Drug Treatment For Prostate Cancer

Many man will require drug treatment for prostate cancer.  Some of the drugs lose their effectiveness and need to have additional therapy.  This blog will discuss drugs that are used to stop the effect or the production of testosterone which is a necessary hormone for prostate cancer growth.

Drugs that stop androgens from working

Anti-androgens

Androgens have to bind to a protein in the cell called an androgen receptor in order to work. Anti-androgens stop androgens from working by binding to the receptors so the androgens can’t.

Drugs of this type, such as flutamide (Eulexin®), bicalutamide (Casodex®), and nilutamide (Nilandron®), are taken daily as pills.

Anti-androgens are not often used by themselves in this country. An anti-androgen may be added to treatment if orchiectomy, an LHRH analog, or LHRH antagonist is no longer working by itself. An anti-androgen is sometimes given for a few weeks when an LHRH analog is first started to prevent a tumor flare.

Anti-androgen treatment may be combined with orchiectomy or LHRH analogs as first-line hormone therapy. This is called combined androgen blockade (CAB). There is still some debate as to whether CAB is more effective in this setting than using orchiectomy or an LHRH analog alone. If there is a benefit, it appears to be small.

Some doctors are testing the use of anti-androgens instead of orchiectomy or LHRH analogs. Several recent studies have compared the effectiveness of anti-androgens alone with that of LHRH agonists. Most found no difference in survival rates, but a few found anti-androgens to be slightly less effective.

In some men, if hormone therapy including an anti-androgen stops working, the cancer will stop growing for a short time from simply stopping the anti-androgen. Doctors call this the anti-androgen withdrawal effect, although they are not sure why it happens.

Enzalutamide (Xtandi®)

This drug is a newer type of anti-androgen. When androgens bind to the androgen receptor, the receptor sends a signal for the cells to grow and divide. Enzalutamide (also known as MDV3100) blocks this signal from the androgen receptor to the cell.

In men with castrate-resistant prostate cancer, enzalutamide can lower PSA levels, shrink or slow the growth of tumors, and help the men live longer.

Enzalutamide is a pill, with the most common dose being 4 pills each day. In studies of this drug, men stayed on LHRH agonist treatment, so it isn’t clear how helpful this drug would be in men with non-castrate levels of testosterone.

Other androgen-suppressing drugs

Estrogens (female hormones) were once the main alternative to orchiectomy for men with advanced prostate cancer. Because of their possible side effects (including blood clots and breast enlargement), estrogens have been largely replaced by LHRH analogs and anti-androgens. Still, estrogens may be tried if androgen deprivation is no longer working.

Ketoconazole (Nizoral®), first used for treating fungal infections, blocks production of certain hormones, including androgens, similarly to abiraterone. It is most often used to treat men just diagnosed with advanced prostate cancer who have a lot of cancer in the body, as it offers a quick way to lower testosterone levels. It can also be tried if other forms of hormone therapy are no longer effective.

Ketoconazole can block the production of cortisol, an important steroid hormone in the body. People treated with ketoconazole often need to take a corticosteroid (like hydrocortisone) to prevent the side effects caused by low cortisol levels.

Possible side effects of hormone therapy

Orchiectomy, LHRH analogs, and LHRH antagonists can all cause similar side effects due to changes in the levels of hormones such as testosterone and estrogen. These side effects can include:

• Reduced or absent libido (sexual desire)
• Impotence (erectile dysfunction)
• Shrinking of testicles and penis
• Hot flashes, which may get better or even go away with time
• Breast tenderness and growth of breast tissue
• Osteoporosis (bone thinning), which can lead to broken bones
• Anemia (low red blood cell counts)
• Decreased mental sharpness
• Loss of muscle mass
• Weight gain
• Fatigue
• Increased cholesterol
• Depression

Anti-androgens have similar side effects. The major difference from LHRH agonists and orchiectomy is that anti-androgens may have fewer sexual side effects. When these drugs are used alone, libido and potency can often be maintained. When these drugs are given to men already being treated with LHRH agonists, diarrhea is the major side effect. Nausea, liver problems, and tiredness can also occur.

Abiraterone does not usually cause major side effects, although it can cause joint or muscle pain, high blood pressure, fluid buildup in the body, hot flashes, upset stomach, and diarrhea.

Enzalutamide can cause diarrhea, fatigue, and worsening of hot flashes. This drug can also cause some neurologic side effects, including dizziness and, rarely, seizures. Men taking this drug are more likely to have problems with falls, which may lead to injuries.

Many side effects of hormone therapy can be prevented or treated. For example:

• Hot flashes can often be helped by treatment with certain antidepressants or other drugs.
• Brief radiation treatment to the breasts can help prevent their enlargement, but it is not effective once breast enlargement has occurred.
• Several different drugs are available to help prevent and treat osteoporosis.
• Depression can be treated by antidepressants and/or counseling.
• Exercise can help reduce many side effects, including fatigue, weight gain, and the loss of bone and muscle mass.

There is growing concern that hormone therapy for prostate cancer may lead to problems with thinking, concentration, and/or memory. But this has not been studied well in men getting hormone therapy for prostate cancer. Studying the possible effects of hormone therapy on brain function is hard, because other factors may also change the way the brain works. A study has to take all of these factors into account. For example, both prostate cancer and memory problems become more common as men get older. Hormone therapy can also lead to anemia, fatigue, and depression – all of which can affect brain function. Still, hormone therapy does seem to lead to memory problems in some men. These problems are rarely severe, and most often affect only some types of memory. More studies are being done to look at this issue.

Bottom line: Many man experience recurrence of their prostate cancer after treatment. Hormone therapy is the most common treatment option for men in this situation.

Treating Prostate Cancer With Hormone Therapy

For men with advanced prostate cancer, hormone therapy is a treatment option. The goal is to reduce levels of male hormones, called androgens or testosterone, in the body, or to prevent them from reaching prostate cancer cells. Using drugs to decrease the testosterone is one of the most common methods of treating advanced prostate cancer.

The main androgens are testosterone and dihydrotestosterone (DHT). Most of the body’s androgens come from the testicles, but the adrenal glands also make a small amount. Androgens stimulate prostate cancer cells to grow. Lowering androgen levels or stopping them from getting into prostate cancer cells often makes prostate cancers shrink or grow more slowly for a time. However, hormone therapy alone does not cure prostate cancer and eventually, it stops helping.

Hormone therapy may be used:

• If you are not able to have surgery or radiation or can’t be cured by these treatments because the cancer has already spread beyond the prostate gland
• If your cancer remains or comes back after treatment with surgery or radiation therapy
• Along with radiation therapy as initial treatment if you are at higher risk of the cancer coming back after treatment (based on a high Gleason score, high PSA level, and/or growth of the cancer outside the prostate)
• Before radiation to try to shrink the cancer to make treatment more effective

Several types of hormone therapy can be used to treat prostate cancer. Some lower the levels of testosterone or other androgens (male hormones). Others block the action of those hormones.

Treatments to lower androgen levels

Orchiectomy (surgical castration)

Even though this is a type of surgery, its main effect is as a form of hormone therapy. In this operation, the surgeon removes the testicles, where most of the androgens (testosterone and DHT) are made. With this source removed, most prostate cancers stop growing or shrink for a time.

This is done as a simple outpatient procedure. It is probably the least expensive and simplest way to reduce androgen levels in the body. But unlike some of the other methods of lowering androgen levels, it is permanent, and many men have trouble accepting the removal of their testicles.

Some men having the procedure are concerned about how it will look afterward. If wanted, artificial silicone sacs can be inserted into the scrotum. These look much like testicles.

Luteinizing hormone-releasing hormone (LHRH) drugs

These drugs lower the amount of testosterone made by the testicles. Treatment with these drugs is sometimes called chemical castration because they lower androgen levels just as well as orchiectomy.

Even though LHRH analogs (also called LHRH agonists) cost more than orchiectomy and require more frequent doctor visits, most men choose this method. These drugs allow the testicles to remain in place, but the testicles will shrink over time, and they may even become too small to feel.

LHRH analogs are injected or placed as small implants under the skin. Depending on the drug used, they are given anywhere from once a month up to once a year. The LHRH analogs available in the United States include leuprolide (Lupron®, Eligard®), goserelin (Zoladex®), triptorelin (Trelstar®), and histrelin (Vantas®).

When LHRH analogs are first given, testosterone levels go up briefly before falling to very low levels. This effect is called flare and results from the complex way in which LHRH analogs work. Men whose cancer has spread to the bones may have bone pain. If the cancer has spread to the spine, even a short-term increase in tumor growth as a result of the flare could compress the spinal cord and cause pain or paralysis. Flare can be avoided by giving drugs called anti-androgens for a few weeks when starting treatment with LHRH analogs. (Anti-androgens are discussed further on.)

Degarelix (Firmagon®)

Degarelix is an LHRH antagonist. LHRH antagonists work like LHRH agonists, but they reduce testosterone levels more quickly and do not cause tumor flare like the LHRH agonists do.

This drug is used to treat advanced prostate cancer. It is given as a monthly injection under the skin and quickly reduces testosterone levels. With degarelix no anti-androgens are necessary. The most common side effects are problems at the injection site (minimal pain, redness, and swelling) and increased levels of liver enzymes on lab tests. Other side effects are discussed in detail below.

Abiraterone (Zytiga®)

Drugs such as LHRH agonists can stop the testicles from making androgens, but other cells in the body, including prostate cancer cells themselves, can still make small amounts, which may fuel cancer growth. Abiraterone blocks an enzyme called CYP17, which helps stop these cells from making certain hormones, including androgens.

Abiraterone can be used in men with advanced castrate-resistant prostate cancer (cancer that is still growing despite low testosterone levels from LHRH agonists, LHRH antagonists, or orchiectomy). Abiraterone has been shown to shrink or slow the growth of some of these tumors and help some of these men live longer.

This drug is a pill and the most common dose is 4 pills every day. Since this drug doesn’t stop the testicles from making testosterone, men who haven’t had an orchiectomy need to continue with treatment to stop the testicles from making testosterone (LHRH agonist or antagonist therapy). Because abiraterone lowers the level of other hormones in the body, prednisone (a cortisone-like drug) needs to be taken during treatment as well to avoid the side effects caused by lower levels of these other hormones.

Bottom Line:  Nearly 250,000 cases of prostate cancer are identified each year.  Nearly 40,000 men die from prostate cancer, second most common cause of death due to dancer after lung cancer.  For men who have elevated PSA levels after treatment, hormonal therapy is a consideration.