Dutasteride (AVODART) to Prevent Prostate Cancer

Dutasteride (AVODART) was first approved by the Food and Drug Administration (FDA) in November 2001 for the treatment of the symptoms of enlarged prostate gland, technically known as benign prostatic hyperplasia (BPH).

More recently, the FDA’s Oncologic Drugs Advisory Committee voted not to recommend dutasteride’s approval to prevent prostate cancer by a vote of 14-2 with two abstentions. The FDA’s own subsequent refusal to approve the drug to prevent prostate cancer was announced on Jan. 26, 2011. On March 23, 2011, Glaxo SmithKline (GSK), the manufacturer, announced that it would no longer pursue global approval for the use of dutasteride to reduce the risk of prostate cancer.

In 2009, more than 3.4 million prescriptions were dispensed for dutasteride in the U.S., with sales exceeding $416 million for that year.

Dutasteride belongs to the family of drugs to treat BPH called 5-alpha reductase inhibitors. The only other member of this family sold in the U.S. is finasteride (PROSCAR). Finasteride is also sold for hair loss as PROPECIA.

The 5-alpha reductase inhibitors work by blocking the conversion of the male sex hormone testosterone to dihydrotestosterone (DHT).

DHT is the compound primarily responsible for the initial development and subsequent enlargement of the prostate gland.

The FDA-approved uses for dutasteride were expanded in October 2002 and October 2007. The drug is now approved for use in combination with tamsulosin (FLOMAX), a member of another family of BPH drugs called alpha-blockers to improve the symptoms of BPH, reduce the risk of acute urinary retention (inability to urinate) and to reduce the risk for BPH-related surgery.

On Dec. 1, 2010, the FDA convened a meeting of its Oncologic Drugs Advisory Committee to evaluate further expanding the use of dutasteride to reduce the risk of prostate cancer in men at increased risk, defined as those who have had a prior negative biopsy due to clinical concern and who also have an elevated serum prostate-specific antigen (PSA). This test is used to screen for and to monitor prostate cancer.

The advisory committee was asked to review the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial submitted by GSK to support the new use for cancer prevention. The REDUCE trial was published in the April 1, 2010, issue of The New England Journal of Medicine.

The REDUCE study involved 8,231 men who were 50 to 75 years of age who had a PSA level of 2.5 to 10 nanograms per milliliter and had had one negative prostate biopsy within six months before the start of the study. These men were randomly assigned to receive 0.5 milligrams daily of dutasteride or a placebo for four years.

Among 6,729 men who underwent a biopsy or prostate surgery, cancer was detected in 659 (20 percent) of the 3,305 men in the dutasteride group, compared to 858 (25 percent) of the 3,424 men in the placebo group. But there were 12 tumors (0.36 percent) with the most aggressive type of prostate tumor in the dutasteride group compared to one in the placebo group (0.03 percent). Less serious tumors were reduced but the more serious tumors were increased in the men receiving dutasteride compared to placebo. Thus, instead of preventing the most serious form of prostate cancer, the drug actually increased the risk 12-fold compared to those getting a placebo.

Finasteride and prostate cancer prevention

Finasteride is the other member of the 5-alpha reductase inhibitor family of BPH drugs. We listed finasteride as a DO NOT USE drug for preventing prostate cancer in the August 2003 Worst Pills, Best Pills News. Our decision was based on a study published in The New England Journal of Medicine on June 24, 2003.

The study was known as the Prostate Cancer Prevention Trial (PCPT) and was sponsored by the U.S. Public Health Service and the National Cancer Institute, one of the U.S. National Institutes of Health.

In the PCPT trial, 18,882 men 55 years of age or older with normal physical examinations and PSA levels of 3 nanograms per milliliter or lower were randomly assigned to receive 5 milligrams per day of finasteride or a placebo for seven years.

After seven years, 803 cases (18 percent) of prostate cancer were diagnosed in the 4,368 men given finasteride. In the group of 4,692 men receiving the placebo, 1,147 men (24 percent) developed prostate cancer. But 5.1 percent of men receiving the placebo and 6.4 percent of those taking finasteride who had biopsies of their prostate glands had developed more serious tumors. This is an increase of 1.3 percent.

Similar to dutasteride, finasteride also reduced the overall number of tumors but increased the more serious variety of tumor.

Why should you be concerned about dutasteride and prostate cancer prevention?

The FDA denied GSK’s application to sell dutasteride to prevent prostate cancer. So why should men be concerned about dutasteride? The problem is that manufacturers sometimes illegally promote their products for unapproved uses. And, doctors are free to prescribe drugs for uses that have never been approved. This is designated as off-label prescribing.

In May 2009, GSK paid for a medical journal advertising supplement that was published in the journal Urology. The articles in the supplement contained information about studies suggesting dutasteride could reduce the risk of developing prostate cancer. This is illegal. The information in journal supplements, not the parent journal, may be of lower quality and can be used as a way around the parent journal’s peer review process.

GSK subsequently wrote a letter to apologize to the doctors who received Urology and the supplement. The letter noted that the company failed to disclose that it helped develop the supplement and select the doctors who were listed as authors. However, the supplement did disclose that funding came from GSK and some authors had financial ties to GSK.

Unfortunately, journal supplements are widely cited in the medical literature despite their questionable status as science. This can lead doctors to prescribe drugs for uses that have not been shown to be safe or effective.

What You Can Do

You should not use dutasteride, or for that matter finasteride, to prevent prostate cancer.

Consumers may report serious adverse events with products to the FDA’s MedWatch Adverse Event Reporting program either online, or by regular mail, fax or phone.

• Online: www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm
• Regular mail: Use postage-paid, pre-addressed FDA form 3500 and mail to MedWatch, 5600 Fishers Lane, Rockville, MD 20852-9787
• Fax: (800) FDA-0178
• Phone: (800) FDA-1088