Prostate Cancer and Prostatic Diseases (2006) 9, 432–438 & 2006 Nature Publishing Group All rights reserved 1365-7852/06 $30.00 www.nature.com/pcan ORIGINAL ARTICLE Efficacy and tolerability of the dual 5a-reductase inhibitor, dutasteride, in the treatment of benign prostatic hyperplasia in African-American men CG Roehrborn1 and P Ray2 1Department of Urology, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA and 2Division of Urology, Cook County Hospital, Chicago, IL, USA The efficacy and tolerability of dutasteride (0.5 mg daily for 2 years) in African-Americans (n ¼ 161), compared with Caucasians (n ¼ 3961), was assessed in a post hoc analysis of data from three Phase III clinical trials. Dutasteride significantly reduced serum dihydrotestosterone levels by 490% and significantly improved subjective (symptom score) and objective (prostate volume, peak urinary flow rate, risk of benign prostatic hyperplasia-related surgery and acute urinary retention) outcomes in both African-Americans and Caucasians. For all efficacy measures, there was no statistically significant treatment-by-race interaction and dutasteride was well tolerated in both racial groups. Therefore, dutasteride demonstrated similar efficacy and safety profiles in African- Americans and Caucasians. Prostate Cancer and Prostatic Diseases (2006) 9, 432–438. doi:10.1038/sj.pcan.4500911; published online 19 September 2006 Keywords: benign prostatic hyperplasia; African-American men; dutasteride Introduction prostate-specific antigen (PSA) levels.18,19 Cultural fac- tors – such as the tendency to report symptoms – and Benign prostatic hyperplasia (BPH) is one of the most behavioural factors – for example, diet – may also 1 common diseases of ageing men, affecting more than contribute to racial differences in the incidence and 50% of men in their sixties and 90% of men over the age progression of BPH. 2 of 70 years. In clinical studies, African-American men In addition to the incidence and progression of BPH, have been shown to have a similar, or greater, risk of these genetic/biological, cultural and behavioural factors 3–7 BPH compared with Caucasian men. In an analysis of may result in racial differences in response to BPH community-based studies, the severity of lower urinary pharmacotherapy. No studies to date have compared the tract symptoms (LUTS) was significantly greater among response to BPH pharmacotherapy in different racial African-Americans compared with Caucasians, although groups, in part owing to the low numbers of minorities African-American men reported less bother for each unit in clinical trials.20,21 The lack of data on the efficacy and 8 increase in LUTS severity. In addition, a recent retro- tolerability of BPH pharmacotherapy in African-Ameri- spective cohort study showed that African-American can men may hinder efforts to optimize management of men have a significantly higher risk of BPH progression the disease in this patient population. 9 than Caucasian-American men. Dutasteride is unique among BPH pharmacotherapies, Racial differences in BPH incidence and progression inhibiting both of the 5a-reductase isoenzymes (type 1 may be due, in part, to genetic/biological factors. Indeed, and type 2) that convert testosterone to DHT, the primary there have been reports of racial differences in circulating androgen responsible for prostate growth.22 Inhibition of testosterone levels and the ratio of dihydrotestosterone both type 1 and type 2 5a-reductase isoenzymes with 10,11 (DHT) to testosterone; variations in the gene encod- dutasteride results in near-maximal (490%) suppression 12,13 ing 5a-reductase type 2; androgen receptor expres- of DHT, which is evident within 2 weeks and sustained 14 sion; levels of insulin growth factor binding protein-3 at 24 and 48 months.23,24 Results of Phase III clinical trials 11,15 and sex hormone binding globulins; prostate volume show that dutasteride improves BPH symptoms, reduces 16,17 and prostate transition zone volume; and serum the incidence of acute urinary retention, decreases the risk of BPH-related surgery and is well tolerated.23,24 The Correspondence: Dr CG Roehrborn, Department of Urology, current post hoc analysis of data from three identically The University of Texas Southwestern Medical Center at Dallas, designed, well-controlled clinical trials involving over 5323 Harry Hines Blvd., J8-130, Dallas, TX 75390-9110, USA. 24,25 E-mail: [email protected] 4000 BPH patients was performed to assess the Received 8 June 2006; accepted 20 July 2006; published online 19 efficacy and tolerability of dutasteride in a sub-popula- September 2006 tion of 161 African-Americans (82 and 79 in dutasteride Dutasteride in African-American men with BPH CG Roehrborn and P Ray and placebo groups, respectively), compared with treatment, race and a treatment-by-race interaction. For 433 Caucasians, over 2 years of treatment. all other efficacy measures and pharmacodynamic measures, treatment-by-race interactions were assessed with t-tests from general linear models that included effects for treatment, race, cluster and baseline as well as Methods a treatment-by-race interaction. Treatment comparisons A post hoc analysis of data from three Phase III, within each of the race subgroups were performed using randomized, double-blind, placebo-controlled trials, the statistical models listed above without the race and during which patients received either dutasteride treatment-by-race interaction terms. Statistics were per- (0.5 mg/day) or placebo, was performed. Men aged 50 formed on both last-observation-carried-forward (LOCF) years or above with moderate-to-severe symptoms of and observed values from each clinic visit. The two BPH (American Urological Association Symptom Index methods yielded similar results; therefore, only LOCF (AUA-SI) score X12),26 an enlarged prostate (X30 cc) results are reported. and a PSA X1.5 ng/ml were evaluated. The methodo- logy and primary outcomes of the studies have been reported previously.24 Results Patients Efficacy and safety analysis Of the 4325 patients randomized to treatment in the three Serum DHT and testosterone levels were measured at studies, 161 were African-American (3.7%), 3961 were baseline and at months 12 and 24, whereas mean PSA Caucasian (91.6%) and 203 were Asian, American levels were assessed at baseline and month 24. Hispanic or of other ethnic origin (4.7%). The term Both objective and subjective efficacy measures were African-American is used to describe the 161 black men, evaluated for the intention-to-treat (ITT) population. of whom only eight were recruited at study sites outside Objective measures included the incidence of acute the USA. Demographics and baseline clinical character- urinary retention (defined as inability to urinate and istics were similar in African-American and Caucasian requirement for bladder catheterization) and the inci- patients, and in the dutasteride and placebo treatment dence of BPH-related surgical intervention over the groups (Table 1). 2-year treatment period. Additional objective measures, assessed at month 24, were the mean percentage change DHT and testosterone concentrations from baseline in total prostate volume and in prostate There were no significant differences in mean baseline transition zone volume (measured by transrectal ultra- serum DHT levels between the dutasteride and placebo sound) and mean change in peak urinary flow rate groups, or between African-Americans (421.9 pg/ml in (Qmax) (measured with a Dantec Uroflow Meter). The the dutasteride group; 389.3 pg/ml in the placebo group) subjective efficacy measure was the mean change from and Caucasians (428.1 pg/ml and 416.7 pg/ml in the baseline in AUA-SI score at month 24. For the AUA- dutasteride and placebo groups, respectively). Mean SI, the total score ranges from 0 to 35 with higher baseline serum testosterone levels were slightly lower scores reflecting a greater impairment. Scores of X8 and among African-American patients compared with Cau- X20 correspond to moderate and severe symptoms, casians in both dutasteride (3718.3 versus 4036.8 pg/ml) respectively.26 and placebo groups (3757.0 versus 4001.0 pg/ml). The incidence of drug-related adverse events is Dutasteride significantly (Po0.001) reduced DHT presented for 6-month time periods throughout the levels from baseline compared with placebo in both treatment. racial groups. At month 24, the adjusted mean changes in DHT levels from baseline in dutasteride and placebo groups, respectively, were À91.8 and þ 9.3% among Statistics African-Americans and À92.6 and þ 0.2% among For acute urinary retention and BPH-related surgical Caucasians. Dutasteride also significantly (Po0.001) intervention, treatment-by-race interaction was assessed increased testosterone levels from baseline compared using a Cox proportional hazards model, with effects for with placebo in both African-Americans (adjusted mean Table 1 Demographics and baseline clinical characteristics of African-American and Caucasian patients in the dutasteride and placebo treatment groups African-Americans Caucasians Dutasteride (n ¼ 82) Placebo (n ¼ 79) Dutasteride (n ¼ 1975) Placebo (n ¼ 1986) Age (years) 64.8 (50–82) 63.7 (47–81) 66.6 (50–91) 66.3 (50–91) Prostate volume (cm3) 54.9 (30.7–161.8) 57.0 (30.6–180.3) 55.0 (19.2–274.2) 54.0 (16.6–177.1) Transition zone volume (cm3) 29.2 (6.2–118.7) 32.0 (7.9–162.5) 26.8 (1.4–146.9) 26.6 (0.8–126.4) Qmax (ml/s) 10.4 (4.9–22.9) 9.4 (3.0–16.5) 10.1 (2.2–33.0) 10.4 (2.5–31.8) Serum PSA (ng/ml) 4.5 (1.5–9.8) 4.3 (1.3–8.8) 4.0 (0.7–13.0) 4.0 (1.1–16.9) AUA-SI score 16.7 (2–33) 17.3 (2–31) 17.1 (1–35) 17.1 (2–35) Abbreviations: AUA-SI, American Urological Association Symptom Index; PSA, prostate-specific antigen; Qmax, peak urinary flow rate.