Antiandrogen Monotherapy in the Treatment of Prostate Cancer

Introduction

The development and subsequent normal physiologic function of the adult prostate gland is heavily dependent upon the presence of androgens. Although between 70% and 90% of testosterone is produced by the testicles, under certain circumstances the contribution by the adrenal glands can also be of importance. For the last 80 years, it has been known that removal of male hormones by surgical or medical castration, or inhibition of their activities by the administration of female hormones, can drastically influence the development of benign and malignant prostate tissue.

Androgen activity is governed by the presence and expression of the androgen receptor and, regardless of the sort of androgens it is exposed to, blockage of this receptor will materially alter the activity of the prostate cell. Because all malignant prostate cells will ultimately become androgen independent, the efficacy of antiandrogen treatment is ultimately of limited palliative use. Debate still continues over whether a percentage of androgen-independent cells are present when cancer is still very small or whether that independence is achieved by changes occurring in the androgen receptor or its expression during the course of hormonal therapy. The corollary of this statement is that all prostate cancer cells are at one time androgen dependent. This is critical when evaluating patients for primary treatment of systemic prostate cancer.

Androgen receptor antagonists, antiandrogens, were developed in the late 1970s and are structurally of two different classes, steroidal and nonsteroidal. Because they can inhibit androgen activity regardless of a testicular or adrenal source, as monotherapy the receptor antagonists have always been of interest. In addition, steroidal androgen receptor antagonists will inhibit production of luteinizing hormone from the pituitary and, therefore, induce a degree of medical castration as well as interrupting the androgen pathway at a cellular level.

In the late 1980s, owing largely to the work of Labrie et al., the concept of removing the testicular source of androgens by surgical castration or the use of the recently developed luteinizing hormone-releasing hormone (LHRH) agonists, combined with the administration of an antiandrogen, the so-called maximal androgen blockade (MAB), became appealing. Many studies since the 1980s have uncovered differences not only between the steroidal and nonsteroidal antiandrogen but also among the nonsteroidal antiandrogens themselves, showing that they probably have different modes and sites of action. The question remained as to whether the different compounds could play different roles in the treatment of advanced prostate cancer. It was not until around the year 2000 that studies began to call into question the equivalence of medical castration, MAB or the use of antiandrogen monotherapy, with systematic reviews demonstrating that in fact, antiandrogen monotherapy is likely to be inferior to medical or surgical castration with regard to progression-free (PFS) and overall survival (OS). As such, antiandrogen monotherapy is now more judicially practiced, usually instituted by practitioners on a case-by-case basis, and represents an important milestone in the evolving treatment of prostate cancer. Often the driving force for the use of androgen monotherapy is the desire to control the cancer while limiting toxicities usually associated with low testosterone.

The androgen receptor

The androgen receptor is a member of the family of nuclear receptor transcription factors. The protein has a DNA-binding domain, a ligand-binding domain, and a number of transactivation domains. The androgen receptor gene is situated on the X Chromosome. Normally the androgen receptor is situated in the cytoplasm but in the presence of androgens migrates into the nucleus. Testosterone is converted by 5-alpha reductase in the prostate cell and as 5-alpha-dihydrotestosterone attaches to the androgen receptor, a dimer of these molecules then makes its way to the nucleus and attaches via the DNA-binding segment to the nuclear DNA. The androgen receptor’s antagonists compete with 5-dihydrotestosterone for the ligand-binding domain of the receptor.

When the activated receptor dimer arrives on the DNA of the prostate cell, it sets into motion a series of transcription events, which stimulate genes in the cell cycle to give rise to cell proliferation, suppresses apoptosis, and also causes the production of a number of proteins of different enzymatic functions, notably prostate-specific antigen (PSA), the most important marker of prostatic cellular activity. In the proliferation pathway the sequence of events involves the production of proteins, which in turn stimulate genes to produce a variety of growth factors, specifically epidermal growth factor (EGF), insulin-like growth factor, and fibroblast growth factor (FGF), which diffuse out of the cell and, by an autocrine or paracrine mechanism via their own specific receptors, stimulate further cellular proliferation. Some of the androgen target genes are the cyclin-dependent kinases CDK-2, CDK-4, and also BCL-2, the most important androgen-regulated gene in apoptosis.

The development of androgen-independent prostate cancer may involve growth factor pathways that completely bypass the androgen receptor and act independently, such as EGP or insulin growth factor pathways, or the development of changes in the receptor itself, leading to overexpression or mutation. Such a mutation has been clearly defined in the LINCaP prostate cancer cell line, where a threonine to alanine substitution at position 877 has led to a dramatic effect on ligand specificity, enabling the cell to proliferate in response, not only to testosterone and dihydrotestosterone, but also to antiandrogens.

That such a mutation occurs clinically has been shown in the clinical manifestation of the antiandrogen withdrawal phenomenon, where patients who have been treated with MAB and who have progressed can respond to withdrawal of the antiandrogen. This phenomenon has been shown with all the antiandrogens, although initially reported with flutamide.

Androgen-dependent and androgen-independent prostate growth

The development of androgen-independent proliferation in prostate cancer is a gradual process and there are a number of locations along the pathway where the careful use of different modalities of endocrine therapy can cause repeated responses in the malignant cells.

Table 55.1 shows the development of the completely endocrine-independent cell occurring in four stages. The hormone-naïve patient, who has been diagnosed as suffering from prostate cancer that is no longer to be cured by radical prostatectomy or radiotherapy, will respond to the use of monotherapy with androgen receptor antagonists, either steroidal or nonsteroidal, or medical or surgical castration. Within a period of 1.5–3 years the cells will show resistance to this monotherapeutic option and require hormone treatment. In patients who have received monotherapy with an antiandrogen, there will still be normal levels of testosterone in the blood, and in some instance the levels may be even slightly elevated. Withdrawal of the patient’s own androgens by means of medical or surgical castration will give rise to further response in approximately half of the patients. In those patients who have been medically or surgically castrated, there will be a response in approximately 30% to the administration of an androgen receptor antagonist, which will block the androgens, or androgen precursors, produced by the adrenal glands. At this point, the patient’s own testosterone will be at castrate level. Although the tumor is probably now androgen resistant, it will still respond to other endocrine manipulations, such as the administration of corticosteroids or, in the case of MAB, to the withdrawal of an antiandrogen. In addition, at this stage, many patients will respond to estrogens, probably as a result of their cytotoxic effects. Only after further proliferation of the cancer cells is there talk of a truly endocrine-independent tumor.

Steroidal antiandrogens