Hormone Therapy for Prostate Cancer

How does hormone therapy work?

Androgens help prostate cancer cells grow. The main androgens in the body are testosterone and dihydrotestosterone (DHT). Most androgens are made by the testicles, but the adrenal glands (glands that sit above your kidneys), as well as the prostate cancer cells themselves, can also make androgens.

Lowering androgen levels or stopping them from getting into prostate cancer cells can often make prostate cancers shrink or grow more slowly for a time. But hormone therapy alone doesn’t cure prostate cancer, and many cancers become resistant to hormone therapy over time.

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When is hormone therapy used?

Hormone therapy may be used:

• Along with radiation therapy as the first treatment for cancer that’s still in or around the prostate, if the cancer is at higher risk for coming back after treatment
• Before radiation, to try to shrink the cancer to make treatment more effective
• If the cancer remains or comes back after treatment with surgery or radiation therapy (especially if the cancer has spread, or if it’s not exactly clear where it is in the body)
• If the cancer has spread too far to be cured by surgery or radiation, or if you can’t have these treatments for some other reason.

To learn more, see Initial Treatment of Prostate Cancer, by Stage and Risk Group and Treating Prostate Cancer That Doesn’t Go Away or Comes Back After Treatment.

Treatment to lower testicular androgen levels

Some hormone treatments use surgery or medicines to lower the levels of androgens made by the testicles.

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 (such as testosterone and DHT) are made. This causes most prostate cancers to stop growing or shrink for a time.

This is done as an outpatient procedure. It is probably the least expensive and simplest form of hormone therapy. But unlike some of the other treatments, it is permanent, and many men have trouble accepting the removal of their testicles. Because of this, they may instead choose treatment with drugs that lower hormone levels (such as an LHRH agonist or antagonist – see below).

Some men having this surgery are concerned about how it will look afterward. If wanted, artificial testicles that look much like normal ones can be placed in the scrotum.

LHRH agonists

Luteinizing hormone-releasing hormone (LHRH) agonists (also called LHRH analogs or GnRH agonists) are drugs that lower the amount of testosterone made by the testicles. Treatment with these drugs is sometimes called medical castration because they lower androgen levels just as well as orchiectomy.

With these drugs, the testicles stay in place, but they will shrink over time, and they may even become too small to feel.

LHRH agonists 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 every 6 months. The LHRH agonists available in the United States include:

• Leuprolide (Lupron, Eligard) and leuprolide mesylate (Camcevi)
• Goserelin (Zoladex)
• Triptorelin (Trelstar)

When LHRH agonists are first given, testosterone levels go up briefly before falling to very low levels. This effect, called tumor flare, results from the complex way in which these drugs work. Some men whose cancer has spread to the bones may have bone pain. Men whose prostate has not been removed may have trouble urinating. If the cancer has spread to the spine, a short-term increase in tumor growth as a result of the flare could, in very rare cases, press on the spinal cord and cause pain or paralysis.

A flare can be avoided by giving drugs called anti-androgens (discussed below) for a few weeks when starting treatment with LHRH agonists.

LHRH antagonists

LHRH antagonists can be used to treat advanced prostate cancer. These drugs work in a slightly different way from the LHRH agonists, but they lower testosterone levels more quickly and don’t cause tumor flare like the LHRH agonists do. Treatment with these drugs can also be considered a form of medical castration.

• Degarelix (Firmagon) is given as a monthly injection under the skin. Some men may notice problems at the injection site (pain, redness, and swelling).
• Relugolix (Orgovyx) is taken as pills, once a day, so it might allow for less frequent office visits.

Possible side effects

Orchiectomy and LHRH agonists and antagonists can all cause similar side effects from lower levels of hormones such as testosterone. These can include:

• Reduced or absent sexual desire
• Erectile dysfunction (impotence)
• Shrinkage of testicles and penis
• Hot flashes, which may get better or go away with time
• Breast tenderness and growth of breast tissue (gynecomastia)
• 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 levels
• Depression or mood swings

Some research has suggested that the risk of high blood pressure, diabetes, strokes, heart attacks, and even death from heart disease is higher in men treated with hormone therapy, although not all studies have found this.

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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 this is not effective once breast enlargement has occurred.
• Several drugs can help prevent and treat osteoporosis.
• Depression can be treated with 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 thinking, concentrating, and/or with memory, but this has not been studied thoroughly. These problems are rarely severe, and most often affect only some types of memory. More studies are being done to look at this issue.

Treatment to lower androgen levels from other parts of the body

LHRH agonists and antagonists can stop the testicles from making androgens, but cells in other parts of the body, such as the adrenal glands and prostate cancer cells themselves, can still make male hormones, which can fuel cancer growth. Some drugs can block the formation of androgens made by these cells.

Abiraterone (Zytiga) blocks an enzyme called CYP17, which helps stop cells in the body from making androgens.

Abiraterone can be used in men with advanced prostate cancer that is either:

• High risk (cancer with a high Gleason score, spread to several spots in the bones, or spread to other organs)
• Castration-resistant (cancer that is still growing despite low testosterone levels from an LHRH agonist, LHRH antagonist, or orchiectomy)

This drug is taken as pills every day.

Abiraterone doesn’t stop the testicles from making testosterone, so men who haven’t had an orchiectomy need to continue treatment with an LHRH agonist or antagonist. Because abiraterone also lowers the level of some other hormones in the body, a low dose of prednisone (a corticosteroid drug) needs to be taken during treatment as well to avoid certain side effects.

Ketoconazole (Nizoral), first used for treating fungal infections, also blocks production of androgens made in the adrenal glands, much like abiraterone. It’s 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 working.

Ketoconazole also can block the production of cortisol, an important steroid hormone in the body, so men treated with this drug often need to take a corticosteroid (such as prednisone or hydrocortisone).

Possible side effects: Abiraterone can cause joint or muscle pain, high blood pressure, fluid buildup in the body, hot flashes, upset stomach, and diarrhea. Ketoconazole can cause elevated liver blood tests, nausea, vomiting, gynecomastia (enlargement of breast tissue in men), and skin rash.

Drugs that stop androgens from working

For most prostate cancer cells to grow, androgens have to attach to a protein in the prostate cancer cell called an androgen receptor.

Anti-androgens, also called androgen receptor antagonists, are drugs that connect to androgen receptors, which stops the androgens from fueling tumor growth.

First-generation anti-androgens

These drugs were the first anti-androgens to become available, and they are often still used. Drugs of this type include:

• Flutamide (Eulexin)
• Bicalutamide (Casodex)
• Nilutamide (Nilandron)

These drugs are taken daily as pills.

In the United States, anti-androgens are most often used along with treatments that lower testosterone levels:

• An anti-androgen may be added to treatment if orchiectomy or an LHRH agonist or antagonist is no longer working by itself.
• An anti-androgen is also sometimes given for a few weeks when an LHRH agonist is first started. This can help prevent a tumor flare.
• An anti-androgen can also be combined with orchiectomy or an LHRH agonist as first-line hormone therapy. This is called combined androgen blockade (CAB).

In some men, if an anti-androgen is no longer working, simply stopping the anti-androgen can cause the cancer to stop growing for a short time. This is called the anti-androgen withdrawal effect, although it is not clear why it happens.

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Possible side effects: Anti-androgens have similar side effects to LHRH agonists, LHRH antagonists, and orchiectomy. When these drugs are used alone, they may have fewer sexual side effects. Sexual desire and erections 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.

Newer (second-generation) anti-androgens

Enzalutamide (Xtandi), apalutamide (Erleada), and darolutamide (Nubeqa) are newer types of anti-androgens. They can sometimes be helpful even when older anti-androgens are not.

• Any of these drugs can be helpful in men with cancer that has not spread but is no longer responding to other forms of hormone therapy (known as non-metastatic castration-resistant prostate cancer (nmCRPC)).
• Any of these drugs can also be used for metastatic castration-sensitive prostate cancer (mCSPC) (cancer that has spread but that is still responding to other forms of hormone therapy).
• Enzalutamide can also be used for non-metastatic castration-sensitive prostate cancer (nmCSPC) that appears to have come back after treatment based on a high PSA level (a biochemical recurrence), and that is thought to be at high risk for spreading to other parts of the body.
• Enzalutamide can also be used for metastatic castration-resistant prostate cancer (mCRPC).

These drugs are taken as pills each day.

Side effects can include diarrhea, fatigue, rash, and worsening of hot flashes. These drugs can also cause some nervous system side effects, including dizziness and, rarely, seizures. Men taking one of these drugs are more likely to fall, which may lead to injuries. Some men have also had heart problems when taking these newer types of anti-androgens.

Other androgen-suppressing drugs

Estrogens (female hormones) were once the main alternative to removing the testicles (orchiectomy) for men with advanced prostate cancer. Because of their possible side effects (including blood clots and breast enlargement), estrogens have been replaced by other types of hormone therapy. Rarely, estrogens may be tried if other hormone treatments are no longer working.

Current issues in hormone therapy

There are many issues around hormone therapy that not all doctors agree on, such as the best time to start and stop it and the best way to give it. Studies are now looking at these issues. A few of them are discussed here.

Treating early-stage cancer

Some doctors have used hormone therapy instead of observation or active surveillance in men with early-stage prostate cancer who do not want surgery or radiation. Studies have not found that these men live any longer than those who don’t get any treatment until the cancer progresses or symptoms develop. Because of this, hormone treatment is not usually advised for early-stage prostate cancer.

Early versus delayed treatment

For men who need (or will eventually need) hormone therapy, such as men whose PSA levels are rising after surgery or radiation or men with advanced prostate cancer who don’t yet have symptoms, it’s not always clear when it is best to start hormone treatment.

Some doctors think that hormone therapy works better if it’s started as soon as possible, even if a man feels well and isn’t having any symptoms. Some studies have suggested that hormone treatment may slow the disease down and perhaps even help men live longer.

But not all doctors agree with this approach. Some are waiting for more evidence of benefit. They feel that because of the side effects of hormone therapy and the chance that the cancer could become resistant to therapy sooner, treatment shouldn’t be started until a man has symptoms from the cancer. This issue is being studied.

Intermittent versus continuous hormone therapy

Some doctors believe that constant androgen suppression might not be needed, so they advise intermittent (on-again, off-again) treatment. This can allow for a break from side effects like decreased energy, sexual problems, and hot flashes.

In one form of intermittent hormone therapy, treatment is stopped once the PSA drops to a very low level. If the PSA level begins to rise, the drugs are started again. Another form of intermittent therapy uses hormone therapy for fixed periods of time – for example, 6 months on followed by 6 months off.

At this time, it isn’t clear how this approach compares to continuous hormone therapy. Some studies have found that continuous therapy might help men live longer, but other studies have not found such a difference.

Combined androgen blockade (CAB)

Some doctors advise androgen deprivation (orchiectomy or an LHRH agonist or antagonist) plus an anti-androgen for initial hormone therapy for advanced prostate cancer. Studies have suggested this may be more helpful than androgen deprivation alone.

Triple androgen blockade (TAB)

Some doctors have suggested taking combined therapy one step further, by adding a drug called a 5-alpha reductase inhibitor – either finasteride (Proscar) or dutasteride (Avodart) – to the combined androgen blockade. There is very little evidence to support the use of this triple androgen blockade at this time.

Castration-sensitive, castration-resistant, and hormone-refractory prostate cancer

These terms are sometimes used to describe how well a man’s prostate cancer is responding to hormone therapy.

• Castration-sensitive prostate cancer (CSPC), also known as hormone-sensitive prostate cancer (HSPC), means the cancer is being controlled by keeping the testosterone level as low as what would be expected if the testicles were removed by castration. Levels can be kept this low with an orchiectomy, or by taking an LHRH agonist or an LHRH antagonist.
• Castration-resistant prostate cancer (CRPC) means the cancer is still growing even when the testosterone levels are at or below the level that would be expected with castration. Some of these cancers might still be helped by other forms of hormone therapy, such as abiraterone or one of the newer anti-androgens.
• Hormone-refractory prostate cancer (HRPC) refers to prostate cancer that is no longer helped by any type of hormone therapy, including the newer medicines.

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