Urologists React to FDA Panel Decision

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Urologists have different opinions about an FDA advisory panel's decision not to recommend drug label changes that would have endorsed the use of dutasteride and finasteride as a way to prevent prostate cancer (PCa).

The Oncologic Drugs Advisory Committee came to its decision despite evidence from the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) and Prostate Cancer Prevention Trial (PCPT) showing that men who took these 5-alpha-reductase inhibitors had a reduced risk of low-grade prostate tumors compared with men who received placebo.

Panel members were concerned about trial data showing that use of the drugs was associated with an increased incidence of high-risk tumors. According to the panel, the benefit of a decreased likelihood of low-risk cancers does not outweigh the potential downside of increasing the likelihood of high-grade tumors.

Based on subsequent analyses, however, researchers believe the reason for the increased incidence relates to the reduction in prostate size brought about by the two drugs, increasing the likelihood that needle biopsies would detect high-risk tumors if they are present.

“I was disappointed in the committee's decision,” said urologist Eric A. Klein, MD, who has a research interest in PCa chemoprevention. “They have missed the important point that a chemoprevention strategy that avoids the morbidity associated with being diagnosed with a disease or condition is as important as one that prevents mortality.”

Dr. Klein, who is Chairman of the Glickman Urological and Kidney Institute at Cleveland Clinic in Ohio, pointed out that no prognostic tests are available today that can reliably distinguish a potentially lethal Gleason 6 tumor from an indolent one. In the face of this uncertainty, he added, about 90% of men with newly diagnosed low-grade disease choose to undergo therapy that has the potential for significant morbidity.

“I have never met a urologist or patient who would rather have a radical prostatectomy than take a 5-alpha reductase inhibitor,” Dr. Klein said.

Furthermore, data from the REDUCE trial and PCPT, as well as the Combination of Avodart and Tamsulosin (CombAT) study, suggest that use of 5-alpha-reductase inhibitors make PSA a better screening test by improving its diagnostic accuracy, resulting in fewer unnecessary biopsies and boosting diagnostic yield by increasing the likelihood that a biopsy actually will find cancer, Dr. Klein said. He added that the sepsis rate from prostate biopsies is about 2% nationally and deaths resulting from prostate biopsies have been reported.

The preponderance of evidence from these trials also suggests these medications enhance the ability to detect high-grade, potentially lethal cancers at an early clinical stage rather than cause them, he said.

Moreover, Dr. Klein said he believes the use of a drug class that reduces the number of unneeded biopsies and the likelihood of having a negative biopsy and improves the chances of detecting high-grade cancers when they are still treatable “add significant value to PSA-based screening.”

“I think the committee was given a very difficult task,” said Gerald L. Andriole, MD, lead investigator for the REDUCE trial. “In effect, they [committee members] were charged to certify that these drugs, if approved for widespread use for prostate cancer risk reduction, would be unambiguously safe. There is no doubt that men who receive these drugs need careful follow-up and close monitoring of their PSA levels. I suppose the committee members were not convinced such close monitoring would occur.”

The REDUCE trial randomized 8,200 high-risk men ages 50 to 75 to receive either dutasteride or placebo, found that dutasteride was associated with a 23% reduced risk of prostate cancer after four years. The PCPT randomized approximately 19,000 healthy men older than 55 years to receive finasteride or placebo, showed that men who received finasteride had a nearly 25% decreased risk of prostate cancer after seven years.

GlaxoSmithKline, which markets dutasteride under the brand name Avodart, had filed a supplemental New Drug Application seeking the expanded indication. The committee voted against this by a vote of 14-2, with two members abstaining.

Merck did not seek a new indication for the use of finasteride, but instead requested a change in the section on “Adverse Reactions” in the product information indicating that the increased prevalence of high-grade disease in treated men was secondary to detection bias from improved sensitivity of PSA and/or prostate shrinkage that made it easier to find it on biopsy. The panel rejected this recommendation by a vote of 17-0, with one abstention.

The design of REDUCE trial and PCPT and the effects of the drugs resulted in significant biases that translated into more high-grade tumors being found on biopsy, Dr. Andriole said. These biases could account for most of the excess high-grade cancers identified in the studies, he said. “Excess high-grade tumors have not been seen in other trials evaluating these drugs for BPH,” said Dr. Andriole, Chief of Urologic Surgery at Siteman Cancer Center, Barnes-Jewish Hospital in St. Louis, and the Robert K. Royce Distinguished Professor at Washington University School of Medicine in St. Louis. “In fact, there are two BPH trials where dutasteride reduced prostate cancer [risk] by 40% to 50% and there was no increase in high-grade tumors. And, in REDUCE, if we create a model to account for the biases against dutasteride, it suggests there are actually fewer high-grade tumors. Similar models are available for PCPT as well.”

In Dr. Andriole's view, urologists who are familiar with the drugs, the trials that studied them, and how the drugs affect PSA levels could continue to use them for prostate cancer risk reduction after discussing the pros and cons with patients, as has been recommended by both the American Society of Clinical Oncology and the American Urological Association (J Clin Oncol. 2009;27:1502-1516).

“Many urologists were surprised and disappointed by this outcome [of the FDA committee meeting] because of the encouraging information they had heard regarding the efficacy and safety of these drugs,” stated Patrick C. Walsh, MD, an invited guest speaker at the committee meeting but was a nonvoting member of the panel. He pointed out, however, that a reanalysis of study data by the committee changed study results.

The panel reviewed the primary data from PCPT and determined that there was confusion about the classification of cases included in the “for-cause” biopsies performed in the first seven years, Dr. Walsh noted. Subjects underwent biopsies if they had an abnormal digital rectal examination or PSA measurement corrected for the effect of the drug. Subjects who had no indication had “end of the study” biopsies.

“Following careful study and reclassification, this changed the results dramatically,” said Dr. Walsh, the University Distinguished Service Professor of Urology at Johns Hopkins Medical Institutions in Baltimore. “In the original report, there was a 25% reduction in the number of cancers diagnosed for-cause during the first seven years and no increase in high-grade cancers in the end of study biopsies. In contrast, after this reanalysis, there was only a 14% reduction in the number of cancers diagnosed for-cause and a 2.3 increased relative risk of Gleason 8-10 disease in the end of study biopsies.” 

In addition, the committee reexamined and rejected the claim that the increase in Gleason 8-10 tumors was caused by improved detection by PSA and/or prostate shrinkage, Dr. Walsh said. The panel also reanalyzed the high-grade cancers that were diagnosed in patients who were treated with dutasteride for four years. In the original publication, at four years, 12 high-grade cancers were detected in the patients treated with dutasteride and one in the control group. Using the modified Gleason score, however, which assigns a higher grade based upon the tertiary pattern, the FDA found 14 patients with Gleason 8-10 disease in the dutasteride recipients compared with none in the control group. Based on these and other observations, the committee concluded that if 200 men were treated with one of these agents, there would be a reduction of three men diagnosed with Gleason 6 disease and an increase in one with Gleason 8-10 disease.

“I believe that these new findings, which gave a much clearer picture of the risk/ benefit ratio, represent the major factors that influenced the committee's decision,” Dr. Walsh observed. “It's important for physicians who are currently using these drugs for prostate cancer prevention to understand this and modify their clinical practice appropriately.  This also has potential implications for the use of these drugs in men with BPH and male pattern baldness.”

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