Androgen Deprivation Therapy (Hormone Therapy)
Androgen deprivation therapy (also called androgen suppression therapy or hormone therapy) uses treatments to reduce levels of male hormones such as testosterone, which stimulate the growth of prostate cells. Androgen deprivation therapy suppresses or blocks testosterone by either:
- Surgical castration. Bilateral orchiectomy is surgical removal of the testicles. This is an irreversible procedure that permanently stops testosterone production.
- Chemical castration. Drugs such as LH-RH agonists or anti-androgens interfere with testosterone production or activity. Once the drug is stopped, testosterone production and action resumes.
Androgen deprivation therapy is not usually recommended as an initial therapy for early-stage prostate cancer. Studies indicate that it does not improve survival for most men with localized prostate cancer. It is mainly used for:
- Advanced (metastatic) cancer that has spread beyond the prostate gland
- Cancer that has failed to respond to surgery or radiation
- Cancer that has recurred
Androgen deprivation therapy may also be used:
- Before radiation or surgery to help shrink tumors
- Along with radiation therapy for cancer that is likely to recur
- Before, during, and after radiation therapy for locally advanced prostate cancer
- As palliative therapy to help ease cancer symptoms, or to prevent symptoms of progressing cancer
Surgical Castration (Orchiectomy)
Bilateral orchiectomy is the surgical removal of both testicles (surgical castration). It is the single most effective method of reducing androgen hormones but its effects are permanent. Orchiectomy plus radical prostatectomy may delay progression in people with cancers that have spread only to the pelvic lymph nodes.
Men who have orchiectomy have reduced sexual function and desire. People do not experience a reversal of sex characteristics and the voice does not change. Like all androgen deprivation therapies, orchiectomy increases the risk for osteoporosis.
Chemical Castration (Hormone Drug Therapy)
LH-RH Agonists and Antagonists
The main drugs used for suppressing androgens are called luteinizing hormone-releasing hormones (LH-RH) agonists. They are also known as gonadotropin-releasing hormone (GnRH) agonists or LH-RH analogs. These drugs block the pituitary gland from producing hormones that stimulate testosterone production.
LH-RH agonists include leuprolide (Lupron, Eligard, Viadur, generic), goserelin (Zoladex), triptorelin (Trelstar), and histrelin (Vantas). These drugs are given as injections or as implants placed under the skin. LH-RH agonists produce a testosterone surge ("flare") in the first week, which may intensify symptoms including bone pain if the cancer has spread to the bones. After this phase, testosterone levels drop to near zero. LHRH agonists can also cause PSA levels to rise temporarily.
LH-RH antagonists work similarly to LH-RH agonists but do not cause a testosterone surge. The FDA has approved the LH-RH antagonist drugs degarelix (Firmagon) and relugolix (Orgovyx) for treatment of advanced prostate cancer.
Common side effects of these drugs include hot flashes, fatigue, testicle shrinkage, and breast enlargement. These drugs may increase blood sugar levels and the risk of developing diabetes. They may also increase risk for heart attack, stroke, and sudden death.
Anti-androgens are drugs used to block the effects of testosterone. Anti-androgens are not typically used by themselves. They are often added when another hormone therapy stops working. They are generally used in combination with LH-RH agonists. This type of treatment is called combined androgen blockade.
The anti-androgen drugs used for prostate cancer treatment include flutamide (Eulexin, generic), nilutamide (Nilandron), both of which are rarely used today. The more commonly used anti-androgen drugs are enzalutamide (Xtandi), apalutamide (Erleada), and bicalutamide (Casodex, generic). They are taken as daily pills. When taken with an LH-RH agonist, hot flashes and breast tenderness is intensified.
All types of hormone drug therapy can help delay cancer growth but this treatment can cause significant side effects including:
- Hot flashes, which may go away over time.
- Sexual dysfunction (erectile dysfunction) and loss of sexual drive (low libido).
- Osteoporosis, the loss of bone density. Medications such as denosumab (Prolia) and zoledronic acid (Zometa) help increase bone mass and prevent bone fractures in men receiving hormone therapy.
- Decrease in HDL (good cholesterol) levels.
- Loss of muscle mass.
- Weight gain.
- Decreased mental alertness.
- Fatigue and depression.
- Swelling and tenderness of the breasts (gynecomastia).
- Anemia (low red blood cell count).
In addition, there is growing evidence that androgen deprivation drug therapy increases the risks for heart attack, stroke, and diabetes. These drugs increase body weight, which can lead to decreased insulin sensitivity and harmful changes in cholesterol levels.
Guidelines recommend that men who receive androgen deprivation therapy should have regular follow-up exams with their primary care doctors within 3 to 6 months after starting therapy. The doctor should monitor the patient's blood pressure and perform blood sugar (glucose) and cholesterol (lipid) laboratory tests at least once a year.
Continuous Versus Intermittent Therapy
When prescribing hormone therapy drugs, some doctors recommend periodically stopping and restarting treatment (intermittent therapy). This approach appears to help reduce erectile dysfunction, hot flashes, and other hormone therapy side effects that impair quality of life.
However, it is not clear if intermittent therapy works as well as continuous therapy for prostate cancer treatment. Some studies indicate that continuous therapy is more effective or that intermittent therapy should only be used for select types of prostate cancer. Other research suggests that intermittent androgen deprivation is as effective as continuous therapy. More research is needed.
Treatments for Castration-Resistant Cancer
Hormone therapy is initially very effective, but after several years the cancer often starts growing again. Prostate cancer that no longer responds to hormonal treatment is called castration-resistant. (It was formerly called hormone-resistant or hormone-refractory cancer.) When castration-resistant prostate cancer advances and spreads throughout the body it is called metastatic castration-resistant prostate cancer (mCRPC). There are several treatment options, including new types of drugs. Most of these therapies prolong survival by a few months.
The American Society of Clinical Oncology (ASCO) has treatment guidelines for mCRPC that take into consideration both the quality of life and survival benefits of various therapies. The ASCO guidelines recommend that for patients with mCRPC, hormone therapy should be continued indefinitely. In addition, men should be offered one of three treatments: abiraterone (Zytiga) plus prednisone, enzalutamide (Xtandi), or radium-223 (Xofigo). Chemotherapy or other select therapies may be options for certain patients. Palliative care (pain-relieving measures) should be offered to all people.
Abiraterone (Zytiga) is a drug that is used for patients with metastatic castration-resistant prostate cancer and for people with high risk castrate-sensitive metastatic cancer. It blocks an enzyme called CYP17. The drug is taken as once-daily pills along with prednisone. Abiraterone is also approved for use for metastatic cancer prior to chemotherapy. Side effects may include joint swelling, fluid build-up in legs and feet, muscle discomfort, hot flashes, high blood pressure, and low levels of potassium in the blood.
Non-steroidal antiandrogens are drugs that block the androgen receptor and thus inhibit the effects of androgens such as testosterone.
Enzalutamide (Xtandi) is an anti-androgen drug for men with castrate-resistant prostate cancer that has or has not spread (metastasized). Enzalutamide is taken as a daily pill. Unlike abiraterone, it does not need to be taken along with prednisone. Its side effects are similar to abiraterone except that enzalutamide may increase the risk for seizures.
Apalutamide (Erleada) is another nonsteroidal anti-androgen recently approved by the FDA for castration-resistant prostate cancer that has not spread (metastasized).
Darolutamide (Nubeqa) is used to treat castration-resistant prostate cancer that has not spread. Used together with castration, darolutamide has side effects including tiredness, rash, and arm and leg pain.
All these non-steroidal antiandrogens are used together with surgical or chemical castration.
Radium-223 injection (Xofigo) is approved for treatment of metastatic castration-resistant prostate cancer that has spread to the bones but not to other organs. Xofigo is a radioactive medicine that binds to the mineral in bones. It targets and delivers radiation directly to bone tumors without damaging surrounding healthy tissue. In clinical trials, men treated with Xofigo lived about 3 months longer than those who did not receive the drug.
The main first-line chemotherapy treatment for mCRPC is docetaxel (Taxotere) combined with the corticosteroid prednisone. Recent evidence suggests that some people with metastatic prostate cancer may benefit more from docetaxel chemotherapy as first-line therapy when combined with androgen deprivation therapy than from androgen therapy alone.
Cabazitaxel (Jevtana) is a newer chemotherapy drug approved for people whose condition has worsened during or after treatment with docetaxel. It is also used in combination with prednisone. Mitoxantrone (Novantrone, generic) plus prednisone is a third option for chemotherapy but it appears to have limited clinical benefit.
Chemotherapy regimens may help extend survival time by several months. Side effects can be serious and may include gastrointestinal problems (nausea, vomiting, or diarrhea), fatigue, low blood cell counts, and increased risk for blood clots. Men who are considering chemotherapy should be sure to discuss with their doctors all potential side effects.
Sipuleucel-T (Provenge) is a cancer "vaccine" approved for select men with advanced prostate cancer. Unlike typical vaccines, it does not prevent disease. Instead, it uses the patient's own immune system to fight the cancer. Each vaccine is individually manufactured by collecting the person's own immune cells from peripheral blood. The cells are then exposed to a special type of protein and infused back into the patient. The American Society of Clinical Oncology (ASCO) recommends this treatment only for men with mCRPC who have few or no symptoms of cancer.
Provenge extends survival time by an average of 4 months. Quality of life benefits are uncertain. In studies, side effects ranged from mild (chills, fatigue, fever, nausea, joint, and muscle aches) to severe (stroke). Provenge is very expensive, but some insurers, offer coverage for it.
PARP inhibitors are a group of drugs that inhibit a type of enzyme necessary to repair damaged DNA inside cells. Some cancers, including prostate cancer, may harbor mutations that cause the tumors to be sensitive to the effects of PARP inhibitors. Two such drugs are currently approved for the treatment of prostate cancer. Olaparib (Lynparza) is approved for men with mCRPC who have previously received abiraterone or enzalutamide and who have been found to have the genetic alterations suggesting a benefit from treatment with a PARP inhibitor. Rucaparib (Rubraca) is another PARP inhibitor approved for prostate cancer treatment in men with genetic mutations who have already received chemotherapy.