Prostate Cancer Treatment: Hormonal Therapy

Hormonal treatment for prostate cancer aims to tamp down testosterone -- the hormone that prostate tumors need to grow.

Hormonal therapy for prostate cancer depends on stopping the male hormone testosterone from interacting with cancer cells.

The prostate is the male gland in the pelvis that wraps around the urethra and produces the fluid portion of semen. Prostate cancer is one of the most common cancers in men.

Prostate cancer is highly sensitive to and dependent on, the level of the male hormone testosterone, which drives the growth of prostate cancer cells in all but the very high-grade or poorly-differentiated forms of prostate cancer. Testosterone belongs to a family of hormones called androgens, and today front-line hormonal therapy for advanced and metastatic prostate cancer is called androgen deprivation therapy (ADT).

In the past, this was accomplished by surgical castration called bilateral orchiectomy. In that procedure, the testes were both removed. Today, doctors can block the function of the testes in a controllable and most often reversible fashion with drugs that prevent the production of testosterone (medical castration). These agents can result in shrinkage of the prostate gland, can stop prostate cancer cells from growing for up to several years, and can relieve pain caused by prostate cancer that has spread or metastasized into the bones by shrinking cancer. The use of ADT does not produce a cure. Over time, the prostate cancer cells will develop an ability to grow despite the lack of hormones (castrate resistance). Another form of hormonal therapy is the use of androgen receptor blockers; these medications prevent testosterone from attaching (binding) to the prostate cancer cell and being absorbed into the cell where it can help the cell survive and grow.

Hormonal treatment today is primarily used in the treatment of locally advanced and metastatic prostate cancer. It may be used in conjunction with primary curative therapies (surgical and radiation-based) to shrink cancer/prostate to increase the likelihood of cure of the treatment, neoadjuvant therapy, and with radiation therapy for several years after treatment (adjuvant therapy). However, the primary role of ADT is in the treatment of widespread or metastatic prostate cancer. While it is not a curative treatment in that setting, it can both reduce symptoms and slow down the growth of prostate cancer to prolong life.

Today medicines used to block testosterone production by the testes include:

• LH-RH agonists: Leuprolide (Lupron), goserelin (Zoladex), histrelin (Supprelin LA), and triptorelin (Trelstar) are examples of these mediations. These are either given by injection into the muscle or under the skin at varying intervals of at least 1 month or longer.
• LH-RH antagonists: Degarelix (Firmagon) is a monthly injection that is given under the skin.

Medications that block the action of testosterone include the androgen receptor blockers

Flutamide (Eulexin), bicalutamide (Casodex), nilutamide (Nilandron), and an even more effective form called enzalutamide (Xtandi): Xtandi is recommended for use only in individuals with castrate-resistant prostate cancer (prostate cancer that is refractory to traditional ADT), including those with and without metastases. Xtandi is different than the other androgen receptor blockers in that it has three mechanisms of action:

1. It prevents androgens (testosterone) from binding to the androgen receptor,
2. it prevents the androgen receptor from moving into the central area (nucleus) of the cell, and
3. it prevents the binding of the androgen receptor to DNA and stimulates growth.

The most common side effects of Xtandi include

• fatigue,
• back pain,
• decreased appetite,
• constipation,
• arthralgia,
• diarrhea,
• hot flush,
• upper respiratory tract infection,
• swelling of the legs,
• shortness of breath with exertion,
• headache,
• hypertension,
• dizziness, and
• weight loss.

Less commonly, seizures and posterior reversible encephalopathy syndrome characterized by seizure, headache, lethargy, confusion, and blindness may occur. A newer androgen receptor blocker with a similar mechanism of action as Xtandi, apalutamide (Erleada), is indicated for use in men with nonmetastatic castrate-resistant prostate cancer.

Both surgical and medical castration result in impotence. They also can cause hot flashes, fatigue, anemia, and thinning of the bones (osteoporosis) over time. These drugs may be given individually or combined with an androgen receptor blocker in what is called a combined androgen blockade.

Other hormonal treatment options include:

Estrogen: This female hormone has been utilized in the treatment of prostate cancer as it also results in medical castration. Its mechanism of action remains under study, and its association with a high risk of heart attack and blood clots when used in high doses has diminished the frequency of its use, particularly in front-line therapy. Other side effects include breast enlargement/pain (gynecomastia). Estrogen and related drugs may still have a role in the treatment of metastatic prostate cancer in select individuals.

Adrenal androgen synthesis inhibitors: The adrenal glands, a pair of small glands that are located above the kidneys, also produce a small amount of testosterone. Individuals on traditional ADT have testicular production of testosterone suppressed but still may have testosterone production from the adrenal glands. In individuals on ADT who have continued growth of the prostate cancer (rising PSA), the use of adrenal androgen synthesis inhibitors may be useful. This group includes a drug called ketoconazole, which was primarily developed to treat fungal infections, but has shown to be effective in the treatment of prostate cancer. More recently, an agent called abiraterone acetate (Zytiga) has been developed. It has a similar effect on androgen synthesis, but it is more powerful than an older agent called ketoconazole (Nizoral) and has fewer side effects. The use of Zytiga in combination with prednisone is considered in individuals failing traditional ADT and individuals who have castrate-resistant prostate cancer (failed first-line ADT). More common side effects of Zytiga include fatigue, back or joint discomfort, peripheral edema, diarrhea, nausea, constipation, and low potassium levels. Blood pressure, liver tests, potassium, and phosphate levels should be monitored regularly when initially using Zytiga.

Steroids: These agents including prednisone may have beneficial hormonal effects in prostate cancer, including slowing the production of androgen by the adrenal glands. They often make the patient feel better but have many side effects including inducing or worsening diabetes, fluid retention, cataract formation, weight gain, and osteoporosis.

Agents that block the conversion of testosterone to its active metabolite: Finasteride (Proscar) and dutasteride (Avodart) are not approved by the Food and Drug Administration (FDA) for the treatment of prostate cancer, however, they have been used (off-label) in treating prostate cancer by preventing the conversion of testosterone to its active metabolite called DHT (dihydrotestosterone). These drugs are frequently utilized for the symptoms of prostate enlargement in men without prostate cancer and appear to reduce the risk of the development of prostate cancer. Their side effects are limited. They are used in combination with other agents to optimize androgen blockade.