A drug already prescribed to shrink benign, enlarged prostates has been shown to reduce the risk of a prostate cancer diagnosis by 23 percent in men with an increased risk of the disease, a large international trial has found. Results are reported April 1 in the New England Journal of Medicine.
The four-year study found that dutasteride (Avodart®) significantly reduced the chances that men would be diagnosed with the tumors that are most often treated excessively: those that fall in the mid-range of aggressiveness. These tumors, which account for the majority of all prostate cancers, grow unpredictably. This uncertainty leads many men to opt for surgery or radiation therapy - treatments that can lead to incontinence and impotence.
"Dutasteride may potentially offer many thousands of men a way to reduce their risk of being diagnosed with prostate cancer," says the study's lead author Gerald Andriole, MD, chief of urologic surgery at Washington University School of Medicine in St. Louis. "This means more men could avoid unnecessary treatment for prostate cancer along with the costs and harmful side effects that can occur with treatment."
Andriole chaired the steering committee that oversaw the trial, known as REDUCE (Reduction by Dutasteride of Prostate Cancer Events), which was conducted at 250 sites in 42 countries. It is the first to evaluate chemoprevention for prostate cancer in men at increased risk of disease. The study was funded by GlaxoSmithKline, the manufacturer of Avodart®.
The trial involved 8,231 men ages 50-75, who were randomly assigned to receive a placebo or a daily 0.5 mg dose of dutasteride, a drug that is known to shrink the prostate. Men in the study were considered to be at increased risk for prostate cancer because they had elevated PSA levels (2.5 ng/ml - 10 ng/ml) but no evidence of cancer on biopsies performed within six months of enrolling in the trial.
"Many men every year are in the situation of having elevated PSA levels but a negative biopsy," Andriole explains. "We know from experience that many of these men are likely to have microscopic prostate tumors that were missed by their original biopsy."
The investigators performed scheduled biopsies on the men two years after they enrolled in the study and again after four years. Over all, 659 men (19.9 percent) taking dutasteride were diagnosed with prostate cancer, compared to 858 men (25.1 percent) taking a placebo. None of the men in the study died of prostate cancer.
Among men with a family history of prostate cancer, the drug reduced the relative risk of a prostate cancer diagnosis by 31.4 percent.
"The most likely explanation for the study's results is that dutasteride is keeping tumors small or even shrinking them to the point that they are unlikely to be detected by a biopsy," says Andriole, who also treats patients at Barnes-Jewish Hospital and the Siteman Cancer Center.
Dutasteride was most effective at reducing the risk of medium-grade tumors, defined as 5-6 on the Gleason scale. The Gleason scoring system measures tumor aggressiveness based on biopsy results and can range from 1-10, with 10 being the most aggressive. Over the study's four years, 70 percent of all men diagnosed with prostate cancer had Gleason 5-6 tumors, roughly the same percentage doctors see in clinical practice. These included 617 men (18.1 percent) taking a placebo and 437 men (13.2 percent) taking dutasteride, a statistically significant difference.
Dutasteride was approved by the U.S. Food and Drug Administration in 2001 for the treatment of benign prostatic hyperplasia (BPH). The condition causes frequent urination that is difficult or painful because the swollen prostate gland blocks urine flow. Dutasteride is not approved for prostate cancer prevention.
The investigators found no significant increase in aggressive, high-grade tumors (defined as a Gleason score 7-10) among men who took dutasteride over four years. There were 220 men (6.7 percent) on dutasteride with aggressive, high-grade tumors, compared with 233 men (6.8 percent) on a placebo. However, they noted a disparity in the most aggressive tumors (defined as a Gleason score 8-10) among men taking dutasteride in years three and four of the study: 12 such tumors were detected in the dutasteride group versus one in the placebo group.
The study was designed so that men were withdrawn after they had a positive tumor biopsy. "But it's likely that if the men in the placebo group who were diagnosed with Gleason score 5-7 tumors in years one and two had remained in the study and been biopsied again, some of their tumors likely would have been upgraded to a Gleason 8-10 in study years three and four," Andriole says. "This so-called tumor upgrading has been observed in other studies."
Moreover, he says, it is well recognized that Gleason scores based on biopsies are more accurate in men on dutasteride or the similar BPH drug finasteride (Proscar®), who have smaller prostates, than in men with larger, growing prostates, where a needle biopsy is more likely to miss a tumor and to underestimate the true Gleason score.
The observation regarding high-grade tumors parallels that in the earlier Prostate Cancer Prevention Trial, which evaluated finasteride in men with no increased risk of the disease. While finasteride was found to lower overall prostate cancer risk, there were more aggressive tumors detected by biopsies in men taking that drug. Later analyses adjusting for prostate size at the time biopsies were performed showed no increase in high-grade tumors.
When researchers in the current study accounted for prostate size at the time of biopsy, their analysis (published in supplementary materials to the NEJM article) also indicated fewer aggressive cancers among men receiving dutasteride. Despite these considerations, the investigators could not completely rule out that some of the most aggressive tumors were due, in part, to dutasteride.
Like finasteride in the Prostate Cancer Prevention Trial, dutasteride also improved the accuracy of the PSA test to detect prostate cancer, particularly when tumors are aggressive, Andriole and his colleagues noted in unpublished results. Dutasteride is known to reduce PSA levels by 50 percent.
"If PSA levels started to rise even slightly in a man taking dutasteride, he had an increased chance of being diagnosed with prostate cancer, compared with men in the placebo group who tended to have PSA levels that naturally fluctuated," he said.
Dutasteride blocks two forms of the enzyme 5-alpha reductase, which converts the hormone testosterone into dihydrotestosterone. In contrast, finasteride inhibits only one form of the enzyme. Dihydrotestosterone is known to drive benign prostate growth and the development of prostate cancer.
Last year, both the American Society of Clinical Oncology and the American Urological Association issued guidelines suggesting that healthy older men who already are taking a 5-alpha reductase inhibitor for BPH or undergoing regular prostate cancer screening tests discuss with their doctors long-term use of the drug for prostate cancer prevention.
The REDUCE investigators also found that dutasteride reduced the risk of urinary retention, urinary tract infection and the need for surgery to alleviate BPH, compared with the placebo.
The two most common side effects associated with dutasteride were low rates of erectile dysfunction and decreased libido, which are consistent with earlier studies of the drug.
While rare, the investigators also noted more occurrences of cardiac failure among men taking dutasteride, compared with those taking a placebo. Thirty (0.7 percent) men on dutasteride and 16 (0.4 percent) men on a placebo received a diagnosis of cardiac failure. There was no significant difference between the two groups in the occurrence of or deaths from cardiovascular problems.
Supplemental data to the NEJM article indicated that cardiac failure was more likely to occur in men taking both alpha blockers and dutasteride. Alpha-blockers are used to treat a range of conditions, including high blood pressure and BPH.
Among U.S. men, prostate cancer is the second most deadly cancer after lung cancer. About 192,000 cases are diagnosed annually and some 27,300 die of the disease, according to the American Cancer Society.
New England Journal of Medicine