The effect of dutasteride on intraprostatic dihydrotestosterone concentrations in men with benign prostatic hyperplasia

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1 ORIGINAL ARTICLE (27) 1, & 27 Nature Publishing Group All rights reserved /7 $3. The effect of dutasteride on intraprostatic dihydrotestosterone concentrations in men with benign prostatic hyperplasia R Wurzel 1, P Ray 2, K Major-Walker 3, J Shannon 4 and R Rittmaster 3 1 Department of Urology, Grove Hill Medical Center, New Britain, CT, USA; 2 Division of Urology, Cook County Hospital, Chicago, IL, USA; 3 Urology Clinical Development and Medical Affairs, GlaxoSmithKline, Research Triangle Park, NC, USA and 4 Biomedical Data Sciences, GlaxoSmithKline, Research Triangle Park, NC, USA The dual 5a-reductase inhibitor, dutasteride has been shown to suppress serum dihydrotestosterone (DHT) by 49%. In the present study, the effect of dutasteride.5 mg/day on intraprostatic DHT levels was investigated. In this multicenter, double-blind trial, 43 men with benign prostatic hyperplasia (BPH) scheduled to undergo transurethral resection of the prostate (TURP) were randomized to receive dutasteride,.5 mg/day or placebo for 3 months before surgery. Intraprostatic DHT, testosterone and dutasteride levels were determined at the time of TURP. Changes in serum DHT and testosterone from baseline, and both serum and intraprostatic dutasteride levels at the time of TURP were also assessed. Dutasteride reduced intraprostatic DHT by 94% relative to placebo (Po.1); the adjusted mean intraprostatic DHT concentration was 3.23 and.29 ng/g in the placebo and dutasteride groups, respectively. In the dutasteride group, serum DHT was reduced from baseline by 93% at month 3, a significantly greater reduction (Po.1) than the 15% decrease observed in the placebo group. There was a reciprocal increase in intraprostatic testosterone but the level of intraprostatic testosterone in the dutasteride group tended to be lower than the intraprostatic DHT level in the placebo group (P ¼.6). Significant intraprostatic DHT suppression was achieved in all subjects who received dutasteride, regardless of the level of intraprostatic dutasteride. There was a strong positive correlation between serum and intraprostatic dutasteride concentrations (R 2 ¼.73). After 3 months of treatment, dutasteride.5 mg/day provided near-complete suppression of both intraprostatic and serum DHT in men with BPH. (27) 1, ; doi:1.138/sj.pcan.45931; published online 26 December 26 Keywords: benign prostatic hyperplasia; dihydrotestosterone; dutasteride Introduction Benign prostatic hyperplasia (BPH) is one of the most common diseases of ageing men, affecting more than 5% of men in their sixties and up to 9% of men in their seventies and eighties. 1 BPH characterized histologically by stromal and epithelial cell hyperplasia and clinically by bothersome lower urinary tract syndrome 2 has a significant, negative impact on the quality of life of patients and is also associated with serious long-term complications, such as acute urinary retention (AUR) and BPH-related surgery. 3 Dihydrotestosterone (DHT), the primary androgen responsible for prostate growth, is synthesized from testosterone by type 1 and type 2 5a-reductase (5AR), both of which are expressed and active in the prostate. 4 6 There is a wealth of evidence for a key role of DHT in the Correspondence: Dr R Wurzel, Department of Urology, Grove Hill Medical Center, 1 Lake Street, New Britain, CT 652, USA. Rwurzel@grovehill.com Received 18 October 26; accepted 24 October 26; published online 26 December 26 development and progression of BPH. 7 Most notably, large-scale clinical trials have demonstrated that the 5AR inhibitors (5ARIs), finasteride and dutasteride by suppressing DHT levels provide significant reductions in prostate volume, improvements in flow rate and symptoms and a decrease in the risk of AUR and diseaserelated surgery in men with BPH. 8,9 In addition to BPH, there is a growing body of evidence, both from histopathological and clinical studies, for a role of DHT in the development of prostate cancer The dual 5ARI, dutasteride (.5 mg/day) provides greater suppression of serum DHT compared with the type 2-selective 5ARI, finasteride (5 mg/day) (49 vs 7%). 13 The near-complete suppression of serum DHT with dutasteride is evident within 1 2 weeks of therapy and is sustained for up to 4 years. 8,14 As the prostate is the main site of action for DHT in the development and progression of BPH, it is of clinical importance to determine the effect of 5ARIs on intraprostatic DHT levels. Treatment with finasteride, 1 or 5 mg/day, for 7 days has been reported to suppress intraprostatic DHT by approximately 85% compared with placebo. 15 A study

2 15 investigating the effects of treatment with the approved dose of finasteride (5 mg/day) demonstrated a 68% suppression of intraprostatic DHT at 6 months. 16 In a previous dutasteride study in men with prostate cancer, treatment with a high dose, 5 mg/day, for 6 1 weeks was associated with a 97% decrease in intraprostatic DHT levels. 1 The present study investigates the effect of the approved dose of dutasteride,.5 mg/day, on intraprostatic DHT levels in men with BPH treated for 3 months before transurethral resection of the prostate (TURP). Materials and methods Patients Men aged X5 years, who had been diagnosed with BPH (evident from their medical history and a physical examination, including a digital rectal examination) and who were scheduled to undergo TURP for BPH and able to wait 3 months for the procedure were included in this study. Patients who went on to have open prostatectomy rather than TURP were still included in the analysis. Exclusion criteria included history or current evidence of prostate cancer and prostate-specific antigen (PSA) level o1.5 or X15 ng/ml (men with PSA X4 ng/ml were only included if they had a negative ultrasound and/or biopsy within 12 months). Patients were also excluded if they had undergone previous prostatic surgery or had received treatment with finasteride or any investigational 5ARIs within 6 months of enrolment. All patients provided written, informed consent. Study design This was a double-blind, randomized and placebocontrolled trial conducted at six centers in the USA. Two weeks after their screening visit, eligible men were randomized to receive dutasteride,.5 mg/day the dose of dutasteride currently approved for the treatment of BPH or placebo for 3 months before TURP. Study medication was provided by GlaxoSmithKline (GSK) and allocated via the registration and medication ordering system. Patients visited the clinic at screening (visit 1), 2 weeks later at randomization (visit 2) and then at month 1 (visit 3), month 2 (visit 4) and finally the morning of TURP (month 3, visit 5). A follow-up phone call was also made 4 months after TURP to assess any adverse effects. Dutasteride.5 mg oral gel-caps or matching placebo was self-administered once daily over the 3 months of treatment, with the exception of the final dose on the day of TURP, which was administered at the study center. The primary end point was the level of intraprostatic DHT measured in prostatic tissue samples taken at the time of TURP or open prostatectomy (month 3). Secondary end points included: intraprostatic testosterone levels; change in serum DHT at 3 months and correlation with intraprostatic DHT at TURP; change in serum testosterone levels and correlation with intraprostatic testosterone levels at TURP; and serum and intraprostatic dutasteride concentrations at TURP in men who had received dutasteride for 3 months. The study protocol was approved by a national, regional or investigational center ethics committee, or an institutional review board at each center. The study was conducted in accordance with Good Clinical Practice and all relevant regulatory requirements including, where applicable, the 1996 Declaration of Helsinki Principles. DHT and testosterone measurements Blood samples for DHT and testosterone analysis were collected at screening and on the day of TURP (month 3), within 6 h of surgery. Serum samples were analyzed by Taylor Technology (Princeton, NJ, USA) using a validated analytical method based on solid phase extraction followed by chemical derivatization and gas chromatography/mass spectroscopy analysis. The lower limit of quantification (LLQ) was 25 pg/ml for testosterone and 5 pg/ml for DHT; the upper limits of quantification (HLQ) were 12 8 and 256 pg/ml for testosterone and DHT, respectively. Owing to a discontinuation of this assay at Taylor Technology, 23 samples were analyzed by Pharmaceutical Product Development (PPD, Richmond, VA, USA) using another validated analytical model based on solvent extraction followed by chemical derivatization and liquid chromatography/mass spectroscopy (LC/MS) analysis. With this method, the LLQ was 5 pg/ml for testosterone and 1 pg/ml for DHT, and the HLQ was 1 and 5 pg/ml for testosterone and DHT, respectively. In a comparison of the serum testosterone data from Taylor and PPD, 83% of the results varied by less than 3%. Serum DHT and testosterone concentrations are expressed in (ng/dl). Multiplicative factors for conversion of serum DHT and testosterone concentrations from (ng/dl) to (nmol/l) are.344 and.347, respectively. Prostate tissue chips collected at the time of TURP were immediately placed on ice and then frozen in liquid nitrogen at approximately 71C, as previously reported. 17,18 Homogenate samples were analyzed for DHT and testosterone by PPD using a qualified analytical method based on solvent extraction followed by chemical derivatization and LC/MS analysis. The LLQ for both testosterone and DHT was 25 pg/g using 2 mg of tissue homogenate. The HLQ was 75 pg/g of tissue homogenate for testosterone and 75 pg/g of tissue homogenate for DHT. Intraprostatic DHT and testosterone concentrations are expressed in (pg/g). Multiplicative factors for conversion of intraprostatic DHT and testosterone concentrations from (ng/g) to (nmol/kg) are 3.44 and 3.47, respectively. For each assay, quality control samples were prepared at three different analyte concentrations and were analyzed with each batch of samples against separately prepared calibration standards. Dutasteride measurements Blood samples for measurement of serum dutasteride concentrations were drawn at month 1, 2 and 3 before the daily dose of dutasteride. Serum dutasteride levels were measured by Quest Pharmaceutical Services (QPS, Newark, DE, USA) using a validated analytical method based on solvent extraction followed by LC/MS analysis.

3 The LLQ and HLQ for dutasteride were.1 and 2 ng/ ml, respectively. Prostate tissue homogenate samples collected at the time of TURP (month 3) were analyzed for dutasteride by QPS, again using a validated analytical method based on solvent extraction followed by LC/MS analysis. In this analysis, the LLQ was.5 ng/ml of tissue homogenate and the HLQ 2 ng/ml of tissue homogenate. Safety The occurrence of adverse events was assessed at each clinic visit and during the follow-up telephone call 4 months after TURP. Clinical laboratory tests, including clinical chemistry, hematology and urinalysis, were performed at the screening visit and 6 h before TURP. Statistical analysis The sample size was calculated from the results of the ARI47 study (GSK, data on file). In ARI47, the mean intraprostatic DHT concentration was.33 ng/g in patients who received dutasteride.5 mg/day for 4 weeks before TURP,.56 ng/g in patients who received placebo for 2 weeks then dutasteride.5 mg/day for 2 weeks before TURP and 3.4 ng/g in patients who received placebo throughout the study. Based on these results, it was calculated that 15 evaluable subjects were required per treatment group to provide 99% power to declare superiority of dutasteride.5 mg/day compared with placebo in the reduction of intraprostatic DHT. This sample size was also estimated to provide sufficient power for comparisons of intraprostatic testosterone levels between treatment groups. To ensure 15 evaluable subjects, approximately 2 subjects were randomized to each treatment group. Statistical comparisons were performed on the intention-to-treat population. Treatment group comparisons of intraprostatic DHT and testosterone were performed in terms of logarithmically transformed data and were based on a t-test from the general linear model with effects for treatment group. Treatment group comparisons of the percent change from baseline in serum DHT and testosterone were in terms of logarithmically transformed data using a t-test from the general linear model with effects for treatment and baseline value included as a covariate. Differences between treatment groups were considered to be statistically significant if the two-sided P-value was p.5. The correlations between intraprostatic and serum DHT and between intraprostatic and serum testosterone were evaluated within each treatment group using Spearman s rank correlation statistics. Intraprostatic and serum trough dutasteride concentrations were summarized by treatment group. Intraprostatic DHT in the placebo group was compared with intraprostatic testosterone in the dutasteride group using the Wilcoxon Rank Sum test. All statistical analyses were performed using the SAS system, Version 8 for UNIX. Results Subject disposition and demographics A total of 43 men with BPH awaiting TURP were randomized to receive dutasteride,.5 mg/day (n ¼ 22) or placebo (n ¼ 21) for 3 months. TURP was performed on 95% (n ¼ 21) of subjects in the dutasteride group and 86% (n ¼ 18) of subjects receiving placebo. None of the subjects underwent an open prostatectomy. A total of 2 and 18 subjects in the dutasteride and placebo groups, respectively, completed the study. Demographic and baseline characteristics were similar in the two treatment groups (Table 1). Intraprostatic and serum DHT After 3 months of treatment, the adjusted mean intraprostatic DHT level was.29 ng/g in the dutasteride group and 3.23 ng/g in the placebo group; dutasteride reduced intraprostatic DHT by approximately 94% compared with placebo (Po.1) (Table 2, Figure 1a). Before treatment, serum DHT levels were slightly higher in the dutasteride group compared with the placebo group (median of 42.1 vs 31.7 ng/dl). On the day of TURP, men who had received dutasteride,.5 mg/day for 3 months demonstrated a 93% reduction in serum DHT levels from baseline, compared with a 15% decrease in the placebo group (Po.1) (Figure 2a). There was no significant correlation between intraprostatic and serum DHT within treatment groups. Table 1 Demographics Dutasteride (n ¼ 22) (n ¼ 21) Age (years) 68.5 (6.62) 65.3 (9.42) Race (%) White Black 9 29 Asian 1 American Hispanic 36 1 Height (cm) 176. (9.96) 177. (8.1) Weight (kg) 84.7 (9.79) 87.6 (14.76) Duration of BPH (years) 7.2 (6.95) 5.2 (3.9) PSA (ng/ml) 6.4 (5.97) 4.4 (3.1) Abbreviations: BPH, benign prostatic hyperplasia; PSA, prostate-specific antigen. Data are presented as mean (s.d.). 151 Table 2 Adjusted mean intraprostatic levels of DHT and testosterone at month 3 in the dutasteride and placebo groups Adjusted mean intraprostatic concentration (ng/g) Ratio of adjusted means (95% CI) P-value Dutasteride DHT (.5,.9) o.1 Testosterone (17.81, 42.81) o.1 Abbreviations: CI, confidence interval; DHT, dihydrotestosterone.

4 152 a 6.6 Intraprostatic testosterone (ng/g) Intraprostatic DHT (ng/g) b Dutasteride.5 mg Dutasteride.5 mg Figure 1 Intraprostatic DHT (a) and testosterone (b) levels at month 3 in the dutasteride and placebo groups. a b Adjusted mean % change in serum DHT from baseline at Month 3 Adjusted mean % change in serum testosterone from baseline at Month % Adjusted mean difference = 77.5% (95% Cl 1.6, 54.4; P<.1) +9.9% 92.7% Adjusted mean difference = 2.1% (95% Cl 25.1, 2.9, P=.85) +7.8% Dutasteride Figure 2 Adjusted mean percentage change in serum DHT (a) and testosterone (b) levels from baseline at month 3 in the dutasteride and placebo groups. The adjusted mean differences in the change in serum levels in the dutasteride group vs the placebo group are presented. Intraprostatic and serum testosterone Intraprostatic testosterone levels at the time of TURP (month 3) were significantly (Po.1) higher in the dutasteride group compared with the placebo group Intraprostatic DHT (ng/g) Intraprostatic dutasteride (ng/g) Figure 3 The relationship between intraprostatic dutasteride concentration and intraprostatic DHT suppression among patients treated with dutasteride. Intraprostatic DHT suppression was achieved with all intraprostatic dutasteride concentrations; there was no significant correlation between the two parameters. The median intraprostatic dutasteride concentration was 26.4 ng/g. (2.54 vs.91 ng/g) (Table 2, Figure 1b). However, the level of intraprostatic testosterone in the dutasteride group tended to be lower than the level of intraprostatic DHT in the placebo group (2.54 vs 3.23 ng/g, P ¼.6). At baseline, serum testosterone levels were higher in the dutasteride group compared with the placebo group (median of 46 vs 367 ng/dl). There was no significant difference in the change in serum testosterone levels at month 3 from baseline between the two treatment groups (Figure 2b). No significant correlations existed between intraprostatic and serum testosterone levels within treatment groups. Intraprostatic and serum dutasteride The median intraprostatic dutasteride concentration at the time of TURP (month 3) was 26.4 ng/g. Intraprostatic dutasteride concentrations ranged from 7.4 to 53. ng/g. However, significant intraprostatic DHT suppression was achieved in all men in the dutasteride group (Figure 3). Serum trough dutasteride concentration increased during the study, from a median of 16.6 ng/ml at month 1 to 28.1 ng/ml at month 3. Steady-state serum concentrations (defined as X8% of the mean serum dutasteride concentration achieved at 1 year, 3.1 ng/ml) were reached in 52.4% of patients in the dutasteride group. There was a strong, statistically significant correlation (R 2 ¼.73, Po.1) between serum and intraprostatic dutasteride concentrations at the time of TURP (month 3) (Figure 4). Safety There was no significant difference between the two treatment groups in the overall frequency of adverse events, frequency of drug-related adverse events, frequency of serious adverse events or frequency of adverse events leading to study discontinuation. The most frequently reported adverse events were urinary tract infection, prostate cancer, headache and micturition

5 Intraprostatic dutasteride (ng/g) Serum dutasteride (ng/ml) disorder, none of which were considered to be related to study medication. In the dutasteride group, two patients presented with an adverse event that led to discontinuation of study medication: one patient experienced a worsening of irritative voiding symptoms and the second patient, moderate angioneurotic edema. Both of these adverse events resolved and were not considered by the investigator to be serious. Discussion Regression Line of unity R 2 =.73 Figure 4 Relationship between serum and intraprostatic dutasteride levels. The graph illustrates the strong correlation between serum and intraprostatic dutasteride levels. The proven clinical benefits of 5ARIs in the treatment of BPH, which include a reduction in prostate volume, improvement in flow rate and symptoms and a decrease in the risk of long-term complications, 8,9 are achieved through inhibition of the conversion of testosterone to DHT the primary androgen responsible for prostate growth. The present study shows that treatment with the approved dose of the dual 5ARI dutasteride (.5 mg/ day) for 3 months reduced DHT levels in the prostate, the principal site of action, by approximately 94% compared with placebo in men with BPH. In addition, dutasteride reduced serum DHT levels from baseline by 93%. Dutasteride was well tolerated. The near-complete suppression of intraprostatic DHT after 3 months of treatment with dutasteride.5 mg/day in men with BPH is consistent with the 97% intraprostatic DHT suppression reported previously in men with prostate cancer who received a 1-fold higher dose of dutasteride (5 mg/day) for 6 weeks. 1 Treatment with finasteride, 1 or 5 mg/day, for 7 days has been shown to reduce intraprostatic DHT by approximately 85% compared with placebo. 15 Intraprostatic DHT suppression was greater with the 1 mg dose than the 1 or 5 mg dose. A later study showed that treatment with finasteride 5 mg/day for 6 months resulted in 68% intraprostatic DHT suppression compared with placebo. 16 Thus, the 94% intraprostatic DHT suppression with dutasteride demonstrated in the present study is greater than the intraprostatic DHT suppression with finasteride reported in the literature. Greater intraprostatic DHT suppression with dutasteride, a dual 5ARI, compared with finasteride, a type 2-selective 5ARI, in men with BPH is consistent with the presence of both isoenzymes in BPH tissue. 4,19 The 49% suppression of serum DHT with dutasteride observed in this study is in agreement with the results of large-scale, long-term clinical trials with dutasteride, 8,2 and is greater than the 7% serum DHT suppression observed with finasteride. 13 As expected, the near-complete suppression of intraprostatic DHT with dutasteride was accompanied by a reciprocal rise in intraprostatic testosterone levels. However, the rise in intraprostatic testosterone tended to be smaller than the rise in DHT in the placebo group. Thus, in addition to DHT being replaced by the weaker androgen, testosterone, 7 the total androgen level in the prostate was lower with dutasteride compared with placebo. There was a strong, statistically significant correlation between serum and intraprostatic dutasteride levels, demonstrating that dutasteride readily distributes to the prostate. Despite the variability in intraprostatic dutasteride levels in this study, near-complete DHT suppression was achieved in all subjects who received the.5 mg dose. Dual inhibition of the two 5AR isoenzymes and the resulting near-complete suppression of DHT may also have relevance for prostate cancer. In localized prostate cancer, type 1 5AR expression is increased and type 2 5AR expression decreased compared with normal and BPH tissue, and expression of both 5AR isoenzymes is increased in advanced prostate cancer. 19 Dutasteride has been shown to increase atrophy and apoptosis in prostate cancer with 6 11 weeks treatment before radical prostatectomy. 1,11 The Prostate Cancer Prevention Trial demonstrated a significant 24.8% reduction in the prevalence of prostate cancer with finasteride compared with placebo. 12 The effects of dutasteride on the risk of prostate cancer in men at high risk of developing the disease are being investigated in the ongoing REduction with DUtasteride in prostate Cancer Events (REDUCE) trial. 21 This study is the first to report on the effects of dutasteride.5 mg/day on intraprostatic DHT in men with BPH. Limitations of this study include the relatively small patient numbers and short duration of the study. The majority of patients achieved steady-state serum dutasteride concentrations during the period of the study and, with the effective penetration of dutasteride into the prostate proven in this study, it seems likely that steady-state or near steady-state concentrations were also achieved in the prostate. Near-complete serum DHT suppression with dutasteride has been reported as early as weeks 1 and 2 into treatment and is sustained for up to 4 years. 8,2 This study provides strong evidence that the well-established, near-complete suppression of serum DHT with dutasteride is accompanied by near-complete intraprostatic DHT suppression. Conclusions Treatment with dutasteride.5 mg/day for 3 months in men with BPH awaiting TURP, was associated with nearcomplete suppression of both intraprostatic and serum DHT. Dutasteride readily distributed to the prostate and significant intraprostatic DHT suppression was achieved with all measured intraprostatic dutasteride levels. The 153

6 154 clinical benefits of DHT suppression in BPH are well established; the potential clinical benefits of the nearcomplete DHT suppression with dutasteride on the risk of prostate cancer are currently being investigated in the REDUCE trial. References 1 National Kidney and Urologic Diseases Information Clearinghouse (NKUDIC). Prostate Enlargement: Benign Prostatic Hyperplasia. NKUDIC is a service of the National Insititute of Diabetes and Digestive Kidney Diseases (NIDDK), which is part of the National Institutes of Health (NIH). NIH publications no : pubs/prostateenlargement/, American Urological Association. AUA Guideline on Management of Benign Prostatic Hyperplasia (23). Chapter 1: diagnosis and treatment recommendations. J Urol 23; 17: Emberton M, Andriole G, de la Rosette JJ, Djavan B, Hoefner K, Vela Navarette R et al. BPH: a progressive disease of aging men. Urology 23; 61: Iehle C, Radvanyi F, Gil Diez de Medina S, Ouafik LH, Gerard H, Chopin D et al. Differences in steroid 5alpha-reductase isoenzymes expression between normal, pathological human prostate tissue. J Steroid Biochem Mol Biol 1999; 68: Berthaut I, Mestayer C, Portois MC, Cussenot O, Mowszowicz I. Pharmacological, molecular evidence for the expression of the two steroid 5 alpha-reductase isozymes in normal, hyperplastic human prostatic cells in culture. Prostate 1997; 32: Bruchovsky N, Rennie PS, Batzold FH, Goldenberg SL, Fletcher T, McLoughlin MG. Kinetic parameters of 5 alpha-reductase activity in stroma, epithelium of normal, hyperplastic, carcinomatous human prostates. J Clin Endocrinol Metab 1988; 67: Andriole G, Bruchovsky N, Chung LW, Matsumoto AM, Rittmaster R, Roehrborn C et al. Dihydrotestosterone, the prostate: the scientific rationale for 5alpha-reductase inhibitors in the treatment of benign prostatic hyperplasia. JUrol24; 172: Roehrborn CG, Boyle P, Nickel JC, Hoefner K, Andriole G. Efficacy, safety of a dual inhibitor of 5-alpha-reductase types 1, 2 (dutasteride) in men with benign prostatic hyperplasia. Urology 22; 6: McConnell JD, Bruskewitz R, Walsh PC, Andriole G, Lieber MM, Holtgrewe HL et al. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. N Engl J Med 1998; 338: Andriole GL, Humphrey P, Ray P, Gleave ME, Trachtenberg J, Thomas LN et al. Effect of the dual 5alpha-reductase inhibitor dutasteride on markers of tumour regression in prostate cancer. JUrol24; 172: Iczkowski KA, Qiu J, Qian J, Somerville MC, Rittmaster RS, Andriole GL et al. The dual 5-alpha-reductase inhibitor dutasteride induces atrophic changes and decreases relative cancer volume in human prostate. Urology 25; 65: Thompson IM, Goodman PJ, Tangen CM, Lucia MS, Miller GJ, Ford LG et al. The influence of finasteride on the development of prostate cancer. N Engl J Med 23; 349: Nickel JC. Comparison of clinical trials with finasteride and dutasteride. Rev Urol 24; 6: S31 S Roehrborn CG, Marks LS, Fenter T, Freedman S, Tuttle J, Gittleman M et al. Efficacy and safety of dutasteride in the four-year treatment of men with benign prostatic hyperplasia. Urology 24; 63: McConnell JD, Wilson JD, George FW, Geller J, Pappas F, Stoner E. Finasteride, an inhibitor of 5 alpha-reductase, suppresses prostatic dihydrotestosterone in men with benign prostatic hyperplasia. J Clin Endocrinol Metab 1992; 74: Span PN, Voller MC, Smals AG, Sweep FG, Schalken JA, Feneley MR et al. Selectivity of finasteride as an in vivo inhibitor of 5alpha-reductase isozyme enzymatic activity in the human prostate. JUrol1999; 161: Thomas LN, Wright AS, Lazier CB, Cohen P, Rittmaster RS. Prostatic involution in men taking finasteride is associated with elevated levels of insulin-like growth factor-binding proteins (IGFBPs)-2, -4, and -5. Prostate 2; 42: Norman RW, Coakes KE, Wright AS, Rittmaster RS. Androgen metabolism in men receiving finasteride before prostatectomy. JUrol1993; 15: Thomas LN, Lazier CB, Gupta R, Norman RW, Troyer DA, O Brien SP et al. Differential alterations in 5alpha-reductase type 1 and type 2 levels during development and progression of prostate cancer. Prostate 25; 63: Roehrborn CG, Marks LS, Fenter T, Freedman S, Tuttle J, Gittleman M et al. Efficacy and safety of dutasteride in the four-year treatment of men with benign prostatic hyperplasia. Urology 24; 63: Andriole G, Bostwick D, Brawley O, Gomella LG, Marberger M, Tindall D et al. Chemoprevention of prostate cancer in high risk men: rationale and design of the REDUCE trial. J Urol 24; 172: