Dutasteride: A Review of Current Data on a Novel Dual Inhibitor of 5a Reductase

Treatment Update

TREATMENT UPDATE Dutasteride: A Review of Current Data on a Novel Dual Inhibitor of 5
Reductase Sibylle Marihart, MD, Mike Harik, MD, Bob Djavan, MD, PhD Department of Urology, University of Vienna, Vienna, Austria Dutasteride is used in the treatment of benign prostatic hyperplasia. Like finasteride, it reduces serum prostate-specific antigen levels by approximately 50% at 6 months and total prostate volume by 25% in 2 years. It differs from finasteride in that it inhibits both isoenzymes of 5
reductase and results in near-complete suppression of serum dihydrotestosterone. Randomized placebo-controlled trials over 2 years have shown the efficacy of dutasteride in symptomatic relief, improvements in quality of life and peak urinary flow rate, and reduction of acute urinary retention events and need for surgery. Side effects occurring in therapy with dutasteride are decreased libido, erectile dysfunction, ejaculation disorders, and gynecomastia. However, when dutasteride treatment is compared with placebo, these sexual adverse events are only modestly elevated. Long-term use over 4 years did not increase side effects. An efficient treatment of side effects is the combination of dutasteride and tamsulosin, especially for patients with large prostate volumes. Finally, the anticancer properties of dutasteride have been shown in placebo-controlled trials and are being investigated in the ongoing Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial. [Rev Urol. 2005;7(4):203-210 ] © 2005 MedReviews, LLC Key words: Benign prostatic hyperplasia • Prostate volume • Efficacy • Sexual adverse events he prevalence of prostatic diseases is very high in the aging male population. It is estimated that 88% of men aged 80 years or more have the pathologic changes of benign prostatic hyperplasia (BPH), and nearly 50% of men aged 50 years or older have lower urinary tract symptoms characteristic of BPH.1 At the same time, prostate cancer is rapidly becoming the most common malignancy in the United States and some other Western countries and will affect approximately 1 in 6 American men during their lives.2 T VOL. 7 NO. 4 2005 REVIEWS IN UROLOGY 203 Dutasteride for BPH continued Testosterone is converted to dihydrotestosterone (DHT) by the enzyme 5
reductase. DHT is necessary for normal growth and function, but it also seems to have a great impact on the development of BPH and on the initiation and maintenance of prostate cancer.3,4 Finasteride, an inhibitor of 5
reductase, has established its role in the management of BPH through a number of wellconducted long-term studies.5,6 Similarly, the recent Prostate Cancer result in greater efficacy than is observed in selective type 2 inhibition, and this dual inhibition could prevent type 1–mediated synthesis of DHT. Efficacy Two-Year, Placebo-Controlled Trials In 2002, the first clinical study reported the efficacy of dutasteride at a dose of 0.5 mg/d.13 This study compared 4325 patients from three randomized, placebo-controlled trials (ARIA 3001 [United States], ARIA Theoretically, the greater suppression of DHT arising from dual 5
-reductase inhibition could result in greater efficacy than is observed in selective type 2 inhibition. Prevention Trial showed that the incidence of prostate cancer was decreased with finasteride over a 7year period.7 Dutasteride, a dual inhibitor of 5
reductase that was introduced at the turn of the 21st century, promised better efficacy than its predecessor finasteride. This review discusses its mechanism of action, efficacy, tolerability, drug interactions, and effects on prostate cancer. Dutasteride: How Does It Work? DHT synthesis is catalyzed intracellularly by 5
reductase types 1 and 2 enzymes. Dutasteride is the first dual inhibitor of both 5
reductase isoenzymes. This leads to near-complete suppression of serum DHT—more than 90%, compared with the 70% seen with finasteride.8,9 Type 2 5
reductase is the predominant isoform in normal prostate and in BPH tissues. Type 1 5
reductase is present in BPH tissue in lower quantities, but it predominates in prostate cancer cell lines and seems to be over-expressed in some prostate cancers.10-12 Theoretically, the greater suppression of DHT arising from the dual 5
-reductase inhibition could 204 VOL. 7 NO. 4 2005 3002 [United States], and ARIA 3003 [19 countries]), covering 400 sites in total, which had identical inclusion and exclusion criteria to allow preplanned pooling of data. A total of 2167 men received dutasteride, and 2158 men received placebo. The median duration of exposure was 604 days for the study medicine and 598 days for placebo. Completing the 2-year study were 66% and 70% of patients in the placebo and dutasteride groups, respectively. The primary endpoints were changes in the American Urological Association Symptom Index (AUA-SI) and the risk of acute urinary retention (AUR). The secondary endpoints described changes in serum prostate-specific antigen (PSA), testosterone, and DHT concentrations, total prostate volume, peak urinary flow rate (Qmax), and surgical interventions. At 24 months, serum DHT was reduced from baseline by a mean of 90.2%, and the total prostate and transition zone volumes were reduced 25.7% and 20.4%, respectively. Serum PSA decreased 52.4% in the dutasteride group, compared with an increased serum PSA level from baseline of 15.8% in the REVIEWS IN UROLOGY placebo group. The symptom score started to improve at 3 months, with pooled significance from 6 months onward and a reduction of 4.5 points (21.4%) at 24 months. The risk reduction of AUR was 57% at 24 months, and the risk of BPH-related surgical interventions was 48% compared with placebo. Qmax started to improve significantly at 1 month, with an increase of 2.2 mL/s reported at 24 months. This study provides early evidence of the efficacy of dutasteride in terms of symptoms, Qmax improvements, and reduction in prostate volume. Table 1 summarizes the mean change from baseline for primary and secondary outcome parameters in the placebo and dutasteride groups. Quality of Life In the same cohort of patients (n  4325), O’Leary and colleagues14 assessed the improvements in quality of life with dutasteride compared with placebo. The BPH Impact Index (BII) consists of 4 questions that measure the impact of urinary problems in terms of physical discomfort, worry about health because of urinary problems, bothersomeness of urinary symptoms, and limitations of activities of daily living because of urinary problems. Dutasteride, but not placebo, showed clinically and statistically significant improvements in mean BII score from 6 months. Treatment with dutasteride improved the scores by an average of 2.41 in patients with a baseline BII score of 5 or more (greatest symptomatic burden), whereas the scores in placebo-treated patients improved by only an average of 1.64. Initially, placebo-treated patients had improvements in BII scores from baseline, but BII scores had deteriorated by 18 to 24 months, showing progressive BPH symptoms and worsening quality of life. In contrast, dutasteride treatment was associated with consistent improvements from 6 months to 2 years. Dutasteride for BPH Table 1 Month 24 Data and Change from Baseline at Month 24 Data for Primary and Secondary Endpoints in the Placebo-Controlled Trials and Values at Month 48 for the Open-Label Extension Dutasteride (n
2167) BetweenGroup Comparison Open-Label Extension Month 48 P/D (n
1152) D/D (n
1188) Parameter Time Placebo (n
2158) Serum testosterone (pg/mL) Month 24 Change P 4002  1481 36  1226 NS 4817  1780 749  1475 .001 .001 4718  1688 4904  2186 Serum DHT (pg/mL) Month 24 Change P 426  197 16  150 .001 40  77 389  228 .001 .001 29.7  63.0 31.1  60.7 Serum PSA (ng/mL) Month 24 Change P 4.3  2.8 0.5  2.1 .001 1.8  1.8 2.2  2.0 .001 .001 2.0  1.8 1.7  1.8 Total prostate volume (cm3) Month 24 Change P 54.1  25.2 0.8  14.3 .040 41.2  20.6 14.6  13.5 .04 .001 42.2  20.2 41.3  23.1 Transition zone volume (cm3) Month 24 Change P 28.4  19.1 1.9  11.2 .001 21.1  13.9 7.1  9.7 .001 .001 22.8  18.8 22.4  16.0 AUA-SI Score Month 24 Change P 14.7  7.2 2.3  6.8 .001 12.2  6.6 4.5  6.6 .001 .001 11.3  6.4 10.2  6.1 Qmax (mL/s) Month 24 Change P 11.2  4.8 0.6  4.7 .001 12.5  5.6 2.2  5.2 .001 .001 12.6  5.1 12.8  5.5 Data presented as mean  standard deviation. D/D, subjects initially treated with dutasteride continuing with dutasteride; P/D, subjects initially given placebo then switched to dutasteride; NS, not significant; DHT, dihydrotestosterone; PSA, prostate-specific antigen; AUA-SI, American Urological Association Symptom Index; Qmax, peak urinary flow. Data from Roehrborn et al13 and Debruyne et al.15 In the analysis of risk factors for bothersomeness at the end of the study, regression analysis showed that men with a combination of a baseline BII score of 3 and a high symptom score (AUA-SI score  20) were more likely to be bothered. Thus, dutasteride not only improves urinary symptoms and flow rate, but it is also associated with significant improvements in BII score, reflecting improvements in quality of life for men with BPH. Long-Term Studies All of the studies mentioned above (ARIA 3001, ARIA 3002, ARIA 3003) had an optional 2-year open-label extension period in which patients initially receiving dutasteride in the double-blind phase were maintained on dutasteride, and those initially receiving placebo were switched to open-label dutasteride.15 In the openlabel phase, 2340 patients (54% participation from the original study population) were included, 1188 of whom previously received dutasteride (D/D group) and 1152 of whom previously received placebo (P/D group). At 48 months, the D/D group was checked for improvements in total prostate volume (25.9%), AUA-SI score (6.5 points), and Qmax (2.5 mL/s). Changes for the P/D group included prostate volume (23.1%), AUA-SI score (5.7 points), and Qmax (0.8 mL/s) (Table 1). In both study groups, there were significant improvements in AUA-SI score and peak urinary flow rates from months 24 to 48. It is important to note that patients in the D/D group had significantly greater improvements in AUA-SI score and Qmax and greater reductions in prostate volume than those in the P/D group at the end of 48 months. During the open-label phase, AUR occurred in a small percentage of men in the P/D VOL. 7 NO. 4 2005 REVIEWS IN UROLOGY 205 Dutasteride for BPH continued group (2.1%), at rates consistent with those seen in the D/D group between months 0 and 24 (1.9%) and between months 24 and 48 (1.2%). Similarly, BPH-related surgery occurred in a small percentage of men in both the P/D (1.1%) and D/D (0.9%) groups. Overall, the cumulative incidences for AUR and BPH-related surgery were significantly lower in the D/D group than in the P/D group (2.4% vs 5.1% and 2.6% vs 4.5%, respectively). Long-term treatment with the dual 5
-reductase inhibitor seems to result in continuing improvements in urinary symptoms and flow rate and, furthermore, seems to lead to a reduction in prostate volumes in men with symptomatic BPH. Moreover, the reduction in risk for AUR and BPHrelated surgery seems to be durable over the 4-year term of the studies. Benefit of Combining
1 Blockers and Dutasteride The aim of a combination study by Barkin and colleagues16 of men with symptomatic BPH was to provide rapid onset of symptom relief, especially for patients with severe symptoms of bladder outlet obstruction. The investigators conducted a prospective study of 327 BPH patients who were randomized to a combination of dutasteride (0.5 mg) and tamsulosin (0.4 mg) for 36 weeks (DT36) or dutasteride (0.5 mg) and tamsulosin (0.4 mg) for 24 weeks, followed by dutasteride and tamsulosinmatched placebo for the remaining 12 weeks (DT24D12). Of the DT24D12 patients, 77% felt better or the same at week 30 compared with week 24 (changes in International Prostate Symptom Scores [IPSS] were consistent with this finding). Of the patients with an IPSS of less than 20 who changed to dutasteride monotherapy at week 24, 84% switched without noticeable deterioration in their symptoms. In the 27% 206 VOL. 7 NO. 4 2005 of men with severe baseline symptoms (IPSS  20) who had withdrawal of tamsulosin therapy at week 24, 42.5% reported a worsening of their symptoms, compared with 14% in the DT36 group. The investigators concluded that combination therapy of dutasteride and tamsulosin for 24 weeks provides a rapid onset of symptom relief for patients at risk for underlying disease progression and that this symptomatic relief is maintained in the majority of patients cidence of abnormalities in clinical laboratory tests, including liver function tests, was less than 1% in both the dutasteride and placebo groups. Of all drug-related adverse events, impotence was the most common reason for discontinuation of patients in the dutasteride group. In summary, dutasteride has a tolerability profile comparable to that of placebo when used daily for up to 2 years, with the exception of gynecomastia, impotence, and decreased li- The investigators concluded that combination therapy of dutasteride and tamsulosin for 24 weeks provides a rapid onset of symptom relief for patients at risk for underlying disease progression. when tamsulosin is removed from the combination. However, a subset of patients with severe symptoms of bladder outlet obstruction might benefit from longer-term therapy. These recommendations were concordant with those of Baldwin and coworkers,17 who suggested that men with severe BPH would require 9 or more months of combination therapy. Safety and Tolerability At 24 Months In the 3 placebo-controlled studies (ARIA 3001, ARIA 3002, ARIA 3003),13 most adverse events were mild to moderate and self-limiting. The only adverse events that investigators considered to be at least possibly drug-related and that occurred in at least 1% of patients treated with dutasteride or placebo over a 2-year period were impotence, ejaculation disorders, decreased libido, and gynecomastia. The incidence of side effects was only slightly higher among dutasteride-treated patients than among placebo-treated patients. Table 2 shows the incidence of the adverse events; the majority occurred in the first year of treatment. The in- REVIEWS IN UROLOGY bido, which occurred at modestly elevated incidences compared with the placebo group. At 48 Months Interestingly, the incidence of most drug-related sexual adverse events decreased among patients who received dutasteride throughout the 48-month study period15 (Table 2). The incidence of such drug-related adverse events that led to withdrawal was less than 1% in the open-label phase. In general, there are no increased adverse events in long-term treatment with dutasteride, and patient compliance is satisfactory. Is There Any Difference in Side Effects Between Dutasteride and Finasteride? GlaxoSmithKline protocol ARI40001 compared dutasteride (0.5 mg/d) with finasteride (5 mg/d) for 1 year.18 There were no significant differences in the incidence of the most common drugrelated adverse events between the dutasteride and finasteride groups (Table 3). The only adverse events that the investigators considered to be drug-related that occurred at an incidence of Dutasteride for BPH apy were comparable to those expected for the individual drugs, and there was no evidence of synergistic interaction. These data suggest that dutasteride and tamsulosin combination treatment is well tolerated over a 36-week period. Table 2 Percentage of Patients Reporting the Most Common Drug-Related Side Effects in the Placebo-Controlled Trials and Open-Label Extension 0-6 7-12 13-18 Months 19-24 24-36 36-48 Patients, n Dutasteride Placebo 2167 2158 1901 1922 1725 1714 1605 1555 2340 No patients 1041 No patients Decreased libido Dutasteride Placebo 3.0%* 1.4% 0.7% 0.6% 0.3% 0.2% 0.3% 0.0% 0.4% - 0.1% - Gynecomastia Dutasteride Placebo 0.5%* 0.2% 0.8%* 0.3% 1.1%* 0.3% 0.6%* 0.1% 0.9% - 0.7% - Impotence Dutasteride Placebo 4.7%* 1.7% 1.4% 1.5% 1.0% 0.5% 0.8% 0.9% 1.4% - 0.4% - Ejaculation disorder Dutasteride Placebo 1.4%* 0.5% 0.5% 0.3% 0.5% 0.1% 0.1% 0.0% 0.3% - 0.1% - * P < .05, dutasteride vs placebo. Data from Roehrborn et al13 and Andriole et al.18 more than 2% were impotence and decreased libido. In addition, the incidence of clinical laboratory abnormalities was less than 1% in either treatment group for any parameter. Side Effects of Combination Therapy with Dutasteride and Tamsulosin In the combination trial,16 sexual adverse events were the most commonly reported class of drug-related side effects. The only adverse events considered to be at least possibly drugrelated and that occurred in at least 5% of patients in either treatment group throughout the 36-week treatment period were ejaculation disorders. The majority of these disorders were related to sperm volume (9% DT36 group; 8% DT24D12 group), decreased libido (5% DT36 group; 6% DT24D12 group), impotence (5% DT36 group; 4% DT24D12 group), and malaise and fatigue (5% DT36 group; 1% DT24D12 group). The drug-related adverse event profiles for combination ther- Does Dutasteride Have Any Effects on Bone Density and Lipid Profiles? GlaxoSmithKline protocol ARIA 1009, a randomized, double-blind study that included a finasteride arm, was conducted to investigate the effects of dutasteride on bone density, bone metabolism markers, and lipid profiles.18 Subjects were randomized to receive dutasteride (0.5 mg), finasteride (5.0 mg), or placebo for 52 weeks and were followed up for a further 24 weeks after the cessation of study medication. Bone density screening by X-ray absorptiometry was conducted between weeks 48 and 52 and again after 20 to 24 weeks of follow-up. Markers for bone resorption and bone formation, such as serum osteocalcin, serum bone alkaline phosphatase, and urinary ntelopeptide, were measured at baseline, at study weeks 8, 16, 24, and 52, and at Table 3 Most Common Drug-Related Adverse Events in a Controlled Comparator Trial of Dutasteride and Finasteride for Benign Prostatic Hyperplasia Adverse Event Finasteride (n
817) Dutasteride (n
813) Impotence 69 (8) 55 (7) Decreased libido 46 (6) 39 (5) Ejaculation disorders 12 (1) 10 (1) 9 (1) 9 (1) Headache 9 (1) 11 (1) Dizziness 11 (1) Malaise/fatigue 12 (1) Gynecomastia 6 (1) 12 (1) Data are presented as n (%). Adverse events reported in  1% of patients in either group are listed. There were no statistically significant differences between dutasteride- and finasteridetreated patients. Reproduced with permission from Andriole et al.18 VOL. 7 NO. 4 2005 REVIEWS IN UROLOGY 207 Dutasteride for BPH continued follow-up weeks 8, 12, and 24. Lipid levels were recorded at baseline, at study weeks 8, 24, and 52, and at follow-up weeks 4, 8, 12, and 24. There were no clinically significant changes in bone density or bone metabolism markers from baseline, or significant differences between treatment groups at weeks 48 to 52 or follow-up weeks 20 to 24. In addition, there were no significant differences between treatment groups in the lipid profiles. These findings show that the change in serum androgen levels induced by dutasteride does not affect the bone mineral density and lipid profile. male subjects were given 1) 0.4 mg/d tamsulosin or 10 mg/d terazosin with dutasteride (40 mg loading dose followed by 0.5 mg/d); 2) warfarin (international normalized ratio of 1.5 to 2.0) with dutasteride (25 mg loading dose followed by 0.5 mg/d for 21 days); 3) 0.25 mg/d digoxin with dutasteride (25 mg loading dose followed by 0.5 mg/d for 21 days; or 4) cholestyramine (single 12 g dose) 1 hour after administration of 0.5 mg of dutasteride. Taken together, these data suggest that dutasteride is a safe drug with a wide therapeutic window and few known drug interactions. Drug Interactions Dutasteride is metabolized by the human cytochrome P-450 isoenzyme CYP3A4. According to in vitro data, Effect on the Development of Prostate Cancer There is abundant evidence that androgens influence the development Care should be taken when administering dutasteride to patients taking potent, chronic CYP3A4 inhibitors, such as ritonavir. blood concentrations of dutasteride might increase in the presence of CYP3A4 inhibitors such as ritonavir, ketoconazole, verapamil, diltiazem, cimetidine, and ciprofloxacin.18 However, the incidence of adverse events among patients receiving concomitant agents that inhibit CYP3A4, including cimetidine, ciprofloxacin, diltiazem, erythromycin, fluconazole, itraconazole, ketoconazole, and verapamil, was similar in both the dutasteride and placebo groups in the 3 placebo-controlled trials (ARIA 3001, ARIA 3002, ARIA 3003).13 Nevertheless, care should be taken when administering dutasteride to patients taking potent, chronic CYP3A4 inhibitors, such as ritonavir. In the studies that examined the drug-interaction profile of dutasteride,18 no pharmacodynamic or pharmacokinetic interactions were observed in studies in which healthy 208 VOL. 7 NO. 4 2005 of prostate cancer. Recently, definitive data have been published on the reduction of prostate cancer risk by 5
-reductase inhibitors.7 In this Prostate Cancer Prevention Trial, a total of 18,882 men aged 55 years or older with PSA levels below 3.0 ng/mL were randomized to finasteride (5 mg/d) or placebo for 7 years. After the 7 years, it was found that finasteride treatment resulted in a 24.8% reduction in the prevalence of prostate cancer compared with placebo. However, tumors with higher Gleason scores (7-10) were more frequent in the finasteridetreated group (37.0% of tumors vs 22.2%, P < .01). The first article about the effect of dutasteride on prostate cancer was published by Andriole and colleagues.19 In this study, patients from the 3 placebo-controlled trials (ARIA 3001, ARIA 3002, ARIA 3003) were REVIEWS IN UROLOGY analyzed for prostate cancer development. The prostate cancer detection rates were determined by non–protocol-mandated biopsies, either during the double-blind phases of the study or during the first 3 months of the openlabel extension. The cumulative incidence of prostate cancer as an adverse event was significantly lower in the dutasteride group than in the placebo group at 24 months (1.1% vs 1.9%, P  .025) and 27 months (1.2% vs 2.5%, P  .002). There were no differences in the diagnosis rates of prostate cancer during the first 15 months, but after that time the prostate cancer detection rate increased in the placebo group and remained low in the dutasteride group. It is important to recognize, however, that the 3 trials were not designed to address prostate cancer prevention and this study was therefore a secondary analysis. Unlike in the Prostate Cancer Prevention Trial, 100% verification of a biopsynegative status was not achieved, and fewer subjects receiving dutasteride had at least 1 biopsy (7.9% vs 10.1% of placebo subjects). Andriole and colleagues20 also performed a study of the effect of dutasteride on markers of tumor regression in prostate cancer. A total of 46 men with localized prostate cancer were randomized to dutasteride (5 mg/d) or placebo for 6 to 10 weeks before radical prostatectomy. Treatment with dutasteride caused a 97% decrease in intraprostatic DHT and was associated with a trend toward increased apoptosis, as evidenced by increased TUNEL and tissue transglutaminase (tTG) staining. In patients receiving dutasteride for 45 days or more, a significant increase in apoptosis and a trend toward decreased microvessel density in prostate cancer tissue were observed. Dutasteride treatment was also associated with an 18% decrease in mean benign epithelial cell width compared with placebo. Dutasteride for BPH Future Trials to Assess the Effect of Dutasteride on Prostate Cancer The Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial, initiated in 2004,21 is a 4-year international, multicenter, randomized, double-blind, placebocontrolled, parallel-group study evaluating the efficacy and safety of oral, once-daily dutasteride (0.5 mg) for men at increased risk for prostate cancer. A total of 8000 eligible men aged 50 to 75 years with a PSA level of 2.5 to 10 ng/mL (for ages 50 to 60 years) or 3.0 to 10 ng/mL (for ages 60 years and older) and a negative prostate biopsy within 6 months of enrollment will be recruited. The primary endpoint is biopsy-detectable prostate cancer at 2 and 4 years of treatment. Secondary endpoints for prostate cancer include Gleason score at diagnosis, high-grade prostatic intraepithelial neoplasia at biopsy, percentage of cores with prostate cancer at diagnosis, number of cancer-positive cores, treatment alteration score, and incidence of intervention for prostate cancer, as well as overall sur- vival. This trial will increase our understanding of the effects of dutasteride on the natural history of prostate cancer in men at increased risk for this malignancy. It also affords a unique opportunity to examine the biomarkers and genetic linkage for prostate cancer and to assess a range of prostate health outcomes. Influence on Daily Clinical Practice What have we learned about this new dual 5
-reductase inhibitor, dutasteride? Current data confirm that dutasteride reduces serum DHT levels by more than 90% at 2 weeks and significantly reduces prostate volume by 1 month, producing approximately 25% reduction at 2 years. In addition, dutasteride reduces total serum PSA concentration approximately 40% after 3 months of treatment and approximately 50% after 6, 12, and 24 months of treatment. This result suggests that, for men beginning dutasteride treatment, a new PSA baseline should be established after 6 months to assess potential cancer-related changes in PSA. Thus, in determining whether isolated PSA values lie within normal ranges, PSA values should be doubled for patients who have received dutasteride for at least 6 months. Moreover, dutasteride was found to improve urinary flow after 1 month of treatment and to produce symptomatic improvement after 3 months of treatment in patients with BPH. For patients with severe bladder outlet obstruction, dutasteride alone might not be sufficient for rapid symptom relief. Because these patients with severe BPH usually have enlarged prostates, combination therapy with a 5
-reductase inhibitor (dutasteride) and an
1-blocker might solve this problem. Depending on the severity of the symptoms, the
1-blocker might be withdrawn after 6 to 12 months of treatment. BPH is known to be a progressive disease, and the development of AUR and the need for BPH surgery are well documented in both longitudinal community studies22 and clinical studies.5,23 Dutasteride has been shown to reduce progression in many long-term studies5,23 and to reduce the incidence of AUR and the need for Main Points • Dihydrotestosterone (DHT) is necessary for normal growth and function but also seems to have a great impact on the development of benign prostatic hyperplasia (BPH) and on the initiation and maintenance of prostate cancer; DHT synthesis is catalyzed intracellularly by 5
reductase type 1 and 2 enzymes. • Dutasteride is the first dual inhibitor of both 5
reductase isoenzymes and produces near-complete (> 90%) suppression of serum DHT. • In 2002, the first clinical study reported the efficacy of dutasteride at a dose of 0.5 mg/d in 4325 patients enrolled in 3 randomized, placebo-controlled trials; the study provided early evidence of dutasteride’s efficacy in terms of symptom and peak urinary flow improvement and reduction in prostate volume. • An analysis of the same cohort showed that dutasteride was also associated with significant improvements in BPH Impact Index score, reflecting improvements in quality of life for men with BPH. • Long-term treatment (up to 4 years) with dutasteride seems to result in continuing improvements in urinary symptoms and flow rate and also seems to produce a reduction in prostate volume in men with symptomatic BPH. • Dutasteride has a tolerability profile comparable to that of placebo when used daily for up to 2 years, with the exception of gynecomastia, impotence, and decreased libido, which occurred at modestly elevated incidences compared with the placebo group. • Dutasteride might be advantageous in the chemoprevention of prostate cancer, owing to its near-complete suppression of serum DHT. VOL. 7 NO. 4 2005 REVIEWS IN UROLOGY 209 Dutasteride for BPH continued surgery. Patients with large prostate volume ( 30 mL) and a serum PSA concentration above 1.5 ng/mL are more likely to have progressive disease and develop complications, such as AUR; therefore, dutasteride might be an ideal drug for this group of patients. The safety and tolerability of a drug is an important factor for longterm consumption. Dutasteride seems to be safe in long-term studies, but the importance of proper patient counseling on related sexual adverse events must be considered. Conclusion Dutasteride is comparable to finasteride with respect to its efficacy for patients with benign prostatic hyperplasia. Dutasteride might be advantageous in the chemoprevention of prostate cancer, owing to its near-complete suppression of serum DHT. The results from the REDUCE trial will provide more information about this issue. However, longer-term placebo-controlled trials are necessary to confirm the durable efficacy of dutasteride. References 1. 2. 210 Napalkov P, Maisonneuve P, Boyle P. Worldwide patterns of prevalence and mortality from benign prostatic hyperplasia. Urology. 1995;46: 41-46. Greenlee RT, Hill-Harmon MB, Murray T, Thun M. Cancer statistics 2001. CA Cancer J Clin. 2001;51:15-37. VOL. 7 NO. 4 2005 3. Petrow V. The dihydrotestosterone (DHT) hypothesis of prostate cancer and its therapeutic implications. Prostate. 1986;9:343-347. 4. Bruchovsky N, Rennie PS, Batzold FH, et al. Kinetic parameters of 5 alpha-reductase activity in stroma and epithelium of normal, hyperplastic, and carcinomatous human prostates. J Clin Endocrinol Metab. 1988;67:806-811. 5. McConnell JD, Bruskewitz R, Walsh P, 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. Finasteride Long-Term Efficacy Safety Study Group. N Engl J Med. 1998;338:557-563. 6. Marberger MJ. Long-term effects of finasteride in patients with benign prostatic hyperplasia: a double-blind, placebo-controlled, multicenter study. PROWESS Study Group. Urology. 1998;51: 677-686. 7. Thompson IM, Goodman PJ, Tangen CM, et al. The influence of finasteride on the development of prostate cancer. N Engl J Med. 2003;349: 215-224. 8. Clark RV, Hermann DJ, Gabriel H, et al. Effective suppression of dihydrotestosterone (DHT) by GI198745, a novel dual alpha-reductase inhibitor [abstract 1037]. J Urol. 1999;161:268. 9. McConnell JD, Watson JD, George FW, et al. Finasteride, an inhibitor of 5 alpha-reductase, suppresses prostatic dihydrotestosterone in men with benign prostatic hyperplasia. J Clin Endocrinol Metab. 1992;74:505-510. 10. Bruchovsky N, Sadar MD, Akakura K, et al. Characterization of 5 alpha-reductase gene expression in stroma and epithelium of human prostate. J Steroid Biochem Mol Biol. 1996;59:397-401. 11. Thigpen AE, Silver RI, Guileyardo JM, et al. Tissue distribution and ontogeny of steroid 5 alpha-reductase isoenzyme expression. J Clin Invest. 1993;92:903-908. 12. Thomas LN, Douglas RC, Vessey JP, et al. 5 alpha-reductase type 1 immunostaining is enhanced in some prostate cancers compared with benign prostatic hyperplasia epithelium. J Urol. 2003;170:2019-2023. 13. Roehrborn CG, Boyle P, Nickel JC, et al. Efficacy and safety of dual inhibitor of 5-alpha-reductase REVIEWS IN UROLOGY 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia. Urology. 2002;60:434-441. O’Leary MP, Roehrborn CG, Andriole G, et al. Improvements in benign prostatic hyperplasiaspecific quality of life with dutasteride, the novel dual 5-alpha-reductase inhibitor. BJU Int. 2003; 92:262-266. Debruyne F, Barkin J, van Erps P, et al. 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