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Clinical Trial Results

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  • Posted: 04/12/2010

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Dutasteride Decreases Prostate Cancer Risk

Results from a large randomized clinical trial indicate that men at an increased risk for prostate cancer reduced their risk with regular use of the drug dutasteride (Avodart). The results came from the REDUCE trial, which is the second largest clinical trial to demonstrate a decreased risk of prostate cancer in men taking an agent from the class of drugs known as 5-α reductase inhibitors (5-αRIs). Previously, the (PCPT) showed that the drug finasteride had a risk reduction similar to what has now been seen in REDUCE.

Findings from this trial suggest “that the major effect of dutasteride is the shrinkage of prostate tumors or inhibition of their growth,” wrote the study’s lead investigator Gerald Andriole, M.D., of the Washington University School of Medicine in St. Louis, and his colleagues in the April 1, 2010, New England Journal of Medicine. GlaxoSmithKline, which funded the trial and manufactures dutasteride, has resubmitted an application with the FDA to market the drug for the prevention of prostate cancer in men at increased risk. Dutasteride is already approved to treat men with benign prostatic hyperplasia, or BPH.

The international trial involved more than 6,700 men between ages 50 and 75 who, at enrollment, had a prostate-specific antigen (PSA) test score between 2.5 and 10 and a negative biopsy in the prior 6 months. Participants, the large majority of who were white, also received biopsies 2 and 4 years after enrollment. After 4 years of follow up, there was a nearly 23 percent reduction in the relative risk of prostate cancer in men who took dutasteride compared with those who took a placebo (659 cancers versus 858 cancers).

Side effects, including erectile dysfunction and decreased libido, were similar to those typically seen with dutasteride use. The only exception was an increased risk of cardiac failure, although it was rare: 30 cases were reported in men taking dutasteride (0.7 percent of men taking the drug) compared with 16 (0.4 percent) of men in the placebo arm. Cardiac failure was more likely in men who were taking both dutasteride and drugs known as alpha blockers, which are commonly used to treat high blood pressure, as well as BPH.

The reduction in prostate cancer risk was found mostly for men diagnosed with Gleason score 6 (intermediate grade prostate cancer) on biopsy. As was the case with finasteride in the PCPT trial, more high-grade cancers (Gleason scores 8–10) were detected among men who received dutasteride than men who received a placebo. This was likely due in part, the authors explained, to the drug’s ability to reduce the volume of the prostate, which in turn improves the ability to identify high-grade tumors in biopsy samples. They did not exclude the possibility, though, that the drug could be responsible for some high-grade tumors.

In an accompanying editorial, Patrick Walsh, M.D., of Johns Hopkins University called it “somewhat disappointing” that dutasteride “was ineffective in reducing these high-grade tumors.” Based on the evidence from the REDUCE and PCPT trials, he also argued that neither of the drugs prevents prostate cancer, but “merely temporarily shrink tumors that have a low potential for being lethal,” because their effect seems to be relegated to tumors with Gleason scores in the 5 to 6 range.

“The ‘prevention’ versus ‘delay’ argument is a distinction without a difference,” noted Howard Parnes, M.D., of NCI’s Division of Cancer Prevention. “We now have two independent, randomized clinical trials showing that 5-αRIs decrease a man’s risk of being diagnosed with prostate cancer.” The benefit of reducing the incidence of Gleason score (GS) 6 prostate cancer should not be discounted, Dr. Parnes continued. “These are the most common prostate cancers and more than 90 percent of men with GS 6 prostate cancer are treated with radical surgery or radiation, both of which are associated with substantial morbidity.”

The higher incidence of cardiac failure associated with dutasteride is not of significant concern, said Brantley Thrasher, M.D., chair of the Department of Urology at the University of Kansas Medical Center. “We’ve been using this class of drugs for a long time and rarely see these types of problems,” he said.

In February 2009, the American Society of Clinical Oncology and the American Urological Association issued guidelines on 5-αRIs for prostate cancer prevention. The guidelines suggested that healthy older men who are already taking a 5-αRI for BPH or are being regularly screened for prostate cancer should discuss the possible long-term use of the treatment for prostate cancer prevention with their doctors.

Dr. Thrasher is already having those discussions with his patients, he said, and a number of them who are at an increased risk for prostate cancer because of factors such as family history or elevated PSA are taking finasteride or dutasteride. FDA approval of dutasteride for a prevention indication, he believes, would prompt many clinicians and patients to use it for that purpose. “I think the average clinician would have confidence to speak with their patients about using [5-αRIs] for prevention.”

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