-independent or hormone-refractory are not appropriate.3 Only one treatment, docetaxel, is approved by the US Food and Drug Administration (FDA) for use, based on trials showing a survival benefit, although several others are approved for palliative indications (figure 2).4, 5, 6
Studies over the past decade have shown that CRPC remains dependent on androgen-receptor function for growth by evolving many mechanisms to reactivate receptor signalling. These mechanisms include: overexpression of the receptor;7, 8, 9 mutations in the receptor that allow activation by anti-androgens or other endogenous steroids, such as progesterone or hydrocortisone;10, 11, 12, 13 ligand-independent activation by growth-factor signalling pathways or loss of phosphatase and tensin homolog;14, 15, 16, 17 changes in levels of androgen-receptor transcriptional cofactors, such as steroid receptor coactivator (SRC) 1, SRC2, CREB-binding protein, and filamin A;18, 19, 20 and upregulation of the enzymes involved in androgen biosynthesis, which have recently been shown to produce higher concentrations of androgen in tumours relative to the blood.8, 21, 22
These insights have led to clinical trials of agents targeting many steps in androgen-receptor activation, including new anti-androgens, androgen-synthesis inhibitors, heat-shock protein (HSP)-90 inhibitors, histone deacytlase inhibitors, and kinase inhibitors.23 Most encouraging are the recent findings from clinical trials of two new compounds targeting the specific alterations in androgen-receptor signalling found in late-state, castration-resistant tumours: MDV3100, an anti-androgen specifically engineered for activity in prostate cancer model systems with overexpressed receptor, and abiraterone acetate, a CYP17A inhibitor that blocks steroid biosynthesis in the adrenal gland and possibly within the tumour (Figure 1, Figure 3). Both agents have shown sufficient promise to justify definitive testing in phase 3 randomised registration trials in the second-line (atypical) setting, where there is no standard of care (figure 2). These patients with CRPC have progressed on docetaxel-based chemotherapy and the endpoint will be survival-based. The trial of abiraterone acetate plus prednisone in the post-chemotherapy setting has completed accrual, and the trial of MDV3100 will begin shortly. This Review will place the development of these and other agents in the context of our understanding of the biology and current management of prostate cancer.
Section snippets
Anti-androgens
Anti-androgens compete with endogenous androgens for binding in the ligand-binding pocket of the androgen receptor, inducing conformational changes that prevent optimum transcriptional activity. There are two general classes of anti-androgens: steroidal and non-steroidal. The steroidal compounds include progesterone analogues RU-486 (mifepristone) and cyproterone acetate, and the mineralocorticoid analogue spironolactone (figure 3). A meta-analysis of randomised trials comparing
New anti-androgens
Investigators have used a mechanistic understanding of the current anti-androgens, along with structure-function relations between the androgen receptor and its ligands, to rationally design and test new compounds. To fully appreciate the initial discovery and subsequent mechanistic studies of these compounds, we will first briefly review our current understanding of how androgen receptors control transcription.
Androgen biosynthesis inhibitors
The testis is not the sole source of androgens, borne out by the fact that ADT via surgical castration or treatment with GnRH agonists does not completely eliminate serum or intratumoral androgens. ADT reduces serum testosterone from a normal range of more than 10 nmol/L to about 0·5 nmol/L; however, ADT does not affect concentrations of adrenal androgens, such as dehydroepiandrosterone (Figure 1, Figure 3). The remaining androgens are synthesised by the adrenal gland, and complete inhibition
Conclusions
The androgen receptor is a validated target in all clinical states of prostate cancer. ADT remains the standard first-line approach for patients with advanced disease and non-castrate concentrations of serum testosterone. Underappreciated are the responses to agents that target the androgen-receptor signalling axis in patients with progressive CRPC (for which use of hormonal agents is often considered), including patients previously treated with cytotoxic drugs. Promising antitumour effects in
Search strategy and selection criteria
References (76)
- et al.
Clinical states in prostate cancer: toward a dynamic model of disease progression
Urology
(2000) - et al.
Hormone-refractory (D3) prostate cancer: refining the concept
Urology
(1995) - et al.
Gene expression analysis of human prostate carcinoma during hormonal therapy identifies androgen-responsive genes and mechanisms of therapy resistance
Am J Pathol
(2004) - et al.
HER2/neu kinase-dependent modulation of androgen receptor function through effects on DNA binding and stability
Cancer Cell
(2004) - et al.
Regulation of androgen receptor activity by tyrosine phosphorylation
Cancer Cell
(2006) - et al.
The transcriptional co-activator cAMP response element-binding protein-binding protein is expressed in prostate cancer and enhances androgen- and anti-androgen-induced androgen receptor function
Am J Pathol
(2003) - et al.
Targeting the androgen receptor pathway in prostate cancer
Curr Opin Pharmacol
(2008) - et al.
Analysis of the androgenic activity of synthetic “progestins” currently used for the treatment of prostate cancer
J Steroid Biochem
(1987) - et al.
Long-term efficacy and safety of nilutamide plus castration in advanced prostate cancer, and the significance of early prostate specific antigen normalization. International Anandron Study Group
J Urol
(1997) - et al.
Clinical benefits of bicalutamide compared with flutamide in combined androgen blockade for patients with advanced prostatic carcinoma: final report of a double-blind, randomized, multicenter trial. Casodex Combination Study Group
Urology
(1997)