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ODAC rejects dutasteride, finasteride for prostate cancer prevention
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The FDA’s Oncologic Drugs Advisory Committee has rejected an application to approve GlaxoSmithKline’s dutasteride and Merck’s finasteride for prostate cancer chemoprevention.
The Oncologic Drugs Advisory Committee (ODAC) rejected dutasteride (Avodart) by a 17-0 vote, with one abstention. The committee voted 14-2, with two abstentions, against finasteride (Proscar).
Both drugs are currently approved to treat benign prostatic hypertrophy. GlaxoSmithKline sought to expand dutasteride’s indication to include reducing the risk for prostate cancer in men who have had a prior negative biopsy and who have an elevated PSA. Merck wanted a change to finasteride’s label to show results from the Prostate Cancer Prevention Trial (PCPT), which demonstrated the drug’s chemopreventive potential.
The FDA usually follows the recommendations of its advisory committees. However, the agency disregarded an unfavorable ODAC decision and approved erlotinib (Tarceva, OSI Pharmaceuticals) as a maintenance therapy for patients with advanced non–small cell lung cancer earlier this year.
In the PCPT, 4,775 men were randomly assigned to 5 mg daily finasteride and 5,123 were randomly assigned to placebo. Participants were aged 55 years or older with normal digital rectal examinations and PSA levels of 3 ng/mL or less.
Cumulative incidence of prostate cancer was 18.4% in the finasteride arm vs. 24.9% in the placebo arm (RR=0.74; 95% CI, 0.69-0.80). After adjusting for age, race and family history, the OR for a diagnosis of prostate cancer was 0.68 (95% CI, 0.62-0.75) in the finasteride arm.
However, a secondary analysis showed that patients assigned to finasteride were at increased risk for high-grade tumors, 6.3% vs. 5% (RR=1.26; 95% CI, 1.07-1.48). Patients with a Gleason score of 8 to 10 had the greatest increase — that group accounted for roughly 75% of the increased incidence of high-grade tumors.
Committee members said the increased risk for poorly differentiated, more aggressive tumors outweighed the potential for chemoprevention associated with finasteride.
GlaxoSmithKline submitted results from the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial to support the new application.
The international, multicenter, randomized study included men who had PSA levels between 2.5 ng/mL and 10 ng/mL (aged 50 to 59 years) or between 3 ng/mL and 10 ng/mL (aged 60 to 75 years) at initial screening. All men had one negative prostate biopsy within 6 months before study entry. Participants were randomly assigned to 0.5 mg daily dutasteride (n=4,126) or placebo (n=4,105), and the study required 10 core biopsies performed at 2 and 4 years.
ODAC members did not disagree with Merck’s contention that treatment with dutasteride was associated with a statistically significant 23% reduction in risk, but they said the reduction was driven by tumors with a Gleason score of 6 or less. The committee said the low-grade tumors pose little threat to men with life expectancy of fewer than 10 to 20 years.
“This study met an un-need,” committee member Patrick Loehrer, MD, director of the Melvin and Bren Simon Cancer Center at Indiana University, said. “It decreased the risk of low-grade cancers.”
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