Treatments that block the action of androgens in the body include:
• Antiandrogens, which are drugs that compete with androgens for binding to the androgen receptor. By competing for binding to the androgen receptor, antiandrogens reduce the ability of androgens to promote prostate cancer cell growth. Because antiandrogens do not block androgen production, they are rarely used on their own to treat prostate cancer. Instead, they are used in combination with orchiectomy or an LHRH agonist. Use of an antiandrogen drug in combination with orchiectomy or an LHRH agonist is called combined androgen blockade, complete androgen blockade, or total androgen blockade. Antiandrogens that are approved in the United States to treat prostate cancer include flutamide, enzalutamide, bicalutamide, and nilutamide. Antiandrogens are given as pills to be swallowed.
Treatments that block the production of androgens throughout the body include:
• Drugs that prevent the production of androgens by the adrenal glands and prostate cancer cells themselves, as well as by the testicles. Neither medical nor surgical castration blocks the adrenal glands and prostate cancer cells from producing androgens. Even though the amounts of androgens they produce are small, these amounts can be enough to support the growth of some prostate cancers. Drugs that prevent the adrenal glands (as well as the testicles and prostate cancer cells) from making androgens, which are called androgen synthesis inhibitors, can lower testosterone levels in a man’s body to a greater extent than any other known treatment. These drugs block testosterone production by inhibiting an enzyme called CYP17. This enzyme, which is found in testicular, adrenal, and prostate tumor tissues, plays a central role in allowing the body to produce testosterone from cholesterol. Three androgen synthesis inhibitors are approved in the United States. All are given as pills to be swallowed. Two of these, ketoconazole and aminoglutethimide, are approved for indications other than prostate cancer but are sometimes used as second-line treatments for castration-resistant prostate cancer. The third, abiraterone acetate, is approved to treat metastatic castration-resistant prostate cancer.
How is hormone therapy used to treat prostate cancer?
Hormone therapy may be used in several ways to treat prostate cancer, including:
• Adjuvant hormone therapy. Hormone therapy that is given after other primary treatments to lower the risk that prostate cancer will come back is called adjuvant hormone therapy. Men with early-stage prostate cancer that has an intermediate or high risk of recurrence may receive adjuvant hormone therapy after radiation therapy or prostatectomy (surgery to remove all or part of the prostate gland).5 Factors that are used to determine the risk of prostate cancer recurrence include the tumor’s grade (as measured by the Gleason score), the extent to which the tumor has spread into surrounding tissue, and whether or not tumor cells are found in nearby lymph nodes. Men who have adjuvant hormone therapy after prostatectomy live longer without having a recurrence than men who have prostatectomy alone, but they do not live longer overall.5 Men who have adjuvant hormone therapy after external beam radiation therapy for prostate cancer live longer, both overall and without having a recurrence, than men who are treated with radiation therapy alone.5,6
• Neoadjuvant hormone therapy. Hormone therapy given before other treatments is called neoadjuvant hormone therapy. Men with early-stage prostate cancer that has an intermediate or high risk of recurrence often receive hormone therapy before or during radiation therapy, in addition to receiving hormone therapy after radiation therapy. Men who receive hormone therapy in combination with radiation therapy live longer overall than men who receive radiation therapy alone.7 The use of neoadjuvant hormone therapy (alone or in combination with chemotherapy) before prostatectomy has not been shown to prolong survival and is not a standard treatment.
• Hormone therapy alone. Hormone therapy is sometimes used alone for palliation or prevention of local symptoms in men with localized prostate cancer who are not candidates for surgery or radiation therapy.8 Such men include those with a limited life expectancy, those with advanced local tumor stage, and/or those with other serious health conditions. Hormone therapy used alone is also the standard treatment for men who have a prostate cancer recurrence documented by CT, MRI, or bone scan after treatment with radiation therapy or prostatectomy. Hormone therapy is often recommended for men who have a “biochemical” recurrence—a rapid rise in prostate-specific antigen (PSA) level—especially if the PSA level doubles in fewer than 12 months. However, a rapid rise in PSA level does not necessarily mean that the prostate cancer itself has recurred. The use of hormone therapy in the case of a biochemical recurrence is somewhat controversial. Finally, hormone therapy used alone is also the standard treatment for men who are found to have metastatic disease (i.e., disease that has spread to other parts of the body) when their prostate cancer is first diagnosed.9 Whether hormone therapy prolongs the survival of men who have been newly diagnosed with advanced disease but do not yet have symptoms is not clear.10,11 Moreover, because hormone therapy can have substantial side effects, some men prefer not to take hormone therapy before symptoms develop.
The length of treatment with hormone therapy for prostate cancer depends on a man’s risk of recurrence, which is based on the clinical stage (the amount or spread of cancer in the body), Gleason score (system of grading prostate cancer tissue based on how it looks when examined under a microscope), and PSA level. For men with intermediate-risk prostate cancer, hormone therapy is generally given for 4 to 6 months; for men with high-risk disease it is generally given for 2 to 3 years.
Many prostate cancers that initially respond to hormone therapy with LHRH agonists, LHRH antagonists, or orchiectomy eventually stop responding to this treatment. This is referred to as castration-resistant prostate cancer. Castration-resistant prostate cancers need much lower levels of androgen to grow than androgen-sensitive cancers.
Several potential mechanisms may allow prostate cancer cells to grow even when androgen levels are very low, including increased production of androgen receptor molecules within the cells (either through an increase in the expression of the androgen receptor gene or an increase in the number of copies of the androgen receptor gene per cell), a change in the androgen receptor gene such that it produces a more active protein, and changes in the activities of proteins that help control the function of the androgen receptor.12,13
Doctors cannot predict how long hormone therapy will be effective in suppressing the growth of any individual man’s prostate cancer. Therefore, men who take hormone therapy for more than a few months will be regularly tested to determine the level of PSA in their blood. An increase in PSA level may indicate that a man’s cancer has started growing again. A PSA level that continues to increase while hormone therapy is successfully keeping androgen levels extremely low is an indicator that a man’s prostate cancer has become resistant to the hormone therapy that is currently being used.