After the phase III studies, finasteride was further evaluated in a 4-yr, multicenter, double-blind, placebo-controlled, randomized study called PLESS or Proscar Long-Term Efficacy and Safety Study (29). The goals of this study were to compare long-term (4-yr) treatment with finasteride 5 mg vs placebo in the following parameters: urinary symptoms, urinary flow rates, incidence of surgery for BPH, and acute urinary retention. There were 3040 men enrolled, with a mean age of 64 yr. To be eligible for randomization, subjects had to exhibit moderate-to-severe urinary symptoms, enlarged prostate gland on digital rectal exam (DRE), serum prostate specific antigen (PSA) concentration < 10 ng/mL, and peak urinary flow rate < 15 mL/s. Furthermore, men with PSA concentrations greater than or equal to 4 mg/mL and < 10 mg/mL had to undergo screening prostate biopsies to rule out the presence of prostate cancer before undergoing randomization.
In this study, 1524 men were randomized to finasteride, and 1516 were randomized to placebo. A total of 1833 patients completed the study, 1000 in the finasteride group and 833 in the placebo group. Differences between the two groups were evident within 4 mo of the start of the study and continued to increase throughout the study. Specifically, 152 patients in the placebo group (10%) and 69 patients in the finasteride group (5%) underwent surgical procedures for BPH. This represented a risk reduction of 55% with finasteride (p < 0.001). Acute urinary retention developed in 99 men in the placebo group (6.5%) and 42 men in the finasteride group (2.8%), a risk reduction of 57% for the finasteride group (p < 0.001). When the issue of retention was examined more closely, patients taking finasteride were found to have a statistically significant decreased risk for both spontaneous and precipitated acute urinary retention. Despite the large risk reduction, it should be noted that the overall risk for retention in both the placebo and finasteride arms of the study was relatively low.
Men in both the finasteride and placebo groups experienced a reduction in symptom scores over the first 8 mo of the study. However, from that point on, only the finasteride group had a continued decline in symptom scores. The mean decrease in symptom scores for men in the finasteride group was 2.6 and 1.0 for men in the placebo group. For men completing PLESS, the finasteride group mean symptom score dropped by 3.3 points, and the mean symptom score for the placebo group dropped by 1.3 points.
Throughout PLESS, the prostate volume for the placebo group progressively increased. In contrast, the patients taking finasteride had a drop in prostate volume during the first year of the study, with no subsequent increase in prostate volume during the remaining years. Among men who completed the study, the mean change in prostate volume was a drop of 18% for patients taking finasteride and a gain of 14% for men on placebo. The mean difference between the two groups was 32% and was statistically significant (p < 0.001).
Men in both the finasteride and placebo groups attained an improvement in maximal urinary flow rate, with a mean increase in the finasteride group of 1.9 mL/s and 0.2 mL/s in the placebo group. This difference was also statistically significant (mean difference = 1.7 mL/s; p < 0.001) but limited. This disparity in improvement in flow rates between the two groups was evident within the first 4 mo and was maintained throughout the study.
No difference in the incidence of serious adverse events between the two groups was observed. In fact, the only adverse effects that were drug-related and for which the incidence was greater than or equal to 1% and greater than placebo were symptoms of sexual dysfunction (impotence, decreased libido, decreased ejaculate volume, ejaculation disorder), breast enlargement/tenderness, and rash. Interestingly, two cases of breast cancer were diagnosed in the placebo group; neither man had an antecedent history of gynecomastia. No cases of breast cancer were detected in the finasteride group during the study.
Serum PSA levels and DREs were closely followed throughout the course of the study. During this time, prostate biopsies were performed in 325 men in the finasteride group and in 320 men in the placebo group. The incidence of prostate cancer was 5% in each group; no difference was observed between those taking finasteride and those taking placebo.
The key result from the PLESS study was that finasteride therapy diminished the risk of both acute urinary retention and the need for prostatic surgery. These findings were observed within the first 4 mo of the study and persisted for the rest of the 4-yr investigational period. The investigators noted that to prevent one event of acute urinary retention or surgery, 15 men would need to be treated for 4 yr (29). Although a-adrenergic antagonists clearly improve urinary symptoms for BPH patients, this class of drugs has not yet been shown to diminish the incidence of acute urinary retention or need for surgical therapy (30,31). The PLESS investigators noted that the decrease in need for surgery is important from a public health and financial standpoint, especially given that TURP is the second most commonly performed operative procedure in men over 65 yr of age (29). However, whereas the drop in relative risk for surgery is notable (55%), the percentage of men confronted with the need for surgery was fairly low (only 10% in the placebo group). Furthermore, when reviewing the PLESS data, it is critical to consider this study's entry criteria. All enrolled subjects had moderate-to-severe symptoms and an enlarged prostate on DRE. The findings of diminished risk of acute urinary retention and decreased likelihood for surgical procedures may not be applicable to patients who do not also have these characteristics.
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