Nonsteroidal antiandrogens in treatment of metastatic prostate cancer


In the 1970s the nonsteroidal antiandrogens were a class of drugs looking for a disease to treat. Then Ferdinand Labrie (in Canada), using these drugs in combination with the LHRH agonist leuprolide acetate, first claimed a significant benefit for flutamide in treatment of metastatic prostate cancer.

Three nonsteroidal antiandrogens have been widely approved for the treatment of advanced forms of prostate cancer:

Over the past 15 years, bicalutamide has become the dominant nonsteroidal antiandrogen, largely because it has fewer side effects than the other two products and because it can be taken as a single tablet once a day in a variety of dosage strengths.

What Are Nonsteroidal Antiandrogens, and How Do They Work?

Nonsteroidal antiandrogens are agents which act on the male hormones (androgens) but have no steroidal effects. In other words they are “pure” antiandrogens. Their methods of action appear to vary in detail from drug to drug. However, bicalutamide, flutamide, and nilutamide all seem to block the action of dihydrotestosterone (DHT) in stimulating the synthesis of new protein in prostate and prostate cancer cells.

In the prostate the male hormone testosterone is converted into a structurally similar biochemical called DHT. DHT is the “active” molecule in the prostate which acts on the prostate and prostate cancer cells to stimulate new growth. The precise details of this mechanism of action are complex and are still not completely understood. However, the antiandrogens interfere with the way in which DHT stimulates prostate cell growth when it is combined with other molecules in the cell. The effect is to drastically slow the growth of new prostate and prostate cancer cells.

The Clinical Effectiveness of Nonsteroidal Antiandrogens in Prostate Cancer

The clinical effectiveness of the nonsteroidal antiandrogens in the treatment of advanced prostate cancer has been tested in many settings and is still a matter of extensive debate. What is certain appears to be the following:

  • Flutamide and bicalutamide both appear to be able to suppress the so-called “flare reaction” associated with the initial injection of LHRH agonists in treatment of advanced forms of prostate cancer.
  • Neither flutamide nor bicalutamide have significant impact as single agents on patient survival in the treatment of stage M1 prostate cancer.
  • In some randomized, double-blind trials, bicalutamide, flutamide, and nilutamide have all shown a small survival benefit when combined with LHRH agonists or orchiectomy for treatment of stage M1 prostate cancer. However, the clinical value and “reality” of this survival benefit has been much debated.

In addition, as will be discussed elsewhere, bicalutamide and flutamide have both indicated a value for antiandrogen therapy in combination with LHRH agonists when used earlier in the disease process (especially as a adjuvant to radiation therapy), and bicalutamide has also established its value when used alone as a method to suppress androgen levels because it does not suppress sexual function (or at least, not to the same extent as the LHRH agonists).

The Side Effects of Nonsteroidal Antiandrogen Therapy

In the treatment of metastatic prostate cancer, all major trials of the nonsteroidal antiandrogens have occurred in combination with either an LHRH agonist or orchiectomy, so it is difficult to know exactly which side effects are exclusive to the use of the nonsteroidal androgens and are liable to occur when such agents are used on their own. However, the following adverse reactions appear to be specific to the nonsteroidal antiandrogens:

  • Gynecomastia or nipple tenderness in which there is mild swelling or at least tenderness of the man’s breasts are relatively common.
  • Diarrhea is observed in a significant percentage of patients receiving flutamide but seem to be less prevalent in patients receiving bicalutamide. Historically, a significant proportion of patients discontinued treatment with flutamide because of this problem.
  • Hepatotoxicity or toxic effects on the liver have been observed in very small numbers of patients but can be very serious.
  • Night blindness appears to be a side effect that is specific to the use of nilutamide, and has not been observed in the use of either bicalutamide or flutamide.

Other side effects which have been observed include nausea and vomiting, headaches, and other less serious adverse reactions.

An important side effect which is not observed in patients receiving monotherapy with nonsteroidal antiandrogens is impotence. Because of this relative benefit, two major trials sought to demonstrate the value of high-dose bicalutamide in the treatment of high-risk prostate cancer immediately post-surgery or post-radiation treatment. The results and long-term outcomes of this trial will be discussed elsewhere.

For full information on the possible adverse events associated with any drug, please see the full prescibing information for that specific product.

Content on this page last reviewed and updated July 21, 2008.
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