By Charles Bankhead
San Francisco—Long-term treatment with the 5-alpha reductase inhibitor finasteride (Propecia) afforded protection against prostate cancer across the entire population of patients enrolled in the Prostate Cancer Prevention Trial (PCPT), according to an updated presentation at the American Urological Association meeting.
Overall, treatment with finasteride reduced prostate cancer incidence by about 25% compared with placebo. The benefits of finasteride spanned older and younger patients and major ethnic groups, those with/without a family history of prostate cancer, and across the range of values for prostate-specific antigen (PSA).
“All men seemed to benefit from treatment with finasteride,” said Ian Thompson, MD, professor of surgery and Chair of Urology, University of Texas Health Science Center, San Antonio.
The PCPT tested the premise that altering the hormonal milieu of the prostate would reduce cancer risk, a premise based on a substantial amount of preclinical and epidemiologic evidence, said Dr Thompson. Between 1994 and 1997, approximately 19,000 men were randomized to finasteride 5 mg/d or placebo and followed for 7 years. The primary end point was total prostate cancer incidence at the end of the study.
The trial ended prematurely after an interim analysis revealed a statistically significant reduction in prostate cancer incidence and in the number of biopsies triggered by abnormal digital rectal exam or increased PSA level. Finasteride-treated patients had a prostate cancer incidence of 18.4% compared with 24.4% for the placebo group, a 24.8% reduction in relative risk (RR) (N EnglJ Med. 2003;349:215-224).
The goal of PCPT was to reduce prostate cancer risk in all patients, but that would require treating all men, when only about 1 in 7 men development prostate cancer. Most men get no benefit from treatment and face a risk of sexual and endocrine side effects.
“Only those men destined to develop prostate cancer actually benefit from treatment,” said Dr Thompson. “That raises the question of whether there is a better way to do chemoprevention. Could we look at just high-risk men?”
Investigators stratified the data by high-risk characteristics, including age, ethnicity, family history, and baseline PSA value. Their analysis revealed consistency of effect across all the subgroups analyzed. With respect to age, for example, the RR reduction with finasteride was 28% in men aged 55 to 59 years, 27% in men 60 to 64 years of age, and 20% in men aged ³65.
Black patients had a higher incidence of prostate cancer compared with whites and Hispanics; however, the magnitude of risk reduction with finasteride was similar across ethnic groups (ie, 20%-25%).
Similar consistency of treatment effect emerged when the data were stratified by family history and PSA values.
“Unfortunately, if we just target high-risk men, we will miss some of the potential benefit for the general population,” said Dr Thompson. Using a combination of characteristics, including genetic markers, to target therapy might improve efficiency of chemoprevention, he added.
The most controversial aspect of the PCPT related to the finding of an increased number of high-grade cancers (Gleason sum 8-10) in finasteride-treated men (90 vs 53 in the placebo group). The finding led to some speculation that finasteride might be potentiating high-grade cancer. To address the issue, Dr Thompson compared the PCPT and the Breast Cancer Prevention Trial (BCPT), which showed an increased incidence of endometrial cancer in women treated with tamoxifen (Nolvadex) (J Natl Cancer Inst. 1998;90:1371-1388).
In the BCPT tamoxifen conferred an increased risk of endometrial cancer that continued throughout the treatment period. The disparity in high-grade prostate cancer in the PCPT emerged in the first year and did not increase thereafter. If finasteride were inducing high-grade cancers, the number of cases would have been expected to increase throughout follow-up, which did not occur. More likely, treatment with finasteride unmasked cancers that were already present when men enrolled in the PCPT, said Dr Thompson.
Despite the lack of guidance about how to target chemoprevention to patients at highest risk, the limitations of the current PSA/digital rectal exam—based approach to prostate cancer screening make a compelling case for prevention, Dr Thompson concluded. Some men with normal PSA values have cancers that are detected too late. In other instances, screening detects some clinically insignificant cancers that do not require treatment. In addition, current methods for assessing prognosis may not be correct.
“All this makes prevention attractive,” said Dr Thompson. “If you are never diagnosed, there is no concern regarding prognosis.”