Efficacy and Tolerability of the Dual 5A-Reductase Inhibitor, Dutasteride, in the Treatment of Benign Prostatic Hyperplasia in African-American Men

Home , Dutasteride

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 factors – 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. Data are presented as mean values (range).

Prostate Cancer and Prostatic Diseases Dutasteride in African-American men with BPH CG Roehrborn and P Ray

434 change þ 21.6 versus À0.9%) and Caucasians (adjusted African-American and Caucasian patients, dutasteride mean change þ 18.6 versus À0.9%) at month 24. Mean significantly (Po0.05) increased Qmax compared with and median concentrations of testosterone remained placebo at month 18 (Figure 2). The magnitude of the within the normal physiological range for both African- increase in Qmax with dutasteride versus placebo was American and Caucasian patients treated with either similar in African-American and Caucasian patients dutasteride or placebo. throughout the treatment period. No statistically

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 dutasteride- treated 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. Figure 1 Adjusted mean percentage change from baseline in prostate volume (PV) (a) and prostate transition zone volume (TZV) Flow rate (b) over the duration of the study in African-Americans and Qmax values at baseline were similar in the two treatment Caucasians treated with dutasteride or placebo. AA, African groups and in the two racial groups (Table 1). In both American; C, Caucasian.

Table 2 Measures of BPH severity at month 24 among African-American and Caucasian patients in dutasteride and placebo treatment groups African-Americans Caucasians Treatment- by-race Dutasteride Placebo Dutasteride Placebo interaction (n ¼ 82) (n ¼ 79) (n ¼ 1975) (n ¼ 1986)

Total prostate volume, % change from baselinea À23.0 À1.2 À26.6 À2.1 ns Prostate transition zone volume, % change from baselinea À24.5 À2.5 À24.2 3.1 ns a Mean change from baseline in Qmax (ml/s) 2.1 1.1 1.8 0.7 ns Mean change from baseline in AUA-SIa À4.4 À2.0 À3.7 À1.7 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; Qmax, peak urinary flow rate. aAdjusted mean values.

Prostate Cancer and Prostatic Diseases Dutasteride in African-American men with BPH CG Roehrborn and P Ray significant treatment-by-race interaction was observed AUA-SI score 435 (Table 2). Baseline AUA-SI scores were similar across treatment groups and across racial groups, and reflected moderate- to-severe symptoms (Table 1). At month 24, the improve- Acute urinary retention and BPH-related surgery ments in symptom scores with dutasteride were Dutasteride, relative to placebo, reduced the risk of acute significantly greater in both African-Americans urinary retention by 58% (95% confidence interval (CI), (Po0.05) and Caucasians (Po0.001), compared with À119 to 92) among African-Americans and by 55% (95% placebo (Figure 3). The adjusted mean changes in CI, 33–69) among Caucasians, and reduced the risk of AUA-SI score from baseline at month 24 for dutasteride BPH-related surgery by 53% (95% CI, À159 to 91) and and placebo groups, respectively, were À4.4 and À2.0 in 48% (95% CI, 25–64) in African-Americans and Cauca- African-Americans and À3.7 and À1.7 in Caucasians. sians, respectively (Table 2). There was no statistically There was no statistically significant treatment-by-race significant treatment-by-race interaction for acute urin- interaction (Table 2). ary retention or BPH-related surgery.

Figure 3 Adjusted mean change from baseline in AUA-SI score over the duration of the study in African-Americans and Cauca-

Figure 2 Adjusted mean change from baseline in Qmax in African- sians treated with dutasteride or placebo. AUA-SI, American Americans and Caucasians treated with dutasteride or placebo. Urological Association Symptom Index; AA, African American; AA, African American; C, Caucasian; Qmax, peak urinary flow rate. 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.

Prostate Cancer and Prostatic Diseases Dutasteride in African-American men with BPH CG Roehrborn and P Ray

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

Prostate Cancer and Prostatic Diseases Dutasteride in African-American men with BPH CG Roehrborn and P Ray 437 In conclusion, the present post hoc analysis of data from 12 Makridakis N, Ross RK, Pike MC, Chang L, Stanczyk FZ, three large, randomized, double-blind, placebo-con- Kolonel LN et al. A prevalent missense substitution that trolled studies shows that the magnitude of improve- modulates activity of prostatic steroid 5alpha-reductase. Cancer ment in efficacy measures with the dual 5a-reductase Res 1997; 57: 1020–1022. inhibitor, dutasteride, relative to placebo, is similar in 13 Salam MT, Ursin G, Skinner EC, Dessissa T, Reichardt JK. African-Americans and Caucasians with BPH. In addi- Associations between polymorphisms in the steroid 5-alpha reductase type II (SRD5A2) gene and benign prostatic hyper- tion to a favourable efficacy profile, dutasteride was well plasia and prostate cancer. 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