The recently approved drugs abiraterone acetate and enzalutamide represent important breakthroughs in androgen deprivation therapy, and more drugs are in clinical trials, promising more sophisticated approaches to the treatment of advanced prostate cancer. “This is something that endocrinologists really should take ownership of,” said Alice Levine, MD, professor of medicine, endocrinology, diabetes, and bone disease, and co-director of the Adrenal Center at the Icahn School of Medicine at Mt. Sinai in New York City. “This explosion of new hormonal treatments is rooted in the basic physiology and biochemistry of the adrenal and testicular steroid hormones and their receptors. And although oncologists and urologists are utilizing these therapies in patients, endocrinologists have a deeper understanding of the molecular pharmacology of these agents and the consequences of blocking steroidogenesis and androgen receptor signaling. Th is is very sophisticated endocrinology.”
Androgen deprivation therapy (ADT) has been the treatment of choice for advanced prostate cancer since the 1940s, when it was first reported that surgical castration or estrogen administration was effective in knocking back bonemetastatic disease. This approach led to the development of medical castration therapies. Drugs were developed to reduce androgen and action signaling, with ADT typically consisting of a gonadotropin-releasing hormone agonist or antagonist often combined with a first-generation nonsteroidal androgen receptor (AR) antagonist.
More than 80% of patients respond to ADT treatment, but that response lasts on average roughly two years. Although most metastatic lesions regress after ADT, they almost uniformly progress after time. Because prostate specific antigen (PSA) is expressed by most prostate cancers and is regulated by the androgens, a rise in PSA levels in a patient on ADT is the earliest sign of disease recurrence.
“In successful hormone therapy, AR activity is suppressed, PSA goes down, and tumor remission results,” said Karen Knudsen, PhD, a professor in the departments of cancer biology, urology, and radiation oncology at Thomas Jefferson University, deputy director of the Kimmel Cancer Center in Philadelphia, and editor of the journal Molecular Cancer Research. “When treatment fails, almost invariably PSA rises prior to visualization of a recurrent tumor. Such ‘biochemical failure’ is evidence that the androgen receptor has been reactivated, and castration-resistant disease is imminent.”
Because the cancer progressed during ADT, clinicians previously referred to this stage as androgen-independent disease. However, as evidence mounted that most of these tumors still express AR and show continued activation of the AR signaling system, they adopted the current term, metastatic castration-resistant prostate cancer, to reflect this new understanding.
Once the disease reaches the CRPC stage, there is no durable cure. The typical treatment has been taxane-based chemotherapy, such as docetaxel, which confers a survival benefit of only a few months.
New Avenues of Attack
The realization that AR is reactivated in CRPC—frequently as a result of restored local androgens—spurred researchers to look for new ways to attack androgen pathways. “When patients have a rising PSA you need to do something to knock androgen receptor activity back down,” Knudsen told Endocrine News. “So people looked at mechanisms of failure, and one of the main mechanisms was that the tumor flips on genes that induce conversion of weak adrenal androgens into testosterone. Tumors themselves are making androgens. This process of intracrine androgen synthesis or intratumor androgen production requires adrenal androgen synthesis.”
Researchers looking for a way to interfere with this adrenal process came up with abiraterone acetate (Zytiga), which works by inhibiting the CYP17 pathway. CYP17 is a critical enzyme for androgen production in the normal adrenal gland as well as in CRPC. It catalyzes two steroid reactions through its 17-hydroxylase and 17,20-lyase activities, and abiraterone interferes with both these steps. Inhibition of 17-hydroxylase results in a blockade of cortisol synthesis, with a resultant rise in adrenocorticotropic hormone that induces mineralocorticoid excess. Co-administration of a glucocorticoid such as prednisone can prevent this side effect.
Because intracrine androgen synthesis is only one mechanism of AR activation, abiraterone acetate works in only a subset of patients, but it has shown marked antitumor effects in them.
In April 2011, the Food and Drug Administration (FDA) approved it for use in combination with prednisone to treat patients with metastatic CRPC who have received docetaxel chemotherapy. In December 2012, the FDA expanded the indication to include use before chemotherapy, which puts it on par with other anti-androgen treatments.
The Next Generation
Enzalutamide (Xtandi) is considered the first of the next generation of AR antagonists. Formerly known as MDV3100, its creators designed it to overcome the limitations of the commonly used AR antagonist bicalutamide by, for example, off ring higher binding affinity and inhibiting AR function by blocking nuclear translocation. In addition, it does not share bicalutamide’s characteristic of having agonistic effects in prostate cancers in which AR is overexpressed.
In August 2012, the FDA gave the nod to enzalutamide for the treatment of metastatic CRPC patients who have previously received docetaxel. Clinical trials are under way aimed at expanding approval to include use before chemotherapy, matching abiraterone.
The increased survival benefit conferred by these drugs is only about four months, but “these people are very end stage, so four months …. in an advanced cancer, that’s significant,” Levine said.
“Although the ultimate goal is to provide a cure, an immediate, achievable goal is to delay the time that you have to start chemotherapy,” Knudsen said. “Hormone therapies are generally well tolerated,” especially compared with chemotherapy. Because prostate cancer is a disease of older men, staving off the need for chemotherapy, and perhaps avoiding it altogether, is a major benefit.
When to Begin ADT
Perhaps with this goal in mind, an increasing number of clinicians have been tempted to use ADT as primary treatment, despite the lack of evidence supporting this approach. “Nobody has ever shown improvement in survival with partial or complete androgen deprivation therapy done early in the disease, except for some trials that combined ADT with external beam radiotherapy,” Levine said.
“If you’ve got an earlier stage prostate cancer, the chances are you are going to live at least 15 to 20 years,” she said. “And androgen deprivation therapy, particularly if it is very potent, is associated with a lot of side effects. It can cause metabolic syndrome, osteoporosis, poor quality of life, fatigue, decreased libido, and increased cardiovascular mortality. So it’s a balancing game. It hasn’t been shown that if you begin it earlier that you improve overall survival except in very specific circumstances.”
Because many of the side eff ects are the direct result of the absence of androgens, it is unlikely that the new agents will lessen them. With other drugs in the pipeline, the new generation will likely be a ripe area for research into the best sequences to give them, best combinations to use, integration with older drugs, and timing of delivery. “Considering that this is a disease for which you really had no new drugs on the market that were useful for decades, it’s a very exciting time,” Knudsen said.
Levine looked forward to even more advances from an old approach: “It’s exciting to me that we can still wring something more out of the androgen signaling system, that we can still prolong life in these very end-stage patients.” Cancer cells exhibit great adaptiveness in avoiding efforts to stop them, but a greater understanding of their molecular pathophysiology could allow researchers to stay a step ahead.
—Seaborg is a freelance writer in Charlottesville, VA, and a regular contributor to Endocrine News.