Efficacy and tolerability of the dual 5a-reductase inhibitor, dutasteride, in the treatment of benign prostatic hyperplasia in African-American men

(2006) 9, 432 438 & 2006 Nature Publishing Group All rights reserved 1365-7852/06 $30.00 ORIGINAL ARTICLE www.nature.com/pcan Efficacy and tolerability of the dual 5a-reductase inhibitor, dutasteride, in the treatment of benign prostatic hyperplasia in African-American men CG Roehrborn 1 and P Ray 2 1 Department of Urology, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA and 2 Division 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. (2006) 9, 432 438. doi:10.1038/sj.pcan.4500911; published online 19 September 2006 Keywords: benign prostatic hyperplasia; African-American men; dutasteride Introduction Benign prostatic hyperplasia (BPH) is one of the most common diseases of ageing men, 1 affecting more than 50% of men in their sixties and 90% of men over the age of 70 years. 2 In clinical studies, African-American men have been shown to have a similar, or greater, risk of BPH compared with Caucasian men. 3 7 In an analysis of community-based studies, the severity of lower urinary tract symptoms (LUTS) was significantly greater among African-Americans compared with Caucasians, although African-American men reported less bother for each unit increase in LUTS severity. 8 In addition, a recent retrospective cohort study showed that African-American men have a significantly higher risk of BPH progression than Caucasian-American men. 9 Racial differences in BPH incidence and progression may be due, in part, to genetic/biological factors. Indeed, there have been reports of racial differences in circulating testosterone levels and the ratio of dihydrotestosterone (DHT) to testosterone; 10,11 variations in the gene encoding 5a-reductase type 2; 12,13 androgen receptor expression; 14 levels of insulin growth factor binding protein-3 and sex hormone binding globulins; 11,15 prostate volume and prostate transition zone volume; 16,17 and serum Correspondence: Dr CG Roehrborn, Department of Urology, The University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd., J8-130, Dallas, TX 75390-9110, USA. E-mail: Claus.Roehrborn@UTSouthwestern.edu Received 8 June 2006; accepted 20 July 2006; published online 19 September 2006 prostate-specific antigen (PSA) levels. 18,19 Cultural factors such as the tendency to report symptoms and behavioural factors for example, diet may also contribute to racial differences in the incidence and progression of BPH. In addition to the incidence and progression of BPH, these genetic/biological, cultural and behavioural factors may result in racial differences in response to BPH pharmacotherapy. No studies to date have compared the response to BPH pharmacotherapy in different racial groups, in part owing to the low numbers of minorities in clinical trials. 20,21 The lack of data on the efficacy and tolerability of BPH pharmacotherapy in African-American men may hinder efforts to optimize management of the disease in this patient population. Dutasteride is unique among BPH pharmacotherapies, inhibiting both of the 5a-reductase isoenzymes (type 1 and type 2) that convert testosterone to DHT, the primary androgen responsible for prostate growth. 22 Inhibition of both type 1 and type 2 5a-reductase isoenzymes with dutasteride results in near-maximal (490%) suppression of DHT, which is evident within 2 weeks and sustained at 24 and 48 months. 23,24 Results of Phase III clinical trials show that dutasteride improves BPH symptoms, reduces the incidence of acute urinary retention, decreases the risk of BPH-related surgery and is well tolerated. 23,24 The current post hoc analysis of data from three identically designed, well-controlled clinical trials involving over 4000 BPH patients 24,25 was performed to assess the efficacy and tolerability of dutasteride in a sub-population of 161 African-Americans (82 and 79 in dutasteride

and placebo groups, respectively), compared with Caucasians, over 2 years of treatment. Methods A post hoc analysis of data from three Phase III, randomized, double-blind, placebo-controlled trials, during which patients received either dutasteride (0.5 mg/day) or placebo, was performed. Men aged 50 years or above with moderate-to-severe symptoms of BPH (American Urological Association Symptom Index (AUA-SI) score X12), 26 an enlarged prostate (X30 cc) and a PSA X1.5 ng/ml were evaluated. The methodology and primary outcomes of the studies have been reported previously. 24 Efficacy and safety analysis Serum DHT and testosterone levels were measured at baseline and at months 12 and 24, whereas mean PSA levels were assessed at baseline and month 24. Both objective and subjective efficacy measures were evaluated for the intention-to-treat (ITT) population. Objective measures included the incidence of acute urinary retention (defined as inability to urinate and requirement for bladder catheterization) and the incidence of BPH-related surgical intervention over the 2-year treatment period. Additional objective measures, assessed at month 24, were the mean percentage change from baseline in total prostate volume and in prostate transition zone volume (measured by transrectal ultrasound) and mean change in peak urinary flow rate (Q max ) (measured with a Dantec Uroflow Meter). The subjective efficacy measure was the mean change from baseline in AUA-SI score at month 24. For the AUA- SI, the total score ranges from 0 to 35 with higher scores reflecting a greater impairment. Scores of X8 and X20 correspond to moderate and severe symptoms, respectively. 26 The incidence of drug-related adverse events is presented for 6-month time periods throughout the treatment. Statistics For acute urinary retention and BPH-related surgical intervention, treatment-by-race interaction was assessed using a Cox proportional hazards model, with effects for treatment, race and a treatment-by-race interaction. For 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 a treatment-by-race interaction. Treatment comparisons within each of the race subgroups were performed using the statistical models listed above without the race and treatment-by-race interaction terms. Statistics were performed on both last-observation-carried-forward (LOCF) and observed values from each clinic visit. The two methods yielded similar results; therefore, only LOCF results are reported. Results Patients Of the 4325 patients randomized to treatment in the three studies, 161 were African-American (3.7%), 3961 were Caucasian (91.6%) and 203 were Asian, American Hispanic or of other ethnic origin (4.7%). The term African-American is used to describe the 161 black men, of whom only eight were recruited at study sites outside the USA. Demographics and baseline clinical characteristics were similar in African-American and Caucasian patients, and in the dutasteride and placebo treatment groups (Table 1). DHT and testosterone concentrations There were no significant differences in mean baseline serum DHT levels between the dutasteride and placebo groups, or between African-Americans (421.9 pg/ml in the dutasteride group; 389.3 pg/ml in the placebo group) and Caucasians (428.1 pg/ml and 416.7 pg/ml in the dutasteride and placebo groups, respectively). Mean baseline serum testosterone levels were slightly lower among African-American patients compared with Caucasians in both dutasteride (3718.3 versus 4036.8 pg/ml) and placebo groups (3757.0 versus 4001.0 pg/ml). Dutasteride significantly (Po0.001) reduced DHT levels from baseline compared with placebo in both racial groups. At month 24, the adjusted mean changes in DHT levels from baseline in dutasteride and placebo groups, respectively, were 91.8 and þ 9.3% among African-Americans and 92.6 and þ 0.2% among Caucasians. Dutasteride also significantly (Po0.001) increased testosterone levels from baseline compared with placebo in both African-Americans (adjusted mean 433 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 (cm 3 ) 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 (cm 3 ) 29.2 (6.2 118.7) 32.0 (7.9 162.5) 26.8 (1.4 146.9) 26.6 (0.8 126.4) Q max (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; Q max, peak urinary flow rate. Data are presented as mean values (range).

434 change þ 21.6 versus 0.9%) and Caucasians (adjusted mean change þ 18.6 versus 0.9%) at month 24. Mean and median concentrations of testosterone remained within the normal physiological range for both African- American and Caucasian patients treated with either dutasteride or placebo. Serum PSA levels Baseline PSA values were slightly higher in African- Americans compared with Caucasians (Table 1). Among African-Americans, the mean baseline PSA value was 4.5 ng/ml (median 3.9 ng/ml) in the dutasteride group and 4.3 ng/ml (median 4.1 ng/ml) in the placebo group, compared with 4.0 ng/ml (median 3.4 ng/ml) and 4.0 ng/ml (median 3.5 ng/ml) in the Caucasian dutasteride and placebo groups, respectively. In dutasteridetreated African-American and Caucasian patients, median PSA values decreased during the first month of treatment, and median reductions from baseline of 40 to 56% were maintained between months 3 and 24. In African-American and Caucasian patients receiving placebo, the percentage change in PSA levels from baseline ranged from 0 to a 12.5% increase between months 3 and 24. Total prostate volume and prostate transition zone volume Mean baseline total prostate volume was similar in the two treatment groups and in the two races studied (Table 1). Dutasteride reduced prostate volume from baseline by 23.0% in African-Americans and by 26.6% in Caucasians, as assessed at month 24 (Table 2 and Figure 1a). In the placebo group, there were only 1 2% reductions in total prostate volume from baseline at month 24 in both racial groups. The effect of dutasteride compared with placebo was significant (Po0.001) for both African-Americans and Caucasians, and the magnitude of the reduction in total prostate volume with dutasteride versus placebo was similar in the two races throughout the treatment period. A similar pattern of results was observed for mean prostate transition zone volume (Table 2 and Figure 1b). There was no statistically significant treatment-by-race interaction for total prostate volume or prostate transition zone volume. Flow rate Q max values at baseline were similar in the two treatment groups and in the two racial groups (Table 1). In both African-American and Caucasian patients, dutasteride significantly (Po0.05) increased Q max compared with placebo at month 18 (Figure 2). The magnitude of the increase in Q max with dutasteride versus placebo was similar in African-American and Caucasian patients throughout the treatment period. No statistically Figure 1 Adjusted mean percentage change from baseline in prostate volume (PV) (a) and prostate transition zone volume (TZV) (b) over the duration of the study in African-Americans and Caucasians treated with dutasteride or placebo. AA, African American; C, Caucasian. Table 2 groups Measures of BPH severity at month 24 among African-American and Caucasian patients in dutasteride and placebo treatment African-Americans Caucasians Treatmentby-race Dutasteride (n ¼ 82) Placebo (n ¼ 79) Dutasteride (n ¼ 1975) Placebo (n ¼ 1986) interaction Total prostate volume, % change from baseline a 23.0 1.2 26.6 2.1 ns Prostate transition zone volume, % change from baseline a 24.5 2.5 24.2 3.1 ns Mean change from baseline in Q max (ml/s) a 2.1 1.1 1.8 0.7 ns Mean change from baseline in AUA-SI a 4.4 2.0 3.7 1.7 ns Incidence of acute urinary retention (%) 2.4 6.3 1.9 4.1 ns Incidence of BPH-related surgery (%) 2.4 5.1 2.2 4.2 ns Abbreviations: AUA-SI, American Urological Association Symptom Index; BPH, benign prostatic hyperplasia; ns, not significant; Q max, peak urinary flow rate. a Adjusted mean values.

significant treatment-by-race interaction was observed (Table 2). Acute urinary retention and BPH-related surgery Dutasteride, relative to placebo, reduced the risk of acute urinary retention by 58% (95% confidence interval (CI), 119 to 92) among African-Americans and by 55% (95% CI, 33 69) among Caucasians, and reduced the risk of BPH-related surgery by 53% (95% CI, 159 to 91) and 48% (95% CI, 25 64) in African-Americans and Caucasians, respectively (Table 2). There was no statistically significant treatment-by-race interaction for acute urinary retention or BPH-related surgery. AUA-SI score Baseline AUA-SI scores were similar across treatment groups and across racial groups, and reflected moderateto-severe symptoms (Table 1). At month 24, the improvements in symptom scores with dutasteride were significantly greater in both African-Americans (Po0.05) and Caucasians (Po0.001), compared with placebo (Figure 3). The adjusted mean changes in AUA-SI score from baseline at month 24 for dutasteride and placebo groups, respectively, were 4.4 and 2.0 in African-Americans and 3.7 and 1.7 in Caucasians. There was no statistically significant treatment-by-race interaction (Table 2). 435 Figure 2 Adjusted mean change from baseline in Q max in African- Americans and Caucasians treated with dutasteride or placebo. AA, African American; C, Caucasian; Q max, peak urinary flow rate. Figure 3 Adjusted mean change from baseline in AUA-SI score over the duration of the study in African-Americans and Caucasians treated with dutasteride or placebo. AUA-SI, American Urological Association Symptom Index; AA, African American; C, Caucasian. Table 3 Percentage of African-American and Caucasian patients in dutasteride and placebo treatment groups with adverse events in 6-month time periods throughout the study African-Americans (%) Caucasians (%) Placebo Dutasteride Placebo Dutasteride Impotence 0 6 months 1.3 (1/79) 2.4 (2/82) 1.7 (34/1986) 4.6 (91/1975) 6 12 months 0 (0/67) 0 (0/70) 1.5 (27/1777) 1.6 (27/1736) 12 18 months 0 (0/56) 1.6 (1/64) 0.5 (8/1587) 1.1 (17/1573) 18 24 months 0 (0/52) 0 (0/59) 0.9 (13/1438) 0.8 (11/1466) Decreased libido 0 6 months 1.3 (1/79) 1.2 (1/82) 1.4 (27/1986) 3.0 (59/1975) 6 12 months 0 (0/67) 1.4 (1/70) 0.6 (10/1777) 0.7 (13/1736) 12 18 months 0 (0/56) 0 (0/64) 0.3 (4/1587) 0.3 (5/1573) 18 24 months 0 (0/52) 0 (0/59) 0.1 (2/1438) 0.3 (4/1466) Ejaculation disorders 0 6 months 1.3 (1/79) 1.2 (1/82) 0.4 (7/1986) 1.5 (29/1975) 6 12 months 0 (0/67) 0 (0/70) 0.3 (5/1777) 0.6 (10/1736) 12 18 months 0 (0/56) 0 (0/64) 0.1 (2/1587) 0.4 (7/1573) 18 24 months 0 (0/52) 0 (0/59) 0 (0/1438) 0.1 (1/1466) Gynaecomastia 0 6 months 0 (0/79) 0 (0/82) 0.3 (5/1986) 0.6 (11/1975) 6 12 months 0 (0/67) 0 (0/70) 0.3 (5/1777) 0.9 (16/1736) 12 18 months 0 (0/56) 1.6 (1/64) 0.3 (5/1587) 1.1 (17/1573) 18 24 months 0 (0/52) 0 (0.59) 0.1 (2/1438) 0.7 (10/1466) The most common adverse events considered to be at least possibly related to study medication are listed.

436 Adverse events The incidence of drug-related adverse events in the dutasteride group was comparable to that in the placebo group, among both African-Americans and Caucasians (Table 3). The most common drug-related adverse events were impotence, decreased libido, ejaculation disorders and gynaecomastia. The incidence of these adverse events, with the exception of gynaecomastia, declined over time. Gynaecomastia was reported at a uniformly low incidence (o2% of patients in any group) throughout the treatment period. Discussion The risk of the development and progression of BPH is similar, or possibly higher, in African-Americans compared with Caucasians, 3,4,6,7,9 yet the majority of clinical trials investigating the efficacy and safety of BPH pharmacotherapies have enrolled predominantly Caucasian men, 27 29 and the degree to which results of these studies can be generalized to African-Americans is unknown. Possible reasons for the low level of participation of minorities in clinical trials include lack of awareness of study programmes, communication barriers, religious beliefs, economic disadvantages and study inclusion and exclusion criteria. 20,30,31 The low numbers of African-Americans in BPH studies may, in part, explain the poor recognition and treatment of BPH in this patient population. In the Flint (Michigan) Men s Health Study, 40% of African-Americans reported moderate to severe LUTS, but only 8% reported an enlarged prostate and only 3% reported receiving BPH therapy. 32 The current post hoc analysis compared the efficacy and tolerability of the new dual 5a-reductase inhibitor, dutasteride, in African-American and Caucasian men enrolled in three randomized, double-blind, placebocontrolled clinical trials. The magnitude of improvement with dutasteride, relative to placebo, was comparable in African-American and Caucasian patients across all efficacy measures. Furthermore, there were no statistically significant treatment-by-race interactions for any of the efficacy measures. Dutasteride was equally well tolerated in African-American and Caucasian patients. Baseline characteristics were generally similar in African-American and Caucasian patients. A slightly larger prostate transition zone volume among African- Americans compared with Caucasians was an exception. However, this result, considered in combination with the observation that total prostate volume was similar in African-Americans and Caucasians in these studies, is consistent with previous reports of a higher transition zone index that is, the ratio of transition zone volume to total prostate volume in African-Americans compared with Caucasians. 17 The clinical efficacy of dutasteride is attributed to its effects on DHT. In the three studies analysed, circulating levels of DHT were reduced by more than 90% after 12 and 24 months of treatment in both African-Americans and Caucasians. Dutasteride inhibits both the type 1 and type 2 5a-reductase isoenzymes, responsible for conversion of testosterone into DHT. In humans, type 1 5areductase is found predominantly in the liver and the skin, whereas type 2 5a-reductase is found predominantly in urogenital tissue, particularly the prostate. Although type 1 was initially thought not to be present in the prostate, recent studies have established that both isoenzymes are present in prostate cells, suggesting that both may play a role in BPH. 33,34 Dutasteride is the only available BPH pharmacotherapy that significantly inhibits both the type 1 and type 2 5a-reductase isoenzymes. Both the 5a-reductase inhibitors, finasteride and dutasteride, have been shown to decrease serum PSA levels, an important screening parameter for prostate cancer, by approximately 50% for up to 4 years. 35,36 In agreement with these findings, dutasteride reduced PSA levels by approximately 45% after 1 and 2 years of treatment in the current study. The magnitude and time course of the decrease in PSA levels with dutasteride were similar in African-Americans and Caucasians. Near-maximal reductions were observed by the sixth month of treatment. Thus, these results provide further support for establishing a new PSA baseline after 6 months of treatment, and for the use of the doubling rule to maintain specificity and sensitivity of PSA levels for prostate cancer detection. 35,36 Furthermore, these results suggest that these approaches are appropriate for both African-Americans and Caucasians. In both African-Americans and Caucasians, dutasteride improved objective efficacy measures, such as prostate volume, transition zone volume, Q max and the risk of AUR and BPH-related surgery, and the subjective efficacy measure, AUA-SI score, compared with placebo. No statistically significant treatment-by-race interactions were observed for any of the efficacy measures. Differences between dutasteride and placebo were less consistently statistically significant among African- Americans compared with Caucasians, but this was most likely owing to the relatively small number of patients and correspondingly low statistical power in the African-American group (n ¼ 161 versus n ¼ 3961 in the Caucasian group). In addition to significant improvements in all efficacy measures, dutasteride demonstrated a favourable safety profile in African-American men with BPH. The most common drug-related adverse events, which were reported with a similar incidence in the two treatment groups among African-Americans and Caucasians, were impotence, decreased libido, ejaculation disorders and gynaecomastia. With the exception of gynaecomastia, which was reported at a uniformly low incidence (o2% of patients in any group) throughout the treatment period, the incidence of drug-related adverse events declined after the first 6 months. It is important to interpret the data from this analysis in the context of its limitations. The data are derived from a post hoc analysis rather than from a prospective study, and the analysis included relatively few African-American patients. In view of the high prevalence of BPH among African-American men, largescale prospective studies, specifically designed to evaluate the efficacy of BPH pharmacotherapies among African-American patients, are merited. However, the data from the current analysis provide the first assessment of the efficacy and tolerability of BPH pharmacotherapy in African-American patients, and serve to highlight the need for further investigation in this patient population.

In conclusion, the present post hoc analysis of data from three large, randomized, double-blind, placebo-controlled studies shows that the magnitude of improvement in efficacy measures with the dual 5a-reductase inhibitor, dutasteride, relative to placebo, is similar in African-Americans and Caucasians with BPH. In addition to a favourable efficacy profile, dutasteride was well tolerated and demonstrated a similar safety profile in African-Americans and Caucasians. These data add to a growing body of evidence establishing dutasteride as an important treatment option for BPH, and show that dutasteride is equally effective and well tolerated in African-Americans and Caucasians. Acknowledgements All studies included in the analysis were funded by GSK. References 1 Roehrborn C, McConnell J. Etiology, pathophysiology, epidemiology and natural history of benign prostatic hyperplasia. In: Walsh P, Retik A, Vaughan EJ, Wein A (eds). Campbell s Urology. 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