BERKELEY, CA (UroToday.com) - In the online edition of the New England Journal of Medicine, a group of authors from the Food and Drug Administration discuss the issues surrounding use of 5α-reductase inhibitors (5ARIs) for prostate-cancer prevention.
Two randomized trials showed a relative reduction in the diagnosis of prostate cancer (CaP) by 23-25% in men taking a 5ARI. The two trials were the Prostate Cancer Prevention Trial (PCPT) and the Reduction by Dutasteride of Prostate Cancer Events (REDUCE). The reduction was only in low-grade Gleason score ≤6 tumors with an increase in the incidence of high-grade tumors in the chemoprevention groups.
In December 2010, the FDA Oncologic Drugs Advisory Committee did not approve finasteride or dutasteride for chemoprevention of CaP. The FDA did agree that there was a 24% reduction in the diagnosis of CaP in the chemoprevention group. In the REDUCE trial they had the pathology specimens re-reviewed according to the modified Gleason scale by an independent pathologist. This made the pathologic review consistent with current recommendations for CaP grading and the grading system used in PCPT. This re-evaluation found no reduction in the incidence of tumors with modified Gleason scores 7-10, but an absolute increase of 0.5% in the incidence of tumors with modified Gleason scores 8-10 (RR=2.06) among men treated with dutasteride. This was similar to the 0.7% increase noted with finasteride. This translated into one man receiving the diagnosis of high-grade CaP for every 150-200 men treated long-term with a 5ARI. The FDA did not agree that there was a PSA detection bias in the treated men, as the increased risk of high-grade tumors in the treated men was independent of PSA results. CaP was diagnosed as a result of scheduled prostate biopsies, not increased PSA in 56% of PCPT cases and 90% of REDUCE cases. They also addressed the increased high-grade CaP detection as a result of reduced prostate volume in the treated men, but when recalculated using Gleason score 8-10 rather than 7-10, the explanation was not supported. The FDA felt that the increased incidence of high-grade CaP was real, and not explicable by the proposed hypothesis. They also felt that the reduction in CaP risk was limited to Gleason score 6 or less tumors, 80% of them meeting the criteria for very low-risk CaP and thus potentially not clinically significant. The trade-off, as the FDA calculated it, was using a 5ARI for CaP prevention means accepting one additional high-grade cancer to avert 3-4 clinically insignificant cancers. This did not meet the risk-benefit ratio profile for chemoprevention according to the committee. To approve a drug for chemoprevention, adverse side effects such as the increase in high-grade cancer must be kept in mind and as such, finasteride and dutasteride now carry this warning on their BPH and male-pattern baldness labels.
Theoret MR, Ning YM, Zhang JJ, Justice R, Keegan P, Pazdur R
N Engl J Med. 2011 Jul 14;365(2):97-9