Everybody would love it if 5-alpha reductase inhibitors - finasteride (Proscar, made by Merck) and Dutasteride (Avodart, made by GlaxoSmithKline) could help prevent prostate cancer. Men would love to be able to lower their risk of cancer by taking a pill. Doctors would love to prescribe something that could help their patients avoid having to get treatment for prostate cancer. Drug companies would love it because they could sell a product that would help thousands of men each year. Sadly, it isn’t going to happen. Although these drugs lower PSA and reduce symptoms in men with benign prostate enlargement (BPH), they do not prevent prostate cancer; in fact, they can make it worse. Two randomized, controlled studies have shown that 5-alpha reductase inhibitors (5-ARIs) can increase a man’s odds of developing aggressive, high-grade disease that is difficult to cure. Because of this, the U.S. Food and Drug Administration has turned down a request by pharmaceutical companies to sell these drugs as preventives for prostate cancer, and has notified health care professionals about a change in the Warnings and Precautions for these drugs.
The FDA’s decision was based on a reexamination of two studies that initially had seemed promising. "Many urologists were surprised and disappointed by this outcome, because of the encouraging information they had heard regarding these drugs," says Patrick C. Walsh, M.D., who has worked in the field of 5-alpha reductase for 42 years and who was an invited guest speaker at the advisory panel's meeting.
Why were 5-ARIs being studied as possible cancer preventives in the first place? Because they block an enzyme, 5-alpha reductase, that prevents testosterone from changing into another male hormone, DHT, which is active in the prostate. Blocking DHT is helpful in treating BPH because this shrinks prostate tissue, and relieves the urinary symptoms that can be so troublesome when the prostate is enlarged. In the process, these drugs cut a man's PSA levels in half. But the problem here is that cancer is a different disease from BPH, because there is very little 5-alpha reductase enzyme in the malignant tissue. Consequently, prostate cancer is driven by testosterone, not DHT.
In one study, the Prostate Cancer Prevention Trial (PCPT), conducted by the National Cancer Institute, nearly 19,000 men were randomly assigned to take either fi nasteride or a placebo for seven years. The men underwent a prostate biopsy if they had an abnormal digital rectal exam or change in PSA, and when the study was over, about a third of the men also underwent biopsies. The other study, called Reduction by Dutasteride of Prostate Cancer Events (REDUCE), tested the effect of that drug in 8,000 men over four years. In both studies, there was no significant decrease in cancer in men who underwent a biopsy because of an abnormal PSA or rectal exam.
“ If you are worried about dying
from prostate cancer, taking a
5-alpha reductase inhibitor is the
last thing you should do. These
drugs do not prevent the disease,
but give a false sense of security
because they lower PSA.”
But there was a troubling increase in the number of men taking the drugs — not the placebos — who were diagnosed with very aggressive cancer (Gleason 8-10).
Also troubling was that fewer men with an abnormal PSA or examination who were taking these drugs underwent biopsies than actually should have. "This was because their PSA was artificially low, and they did not think it was significant enough to worry about," says Walsh. "The only way finasteride and dutasteride reduce the number of patients with cancer is by fooling men into believing that their PSA is lower than it really is, so that they don't get a biopsy. These agents don't prevent cancer; they merely prevent biopsies."
When the FDA advisory panel met to evaluate two proposals for allowing 5-ARIs to be used as preventive agents to reduce the risk of prostate cancer, Merck did not seek a new indication for the use of Proscar, but instead requested a change in the section on "Adverse Reactions" in the product information – so it would say that the increased prevalence of high-grade disease in men who took Proscar was an artifact caused by improved sensitivity of PSA and/ or prostate shrinkage that made it easier to find high-grade cancer on a biopsy. This was rejected by the panel by a vote of 17-0 with one abstention. The application for approval of Avodart as a way to reduce prostate cancer in men at “increased risk” – men who have had a negative biopsy but still had an elevated PSA – was also rejected by a vote of 14-2, with two abstentions.
In March 2011, GlaxoSmithKline announced that it would no longer pursue global marketing of dutasteride for use in the prevention of prostate cancer. Merck's revised product insert concluded that Proscar is not approved to reduce the risk of prostate cancer. “If the pharmaceutical companies that actually make these drugs do not believe that they are safe and effective in preventing prostate cancer, urologists should not be offering them to patients for that purpose," says Walsh. "If you are worried about dying from prostate cancer, taking a 5-alpha reductase inhibitor is the last thing you should do. These drugs do not prevent the disease, but give a false sense of security because they lower PSA. If you take one of these drugs and develop prostate cancer, it may delay your diagnosis until you have aggressive disease that may not be curable." These fi ndings also have potential implications for the use of these drugs in men with BPH and male-pattern baldness, Walsh adds.
“ If you take one of these drugs and
develop prostate cancer, it may
delay your diagnosis until you
have aggressive disease that may
not be curable.”
Still, some interest remains for using 5-ARIs in men diagnosed with very low-risk prostate cancer to lengthen the time that slow-growing disease takes to become significant and need treatment. To investigate this, Hopkins scientists studied 5-ARI use among men with very low-risk prostate cancer in the Active Surveillance Program. Ashley Ross, Walsh, H. Ballentine Carter, Bruce Trock and Ed Schaeffer, found that among these men, 5-ARI use did not decrease the risk of progression of the disease. While the final answer awaits the results of a randomized, controlled trial, these findings suggest that 5-ARIs should not be used to attempt to slow or stop cancer progression in men with low-risk prostate cancer.