Targeting the Androgen Receptor: New Hope for Aggressive Forms of Prostate and Breast Cancer

OncologyLive, August 2014, Volume 15, Issue 8

Although hormone-targeting strategies have been a mainstay of prostate and breast cancer therapies for decades, an improved understanding of the mechanisms underlying these malignancies has led researchers to focus fresh attention on the complex activity of the androgen receptor (AR) as a point of attack.

Although hormone-targeting strategies have been a mainstay of prostate and breast cancer therapies for decades, an improved understanding of the mechanisms underlying these malignancies has led researchers to focus fresh attention on the complex activity of the androgen receptor (AR) as a point of attack.

It has long been appreciated that prostate cancer is an androgen-driven disease, but androgen deprivation therapies aimed at reducing the levels of circulating androgens have no effect in castration- resistant prostate cancer (CRPC). In recent years, it has become clear that androgens and androgen- driven signaling through the AR are important not only for development of prostate cancer but also as a driving force in the development of CRPC.

The outlook for patients with CRPC is beginning to brighten as a result of the development of more rationally designed AR-targeting therapies based on our improved understanding of the biology of this disease.

In breast cancer, researchers have attempted to unravel the role that androgens play in promoting tumors since the early 20th century, but the success of estrogen-targeting agents pushed such inquiries to the side.

The advent of genomic profiling has opened a new window into the AR in breast cancer, resulting in attempts to determine whether drugs developed for the treatment of prostate cancer can also help individuals with breast cancer, particularly triple-negative breast cancer (TNBC).

AR Signaling Networks

Many cellular processes are activated in AR signaling, with the MAPK and PI3K-Akt pathways, illustrated at right, among the best characterized networks. The process of androgen metabolism through testosterone is shown at left.

AR indicates androgen receptor; ARE, androgen response elements; PIP, phosphatidylinositol phosphate; DHEA, dehydroepiandrosterone; DHT, dihydrotestosterone; hsp, heat shock protein; P, phosphorylation. Adapted from Girling JS et al. Pathogenesis of prostate cancer and hormone refractory prostate cancer. Indian J Urol. 2007;23(1):35-42.

A Driving Force for Prostate Cancer

The AR is a member of the nuclear steroid hormone family that also includes the progesterone receptor (PR) and the estrogen receptor (ER). It is responsible for mediating the effects of male hormones, known as androgens, which are synthesized primarily by the testes and play an important role in the development and maintenance of the male reproductive tissues.

Predominantly found in an inactive state in the cytoplasm in a complex with other proteins, including heat-shock proteins (HSPs), the AR is activated upon binding of androgens in target tissues, including the prostate. The main androgens in humans are testosterone and its more active metabolite, 5-alpha-dihydrotestosterone (DHT).

Binding of androgens frees the AR from its protein complex and allows it to move into the nucleus where it acts as a transcription factor, binding to target genes through androgen response elements.

Many of the genes targeted by the AR are involved in the growth and survival of prostate cancer cells; therefore, dysregulation of AR activity is strongly implicated in prostate cancer development. Indeed, around 15% of the mutations identified in the AR to date have been shown to be responsible for increased predisposition to prostate cancer in males.

Preventing Androgen-Stimulated Growth

Since prostate cancer is an androgen-driven disease, treatment strategies have focused on finding ways to lower circulating androgen levels. An effective way to achieve this is via castration, either surgically (by removal of the testes) or chemically (through the use of gonadotropin-releasing hormone [GnRH] agonists and antagonists). GnRH regulates synthesis of testosterone in the testes; antagonists reduce testosterone levels directly, while agonists cause an initial increase followed by a huge decrease.

Since testosterone can be synthesized elsewhere in the body (eg, adrenal glands) neither surgical nor chemical castration are completely effective at reducing circulating androgen levels. An alternative form of androgen-deprivation therapy (ADT) involves the use of antiandrogens, drugs that block the body’s ability to use androgens.

While these treatments have become standard of care for patients with prostate cancer, they do not currently provide a cure and the disease inevitably progresses to CRPC.

An Unexpected Role in CRPC

CRPC is a clinical state in which the tumor grows in spite of reduced levels of testosterone induced by the treatment options discussed above. Initially, it was believed that prostate cancer cells in patients with CRPC were androgen-independent.

Castration-resistant has replaced this term as improved understanding of the mechanisms underlying the development of CRPC have made it clear that, in fact, the AR and AR-driven signaling are frequently still active in these cells.

Several molecular mechanisms leading to the development of CRPC and the persistence of AR signaling in a low-androgen environment have been proposed. These include AR over-expression due to AR gene amplification or mutations in the ligand-binding domain that sensitize the AR to lower androgen concentrations or allow it to be activated by ligands other than testosterone or DHT. A number of AR gene variants that lack the ligand-binding domain and are constitutively active have also been described.

As a result of these findings, researchers have begun to focus on ways to inactivate the AR signaling axis in CRPC and a variety of novel strategies have begun to bear fruit.

Next Generation Antiandrogens and Other AR-Targeted Therapies

AR antagonists

The prototypical antiandrogens were designed to be AR antagonists, inhibiting the binding of androgens to the AR by competing for ligand binding sites. Both steroidal and nonsteroidal antagonists were initially developed; however, the steroidal form had limited clinical application due to undesirable side effects.

Among the first generation of nonsteroidal AR antagonists, bicalutamide, flutamide, and nilutamide progressed furthest in clinical development.

The FDA approved all three agents for the treatment of prostate cancer from the late 1980s through the mid-1990s, though flutamide has mostly been replaced by bicalutamide and nilutamide.

The proposed advantage of these nonsteroidal AR antagonists was that they were pure antagonists and did not develop AR agonist activity leading to increased circulating testosterone levels, as occurred with the steroidal forms. However, eventually even the nonsteroidal AR antagonists developed agonist activity, particularly in the presence of high levels of AR, which are often observed in patients with CRPC, limiting their use in this form of the disease.

The development of next-generation AR antagonists has focused on the search for truly pure antagonists that do not display any agonist activity and may prove more useful in CRPC. This has resulted in the development and subsequent FDA approval of enzalutamide (Xtandi). In the phase III AFFIRM trial in patients with metastatic CRPC previously treated with docetaxel, enzalutamide demonstrated a significant improvement in overall survival (OS) and subsequently received FDA approval for this indication in 2012.

Numerous clinical trials of enzalutamide are ongoing, including the phase III PREVAIL and PROSPER trials. Results from the PREVAIL trial, in which the use of enzalutamide prior to chemotherapy is being evaluated, were recently published in The New England Journal of Medicine.

The study was stopped early due to positive results; there was an 81% reduction in the risk of radiographic progression and a 29% reduction in the risk of death.

Although enzalutamide is generally safe and well tolerated, there have been reports of an increased risk of seizures. Additional next-generation AR antagonists are building on the success of enzalutamide; ARN-509 is a more potent and effective AR antagonist that is currently being evaluated in the phase III SPARTAN trials in men with nonmetastatic CRPC. Since this agent can be used at a lower dose, the risk of side effects is reduced and there have been no reports of seizures thus far.

ODM-201 is earlier on in clinical development and, like ARN-509, binds to the AR with higher affinity than enzalutamide. The results of the phase I/II ARADES trial were recently reported in The Lancet journal and demonstrated the efficacy and safety of this agent in patients with CRPC. Uniquely, preclinical studies demonstrated that ODM-201 does not enter the brain like other AR antagonists and should not cause seizures or have any agonist activity.

CYP17A inhibitors

An alternative means of indirectly inhibiting the AR pathway is to target the 17α-hydroxylase/ C17,20-lyase (CYP17A), a member of the cytochrome P450 superfamily of enzymes that play a critical role in androgen synthesis. Inhibitors of CYP17A have been developed to reduce the levels of circulating testosterone. In fact, the first FDA-approved hormonal agent for prostate cancer was actually a CYP17A inhibitor.

Abiraterone acetate (Zytiga) is a synthetic analog of the antifungal ketoconazole, which was also originally tested in the treatment of prostate cancer but has since been replaced by abiraterone, though some phase II studies are ongoing. Following demonstrations of improved OS in phase III trials in combination with prednisone in patients with metastatic CRPC previously treated with docetaxel, the FDA approved abiraterone for this indication in 2011. Approval was then expanded for use prior to chemotherapy following phase III trials demonstrating improved OS and radiographic progression-free survival (PFS).

An issue that has arisen with abiraterone is that it increases the level of corticosteroids as an indirect result of inhibiting the CYP family of enzymes, which can cause significant toxicity.

Researchers are exploring more selective CYP17A inhibitors that much more specifically target this enzyme and may prove to be safer since they have no significant impact on corticosteroid levels. Orteronel (TAK-700) was among the most promising of these agents until disappointing phase III clinical trial results prompted the Takeda Pharmaceutical Company to terminate the development program in prostate cancer in June.

Other agents

A variety of other agents with different mechanisms of action are also in development. Galeterone (TOK-001) is a combined AR antagonist and CYP17A inhibitor, with an additional mechanism of AR degradation. Phase II trials are currently under way in CRPC and the results of the ARMOR2 trial were recently reported at the 2014 American Society of Clinical Oncology (ASCO) Annual Meeting.

Among 51 treatment-naïve patients with CRPC, 82% achieved maximal reduction in prostate-specific antigen (PSA) levels of at least 30% (PSA30) and 75% achieved PSA50. Among the 39 patients within this group with metastatic disease, 85% achieved PSA30 and 77% achieved PSA50. Four patients had AR splice variants or mutations commonly associated with abiraterone resistance and all achieved PSA50 or greater, highlighting the potential for this agent among abiraterone-refractory patients. Another agent in the early stages of clinical testing is AZD3514, a novel selective downregulator of the AR that inhibits both androgen-dependent and —independent AR signaling.

Finally, the role of HSPs in AR signaling is also an area of emerging research. HSPs, particularly HSP90, have been shown to maintain the inactive AR in the cytoplasm in a form that is able to bind androgens and other ligands. Targeting HSPs could therefore prevent the AR from being activated by androgens. As a result, several HSP90 inhibitors are being evaluated in prostate cancer.

AR Signaling in TNBC

Although breast cancer also is hormonally driven, drug development has focused on targeting the predominant female hormone receptors ER and PR. However, androgens also play a role in the normal physiology of the breast and in the development of breast cancer; in fact, AR expression is actually higher than ER/PR expression in breast cancers. Furthermore, genomic profiling studies of breast cancer have identified a TNBC subgroup that is defined by the presence of the AR.

Recent studies have helped to further elucidate the role of the AR in breast cancer development and have also suggested a potential role for the AR in driving resistance to hormonal therapy and human epidermal growth factor receptor 2 (HER2)-targeted agents. Therapies targeting the AR are re-emerging as breast cancer treatments.

Conversely, several decades ago, numerous studies suggested that activating as well as inhibiting the AR in breast cancer could suppress growth. Nonselective androgens were administered to patients who progressed on tamoxifen, resulting in objective response rates between 20% and 60%. Research was mostly abandoned, however, since there were conflicting results and unwanted side effects.

Today, researchers are exploring enzalutamide and abiraterone to determine whether they can be used effectively to treat breast cancer. Enzalutamide is being explored in phase II trials in different patient populations based on ER, PR, and HER2 status. An ongoing trial will evaluate abiraterone in women with ER-positive, HER2-negative metastatic breast cancer.

A new agent in development is enobosarm, a selective androgen receptor modulator (SARM) that in turn is part of a novel class of selective androgen ligand. Enobosarm is currently being evaluated in a phase II study in metastatic breast cancer, interim results of which were presented at the 2014 ASCO Annual Meeting. Preliminary data from 16 patients after a median follow-up of 85 days demonstrated stable disease (SD) as best response in eight patients. Three patients who were AR-positive had SD and increased PSA.

Jane de Lartigue, PhD, is a freelance medical writer and editor based in Davis, California.

Key Research

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