FDA Advisors Nix Proscar, Avodart Prevention Claims

Janis C. Kelly

December 02, 2010

December 2, 2010 — The Oncologic Drugs Advisory Committee (ODAC) of the US Food and Drug Administration (FDA) recommended against prostate cancer chemoprevention labeling for the 5α-reductase inhibitors finasteride (Proscar) and dutasteride (Avodart), because both agents increase the likelihood of high-grade tumors when given as preventive agents to healthy men.

Panelists and FDA reviewers shared 3 main concerns about the drugs: the risk of exposing currently healthy people to an increased risk for high-grade tumors, the fact that risk reduction was only in low-grade tumors, and the doubt that the supporting clinical studies are generalizable to clinical practice in the American population.

The unusually contentious ODAC meeting — which at one point required the calming intervention of FDA Office of Oncology Drug Products director Richard Pazdur, MD — pitted the ODAC panel, most of whom are oncologists, against researchers and experts from Merck & Company (makers of finasteride) and GlaxoSmithKline (GSK, makers of dutasteride).

The Merck team, led by Ian Thompson, MD, who headed the Prostate Cancer Prevention Trial (PCPT), tried but failed to convince the ODAC that the increase in high-grade prostate cancers in otherwise healthy men treated with finasteride was a statistical artifact. Dr. Thompson is chair of the Department of Urology at the University of Texas Health Sciences Center in San Antonio. The final vote was 18 to 0 against the proposal that the finasteride risk/benefit profile is favorable for reducing prostate cancer risk in men older than 55 years with a normal digital rectal examination and a prostate-specific antigen (PSA) level of 3.0 ng/mL or less.

A feisty GSK team, which included Gerald L. Andriole, Jr., MD, director of the Men's Health Center at Washington University in St. Louis, Missouri, and Christopher J. Logothetis, MD, chair of the Department of Genitourinary Medical Oncology at the University of Texas M.D. Anderson Cancer Center in Houston, did not convince the ODAC that, even in high-risk men, the benefits of dutasteride for the many outweighed the risk for high-grade tumors in the few. The panel also voted 14 to 2 (with 2 abstentions) against the proposal that the dutasteride risk/benefit profile is favorable for reducing prostate cancer risk in men with a previous negative biopsy (due to clinical concern) and an elevated PSA level.

Interestingly, Merck was not asking for a new indication for finasteride, but wanted to have the results of the PCPT tucked into the Clinical Studies section of the product labeling. The FDA reviewers appeared to view this as an attempted end-run around New Drug Application requirements, and the FDA briefing document presented at the meeting stated bluntly that "the proposed changes could be interpreted to suggest that Proscar is safe and effective for the prevention of prostate cancer in healthy men." GSK, which was asking for a new chemoprevention indication for dutasteride, based that request mainly on the phase 3 Reduction by Dutasteride of Prostate Cancer Events (REDUCE) study.

The finasteride and dutasteride studies showed a 23% reduction in the relative risk for prostate cancer in the active-treatment group, compared with placebo, but for both drugs, the reduction was only in low-grade tumors (Gleason score ≤6), and both were associated with an unexpected increase in high-grade tumors (Gleason score, 8 to 10).

In addition to these 2 concerns, ODAC director Dr. Pazdur asked whether the beneficial effects of what would be long-term therapy were generalizable to the American population, because of concerns about the clinical trial design, about the patient populations, and about the relatively brief (4- and 7-year) trials.

One design issue was that study data were based on mandated and scheduled biopsies rather than the "for-cause" biopsies characteristic of clinical practice. The concern was that the scheduled biopsies might have picked up indolent tumors that would not have caused morbidity or mortality for most men, and that conclusions based on those biopsies might not be applicable in "real world" terms. According to the FDA briefing document, autopsy data show latent prostate cancer in 30% to 70% of men 50 to 80 years of age.

Another problem was that neither study included many African American men, despite the high incidence of prostate cancer in this population and a possibly greater susceptibility to high-grade disease.

A major clinical concern was that the 5α-reductase inhibitors, by suppressing tumors with a Gleason score of 6 (the detection of which often triggers more intensive intervention), might be delaying detection of more deadly tumors (Gleason score, 8 to 10), or even contributing to the development of such tumors. ODAC chair Wyndham Wilson, MD, PhD, chief of lymphoma therapeutics at the National Cancer Institute's Center for Cancer Research in Rockville, Maryland, compared this to "hiding our heads in the sand" until prostate cancers become too advanced to treat successfully.

GSK researchers argued that the increased detection of high-grade tumors was the result of treatment-related prostate shrinkage, which might have improved detection sensitivity. Invited speaker Patrick Walsh, MD, professor of urology at the Johns Hopkins University School of Medicine in Baltimore, Maryland, reviewed data on prostate shrinkage, and concluded that "shrinkage does not make it easier to detect high-grade disease. More high-grade disease is found because there is more to find."

The PCPT was a 7-year, placebo-controlled trial that randomized nearly 19,000 men 55 years and older with a normal digital rectal examination and a PSA level of 3.0 ng/mL or less to either finasteride or placebo. At end of the study, prostate cancer was detected by needle biopsy in 18.4% of men in the finasteride group and in 24.4% in the placebo group, for a relative risk of 0.74. The reduced risk was driven by decreases in low-risk tumors (Gleason score ≤6).

REDUCE randomized more than 8000 men at high risk of being diagnosed with prostate cancer to daily dutasteride or placebo for 4 years. The results showed that men in the dutasteride group had a 23% lower risk of being diagnosed with biopsy-detectable prostate cancer than men in the placebo group (P < .0001), but this risk reduction was due to the decrease in low-risk tumors (Gleason score, 5 to 6).

Dr. Thompson, Dr. Wilson, and Dr. Walsh have disclosed no relevant financial relationships. Dr. Andriole and Dr. Logothetis report receiving research support and travel funding from GSK.

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