DUTASTERIDE PROSTATE CANCER PREVENTION

March 31, 2010 — New results showing that dutasteride (Avodart, GlaxoSmithKline) reduces the risk for prostate cancer have propelled the subject of chemoprevention for prostate cancer into the spotlight once again.

But the latest results do not convince an expert who has spoken out against this approach in the past; he does so again in an editorial accompanying the study in the March 31 issue of the New England Journal of Medicine.

The study, known as Reduction by Dutasteride of Prostate Cancer Events (REDUCE), was conducted in men considered to be at a high risk for prostate cancer because of their age (50 to 75 years of age), an elevated level of prostate-specific antigen (PSA), or because they had already had a prostate biopsy because of suspicion of prostate cancer.

Over the course of 4 years, significantly fewer prostate cancers were detected in men taking dutasteride than in those taking placebo, representing a relative risk reduction of 22.8% (P < .001).

The researchers, headed by Gerald Andriole, MD, chief of urologic surgery at Washington University School of Medicine in St. Louis, Missouri, conclude that dutasteride "may be considered as a treatment option for men who are at high risk of prostate cancer."

The data from this trial, which was sponsored by the manufacturer of dutasteride, have been submitted for approval for the indication of prostate cancer risk reduction, Dr. Andriole told Medscape Oncology. Currently, dutasteride is marketed for use in benign prostatic hyperplasia.

Nothing New?

Editorialist Patrick Walsh, MD, from the James Buchanan Brady Urological Institute at Johns Hopkins Medical Institutions in Baltimore, Maryland, told Medscape Oncology that the new data on dutasteride are similar to what has been seen with finasteride (Proscar, Merck & Co), and he believes that neither drug should be prescribed for the chemoprevention of prostate cancer.

"Dutasteride and finasteride do not prevent prostate cancer, but merely temporarily shrink tumors that have a low potential for being lethal," Dr. Walsh writes in his editorial.

Furthermore, the use of these drugs for prevention may be somewhat risky," he warned.

These drugs suppress PSA levels, Dr. Walsh told Medscape Oncology. This is "worrisome," he explained, because a decrease in PSA might convince men that the drug is preventing prostate cancer and lull them into a false sense of security that could delay a diagnosis "until they have disease that is difficult to cure," he said.

"Major Distinction" Between Findings

Dr. Andriole agreed that the broad results for the 2 drugs are similar — dutasteride was shown to reduce the risk for prostate cancer by 23%, which is close to the 25% reduction seen with finasteride.

But there is a "major distinction" between the 2 drugs in the findings of high-grade tumors, he told Medscape Oncology.

This has been a major concern with the finasteride data. The 7-year Prostate Cancer Prevention Trial found a reduction in low-grade tumors, but at the same time found an increase in high-grade tumors in the drug group over the placebo group. However, later analyses suggested that the effect of finasteride that reduced the size of the prostate made these high-grade tumors easier to find, rather than increasing their incidence.

In the just-published REDUCE trial, Dr. Andriole said there was "no increase in high-grade tumors in the raw data."

Although the numbers show a significant increase in high-grade tumors in the dutasteride group, compared with the placebo group (12 vs 1; P = .003), Dr. Andriole asserted that this imbalance can be explained by the men in the placebo group being excluded from the trial if their first biopsy found a tumor. If those men had remained in the study and been biopsied again a few years later, some of their tumors "likely would have been upgraded," he explained, and this would have resulted in the number of high-grade tumors in the 2 groups being comparable. "This so-called tumor upgrading has been observed in other studies," he said, adding that this point is elaborated upon in the discussion section of their paper.

Dr. Andriole also noted that if the mathematical modeling that was applied to the finasteride data was applied to the dutasteride data, it would actually show a statistically significant 38% reduction in the risk for high-grade tumors. This is not detailed in their paper, but is explained in a supplementary appendix, he said.

Recommended for Men at High Risk

Dr. Andriole told Medscape Oncology that he recommends prescribing dutasteride to men who are at high risk for prostate cancer (because of elevated levels of PSA, such as in this trial, or because of a family history of the disease). "This drug can reduce the man's chance of being overdiagnosed and overtreated for prostate cancer," he added.

In addition, he believes that the benefits of reducing the risk for prostate cancer and the improvement seen in outcomes related to benign prostatic hyperplasia outweigh the risk for adverse effects, which include sexual dysfunction and, in this trial, heart failure.

The sexual adverse effects, which include erectile dysfunction (reported in 9% of men taking dutasteride and in 5.7% of men taking placebo; P < .001), are reversible, Dr. Andriole said, and if they do appear, the drug can be discontinued, he added. Heart failure (reported in 0.7% of men taking dutasteride and in 0.4% of men taking placebo; P = .03) has not been reported as an adverse effect with these drugs, he noted. He suspects that the cases seen in this trial are related to the concomitant use of alpha blockers, although he admitted that this is "speculation."

Use Recommended by ASCO and AUA

The American Society of Clinical Oncology (ASCO) and the American Urological Association (AUA) jointly recommended the use of both dutasteride and finasteride in asymptomatic men to reduce the risk for prostate cancer in new guidelines issued in February 2009.

However, to date there has been little use of these drugs for this indication, several experts have told Medscape Oncology in previous interviews. This is an off-label use at present; both drugs are marketed for benign prostatic hypertrophy (finasteride is also marketed for male pattern baldness).

Dr. Andriole agreed that there has been little use of finasteride for reducing the risk for prostate cancer, and believes that this stems from concern over the high-grade tumor findings. He believes that the new data on dutasteride will "lay that anxiety to rest," and that these latest data will lead to an increase in the use of dutasteride for this indication.

Expert Discourages Use for Prevention

Dr. Walsh is firmly opposed to the use of these drugs for prostate cancer risk reduction. He has spoken out against finasteride in comments made in response to an article about the drug preventing cancer that made the front page of the New York Times (June 15, 2008).

"I am very concerned about encouraging patients and general physicians to use this drug," he wrote in the winter 2009 issue of Prostate Cancer Discovery. He notes finasteride does not prevent prostate cancer, "it just prevents men from knowing they have it!"

"First, it has no primary effect in reducing the number of men who will have a positive biopsy," he writes. "Second, men will believe that it prevents cancer, will be pleased that their PSA levels fall, and will not understand the potential danger of undiagnosed high-grade disease."

Dr. Walsh told Medscape Oncology that the comments he made about finasteride at that time apply equally to dutasteride.

"[REDUCE] showed that there was a 23% reduction in low-grade tumors that the patients would never have known they had," he said. "Does this sound like an indication to take a pill with sexual side effects that costs $4 a day?"

In his editorial, Dr. Walsh reviews previous studies on finasteride and the latest study on dutasteride. He points out that neither drug "significantly reduced the risk of prostate cancer among men who were followed closely and who underwent a biopsy because of an elevated PSA level (corrected for the effect of the drug) or an abnormal digital rectal examination." He adds that, "unfortunately, this is the setting that would be used for prevention."

But this approach "will continue to be pushed because of financial interests," he told Medscape Oncology. The clinical trials have been huge and the companies involved "must have spent a ton of money on it," he noted.

The REDUCE trial was supported by GlaxoSmithKline, manufacturer of dutasteride, and 4 of the coauthors are employees of the company. Dr. Andriole reports receiving consulting or advisory fees from GlaxoSmithKline and 8 other pharmaceutical companies; several coauthors report receiving consulting, advisory, or lecture fees from GlaxoSmithKline. Details are in the paper. Dr. Walsh has disclosed no relevant financial relationships.

N Engl J Med. 2010;363;1192-1202, 1237-1238.