Shedding light on the prostate drug dilemma: benign prostate disease - includes a related article on the treatment options

Harvard Health Letter, Jan, 1997 by Leah R. Garnett

After researchers reported last summer that finasteride, one of the leading drugs for prostate enlargement, was no better than a dummy pill, thousands of American men were in a quandary. Should they stop taking it? And if they weren't on the medication, what would they do if their physician recommended it?

The study, which was published in the august 22, 1996, issue of the New England Journal of Medicine, was a head-to-head comparison of finasteride, marketed by Merck & Co. as Proscar, and terazosin, sold as Hytrin by Abbott Laboratories. Both companies paid for the investigation, which was conducted by researchers from the Veterans Administration (VA) Medical Center in New York and New York University.

The VA study found that treatment with Hytrin improved urinary troubles and flow rate significantly, while Proscar reduced the size of the prostate but had no more effect on symptoms or flow rate than a placebo. A combination of the two drugs was found to be no more effective than Hytrin alone.

Read all about it

The findings were highly publicized in the media, but many news organizations stopped short of putting the data in perspective. For one, the VA results conflict with those of two large, randomized controlled trials showing that finasteride is an effective treatment for urinary problems associated with an enlarged prostate--known as benign prostatic hyperplasia or BPH.

In addition, the 1,229 men in the VA study had an average prostate volume of 37 grams, which is not considered unusually large and does not substantially differ from that of healthy men. Both of these discrepancies were pointed out in an editorial that accompanied the study.

"The headline `Proscar Doesn't Work' sells papers, hut an editorial that questions that premise apparently isn't as exciting," said Kevin Loughlin, associate professor of surgery at Harvard Medical School and a urologist at Brigham and Women's Hospital in Boston. "Many of us believe that the study was incomplete and flawed and that it doesn't prove that one drug is better than the other."

The finasteride studies contradict each other, say critics, because they're comparing apples and oranges. The men in the VA study had, on average, smaller prostates than those in the two previous trials, which found that Proscar was beneficial. In those studies, the average prostate volume was 60 grams in one and 47 grams in the other--10-23 grams larger than in the VA trial.

Only a month after the VA results were published, an analysis of six randomized trials comparing finasteride to a placebo appeared in the journal Urology. It concluded that finasteride works best in men with large prostates and that it may not be the drug of choice for those with smaller glands. The analysis was conducted, conducted by researchers at the European Institute of Oncology and the University of Texas Southwestern Medical Center and was partially funded by Merck. (See"How Big Is Big?")

Defining the problem

Men with BPH may urinate frequently, experience incomplete emptying of the bladder, have a sense of urgency and dribling, and get up to urinate in the middle of the night. About half of all men over 50 are affected by this annoying--but not cancerous--condition.

Although men with BPH share a common set of symptoms, the disorder is no longer seen as having a single cause. For this reason, "it is clear that no one type of drug therapy would be expected to be effective in all men," said Patrick Walsh, professor of urology and director of the Brady Urological Institute at Johns Hopkins Hospital in Baltimore, who wrote the editorial that accompanied the VA study.

It is unclear exactly how BPH causes urinary problems or how many forms of the condition there are. Men with the largest glands, for example, don't necessarily have the worst symptoms. Physicians do know that Proscar and Hytrin work by different mechanisms, and this may help shed light on the varying forms of BPH. Proscar shrinks the prostate gland by blocking the formation of the hormone dihydrotestosterone; Hytrin--originally approved as a high blood pressure medicine--relaxes smooth muscle that surrounds the gland.

What is known

Men with large prostates are more likely to have an overgrowth of epithelial tissue that mechanically obstructs the urethra; those with smaller glands may experience pressure on the urethra due to a contraction of smooth muscle tissue. Thus it makes sense that a man with a large prostate might find relief from a drug that shrinks the gland; whereas one with a smaller prostate might benefit from a medication that relaxes it. "We may need to have several drugs to treat BPH in the same way we treat one type of heart disease with one drug and a second type with another," said Harvard's Dr. Loughlin.

Until a few years ago, the only way to restore urinary flow among men with BPH was to surgically remove a portion of the gland. In 1992, the Food and Drug Administration approved Proscar; a year later, Hytrin was given the nod for BPH.