- Email: [email protected]
Dutasteride Improves Outcomes of Benign Prostatic Hyperplasia When Evaluated for Prostate Cancer Risk Reduction: Secondary Analysis of the REduction by Dutasteride of Prostate Cancer Events (REDUCE) Trial
Prostatic Diseases and Male Voiding Dysfunction Dutasteride Improves Outcomes of Benign Prostatic Hyperplasia When Evaluated for Prostate Cancer Risk Reduction: Secondary Analysis of the REduction by Dutasteride of Prostate Cancer Events (REDUCE) Trial Claus G. Roehrborn, J. Curtis Nickel, Gerald L. Andriole, R. Paul Gagnier, Libby Black, Timothy H. Wilson, and Roger S. Rittmaster OBJECTIVE
METHODS
RESULTS
CONCLUSION
To investigate the effect of dutasteride versus placebo on the symptoms and associated complications of male lower urinary tract symptoms and benign prostatic hyperplasia (BPH) across a range of prostate volumes and BPH symptoms in men evaluated for prostate cancer risk reduction in the 4-year REduction by DUtasteride of prostate Cancer Events (REDUCE) trial. REDUCE was a multicenter, randomized, double-blind, placebo-controlled study of prostate cancer risk reduction with daily dutasteride 0.5 mg or placebo. Eligible men were aged 50-75 years, with a prostate-specific antigen level of 2.5-10 ng/mL and a prostate volume of ⱕ80 cm3. The prespecified and post hoc analyses were performed on the incidence of acute urinary retention, BPH-related surgery, and urinary tract infections, as well as on changes in prostate volume, International Prostate Symptom Score, BPH Impact Index, and maximal urinary flow rate (Qmax). A total of 8122 men were included in the efficacy population. During the 4-year study, the International Prostate Symptom Score increased in placebo-treated patients, while dutasteridetreated patients had a stabilized or decreased International Prostate Symptom Score and improved BPH Impact Index and quality of life due to urinary symptom scores across all prostate volume quintiles (including prostate glands smaller than those studied in previous dutasteride trials). 48 months, the incidence of acute urinary retention or BPH-related surgery was significantly less in the dutasteride group (2.5%) than in the placebo group (9%) overall (P ⬍ .001) and in each baseline prostate volume quintile (P ⬍ .01). During the 4-year study, dutasteride was associated with a decreased risk of BPH progression in men with mild-to-moderate symptoms and normal or enlarged prostates. UROLOGY 78: 641– 647, 2011. © 2011 Elsevier Inc.
B
enign prostatic hyperplasia (BPH) is a common chronic disease in aging men and is often associated with bothersome lower urinary tract symptoms. The disease is usually progressive and can result in
Funding Support: C. Roehrborn has received financial compensation as an adviser/ consultant/investigator from GlaxoSmithKline, Sanofi Aventis, Lilly, Neotract, AMS, and Pfizer. C. Nickel has received some financial compensation as a consultant/investigator from GlaxoSmithKline, Watson, Pfizer, and Johnson & Johnson, and financial compensation as a consultant/meeting participant from Astellas, and as a consultant from Toris, Foss Laboratories, and Triton. G. Andriole has received financial compensation as a consultant/ adviser from AEterna Zentaris, Amgen EMD Serono, Ferring Pharmaceuticals, GenProbe, Myriad Genetics, Nema Steba, Onconome, and Veridex; has stock ownership in Cambridge Enao, Envisioneering Medical and Viking Medical; and has received financial compensation as a consultant/adviser/member of the speaker’s bureau from GlaxoSmithKline. P. Gagnier, L. Black, T. H. Wilson, and R. Rittmaster are employees of GlaxoSmithKline.
© 2011 Elsevier Inc. All Rights Reserved
complications, such as acute urinary retention (AUR) and BPH-related surgery.1,2 5␣-reductase inhibitors reduce prostate volume, provide long-term relief of BPH symptoms, and lower the risk of long-term complications associated with BPH progression.3-7 Trials investigating the efficacy of 5␣Responsibility for the opinions, conclusions, and interpretation of data lies with the authors. From the Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas; Department of Urology, Queen’s University, Kingston General Hospital, Kingston, Ontario, Canada; Washington University School of Medicine, St. Louis, Missouri; and GlaxoSmithKline, Research Triangle Park, Durham, North Carolina Reprint requests: Claus G. Roehrborn, M.D., Univeristy of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390-9110. E-mail: [email protected] Submitted: February 21, 2011, accepted (with revisions): March 8, 2011
0090-4295/11/$36.00 doi:10.1016/j.urology.2011.03.063
641
reductase inhibitors in the treatment of BPH have usually been limited to men with moderate-to-severe BPH,6-9 making the study of the natural history of BPH progression challenging. The REduction by DUtasteride of prostate Cancer Events (REDUCE) trial investigated prostate cancer risk reduction and showed that over 48 months dutasteride reduced the risk of biopsy-detectable prostate cancer by 22.8% in men aged ⱖ50 years at increased risk of this disease as determined by a serum prostate-specific antigen (PSA) level ⬎2.5 ng/mL.10 BPH symptoms and complications were included as secondary endpoints in the trial. In contrast to most studies investigating the efficacy of 5␣-reductase inhibitors in the treatment of BPH, the REDUCE trial had no minimal inclusion criteria for BPH symptoms or prostate volume.11 An ideal population for studying the natural history of BPH would be a cohort of community dwelling men, such as those analyzed in the Olmsted County study. It is also possible to assess men in the placebo arms of BPH studies, although the inclusion and exclusion criteria have limited the extent to which such analyses can be applied to the general population.12 Thus, the evaluation of BPH-related symptoms and outcomes in men from the REDUCE trial might reflect the spectrum of disease severity and treatment in everyday clinical practice better than the clinical trials of BPH treatment. The men included in the REDUCE trial had elevated PSA values and, therefore, even in the absence of symptoms, could be at risk of BPH progression and complications.1,5,13,14 The REDUCE trial is an interesting vehicle from which to evaluate both the natural history of the disease and the effect of dutasteride on BPH outcomes in a trial in which the primary focus was not BPH symptoms or disease progression, in a population different from that studied in all previous dutasteride BPH studies. We report the prespecified and post hoc analyses of the effect of dutasteride compared with placebo on the symptoms and outcomes of BPH.
MATERIAL AND METHODS Participants The design of the REDUCE study has been previously reported.11 Eligible men were aged 50-75 years, had a serum PSA level of 2.5-10 ng/mL if 50-60 years old or 3.0-10 ng/mL if ⬎60 years old, and had undergone a single prostate biopsy (6-12 cores) with negative findings within 6 months before study enrollment. The use of ␣-blockers to control BPH-related symptoms was permitted, as clinically indicated. Men were not eligible if they had undergone previous prostate surgery, reported severe BPH-related symptoms on screening (International Prostate Symptom Score [IPSS] ⱖ25 or IPSS ⱖ20 if taking ␣-blockers), had a baseline prostate volume ⬎80 cm3, had a maximal urinary flow rate (Qmax) ⬍5 mL/s, or if the entry biopsy findings showed histologic evidence of prostate cancer or precancerous lesions in the prostate. 642
Study Design The REDUCE study was an international, 4-year, randomized, double-blind, placebo-controlled, parallel-group study designed to test the efficacy of dutasteride 0.5 mg, administered orally once daily, in reducing the risk of prostate cancer in men with an increased risk of this disease. After a 4-week placebo run-in, eligible patients were randomized to the treatment or placebo group. Protocol-dependent 10-core transrectal ultrasound-guided biopsies were performed at 2 and 4 years, with for-cause biopsies performed as required at other times. Prostate volume was measured on ultrasound at baseline and at 2 and 4 years. The Qmax was assessed at screening and annually throughout the study, and the IPSS was measured at screening and every 6 months. The incidence of acute urinary retention (AUR), BPH-related surgery, and urinary tract infections (UTIs) were recorded on the case report form every 6 months. In addition to assessing the IPSS (including question 8, the quality of life due to urinary symptoms [QOLUS] score), the BPH Impact Index (BII), which measures BPH-associated physical discomfort, worry, and bothersomeness, was administered at baseline and every 6 months. The BPH-related endpoints included the change in prostate volume, Qmax, and BPH symptom scores from baseline and the proportion of subjects who reported AUR, BPH-related surgery, or UTIs. Patients diagnosed with prostate cancer during the study discontinued the study drug and were interviewed by telephone 4 months later for a safety follow-up call; however, they were not necessarily withdrawn from the study. If these subjects chose to remain in the study, they returned for clinic visits every 6 months according to the original randomization schedule, and a safety follow-up telephone interview was completed 4 months after the last dose of the study drug. The mean study drug exposure was almost identical between the treatment groups, with a mean exposure of 1184 days in the placebo group compared with a mean exposure of 1190 days in the dutasteride group.
Statistical Analysis The efficacy population included all randomized subjects with an eligible entry prostate biopsy that had been reviewed centrally and who had received ⱖ1 dose of the study medication.10 All analyses were performed on the efficacy population, and a 2-sided P value with ␣ ⫽ 0.01 was used to define statistical significance. For the BPH-related endpoints, log-rank tests of the time to the first event of AUR, BPH-related surgery and UTI were performed and are displayed as Kaplan-Meier graphs for AUR and BPH-related surgery. The BPH-related endpoints were examined by prespecified subgroups according to the IPSS (⬍8 and ⱖ8) and post hoc subgroups according to prostate volume. The population was divided by the baseline prostate volume into convenience quintiles (ie, not exact percentage quintiles, but quintiles adjusted by rounding to increments of 10 cm3 [⬍30, 30-⬍40, 40-⬍50, 50-⬍60, and 60-ⱕ 80 cm3]), hereafter referred to as quintiles. This adjustment was performed to account for any differences in the baseline parameters between treatment groups within a quintile and for the ease of reporting and interpretation in a clinical setting. The IPSS, BII, QOLUS, and Qmax were analyzed using the last observation carried forward approach, as well as the observed cases approach to handle missing values. UROLOGY 78 (3), 2011
Table 1. Demographics and baseline characteristics Characteristic
Placebo (n ⫽ 4073)
Dutasteride (n ⫽ 4049)
62.7 ⫾ 6.09 3701 (91%) 8.6 ⫾ 5.61 45.8 ⫾ 18.80 5.91 ⫾ 2.00 15.3 ⫾ 15.48 46.3 ⫾ 48.00 2685 (66%) 2.1 ⫾ 1.38 2.2 ⫾ 2.43
62.7 ⫾ 6.02 3696 (91%) 8.7 ⫾ 5.70 45.7 ⫾ 17.91 5.92 ⫾ 1.97 15.2 ⫾ 12.04 46.7 ⫾ 48.67 2683 (66%) 2.1 ⫾ 1.34 2.2 ⫾ 2.44
Age (y) White Mean total IPSS* (score range 0-ⱖ25) Mean prostate volume† (cm3) Serum PSA‡ (ng/mL) Qmax§ (mL/s) Postvoid residual volume§ (mL) BPH as current medical condition¶ (%) QOLUS score§ (score range 0-6) BII score§ (score range 0-13)
Data presented mean ⫾ standard deviation for efficacy population. * Exclusion criterion was IPSS ⱖ25 or ⱖ 20 if taking ␣-blockers. † Exclusion criterion ⬎ 80 cm3. ‡ Inclusion criterion 2.5-10.0 ng/mL. § No inclusion/exclusion criteria. ¶ BPH as a medical condition recorded on case report form but no definition of BPH was provided to the physician.
Statistical analyses of the change from baseline for the continuous parameters (IPSS, BII, QOLUS, and Qmax) were performed with a general linear model using the t test. When the results were stratified by the baseline prostate volume quintiles, the mean values were adjusted to compensate for the difference in baseline values within a quintile between treatment groups. The relative risks were calculated using the Cox proportional hazards model.
RESULTS The efficacy population included 8122 men. The demographics and BPH-related baseline characteristics of the participants are listed Table 1. No major differences were found in the baseline characteristics between the treatment groups. The baseline characteristics showed that in general the men in the REDUCE trial had mild-tomoderate BPH symptoms, with slightly enlarged prostates, elevated PSA values, and Qmax values in the normal range. The mean IPSS at baseline was 8.6 in the placebo group and 8.7 in the dutasteride group. At 48 months, the mean score was 10 in the placebo group and 8.2 in the dutasteride group. The adjusted mean change in the IPSS from baseline in patients in the placebo group versus those in the dutasteride group was statistically significant (P ⬍ .01) from month 6 (⫺0.1 in the placebo group and ⫺0.42 in the dutasteride group) to month 48 (1.35 in the placebo group and ⫺0.46 in the dutasteride group; Fig. 1). This finding is noteworthy, because in the absence of a lower symptom threshold, no regression to the mean occurs; thus, no placebo effect is noted, rather a slow, but steady, worsening of symptoms.15 In patients with a baseline IPSS ⬍8, the symptom score for men receiving dutasteride therapy remained stable. In contrast, the symptom score for men receiving placebo deteriorated significantly from month 18 (Fig. 1; P ⬍ .01). As previously published,10 there was an increase in mean prostate volume in the placebo group and a decrease in the dutasteride group (⫹19.7% for placebo UROLOGY 78 (3), 2011
Figure 1. Adjusted mean change from baseline in IPSS by visit and treatment group, overall and stratified by baseline IPSS. Number of patients: IPSS overall, placebo ⫽ 4073, dutasteride ⫽ 4049; IPSS ⬍8, placebo ⫽ 1947, dutasteride ⫽ 1949; IPSS ⱖ8, placebo ⫽ 2038, dutasteride ⫽ 2014.
vs ⫺17.5% for dutasteride; P ⬍ .001). When the IPSS data were analyzed by baseline prostate volume quintiles, the difference between the placebo and dutasteride groups was statistically significant for months 12-48 for the lowest and highest volume quintiles (⬍30 and 60-ⱕ80 cm3) and for months 18-48 for the remaining quintiles (30-⬍40, 40-⬍50, and 50-⬍60 cm3; P ⬍ .01; Fig. 2A). Symptoms stabilized or improved in the dutasteride group in each prostate volume quintile during the study period. In contrast, symptoms deteriorated during the 48 months in the placebo group in each prostate volume quintile. According to the Kaplan-Meier analysis, the interval to the first episode of AUR or BPH-related surgery was significantly different in favor of dutasteride compared with placebo (P ⬍ .01; Fig. 3). At 48 months, 6.7% of men receiving placebo experienced AUR compared with 1.6% of men receiving dutasteride (77.3% risk reduction, 95% confidence interval 70.1-82.7; P ⬍ .001). Also, 5.1% of the placebo group required BPH-related surgery compared with 1.4% of the dutasteride group (73.0% risk reduction, 95% 643
Figure 2. Adjusted mean change from baseline in key parameters by visit and treatment group for prostate volume overall and stratified by prostate volume quintiles. (A) Adjusted mean change from baseline in IPSS by visit and treatment group. (B) Adjusted mean change from baseline in Qmax by visit and treatment group. (C) Adjusted mean change from baseline in QOLUS score (IPSS question 8) by visit and treatment group. (D) Adjusted mean change from baseline in BII by visit and treatment group. Number of patients: prostate volume overall, placebo ⫽ 4073, dutasteride ⫽ 4049; prostate volume ⬍30 cm3, placebo ⫽ 807, dutasteride ⫽ 774; prostate volume 30-⬍40 cm3, placebo ⫽ 896, dutasteride ⫽ 925; prostate volume 40-⬍50 cm3, placebo ⫽ 894, dutasteride ⫽ 878; prostate volume 50-⬍60 cm3, placebo ⫽ 675, dutasteride ⫽ 667; prostate volume 60-ⱕ80 cm3, placebo ⫽ 715, dutasteride ⫽ 698.
Figure 3. Kaplan-Meier plot of time to first episode of AUR or BPH-related surgery by treatment group.
confidence interval 63.8-79.9; P ⬍ .001). As previously published,10 dutasteride also significantly reduced the risk of time to first event of AUR, BPH-related surgery, and UTI compared with placebo. When analyzed by quintiles, the incidence of AUR or BPH-related surgery at 48 months was significantly less in the dutasteride group than in the placebo group in each prostate volume quintile (P ⬍ .01). The relative risk 644
reduction of developing AUR or undergoing BPH-related surgery in the dutasteride group compared with the placebo group was ⬎50% for each prostate volume quintile. At 48 months, the incidence of UTI was significantly less in the dutasteride group compared with the placebo group for the 40-⬍50, 50-⬍60, and 60-ⱕ80 cm3 quintiles (P ⬍ .01), with a relative risk reduction of 34% (30-⬍40cm3 quintile) to 45.6% (50-⬍60-cm3 quintile). UROLOGY 78 (3), 2011
Postbaseline Qmax measurements were obtained for 33.8% of the study participants (2749 of 8122). Dutasteride improved the Qmax compared with placebo, and the difference reached significance at 48 months. For prostate volume overall, the adjusted mean change for placebo was ⫺0.90 and for dutasteride was 0.41 at month 48 (P ⬍ .01; Fig. 2B). The Qmax decreased steadily during the 48-month study period in the placebo group. Dutasteride improved the quality-of-life score as measured in the IPSS questionnaire (QOLUS score, question 8) at 48 months compared with the score at baseline in patients overall and at any baseline prostate volume quintile (Fig. 2C). The difference in QOLUS score between the placebo and dutasteride groups was significant at month 48 within each prostate volume quintile (P ⬍ .01; Fig. 2C). Overall, the BII score was stable or improved in the dutasteride group but deteriorated through 48 months in the placebo group. The difference in the BII score between the placebo-treated and dutasteride-treated patients was statistically significant in all prostate volume quintiles from month 30 (P ⬍ .01; Fig. 2D) and at earlier points for some quintiles (from month 12 for a prostate volume of 60-ⱕ80 cm3, from month 18 for a prostate volume of 40-⬍50 cm3, and from month 24 for a prostate volume of ⬍30 and 50-⬍60). The nature and frequency of common adverse events with dutasteride were similar to those of previous studies of dutasteride in men with BPH.10
COMMENT These analyses of 4-year data from the REDUCE trial provide insights into the effect of dutasteride on BPH symptoms before the development of severe symptoms and on the natural history of disease progression in the placebo group. Dutasteride significantly improved symptoms over 48 months, as measured by the IPSS, regardless of prostate volume. In contrast, symptoms of the patients in the placebo group deteriorated during the same period. At 48 months, the adjusted mean change from baseline in prostate volume in the placebo group was ⫹19.7% and in the dutasteride group was ⫺17.5% (P ⬍ .001).10 Unlike in the Phase IIIa trials with dutasteride in which little increase in the total prostate volume was observed in the placebo group (mean change ⫹1.7 at 24 months),6 a substantial increase in the total prostate volume was observed in the placebo group (adjusted mean change of ⫹13 at 24 months) in the REDUCE trial. This was probably because the regression to the mean (in which the minimal prostate volume criterion typical of BPH trials leads to an artificial reduction in prostate volume during the trial) was minimal.15 The participants in the REDUCE study were selected on the basis of a PSA level of 2.5-10 ng/mL, age 50-75 years old, and negative biopsy findings within 6 months of study entry. The study selection criteria did not include the IPSS or prostate UROLOGY 78 (3), 2011
volume, except for an upper limit to the prostate volume of 80 cm3. The overall and stratified changes in IPSS, BII, and Qmax were also of interest. Normally, low or high thresholds are imposed for these parameters in BPH trials to ensure enrollment of patients with moderate to severe symptoms and obstructions. This results in greater mean IPSSs and BII scores and lower mean Qmax values at baseline. Thus, in most, if not all, BPH studies, a regression to the mean effect15 is observed by which the IPSS and BII at the next subsequent visit are lower (ie, “improved”) and the Qmax values are higher (“improved”). This has traditionally been labeled as the placebo effect; however, at least to some degree, it is a regression to the mean artifact.15 This makes studying the natural history of the disease from BPH trials difficult, if not impossible. In the REDUCE trial, no such criteria were used, and the enrollees had a low baseline IPSS and relatively high Qmax values, such that these would typically be expected to worsen. As seen in Figure 2, in the first of the 6 graphs in each panel, the overall trend in the placebo group was a worsening of the IPSS, QOLUS, and BII and a reduction in the Qmax, consistent with the natural history of the condition, but not a regression to the mean or “placebo” effect. In contrast, the dutasteride-treated patients experienced a measurable, albeit small, improvement in these parameters. The subsequent graphs in each panel show an increasing gap between the placebo- and dutasteride-treated patients, stratified by prostate volume. This suggests that with an increasing prostate volume, the natural history results in faster and more profound deterioration of the IPSS, BII, and Qmax, but the efficacy of dutasteride increases, even in a population that is not severely symptomatic. This is demonstrated in Figure 1, which shows the IPSS for all patients and stratified by baseline IPSS ⬍8 and/or IPSS ⱖ8 points. The graph for IPSS ⱖ8 points represents the expected outcome in a typical BPH study, with a regression to the mean in the placebo group, followed by a return to baseline, and a deep and lasting improvement in the dutasteride group. The reduction in prostate volume and improved urinary flow (as measured by the Qmax) achieved with dutasteride was accompanied by a significant decrease in the risk of AUR and BPH-related surgery, which were reduced by 77% and 73%, respectively, compared with placebo. These results are similar to the data obtained in the Combination of Avodart and Tamsulosin trial on the effect of dutasteride on clinical parameters and symptoms of BPH, although in that study, the risk reduction was measured against the ␣-blocker tamsulosin and not a placebo.7 These effects should be balanced against the sexual function adverse events seen in ⬍10% of patients receiving dutasteride, typically in the early months, with decreasing de novo incidence in the longer term.7,16 The significant 645
improvements in the BII and QOLUS scores suggest that the effect of dutasteride on clinical parameters translated into an improvement in quality of life for patients. The present analysis of the REDUCE data suggests that the fundamental observations regarding the risk of AUR and BPH-related surgery according to the serum PSA level and prostate volume hold true even in men with a symptom severity comparable to that observed in men enrolled in BPH trials. Before recommending treatment with dutasteride for less symptomatic patients, however, several factors should be carefully considered: (a) the cost of such treatment and the cost-effectiveness, (b) the benefit/risk ratio, and (c) the reduced degree of risk reduction in less symptomatic men. Nonetheless, given the demonstrated effects of dutatseride in reducing the risk of AUR and BPH-related surgery and in stabilizing or improving symptoms compared with the (nearly) inevitable symptom progression over time in untreated men, it is tempting to consider treatment intervention triggered by PSA- and prostate volume-based risk assessment independent of symptom severity. The potential limitations of the REDUCE trial for investigating the effect of dutasteride on BPH symptoms and outcome measures include the upper limit for both prostate volume and IPSS, as defined in the exclusion criteria, which aimed to reduce the incidence of retention and BPH-related surgery that would have reduced the number of men available for assessment of the primary endpoint. Therefore, the REDUCE population excluded men with severe symptoms and very large prostates which could have resulted in a regression to the mean toward lower symptom scores. The inclusion criteria included a lower limit for PSA values such that the REDUCE population had greater PSA values than a typical population. This could have led to artifacts in the behavior of the population with respect to the BPH outcomes.
CONCLUSIONS Over the 4-year period, dutasteride decreased the risk of BPH progression in men with mild-to-moderate symptoms and normal or enlarged prostates. The deterioration of BPH symptoms in the placebo group reflected the natural history of disease progression. Dutasteride not only reduces the incidence of prostate cancer in men at increased risk of prostate cancer,10 but also has the added benefit of improving BPH outcomes in this population. Acknowledgment. To Elaine Bell of Choice Pharma, who provided medical writing support in the form of writing the draft paper and preparing the figures and tables with funding from GlaxoSmithKline.
References 1. Anderson JB, Roehrborn CG, Schalken JA, et al. The progression of benign prostatic hyperplasia: examining the evidence and determining the risk. Eur Urol. 2001;39:390-399.
646
2. Emberton M, Andriole GL, de la Rosette J, et al. Benign prostatic hyperplasia: a progressive disease of aging men. Urology. 2003;61: 267-273. 3. McConnell JD, Roehrborn CG, Bautista OM, et al. The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med. 2003;349:2387-2398. 4. Madersbacher S, Marszalek M, Lackner J, et al. The long-term outcome of medical therapy for BPH. Eur Urol. 2007;51:1522-1533. 5. Roehrborn CG, Boyle P, Bergner D, et al, for the PLESS Study Group. Serum prostate-specific antigen and prostate volume predict long-term changes in symptoms and flow rate: results of a four-year, randomized trial comparing finasteride versus placebo. Urology. 1999;54:662-669. 6. Roehrborn CG, Boyle P, Nickel JC, et al. Efficacy and safety of a dual inhibitor of 5-alpha-reductase types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia. Urology. 2002;60:434-441. 7. Roehrborn CG, Siami P, Barkin J, et al. The effects of combination therapy with dutasteride and tamsulosin on clinical outcomes in men with symptomatic benign prostatic hyperplasia: 4-year results from the CombAT study. Eur Urol. 2010;57:123-131. 8. Lam JS, Romas NA, Lowe FC. Long-term treatment with finasteride in men with symptomatic benign prostatic hyperplasia: 10year follow-up. Urology. 2003;61:354-358. 9. 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 and Safety Study Group. N Engl J Med. 1998;338:557-563. 10. Andriole GL, Bostwick DG, Brawley OW, et al. Effect of dutasteride on the risk of prostate cancer. N Engl J Med. 2010;362:11921202. 11. Andriole G, Bostwick D, Brawley O, et al. Chemoprevention of prostate cancer in men at high risk: rationale and design of the reduction by dutasteride of prostate cancer events (REDUCE) trial. J Urol. 2004;172:1314-1317. 12. Fitzpatrick JM. The natural history of benign prostatic hyperplasia. BJU Int. 2006;97(suppl 2):3-6, 21-22. 13. Roehrborn CG, McConnell J, Bonilla J, et al. Serum prostate specific antigen is a strong predictor of future prostate growth in men with benign prostatic hyperplasia. Proscar long-term efficacy and safety study. J Urol. 2000;163:13-20. 14. Siami P, Roehrborn CG, Barkin J, et al. Combination therapy with dutasteride and tamsulosin in men with moderate-to-severe benign prostatic hyperplasia and prostate enlargement: the CombAT (Combination of Avodart and Tamsulosin) trial rationale and study design. Contemp Clin Trials. 2007;28:770-779. 15. Sech SM, Montoya JD, Bernier PA, et al. The so-called “placebo effect” in benign prostatic hyperplasia treatment trials represents partially a conditional regression to the mean induced by censoring. Urology. 1998;51:242-250. 16. Debruyne F, Barkin J, van Erps P, et al. Efficacy and safety of long-term treatment with the dual 5 alpha-reductase inhibitor dutasteride in men with symptomatic benign prostatic hyperplasia. Eur Urol. 2004;46:488-495.
EDITORIAL COMMENT The present article—a preplanned secondary analysis of the REduction by Dutasteride of Prostate Cancer Events (REDUCE) trial—provides unique insights into the natural history of lower urinary tract symptoms (LUTS), the risk of progression, and the effect of the dual 5␣-reductase inhibitor dutasteride in men with rather low symptoms at baseline and a greater risk of disease progression. In contrast to long-term medical benign prostatic hyperplasia (BPH) trials, patients were not recruited according to their degree of LUTS but on the risk UROLOGY 78 (3), 2011
METHODS
RESULTS
CONCLUSION
To investigate the effect of dutasteride versus placebo on the symptoms and associated complications of male lower urinary tract symptoms and benign prostatic hyperplasia (BPH) across a range of prostate volumes and BPH symptoms in men evaluated for prostate cancer risk reduction in the 4-year REduction by DUtasteride of prostate Cancer Events (REDUCE) trial. REDUCE was a multicenter, randomized, double-blind, placebo-controlled study of prostate cancer risk reduction with daily dutasteride 0.5 mg or placebo. Eligible men were aged 50-75 years, with a prostate-specific antigen level of 2.5-10 ng/mL and a prostate volume of ⱕ80 cm3. The prespecified and post hoc analyses were performed on the incidence of acute urinary retention, BPH-related surgery, and urinary tract infections, as well as on changes in prostate volume, International Prostate Symptom Score, BPH Impact Index, and maximal urinary flow rate (Qmax). A total of 8122 men were included in the efficacy population. During the 4-year study, the International Prostate Symptom Score increased in placebo-treated patients, while dutasteridetreated patients had a stabilized or decreased International Prostate Symptom Score and improved BPH Impact Index and quality of life due to urinary symptom scores across all prostate volume quintiles (including prostate glands smaller than those studied in previous dutasteride trials). 48 months, the incidence of acute urinary retention or BPH-related surgery was significantly less in the dutasteride group (2.5%) than in the placebo group (9%) overall (P ⬍ .001) and in each baseline prostate volume quintile (P ⬍ .01). During the 4-year study, dutasteride was associated with a decreased risk of BPH progression in men with mild-to-moderate symptoms and normal or enlarged prostates. UROLOGY 78: 641– 647, 2011. © 2011 Elsevier Inc.
B
enign prostatic hyperplasia (BPH) is a common chronic disease in aging men and is often associated with bothersome lower urinary tract symptoms. The disease is usually progressive and can result in
Funding Support: C. Roehrborn has received financial compensation as an adviser/ consultant/investigator from GlaxoSmithKline, Sanofi Aventis, Lilly, Neotract, AMS, and Pfizer. C. Nickel has received some financial compensation as a consultant/investigator from GlaxoSmithKline, Watson, Pfizer, and Johnson & Johnson, and financial compensation as a consultant/meeting participant from Astellas, and as a consultant from Toris, Foss Laboratories, and Triton. G. Andriole has received financial compensation as a consultant/ adviser from AEterna Zentaris, Amgen EMD Serono, Ferring Pharmaceuticals, GenProbe, Myriad Genetics, Nema Steba, Onconome, and Veridex; has stock ownership in Cambridge Enao, Envisioneering Medical and Viking Medical; and has received financial compensation as a consultant/adviser/member of the speaker’s bureau from GlaxoSmithKline. P. Gagnier, L. Black, T. H. Wilson, and R. Rittmaster are employees of GlaxoSmithKline.
© 2011 Elsevier Inc. All Rights Reserved
complications, such as acute urinary retention (AUR) and BPH-related surgery.1,2 5␣-reductase inhibitors reduce prostate volume, provide long-term relief of BPH symptoms, and lower the risk of long-term complications associated with BPH progression.3-7 Trials investigating the efficacy of 5␣Responsibility for the opinions, conclusions, and interpretation of data lies with the authors. From the Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas; Department of Urology, Queen’s University, Kingston General Hospital, Kingston, Ontario, Canada; Washington University School of Medicine, St. Louis, Missouri; and GlaxoSmithKline, Research Triangle Park, Durham, North Carolina Reprint requests: Claus G. Roehrborn, M.D., Univeristy of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390-9110. E-mail: [email protected] Submitted: February 21, 2011, accepted (with revisions): March 8, 2011
0090-4295/11/$36.00 doi:10.1016/j.urology.2011.03.063
641
reductase inhibitors in the treatment of BPH have usually been limited to men with moderate-to-severe BPH,6-9 making the study of the natural history of BPH progression challenging. The REduction by DUtasteride of prostate Cancer Events (REDUCE) trial investigated prostate cancer risk reduction and showed that over 48 months dutasteride reduced the risk of biopsy-detectable prostate cancer by 22.8% in men aged ⱖ50 years at increased risk of this disease as determined by a serum prostate-specific antigen (PSA) level ⬎2.5 ng/mL.10 BPH symptoms and complications were included as secondary endpoints in the trial. In contrast to most studies investigating the efficacy of 5␣-reductase inhibitors in the treatment of BPH, the REDUCE trial had no minimal inclusion criteria for BPH symptoms or prostate volume.11 An ideal population for studying the natural history of BPH would be a cohort of community dwelling men, such as those analyzed in the Olmsted County study. It is also possible to assess men in the placebo arms of BPH studies, although the inclusion and exclusion criteria have limited the extent to which such analyses can be applied to the general population.12 Thus, the evaluation of BPH-related symptoms and outcomes in men from the REDUCE trial might reflect the spectrum of disease severity and treatment in everyday clinical practice better than the clinical trials of BPH treatment. The men included in the REDUCE trial had elevated PSA values and, therefore, even in the absence of symptoms, could be at risk of BPH progression and complications.1,5,13,14 The REDUCE trial is an interesting vehicle from which to evaluate both the natural history of the disease and the effect of dutasteride on BPH outcomes in a trial in which the primary focus was not BPH symptoms or disease progression, in a population different from that studied in all previous dutasteride BPH studies. We report the prespecified and post hoc analyses of the effect of dutasteride compared with placebo on the symptoms and outcomes of BPH.
MATERIAL AND METHODS Participants The design of the REDUCE study has been previously reported.11 Eligible men were aged 50-75 years, had a serum PSA level of 2.5-10 ng/mL if 50-60 years old or 3.0-10 ng/mL if ⬎60 years old, and had undergone a single prostate biopsy (6-12 cores) with negative findings within 6 months before study enrollment. The use of ␣-blockers to control BPH-related symptoms was permitted, as clinically indicated. Men were not eligible if they had undergone previous prostate surgery, reported severe BPH-related symptoms on screening (International Prostate Symptom Score [IPSS] ⱖ25 or IPSS ⱖ20 if taking ␣-blockers), had a baseline prostate volume ⬎80 cm3, had a maximal urinary flow rate (Qmax) ⬍5 mL/s, or if the entry biopsy findings showed histologic evidence of prostate cancer or precancerous lesions in the prostate. 642
Study Design The REDUCE study was an international, 4-year, randomized, double-blind, placebo-controlled, parallel-group study designed to test the efficacy of dutasteride 0.5 mg, administered orally once daily, in reducing the risk of prostate cancer in men with an increased risk of this disease. After a 4-week placebo run-in, eligible patients were randomized to the treatment or placebo group. Protocol-dependent 10-core transrectal ultrasound-guided biopsies were performed at 2 and 4 years, with for-cause biopsies performed as required at other times. Prostate volume was measured on ultrasound at baseline and at 2 and 4 years. The Qmax was assessed at screening and annually throughout the study, and the IPSS was measured at screening and every 6 months. The incidence of acute urinary retention (AUR), BPH-related surgery, and urinary tract infections (UTIs) were recorded on the case report form every 6 months. In addition to assessing the IPSS (including question 8, the quality of life due to urinary symptoms [QOLUS] score), the BPH Impact Index (BII), which measures BPH-associated physical discomfort, worry, and bothersomeness, was administered at baseline and every 6 months. The BPH-related endpoints included the change in prostate volume, Qmax, and BPH symptom scores from baseline and the proportion of subjects who reported AUR, BPH-related surgery, or UTIs. Patients diagnosed with prostate cancer during the study discontinued the study drug and were interviewed by telephone 4 months later for a safety follow-up call; however, they were not necessarily withdrawn from the study. If these subjects chose to remain in the study, they returned for clinic visits every 6 months according to the original randomization schedule, and a safety follow-up telephone interview was completed 4 months after the last dose of the study drug. The mean study drug exposure was almost identical between the treatment groups, with a mean exposure of 1184 days in the placebo group compared with a mean exposure of 1190 days in the dutasteride group.
Statistical Analysis The efficacy population included all randomized subjects with an eligible entry prostate biopsy that had been reviewed centrally and who had received ⱖ1 dose of the study medication.10 All analyses were performed on the efficacy population, and a 2-sided P value with ␣ ⫽ 0.01 was used to define statistical significance. For the BPH-related endpoints, log-rank tests of the time to the first event of AUR, BPH-related surgery and UTI were performed and are displayed as Kaplan-Meier graphs for AUR and BPH-related surgery. The BPH-related endpoints were examined by prespecified subgroups according to the IPSS (⬍8 and ⱖ8) and post hoc subgroups according to prostate volume. The population was divided by the baseline prostate volume into convenience quintiles (ie, not exact percentage quintiles, but quintiles adjusted by rounding to increments of 10 cm3 [⬍30, 30-⬍40, 40-⬍50, 50-⬍60, and 60-ⱕ 80 cm3]), hereafter referred to as quintiles. This adjustment was performed to account for any differences in the baseline parameters between treatment groups within a quintile and for the ease of reporting and interpretation in a clinical setting. The IPSS, BII, QOLUS, and Qmax were analyzed using the last observation carried forward approach, as well as the observed cases approach to handle missing values. UROLOGY 78 (3), 2011
Table 1. Demographics and baseline characteristics Characteristic
Placebo (n ⫽ 4073)
Dutasteride (n ⫽ 4049)
62.7 ⫾ 6.09 3701 (91%) 8.6 ⫾ 5.61 45.8 ⫾ 18.80 5.91 ⫾ 2.00 15.3 ⫾ 15.48 46.3 ⫾ 48.00 2685 (66%) 2.1 ⫾ 1.38 2.2 ⫾ 2.43
62.7 ⫾ 6.02 3696 (91%) 8.7 ⫾ 5.70 45.7 ⫾ 17.91 5.92 ⫾ 1.97 15.2 ⫾ 12.04 46.7 ⫾ 48.67 2683 (66%) 2.1 ⫾ 1.34 2.2 ⫾ 2.44
Age (y) White Mean total IPSS* (score range 0-ⱖ25) Mean prostate volume† (cm3) Serum PSA‡ (ng/mL) Qmax§ (mL/s) Postvoid residual volume§ (mL) BPH as current medical condition¶ (%) QOLUS score§ (score range 0-6) BII score§ (score range 0-13)
Data presented mean ⫾ standard deviation for efficacy population. * Exclusion criterion was IPSS ⱖ25 or ⱖ 20 if taking ␣-blockers. † Exclusion criterion ⬎ 80 cm3. ‡ Inclusion criterion 2.5-10.0 ng/mL. § No inclusion/exclusion criteria. ¶ BPH as a medical condition recorded on case report form but no definition of BPH was provided to the physician.
Statistical analyses of the change from baseline for the continuous parameters (IPSS, BII, QOLUS, and Qmax) were performed with a general linear model using the t test. When the results were stratified by the baseline prostate volume quintiles, the mean values were adjusted to compensate for the difference in baseline values within a quintile between treatment groups. The relative risks were calculated using the Cox proportional hazards model.
RESULTS The efficacy population included 8122 men. The demographics and BPH-related baseline characteristics of the participants are listed Table 1. No major differences were found in the baseline characteristics between the treatment groups. The baseline characteristics showed that in general the men in the REDUCE trial had mild-tomoderate BPH symptoms, with slightly enlarged prostates, elevated PSA values, and Qmax values in the normal range. The mean IPSS at baseline was 8.6 in the placebo group and 8.7 in the dutasteride group. At 48 months, the mean score was 10 in the placebo group and 8.2 in the dutasteride group. The adjusted mean change in the IPSS from baseline in patients in the placebo group versus those in the dutasteride group was statistically significant (P ⬍ .01) from month 6 (⫺0.1 in the placebo group and ⫺0.42 in the dutasteride group) to month 48 (1.35 in the placebo group and ⫺0.46 in the dutasteride group; Fig. 1). This finding is noteworthy, because in the absence of a lower symptom threshold, no regression to the mean occurs; thus, no placebo effect is noted, rather a slow, but steady, worsening of symptoms.15 In patients with a baseline IPSS ⬍8, the symptom score for men receiving dutasteride therapy remained stable. In contrast, the symptom score for men receiving placebo deteriorated significantly from month 18 (Fig. 1; P ⬍ .01). As previously published,10 there was an increase in mean prostate volume in the placebo group and a decrease in the dutasteride group (⫹19.7% for placebo UROLOGY 78 (3), 2011
Figure 1. Adjusted mean change from baseline in IPSS by visit and treatment group, overall and stratified by baseline IPSS. Number of patients: IPSS overall, placebo ⫽ 4073, dutasteride ⫽ 4049; IPSS ⬍8, placebo ⫽ 1947, dutasteride ⫽ 1949; IPSS ⱖ8, placebo ⫽ 2038, dutasteride ⫽ 2014.
vs ⫺17.5% for dutasteride; P ⬍ .001). When the IPSS data were analyzed by baseline prostate volume quintiles, the difference between the placebo and dutasteride groups was statistically significant for months 12-48 for the lowest and highest volume quintiles (⬍30 and 60-ⱕ80 cm3) and for months 18-48 for the remaining quintiles (30-⬍40, 40-⬍50, and 50-⬍60 cm3; P ⬍ .01; Fig. 2A). Symptoms stabilized or improved in the dutasteride group in each prostate volume quintile during the study period. In contrast, symptoms deteriorated during the 48 months in the placebo group in each prostate volume quintile. According to the Kaplan-Meier analysis, the interval to the first episode of AUR or BPH-related surgery was significantly different in favor of dutasteride compared with placebo (P ⬍ .01; Fig. 3). At 48 months, 6.7% of men receiving placebo experienced AUR compared with 1.6% of men receiving dutasteride (77.3% risk reduction, 95% confidence interval 70.1-82.7; P ⬍ .001). Also, 5.1% of the placebo group required BPH-related surgery compared with 1.4% of the dutasteride group (73.0% risk reduction, 95% 643
Figure 2. Adjusted mean change from baseline in key parameters by visit and treatment group for prostate volume overall and stratified by prostate volume quintiles. (A) Adjusted mean change from baseline in IPSS by visit and treatment group. (B) Adjusted mean change from baseline in Qmax by visit and treatment group. (C) Adjusted mean change from baseline in QOLUS score (IPSS question 8) by visit and treatment group. (D) Adjusted mean change from baseline in BII by visit and treatment group. Number of patients: prostate volume overall, placebo ⫽ 4073, dutasteride ⫽ 4049; prostate volume ⬍30 cm3, placebo ⫽ 807, dutasteride ⫽ 774; prostate volume 30-⬍40 cm3, placebo ⫽ 896, dutasteride ⫽ 925; prostate volume 40-⬍50 cm3, placebo ⫽ 894, dutasteride ⫽ 878; prostate volume 50-⬍60 cm3, placebo ⫽ 675, dutasteride ⫽ 667; prostate volume 60-ⱕ80 cm3, placebo ⫽ 715, dutasteride ⫽ 698.
Figure 3. Kaplan-Meier plot of time to first episode of AUR or BPH-related surgery by treatment group.
confidence interval 63.8-79.9; P ⬍ .001). As previously published,10 dutasteride also significantly reduced the risk of time to first event of AUR, BPH-related surgery, and UTI compared with placebo. When analyzed by quintiles, the incidence of AUR or BPH-related surgery at 48 months was significantly less in the dutasteride group than in the placebo group in each prostate volume quintile (P ⬍ .01). The relative risk 644
reduction of developing AUR or undergoing BPH-related surgery in the dutasteride group compared with the placebo group was ⬎50% for each prostate volume quintile. At 48 months, the incidence of UTI was significantly less in the dutasteride group compared with the placebo group for the 40-⬍50, 50-⬍60, and 60-ⱕ80 cm3 quintiles (P ⬍ .01), with a relative risk reduction of 34% (30-⬍40cm3 quintile) to 45.6% (50-⬍60-cm3 quintile). UROLOGY 78 (3), 2011
Postbaseline Qmax measurements were obtained for 33.8% of the study participants (2749 of 8122). Dutasteride improved the Qmax compared with placebo, and the difference reached significance at 48 months. For prostate volume overall, the adjusted mean change for placebo was ⫺0.90 and for dutasteride was 0.41 at month 48 (P ⬍ .01; Fig. 2B). The Qmax decreased steadily during the 48-month study period in the placebo group. Dutasteride improved the quality-of-life score as measured in the IPSS questionnaire (QOLUS score, question 8) at 48 months compared with the score at baseline in patients overall and at any baseline prostate volume quintile (Fig. 2C). The difference in QOLUS score between the placebo and dutasteride groups was significant at month 48 within each prostate volume quintile (P ⬍ .01; Fig. 2C). Overall, the BII score was stable or improved in the dutasteride group but deteriorated through 48 months in the placebo group. The difference in the BII score between the placebo-treated and dutasteride-treated patients was statistically significant in all prostate volume quintiles from month 30 (P ⬍ .01; Fig. 2D) and at earlier points for some quintiles (from month 12 for a prostate volume of 60-ⱕ80 cm3, from month 18 for a prostate volume of 40-⬍50 cm3, and from month 24 for a prostate volume of ⬍30 and 50-⬍60). The nature and frequency of common adverse events with dutasteride were similar to those of previous studies of dutasteride in men with BPH.10
COMMENT These analyses of 4-year data from the REDUCE trial provide insights into the effect of dutasteride on BPH symptoms before the development of severe symptoms and on the natural history of disease progression in the placebo group. Dutasteride significantly improved symptoms over 48 months, as measured by the IPSS, regardless of prostate volume. In contrast, symptoms of the patients in the placebo group deteriorated during the same period. At 48 months, the adjusted mean change from baseline in prostate volume in the placebo group was ⫹19.7% and in the dutasteride group was ⫺17.5% (P ⬍ .001).10 Unlike in the Phase IIIa trials with dutasteride in which little increase in the total prostate volume was observed in the placebo group (mean change ⫹1.7 at 24 months),6 a substantial increase in the total prostate volume was observed in the placebo group (adjusted mean change of ⫹13 at 24 months) in the REDUCE trial. This was probably because the regression to the mean (in which the minimal prostate volume criterion typical of BPH trials leads to an artificial reduction in prostate volume during the trial) was minimal.15 The participants in the REDUCE study were selected on the basis of a PSA level of 2.5-10 ng/mL, age 50-75 years old, and negative biopsy findings within 6 months of study entry. The study selection criteria did not include the IPSS or prostate UROLOGY 78 (3), 2011
volume, except for an upper limit to the prostate volume of 80 cm3. The overall and stratified changes in IPSS, BII, and Qmax were also of interest. Normally, low or high thresholds are imposed for these parameters in BPH trials to ensure enrollment of patients with moderate to severe symptoms and obstructions. This results in greater mean IPSSs and BII scores and lower mean Qmax values at baseline. Thus, in most, if not all, BPH studies, a regression to the mean effect15 is observed by which the IPSS and BII at the next subsequent visit are lower (ie, “improved”) and the Qmax values are higher (“improved”). This has traditionally been labeled as the placebo effect; however, at least to some degree, it is a regression to the mean artifact.15 This makes studying the natural history of the disease from BPH trials difficult, if not impossible. In the REDUCE trial, no such criteria were used, and the enrollees had a low baseline IPSS and relatively high Qmax values, such that these would typically be expected to worsen. As seen in Figure 2, in the first of the 6 graphs in each panel, the overall trend in the placebo group was a worsening of the IPSS, QOLUS, and BII and a reduction in the Qmax, consistent with the natural history of the condition, but not a regression to the mean or “placebo” effect. In contrast, the dutasteride-treated patients experienced a measurable, albeit small, improvement in these parameters. The subsequent graphs in each panel show an increasing gap between the placebo- and dutasteride-treated patients, stratified by prostate volume. This suggests that with an increasing prostate volume, the natural history results in faster and more profound deterioration of the IPSS, BII, and Qmax, but the efficacy of dutasteride increases, even in a population that is not severely symptomatic. This is demonstrated in Figure 1, which shows the IPSS for all patients and stratified by baseline IPSS ⬍8 and/or IPSS ⱖ8 points. The graph for IPSS ⱖ8 points represents the expected outcome in a typical BPH study, with a regression to the mean in the placebo group, followed by a return to baseline, and a deep and lasting improvement in the dutasteride group. The reduction in prostate volume and improved urinary flow (as measured by the Qmax) achieved with dutasteride was accompanied by a significant decrease in the risk of AUR and BPH-related surgery, which were reduced by 77% and 73%, respectively, compared with placebo. These results are similar to the data obtained in the Combination of Avodart and Tamsulosin trial on the effect of dutasteride on clinical parameters and symptoms of BPH, although in that study, the risk reduction was measured against the ␣-blocker tamsulosin and not a placebo.7 These effects should be balanced against the sexual function adverse events seen in ⬍10% of patients receiving dutasteride, typically in the early months, with decreasing de novo incidence in the longer term.7,16 The significant 645
improvements in the BII and QOLUS scores suggest that the effect of dutasteride on clinical parameters translated into an improvement in quality of life for patients. The present analysis of the REDUCE data suggests that the fundamental observations regarding the risk of AUR and BPH-related surgery according to the serum PSA level and prostate volume hold true even in men with a symptom severity comparable to that observed in men enrolled in BPH trials. Before recommending treatment with dutasteride for less symptomatic patients, however, several factors should be carefully considered: (a) the cost of such treatment and the cost-effectiveness, (b) the benefit/risk ratio, and (c) the reduced degree of risk reduction in less symptomatic men. Nonetheless, given the demonstrated effects of dutatseride in reducing the risk of AUR and BPH-related surgery and in stabilizing or improving symptoms compared with the (nearly) inevitable symptom progression over time in untreated men, it is tempting to consider treatment intervention triggered by PSA- and prostate volume-based risk assessment independent of symptom severity. The potential limitations of the REDUCE trial for investigating the effect of dutasteride on BPH symptoms and outcome measures include the upper limit for both prostate volume and IPSS, as defined in the exclusion criteria, which aimed to reduce the incidence of retention and BPH-related surgery that would have reduced the number of men available for assessment of the primary endpoint. Therefore, the REDUCE population excluded men with severe symptoms and very large prostates which could have resulted in a regression to the mean toward lower symptom scores. The inclusion criteria included a lower limit for PSA values such that the REDUCE population had greater PSA values than a typical population. This could have led to artifacts in the behavior of the population with respect to the BPH outcomes.
CONCLUSIONS Over the 4-year period, dutasteride decreased the risk of BPH progression in men with mild-to-moderate symptoms and normal or enlarged prostates. The deterioration of BPH symptoms in the placebo group reflected the natural history of disease progression. Dutasteride not only reduces the incidence of prostate cancer in men at increased risk of prostate cancer,10 but also has the added benefit of improving BPH outcomes in this population. Acknowledgment. To Elaine Bell of Choice Pharma, who provided medical writing support in the form of writing the draft paper and preparing the figures and tables with funding from GlaxoSmithKline.
References 1. Anderson JB, Roehrborn CG, Schalken JA, et al. The progression of benign prostatic hyperplasia: examining the evidence and determining the risk. Eur Urol. 2001;39:390-399.
646
2. Emberton M, Andriole GL, de la Rosette J, et al. Benign prostatic hyperplasia: a progressive disease of aging men. Urology. 2003;61: 267-273. 3. McConnell JD, Roehrborn CG, Bautista OM, et al. The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med. 2003;349:2387-2398. 4. Madersbacher S, Marszalek M, Lackner J, et al. The long-term outcome of medical therapy for BPH. Eur Urol. 2007;51:1522-1533. 5. Roehrborn CG, Boyle P, Bergner D, et al, for the PLESS Study Group. Serum prostate-specific antigen and prostate volume predict long-term changes in symptoms and flow rate: results of a four-year, randomized trial comparing finasteride versus placebo. Urology. 1999;54:662-669. 6. Roehrborn CG, Boyle P, Nickel JC, et al. Efficacy and safety of a dual inhibitor of 5-alpha-reductase types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia. Urology. 2002;60:434-441. 7. Roehrborn CG, Siami P, Barkin J, et al. The effects of combination therapy with dutasteride and tamsulosin on clinical outcomes in men with symptomatic benign prostatic hyperplasia: 4-year results from the CombAT study. Eur Urol. 2010;57:123-131. 8. Lam JS, Romas NA, Lowe FC. Long-term treatment with finasteride in men with symptomatic benign prostatic hyperplasia: 10year follow-up. Urology. 2003;61:354-358. 9. 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 and Safety Study Group. N Engl J Med. 1998;338:557-563. 10. Andriole GL, Bostwick DG, Brawley OW, et al. Effect of dutasteride on the risk of prostate cancer. N Engl J Med. 2010;362:11921202. 11. Andriole G, Bostwick D, Brawley O, et al. Chemoprevention of prostate cancer in men at high risk: rationale and design of the reduction by dutasteride of prostate cancer events (REDUCE) trial. J Urol. 2004;172:1314-1317. 12. Fitzpatrick JM. The natural history of benign prostatic hyperplasia. BJU Int. 2006;97(suppl 2):3-6, 21-22. 13. Roehrborn CG, McConnell J, Bonilla J, et al. Serum prostate specific antigen is a strong predictor of future prostate growth in men with benign prostatic hyperplasia. Proscar long-term efficacy and safety study. J Urol. 2000;163:13-20. 14. Siami P, Roehrborn CG, Barkin J, et al. Combination therapy with dutasteride and tamsulosin in men with moderate-to-severe benign prostatic hyperplasia and prostate enlargement: the CombAT (Combination of Avodart and Tamsulosin) trial rationale and study design. Contemp Clin Trials. 2007;28:770-779. 15. Sech SM, Montoya JD, Bernier PA, et al. The so-called “placebo effect” in benign prostatic hyperplasia treatment trials represents partially a conditional regression to the mean induced by censoring. Urology. 1998;51:242-250. 16. Debruyne F, Barkin J, van Erps P, et al. Efficacy and safety of long-term treatment with the dual 5 alpha-reductase inhibitor dutasteride in men with symptomatic benign prostatic hyperplasia. Eur Urol. 2004;46:488-495.
EDITORIAL COMMENT The present article—a preplanned secondary analysis of the REduction by Dutasteride of Prostate Cancer Events (REDUCE) trial—provides unique insights into the natural history of lower urinary tract symptoms (LUTS), the risk of progression, and the effect of the dual 5␣-reductase inhibitor dutasteride in men with rather low symptoms at baseline and a greater risk of disease progression. In contrast to long-term medical benign prostatic hyperplasia (BPH) trials, patients were not recruited according to their degree of LUTS but on the risk UROLOGY 78 (3), 2011