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`Hormone Therapy for Prostate Cancer
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`PROSTATE CANCER
`
`TREATING PROSTATE CANCER
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`Hormone Therapy for Prostate Cancer
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`Hormone therapy is also called androgen deprivation therapy (ADT) or androgen
`suppression therapy. The goal is to reduce levels of male hormones, called androgens, in
`the body, or to stop them from affecting prostate cancer cells.
`
`Androgens stimulate prostate cancer cells to grow. The main androgens in the body are
`testosterone and dihydrotestosterone (DHT). Most of the androgens are made by the testicles,
`but the adrenal glands (glands that sit above your kidneys) also make a small amount.
`Lowering androgen levels or stopping them from getting into prostate cancer cells often makes
`prostate cancers shrink or grow more slowly for a time. But hormone therapy alone does not
`cure prostate cancer.
`
`When is hormone therapy used?
`
`Hormone therapy may be used:
`
`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
`
`If the 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
`
`Types of hormone therapy
`
`Several types of hormone therapy can be used to treat prostate cancer.
`
`https://www.cancer.org/content/cancer/en/cancer/prostate-cancer/treating/hormone-therapy[4/10/2017 3:01:01 PM]
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`MYLAN PHARMS. INC. EXHIBIT 1092 PAGE 1
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`Hormone Therapy for Prostate Cancer
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`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. 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.
`
`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 inserted into 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 chemical castration or medical castration because they
`lower androgen levels just as well as orchiectomy.
`
`Even though LHRH agonists cost more than orchiectomy and require more frequent doctor
`visits, most men choose this method. With these drugs, the testicles remain 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 a year. The LHRH
`agonists available in the United States include:
`
`Leuprolide (Lupron, Eligard)
`
`Goserelin (Zoladex)
`
`Triptorelin (Trelstar)
`
`Histrelin (Vantas)
`
`https://www.cancer.org/content/cancer/en/cancer/prostate-cancer/treating/hormone-therapy[4/10/2017 3:01:01 PM]
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`MYLAN PHARMS. INC. EXHIBIT 1092 PAGE 2
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`Hormone Therapy for Prostate Cancer
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`When LHRH agonists 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 these drugs 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 press on
`the spinal cord and cause pain or paralysis. Flare can be avoided by giving drugs called anti-
`androgens (discussed below) for a few weeks when starting treatment with LHRH agonists.
`
`LHRH antagonist
`
`Degarelix (Firmagon) is an LHRH antagonist. It works like the LHRH agonists, but it lowers
`testosterone levels more quickly and doesn’t cause tumor flare like the LHRH agonists do.
`Treatment with this drug can also be considered a form of medical castration.
`
`This drug is used to treat advanced prostate cancer. It is given as a monthly injection under
`the skin. The most common side effects are problems at the injection site (pain, redness, and
`swelling) and increased levels of liver enzymes on lab tests. Other side effects are discussed
`in detail below.
`
`CYP17 inhibitor
`
`LHRH agonists and antagonists can stop the testicles from making androgens, but other cells
`in the body, including prostate cancer cells themselves, can still make small amounts, which
`can fuel cancer growth. Abiraterone (Zytiga) blocks an enzyme called CYP17, which helps
`stop these cells from making androgens.
`
`Abiraterone can be used in men with advanced castrate-resistant prostate cancer (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. It 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,
`prednisone (a cortisone-like drug) needs to be taken during treatment as well to avoid certain
`side effects.
`
`Drugs that stop androgens from working
`
`Anti-androgens
`
`https://www.cancer.org/content/cancer/en/cancer/prostate-cancer/treating/hormone-therapy[4/10/2017 3:01:01 PM]
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`MYLAN PHARMS. INC. EXHIBIT 1092 PAGE 3
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`Hormone Therapy for Prostate Cancer
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`Androgens have to bind to a protein in the prostate cell called an androgen receptor to work.
`Anti-androgens are drugs that bind to these receptors so the androgens can’t.
`
`Drugs of this type include:
`
`Flutamide (Eulexin)
`
`Bicalutamide (Casodex)
`
`Nilutamide (Nilandron)
`
`They are taken daily as pills.
`
`Anti-androgens are not often used by themselves in the United States. 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 to 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). There is still some
`debate as to whether CAB is more effective in this setting than using orchiectomy or an LHRH
`agonist alone. If there is a benefit, it appears to be small.
`
`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. Doctors call this the anti-androgen
`withdrawal effect, although they are not sure why it happens.
`
`Enzalutamide (Xtandi) is a newer type of anti-androgen. Normally when androgens bind to
`their receptor, the receptor sends a signal to the cell’s control center, telling it to grow and
`divide. Enzalutamide blocks this signal. It is taken as pills each day.
`
`Enzalutamide can often be helpful in men with castrate-resistant prostate cancer. In most
`studies of this drug, men were also treated with an LHRH agonist, so it isn’t clear how helpful
`this drug would be in men with non-castrate levels of testosterone.
`
`Other androgen-suppressing drugs
`
`https://www.cancer.org/content/cancer/en/cancer/prostate-cancer/treating/hormone-therapy[4/10/2017 3:01:01 PM]
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`MYLAN PHARMS. INC. EXHIBIT 1092 PAGE 4
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`Hormone Therapy for Prostate Cancer
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`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 replaced by other types of hormone therapy. Still,
`estrogens may be tried if other hormone treatments are no longer working.
`
`Ketoconazole (Nizoral), first used for treating fungal infections, blocks production of certain
`hormones, including androgens, 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 of hormone therapy
`
`Orchiectomy and LHRH agonists and antagonists can all cause similar side effects from lower
`levels of hormones such as testosterone. These side effects 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
`
`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
`
`https://www.cancer.org/content/cancer/en/cancer/prostate-cancer/treating/hormone-therapy[4/10/2017 3:01:01 PM]
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`MYLAN PHARMS. INC. EXHIBIT 1092 PAGE 5
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`Hormone Therapy for Prostate Cancer
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`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.
`
`Anti-androgens have similar side effects. The major difference from LHRH agonists and
`antagonists and orchiectomy is that anti-androgens may have fewer sexual side effects. When
`these drugs are used alone, 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.
`
`Abiraterone 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 nervous system side effects, including dizziness and, rarely, seizures. Men taking
`this drug are more likely to fall, 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 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. 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.
`
`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
`
`https://www.cancer.org/content/cancer/en/cancer/prostate-cancer/treating/hormone-therapy[4/10/2017 3:01:01 PM]
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`MYLAN PHARMS. INC. EXHIBIT 1092 PAGE 6
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`Hormone Therapy for Prostate Cancer
`
`issues. A few of them are discussed here.
`
`Treating early-stage cancer: Some doctors have used hormone therapy instead of watchful
`waiting 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 is not having any symptoms. Some
`studies have shown 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: Most prostate cancers treated with
`hormone therapy become resistant to this treatment over a period of months or years. Some
`doctors believe that constant androgen suppression might not be needed, so they advise
`intermittent (on-again, off-again) treatment. The hope is that giving men a break from
`androgen suppression will also give them 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 treat patients with both androgen
`deprivation (orchiectomy or an LHRH agonist or antagonist) plus an anti-androgen. Some
`
`https://www.cancer.org/content/cancer/en/cancer/prostate-cancer/treating/hormone-therapy[4/10/2017 3:01:01 PM]
`
`MYLAN PHARMS. INC. EXHIBIT 1092 PAGE 7
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`

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`Hormone Therapy for Prostate Cancer
`
`studies have suggested this may be more helpful than androgen deprivation alone, but others
`have not. Most doctors are not convinced there’s enough evidence that this combined therapy
`is better than starting with one drug alone when treating prostate cancer that has spread to
`other parts of the body.
`
`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.
`
`Castrate-resistant versus hormone-refractory prostate cancer: Both these terms are
`sometimes used to describe prostate cancers that are no longer responding to hormones,
`although there is a difference between the two.
`
`Castrate-resistant means the cancer is still growing even when the testosterone levels
`are as low as what would be expected if the testicles were removed (called castrate
`levels). Levels this low could be from an orchiectomy, an LHRH agonist, or an LHRH
`antagonist. Some men might be uncomfortable with this term, but it’s specifically meant to
`refer to these cancers, some of which might still be helped by other forms of hormone
`therapy, such as the drugs abiraterone and enzalutamide. Cancers that still respond to
`some type of hormone therapy are not completely hormone-refractory.
`
`Hormone-refractory refers to prostate cancer that is no longer helped by any type of
`hormone therapy, including the newer medicines.
`
`Written by
`
`References
`
`The American Cancer Society medical and editorial content team
`
`
` Our team is made up of doctors and master’s-prepared nurses
`with deep knowledge of cancer care as well as journalists, editors,
`and translators with extensive experience in medical writing.
`
`Last Medical Review: February 16, 2016
`
`Last Revised: March 11, 2016
`
`American Cancer Society medical information is copyrighted material. For reprint requests,
`please see our Content Usage Policy.
`
`https://www.cancer.org/content/cancer/en/cancer/prostate-cancer/treating/hormone-therapy[4/10/2017 3:01:01 PM]
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`MYLAN PHARMS. INC. EXHIBIT 1092 PAGE 8
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`Hormone Therapy for Prostate Cancer
`
`TREATING PROSTATE CANCER
`
`Watchful Waiting or Active Surveillance for Prostate Cancer
`
`Surgery for Prostate Cancer
`
`Radiation Therapy for Prostate Cancer
`
`Cryotherapy for Prostate Cancer
`
`Hormone Therapy for Prostate Cancer
`
`Chemotherapy for Prostate Cancer
`
`Vaccine Treatment for Prostate Cancer
`
`Preventing and Treating Prostate Cancer Spread to Bones
`
`Considering Prostate Cancer Treatment Options
`
`Initial Treatment of Prostate Cancer, by Stage
`
`Following PSA Levels During and After Prostate Cancer Treatment
`
`Treating Prostate Cancer That Doesn’t Go Away or Comes Back After Treatment
`
`MORE IN PROSTATE CANCER
`
`About Prostate Cancer
`
`Causes, Risk Factors, and Prevention
`
`Early Detection, Diagnosis, and Staging
`
`https://www.cancer.org/content/cancer/en/cancer/prostate-cancer/treating/hormone-therapy[4/10/2017 3:01:01 PM]
`
`MYLAN PHARMS. INC. EXHIBIT 1092 PAGE 9
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`

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`Hormone Therapy for Prostate Cancer
`
`Treatment
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`https://www.cancer.org/content/cancer/en/cancer/prostate-cancer/treating/hormone-therapy[4/10/2017 3:01:01 PM]
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`MYLAN PHARMS. INC. EXHIBIT 1092 PAGE 10
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`Hormone Therapy for Prostate Cancer
`
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`https://www.cancer.org/content/cancer/en/cancer/prostate-cancer/treating/hormone-therapy[4/10/2017 3:01:01 PM]
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`MYLAN PHARMS. INC. EXHIBIT 1092 PAGE 11
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