Clinical studies with finasteride in men with benign prostatic hyperplasia

Early studies with finasteride in men with benign prostatic hyperplasia (BPH) were designed to confirm the biochemical efficacy of the drug. Prior studies had identified the predominance of DHT, compared to testosterone, within the prostate due to intraprostatic type 2 5aR activity (Bruchovsky and Wilson 1968). In several studies evaluating the ability of finasteride to reduce DHT formation within the prostate, suppression of intraprostatic DHT levels up to 95%, exceeding the maximal suppression of serum DHT (~70%), were demonstrated in a dose-dependent manner (Geller 1990; McConnell etal. 1992; Norman etal. 1993).

18.4.1 Efficacy based on prostate volume and symptoms

Several controlled studies have established the utility of finasteride 5 mg in the treatment of men with benign prostatic hyperplasia. Early clinical efficacy studies with finasteride in men with BPH demonstrated that the biochemical efficacy of the drug, defined by reductions in serum and intraprostatic DHT levels, were associated with significant reductions (~20%) in prostate volume (Stoner et al. 1994). Dose-ranging studies established the optimal dose for treatment of men with BPH to be between 1 and 5 mg per day, based on prostate volume reduction and improvements in BPH symptoms. Subsequent replicate, definitive, multicenter studies demonstrated the superiority of the higher dose and established 5 mg/day as the optimal dose for the treatment of men with this disease. Efficacy was established based on patient self-reported improvement in the symptoms associated with BPH using a validated symptom score questionnaire, and improvement in maximum urinary flow (increase of ~1.5 mL/sec), with these benefits associated with reductions in prostate volume and circulating DHT (Gormley et al. 1992; Finasteride Study Group 1993). Finasteride 5 mg (Proscar™) was first approved for marketing in 1992 and is currently marketed in over 100 countries for the treatment of men with symptomatic BPH.

18.4.2 Long-term effects on disease progression

Two long-term, multicenter studies demonstrated the sustained effects of finasteride 5 mg on BPH symptoms and, more significantly, on the impact of therapy on disease progression.

The Proscar Long-Term Efficacy and Safety Study (PLESS; Roehrborn et al. 1999a), a placebo-controlled multicenter study in which 3040 men with symptomatic BPH were randomized (1:1) to finasteride 5 mg or placebo for four years, demonstrated that treatment with finasteride led to sustained improvements in BPH symptoms and reduced the risks of acute urinary retention and need for BPH-related surgery by approximately 50% within four months of treatment and throughout the fouryears of controlled clinical observation (McConnell etal. 1998). While prostate volume and serum prostate-specific antigen (PSA) level were strong predictors of risk of these sequelae of BPH (Roehrborn etal. 1999a), risk reduction due to finasteride treatment was observed irrespective of baseline prostate volume or serum PSA level (Roehrborn et al. 1999b) (Fig. 18.4). This study was the first of its kind, establishing the concept that medical intervention could favorably alter the natural course of BPH and confirming the hypothesis that chronic inhibition of DHT formation through type 2 5aR inhibition would reduce the undesirable sequelae of the disease.

The MTOPS (Medical Therapy of Prostatic Symptoms) study (McConnell etal. 2003), a multicenter factorial study sponsored by the U.S. National Institutes of Health-National Institute of Diabetes and Digestive and Kidney Diseases (NIH-NIDDK), randomized 3047 patients with symptomatic BPH equally to receive one of four treatments: finasteride 5 mg/day; doxazosin (Cardura™), an a-adrenergic receptor antagonist used in the treatment of men with BPH, 4 to 8 mg/day; both treatments; or placebo. Patients were followed for four to six years. Results of this study confirmed the findings observed in PLESS: treatment with finasteride 5 mg administered alone, or concomitantly with doxazosin, produced significant reductions in the incidences of acute urinary retention and need for BPH-related surgery compared to placebo. While these reductions were not observed in patients treated with doxazosin alone, treatment with either doxazosin or finasteride 5 mg reduced clinical deterioration in BPH symptoms, defined as a > 4-point rise from baseline AUA Symptom Score (baseline symptom score at study entry = 8 to 30). Based on a composite endpoint of clinical progression of BPH, all active treatments were superior to placebo, while concomitant treatment with finasteride 5 mg and doxazosin was found to be superior to either agent alone. The results of the MTOPS study

ra CL

24 20 16 12

143%

0 to 1.3 1.4 to 3.2 3.3 to 12 (Low-Tertile) (Mid-Tertile) (High-Tertile)

Baseline PSA (ng/mL)

6.8%

5.6%

■f

m

r

m +

(Low-Tertile) (Mid-Tertile) (High-Tertile)

Baseline Prostate Volume (cc)

(Low-Tertile) (Mid-Tertile) (High-Tertile)

Baseline Prostate Volume (cc)

Fig. 18.4 Effects of finasteride 5mg and placebo on men with BPH: four-year incidences of acute urinary retention or BPH-related surgery over four years in patients grouped by tertiles of: (A) baseline serum prostate-specific antigen (PSA) level, or (B) baseline prostate volume (tone placebo patient had a prostate volume of 222) (adapted from Roehrborn etal. 1999b).

confirm the results obtained previously in PLESS and provide new information on the long-term effects of these two agents used in the treatment of men with BPH.

18.4.3 Safety

Based on multiple controlled clinical trials in men with BPH, treatment with finasteride has been shown to be generally well tolerated. Side-effects of treatment are generally transient and usually do not result in discontinuation of drug use. The most frequently reported side-effects include impairment of sexual function (decreased libido, erectile dysfunction, and decreased ejaculate volume). There is no evidence of increased side-effects with increased duration of treatment. Some patients have reported development of breast tenderness or enlargement: in controlled clinical trials, the incidence of breast enlargement reported with finasteride

5 mg was approximately 1% greater than that reported with placebo. Breast neoplasms have also been reported in men receiving finasteride. In the MTOPS study, which randomized 3047 patients to one of four treatment arms (1:1:1:1) over four to six years of observation, breast cancer was reported in four men randomized to the two treatment arms that included finasteride (finasteride alone or finasteride plus doxazosin), with no cases reported in men randomized to the two treatment arms that did not include finasteride (doxazosin alone or placebo). However, in PLESS, which randomized 3040 patients to finasteride 5 mg or placebo (1:1) over four years of observation, two cases of breast cancer were reported in men receiving placebo, with no cases reported in men receiving finasteride, and in the largest and longest study, the Prostate Cancer Prevention Trial (PCPT; see Feigl etal. 1995 and Section 18.9.1), which randomized 18,882 men to finasteride 5 mg or placebo (1:1) over seven years of observation, an equal number of cases of breast cancer was reported in men in each treatment group (one in the group receiving finasteride 5 mg and one in the group receiving placebo).

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