Alpha-BlockerTherapy Can Be Withdrawn in the Majority of Men Following Initial CombinationTherapy with the Dual 5a-Reductase Inhibitor Dutasteride

European Urology European Urology 44 (2003) 461 466 Alpha-BlockerTherapy Can Be Withdrawn in the Majority of Men Following Initial CombinationTherapy with the Dual 5a-Reductase Inhibitor Dutasteride J. Barkin a,*, M. Guimarães b, G. Jacobi c, D. Pushkar d, S. Taylor e, O.B. van Vierssen Trip f on behalf of the SMART-1 Investigator Group 1 a Humber River Regional Hospital/The Male Health Centres CMX, Suite 404, 960 Lawrence Avenue West, Toronto, ON, Canada M6A 3B5 b Servico de Urologia Hospital de Santa Luzia, Viana do Castelo, Portugal c Praxis Dr Jacobi, Duisburg, Germany d Moscow State Medical Stomatological University, Urology Department, Moscow, Russia e Chorley Clinical Research Centre, Synexus Ltd., Chorley, Lancashire, UK f Poli Urologie, Ziekenhuis Gelderse Vallei, Ede, The Netherlands First published online 29 July 2003 Abstract Objectives: The Symptom Management After Reducing Therapy (SMART-1) study examined the combination of the dual action 5a-reductase inhibitor (5ARI) dutasteride, and a 1 -blocker tamsulosin, followed by withdrawal of tamsulosin in men with symptomatic BPH. Methods: 327 BPH patients were randomised to 0.5 mg dutasteride and 0.4 mg tamsulosin for 36 weeks () or 0.5 mg dutasteride and 0.4 mg tamsulosin for 24 weeks followed by dutasteride and tamsulosin matched placebo for the remaining 12 weeks (DT24 þ D12). Patients assessment of their symptoms, IPSS at weeks 24, 30, and drug safety were evaluated. Results: 77% of DT24 þ D12 patients felt the same/better at week 30 compared with week 24 (changes in IPSS were consistent with this finding). Of those subjects with an IPSS <20 who changed to dutasteride monotherapy at week 24, 84% switched without a noticeable deterioration in their symptoms. In the 27% 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 group. The regimens were well tolerated. Conclusions: Dutasteride can be used in a 24-week combination with tamsulosin, to achieve rapid onset of symptom relief in patients at risk of underlying disease progression. This symptom relief is maintained in the majority of patients after the a 1 -blocker is removed from the combination. Patients with severe symptoms may benefit from longer-term combination therapy. # 2003 Elsevier B.V. All rights reserved. Keywords: Dutasteride; Tamsulosin; Combination therapy; BPH 1. Introduction Data from both longitudinal studies, and the placebo arms of clinical trials, have shown that benign prostatic * Corresponding author. Tel. þ1-416-256-2737; Fax: þ1-416-256-6095. E-mail address: j.barkin@rogers.com (J. Barkin). 1 Members of the SMART-1 Investigator Group are listed in the Appendix A. hyperplasia (BPH) is a progressive disease in many men [1 3]. Prostate volume increases with advancing age: a change that is associated with decreased urinary flow, increasing symptom severity, increased risks of acute urinary retention (AUR) and the need for BPH-related surgery [1 3]. Currently, two therapeutic drug classes with differing modes of action provide the mainstay of pharmacotherapy for BPH. 5a-reductase inhibitors (5ARIs) 0302-2838/$ see front matter # 2003 Elsevier B.V. All rights reserved. doi:10.1016/s0302-2838(03)00367-1

462 J. Barkin et al. / European Urology 44 (2003) 461 466 impede the conversion of testosterone to dihydrotestosterone (DHT), which is the primary androgen driving both normal prostate development, and the hyperplasia of the prostatic transitional zone that is responsible for the development of BPH. The dual-action 5ARI dutasteride, which inhibits both the type 1 and 2 isoforms of 5AR, has been shown to achieve 90% DHT suppression in >85% of subjects [4]. 5ARIs have been shown to significantly reduce total and transitional zone prostate volume in men with BPH and enlarged prostates (>30 cc) compared with placebo. This reduction in the static component of bladder outlet obstruction (BOO) results in significant improvements in lower urinary tract symptoms (LUTS) and maximum urinary flow rate (Q max ). Furthermore, long-term, placebo-controlled studies have shown that 5ARIs significantly reduce the risk of both AUR and BPH-related surgery in men with BPH [3,5,6]. a 1 -adrenoceptor blockers target the dynamic component of BOO by decreasing smooth muscle tone in the prostate gland, prostatic capsule, prostatic urethra and bladder [7]. The dynamic component accounts for up to 40% of the obstruction seen in BPH [8]. Although a 1 -blocker therapy is associated with a rapid onset of symptom relief and improvement in Q max in men with BPH, they lack the effect of the 5ARIs on prostate volume. This may explain the finding that a 1 -blockers can delay AUR or the need for BPH-related surgery, but they do not lower the long-term risk of these events [6]. Their inability to reduce prostate volume may also account for the finding that rates of treatment failure with a 1 -blockers are higher in men with larger (>40 cc), versus smaller prostate volumes [8,9]. Improvements in symptoms observed with 5ARIs may not be observed until 3 6 months of therapy. This suggests an initial short-term role for a 1 -blockers in men for whom a more rapid onset of symptom relief is required, with withdrawal of the a 1 -blocker following an initial period of combination therapy. Baseline, long-term therapy with a 5ARI is maintained to reduce prostate volume and positively impact on the long-term risk of BPH progression, reducing the risk of AUR- and BPH-related surgery. This hypothesis has been examined in a study in which 111 men with a prostate mass 40 g, and severe symptoms (International Prostate Symptom Score, IPSS 20) were initially treated with both finasteride and doxazosin [10]. Of these, 100 responded to treatment, and a 1 -blocker-therapy was withdrawn at 3, 6, 9 or 12 months. Success rates (defined as no increase in IPSS and responding no to the question Would you like to restart the doxazosin? ) for discontinuation were 20%, 48%, 84% and 84% respectively, suggesting that, for this severe patient population, a period of nine months or more of combination therapy was preferable. The primary objective of the Symptom Management After Reducing Therapy (SMART-1) study was to investigate whether men with symptomatic BPH, who are at higher risk of progression due to an enlarged prostate, receiving a combination of the dual-action 5ARI dutasteride and the a 1 -blocker tamsulosin, would experience deterioration in their symptoms following withdrawal of the a 1 -blocker. SMART-1 was designed to provide information that would be of use for clinicians making decisions on how to manage combination therapy in men with BPH. 2. Subjects and methods 2.1. Subjects The SMART-1 Phase 3B clinical study was conducted at 32 centres in six countries: Canada, Germany, the Netherlands, Portugal, Russia and the UK. Patients at risk for BPH progression were recruited into the study. Inclusion criteria were: 45 years of age or over with a diagnosis of BPH, including moderate to severe urinary symptoms (IPSS 12) and a prostate volume 30 cc as determined by digital rectal examination (DRE). Patients with a prostate-specific antigen (PSA) value <1.5 ng/ml or >10 ng/ml were excluded from the study. A schematic of the study design is shown in Fig. 1. 2.2. Methods All study subjects entered a single-blind phase consisting of a 4 week placebo run-in followed by randomisation and treatment with a combination of 0.5 mg dutasteride and 0.4 mg tamsulosin daily for 24-weeks. At week 24 patients entered the double-blind phase, and in accordance with the pre-determined randomisation either continued the co-prescription treatment for a further 12 weeks (group ) or switched to dutasteride monotherapy plus placebotamsulosin (group DT24 þ D12). All patients then underwent a further 1-week single-blind washout placebo phase to monitor any rebound effects of the tamsulosin withdrawal in the group. Placebo run-in 4 weeks Single-blind Combination 0.5 mg dutasteride + 0.4 mg tamsulosin once daily 24 weeks Single-blind 0.5 mg dutasteride + tamsulosin placebo Combination 12 weeks Double-blind Placebo 1 week Singleblind Fig. 1. SMART-1 study design. DT24 þ D12: dutasteride and tamsulosin combination therapy for 24 weeks followed by 12 weeks of dutasteride monotherapy and tamsulosin placebo. : dutasteride and tamsulosin combination therapy for 36 weeks.

J. Barkin et al. / European Urology 44 (2003) 461 466 463 The primary study endpoint was the proportion of subjects in each treatment group experiencing an improvement or no change in their urinary symptoms between weeks 24 and 30 post-baseline. This was measured according to the response at Week 30 to the question: Over the past 2 weeks, on average have you felt better, worse or the same with respect to your urinary symptoms, than at your last visit? This question was asked at each post-baseline visit (weeks 4, 12, 24, 30 and 36) to keep subjects blinded to thetiming of any potential change in therapy at week 24. The main secondary endpoints of the study were: mean change in the International Prostate Symptom Score (IPSS); the proportion of patients with no change or an improvement in IPSS following withdrawal of tamsulosin; and mean change in the QOL score of the IPSS. The QOL question in the IPSS questionnaire is: If you were to spend the rest of your life with your urinary condition just the way it is now, how would you feel about that? which was scored as 0 6 for delighted to terrible. In addition to these endpoints, safety and tolerability of the treatment arms were evaluated by monitoring adverse events, clinical laboratory tests, serum PSA, and by routine physical examination. 2.3. Statistical analyses For this study, it was estimated that a total of 250 subjects would be sufficient to demonstrate efficacy of dutasteride similar to combination therapy to within 20% for the primary endpoint. This was based on a 50% responder rate (response was defined as feeling better or the same at week 30 compared with week 24), and allowing for a 20% drop-out rate. The primary efficacy population for the weeks 30 and 36 assessments included all subjects that completed the week 24 assessment. The proportion of these subjects in each treatment group reporting an improvement or no change in their urinary symptoms at week 30 was analysed using a Mantel-Haenszel test controlling for investigator country. A 95% confidence interval was used to conclude if dutasteride monotherapy was no worse than continued combination treatment. This method was repeated for the week 36 assessment. 3. Results 3.1. Baseline demographics and study conduct A total of 327 subjects were included in the two treatment arms. The two study groups were comparable for mean baseline age (67:6 7:1 and66:9 7:5 years), IPSS (16:4 5:8 and 16:5 5:2) and serum PSA level (4:3 2:2 and 4:3 2:3 ng/ml, for the and DT24 þ D12 groups, respectively). A total of 154 (94%) and 151 (93%) subjects from the and the DT24 þ D12 groups completed the first 24 weeks of the study. Ninety-one percent of subjects from both treatment groups completed the 36-week study. The most common reason for discontinuation in weeks 0 24 of the study was an adverse event (4% in each group). During weeks 24 36 only one of the discontinuations (<1%) was due to an adverse event. 3.2. Primary endpoint The proportions of subjects who responded feeling better/same or worse at week 30 are shown in Fig. 2. Patients (%) 100 80 60 40 20 0 91% 9% % Subjects better/same % Subjects worse 77% 23% (n=153) (n =149) Fig. 2. Primary endpoint question at week 30. At week 30, 77% of subjects in the DT24 þ D12 group, where tamsulosin therapy was withdrawn at week 24 leaving dutasteride monotherapy for weeks 24 36, reported feeling the better/same with respect to their urinary symptoms at week 30 compared with their previous visit at week 24. The equivalent figure for subjects who continued on combination therapy () was 91% (95% C.I. 18%, 4%; p ¼ 0:001 versus DT24 þ D12 group). Symptom control continued to be maintained/improved for up to 12 weeks of follow-on dutasteride monotherapy, with 93% of the subjects in the DT24 þ D12 group who felt better/same at week 30 also feeling better/same at week 36, compared with 96% for subjects in the group. Seventy-three percent of subjects assessed at week 30 had moderate symptoms at baseline (IPSS <20). Of those subjects with an IPSS <20 who changed to dutasteride monotherapy at week 24, 84% switched without a noticeable deterioration in their symptoms (Fig. 3). In those subjects with severe baseline symptoms Patients (%) 100 80 60 40 20 0 Moderate (Baseline IPSS <20) (n=220) 93% 84% 7% (n=111) 16% (n=109) % Subjects better/same % Subjects worse Severe (Baseline IPSS 20) (n=82) 86% 14% (n=42) 57.5% 42.5% (n=40) Fig. 3. Primary endpoint question at week 30 according to baseline symptom score (IPSS).

464 J. Barkin et al. / European Urology 44 (2003) 461 466 Total IPSS score 19 17 15 13 11 9 7 5 3 1 16.5 16.4 Baseline 12.6 12.0 11.4 Alpha 1 -blocker withdrawn (IPSS 20) who had withdrawal of tamsulosin therapy at week 24, 42.5% reported a worsening of their symptoms compared with 14% in the group. 3.3. Secondary endpoints The means of the symptoms scores (IPSS) for the two study groups at baseline and weeks 4, 12, 24, 30 and 36 are shown in Fig. 4. The mean IPSS improved substantially between baseline and week 4 in both study groups, with further but smaller improvements occurring until week 24. From weeks 24 to 36, the group experienced a decrease in IPSS. A small decrease was also seen between weeks 24 and 36 in the DT24 þ D12 group, but this followed a transient increase in mean IPSS between weeks 24 and 30, following discontinuation of tamsulosin. Overall, relative to baseline, 79% and 86% of patients in the DT24 þ D12 and groups respectively maintained or improved their IPSS by week 30. At week 36, these figures were 85% and 88% respectively. In order to further investigate the possibility that the transient increase in IPSS seen in the DT24 þ D12 group at week 30 was due to increases in subjects with severe baseline symptoms, the IPSS scores were examined by baseline symptom severity. These data showed a mean increase in IPSS of 0.6 in subjects with a baseline IPSS <20 (moderate symptoms) versus 2.8 in subjects with a baseline IPSS of 20 (severe symptoms). Overall patients who reported feeling better on the primary endpoint question at week 30 had a median change in IPSS of 2.0 (interquartile range 4.0, 0.0), patients who reported feeling worse showed a median increase in IPSS of 4.0 (interquartile range 2.0, 9.5), and there was little change (median of 0.0) in IPSS for those patients who reported that they felt the same (interquartile range 1.0, 2.0). There was a mean improvement in the IPSS quality of life question from baseline for all patients, which 11.2 11.0 11.0 12.2 10.8 11.1 10.3 Week 4 Week 12 Week 24 Week 30 Week 36 Fig. 4. Mean total IPSS (at visit) for groups receiving combination therapy for 36 weeks () and those in whom tamsulosin was withdrawn at 24 weeks ( þ D12). Table 1 The most commonly reported adverse events between baseline and week 24 and between weeks 24 and 36 was seen from week 4 (mean change in both treatment groups combined, 0.6). At week 24, there were equivalent improvements in the quality-of-life score of 1.0 in both treatment groups. At week 36, both treatment groups had an equivalent improvement of 1.1 compared with baseline. 3.4. Safety The incidence of drug-related adverse events was 25% for all patients between baseline and week 24 and 7% and 3% for the and DT24 þ D12 groups respectively between weeks 24 and 36. The most commonly reported adverse events in the two treatment groups are shown in Table 1. As expected, treatment with dutasteride resulted in reductions in serum prostate specific antigen (PSA) levels. There was a median percentage decrease from baseline to week 36 of 50% for subjects receiving dutasteride in either treatment group. The PSA doubling factor that is recommended for subjects receiving dutasteride therapy for more than 6 months is therefore also valid for those receiving a combination of dutasteride and tamsulosin. 4. Discussion (n ¼ 164) (%) DT24 þ D12 (n ¼ 163) (%) Events between baseline and week 24 (5% within either treatment group) Ejaculation disorders 7 7 Decreased libido 4 6 Impotence 5 2 Malaise and fatigue 6 2 Events between weeks 24 and 36 (2% within either treatment group) Dysuria 2 2 Urinary frequency 1 2 Urinary infections 2 Ejaculation disorders 1 2 Musculoskeletal pain 2 2 Viral respiratory tract infection 2 2 p ¼ ns between treatment groups for all events. This study defines a role for the addition of short-term (6 months) a 1 -blocker therapy, to a foundation of 5ARI therapy, in providing symptomatic improvement among patients who require rapid symptom relief to cover the lag in onset of symptom relief seen with 5ARI monotherapy. The primary finding from this study is that in men with BPH initially treated with a combination of dutasteride and tamsulosin, the a 1 -blocker can be withdrawn in the majority of patients (77%) after 6 months

J. Barkin et al. / European Urology 44 (2003) 461 466 465 with maintenance or improvement of symptom relief, as judged by the patients themselves. These findings are concordant with those of Baldwin et al., who observed that a 1 -blocker therapy could be withdrawn in the majority of men (84%) following 9 or 12 months of combination therapy [10]. In men with an enlarged prostate (>30 cc) and a serum PSA >1.5 ng/ml, who are therefore at greater risk of BPH progression, 5ARI monotherapy provides the foundation for long-term reductions in the risks of AUR and BPH-related surgery, and sustainable improvements in symptoms, urinary flow and quality of life mediated through a reduction in prostate volume. The IPSS data appear to be concordant with the primary endpoint, with subjects withdrawn from a 1 -blocker therapy maintaining symptom relief at 36 weeks compared with their pre-withdrawal symptom score at 24 weeks. Interestingly, perception of improvement is associated with smaller absolute changes in IPSS than perception of deterioration. The mean and median change for patients who felt better was similar at 2.0 to the mean of 1.9 units estimated by Barry et al. [11]. The median for patients with deterioration of þ4.0 units corresponds to the definition of symptom deterioration used in the MTOPS study [6]. These IPSS data demonstrate that the combination of an a 1 -blocker and a 5ARI is effective in lowering and maintaining symptom scores for six months, but that these benefits can be maintained with dutasteride monotherapy in the majority of men after this initial period. However, although the majority of patients maintained symptom relief following withdrawal of the alpha-blocker, it seemed that a small proportion of patients benefited from longer combination treatment (represented by the difference between the 91% of patients in the group whose symptoms were maintained or improved at week 30 versus 77% in the group where tamsulosin was withdrawn). The analysis of the primary endpoint by baseline symptom severity presented in Fig. 3 shows that patients with severe baseline symptoms report a higher rate of worsening of symptoms when the a 1 -blocker therapy is withdrawn compared with patients with moderate symptoms (42.5% versus 16%). The IPSS data appear to support this in that, between weeks 24 and 36, subjects receiving dutasteride monotherapy experienced a transient rise in mean symptom score at week 30, which appears to be largely due to a sizeable increase in subjects with severe baseline symptoms. This suggests that this subgroup of patients (27% in this study) may benefit from longer-term combination therapy. However, this study did not evaluate the benefit of combination therapy beyond 6 months. Data from three recently published placebo-controlled Phase 3 clinical trials with the dual-action 5ARI dutasteride demonstrate significant decreases in total and transitional zone prostate volume at 1, 3 and 6 months versus baseline, with this improvement continuing at 12 and 24 months [5]. The finding that decreases in prostate volume are still occurring beyond six months suggests that in at least some patients with severe baseline symptoms, the a 1 -blocker could be withdrawn after a longer period (>6 months) of combination therapy. The benefit of longer term combination in selected patients is supported by the study by Baldwin et al. [10]. In this group of men with severe symptoms, increasing duration of combination therapy prior to withdrawal of the a 1 -blocker predicted a better outcome with up to 84% perceiving no deterioration after a 1 -blocker (2 mg) withdrawal at 9 and 12 months compared with 48% at 6 months. Additionally, the Medical Therapy of Prostatic Symptoms (MTOPS) study [6], which randomised 3047 men with BPH to 4 years of treatment with placebo, doxazosin, finasteride or a combination of doxazosin and finasteride, shows that there are additive benefits of receiving long-term combination treatment with a 5ARI and an a 1 -blocker. Symptom deterioration resulting from underlying BPH progression was observed to be less in patients receiving the combination than with those receiving either monotherapy singly. The 5ARI, but not the a 1 -blocker, was shown to significantly reduce prostate volume and lower the risk of AUR and surgery compared with placebo. In patients receiving a 1 -blocker monotherapy, prostate volume continued to grow at a similar rate to placebo. Taken together these studies suggest 5ARIs are the foundation of BPH treatment for men with enlarged prostates, who are at greater risk of BPH progression. However, in some patients the addition of an a 1 -blocker for rapid symptom relief is warranted. Overall, the combination of dutasteride and tamsulosin was well tolerated in SMART-1. This is concordant with the findings of the MTOPS study, which demonstrated that combination therapy was well tolerated over the median follow-up period of 4.5 years [6]. The most commonly reported adverse events in SMART-1 were consistent with the mechanisms of action of 5ARIs and a 1 -blockers. Ejaculation disorders were the most frequently reported events in the first 24 weeks of the study at 7%. Although it is not possible to separate the adverse events associated with tamsulosin and dutasteride specifically, large-scale, two-year studies have shown that dutasteride is associated with an incidence of ejaculation disorders of 2%, which is substantially lower than that seen in SMART-1 [5].

466 J. Barkin et al. / European Urology 44 (2003) 461 466 The predominant cause of these disorders in SMART-1 was retrograde ejaculation, which seems likely to have resulted from tamsulosin therapy. Appendix A The members of the Symptom Management After Reducing Therapy (SMART-1) Investigator Group were as follows: Canada Principal investigators: CR Faucher, J-M Paquin, PJ Pommerville; Sub-investigators: JF Kinahan, L Valiquette; Germany Principal investigators: L Bauer, W Bischoff, G Jacobi; Netherlands Principal investigators: EJ Barten, GA Dijkman, PJM Kil, JJM Kums, JAF Leenarts, OB van Vierssen Trip; Portugal Principal investigators: A Fraga, M Guimarães, A Malheiro, J Neves, A Pimenta, L Vasconcelos Dias; Russia Principal investigators: YG Aljaev, OB Loran, VN Stepanov; Sub-investigators: AN Bernikov, KL Lokshin, DY Pushkar, PI Rasner, AV Seriogin, LG Spivak, LV Tsyganko, AZ Vinarov; United Kingdom Principal investigators: IR Bowen, GJ Chartwood; Sub-investigators: SE Burgess, RW Howe, AM Iredale. References [1] Anderson JB, Roehrborn CG, Schalken JA, Emberton M. The progression of benign prostatic hyperplasia: examining the evidence and determining the risk. Eur Urol 2001;39:390 9. [2] Emberton M, Andriole G, de la Rosette JJ, et al. BPH: a progressive disease of the ageing male. Urology 2002;61:267 73. [3] McConnell JD, Bruskewitz R, Walsh PC, 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. N Engl J Med 1998;338:557 63. [4] Roehrborn CG, Andriole G, Schalken JA, Wilson T, Clark RV. Dutasteride, a novel dual 5-alpha reductase inhibitor, reduces serum DHT to a greater extent versus finasteride and achieves finasteride maximal reduction in a larger proportion of patients. Eur Urol Suppl 2003;2(1):161 [Abstract 635]. [5] Roehrborn CG, Boyle P, Nickel JC, Hoefner K, Andriole G. 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 41. [6] The impact of medical therapy on the clinical progression of BPH: results of the MTOPS trial. The MTOPS Research Group. Abstract presented at the American Urological Association Annual Meeting 2002. [7] Dunn CJ, Matheson A, Faulds DM. Tamsulosin: a review of its pharmacology and therapeutic efficacy in the management of lower urinary tract symptoms. Drugs Aging 2002;19:135 61. [8] de la Rosette JJ, Kortmann BB, Rossi C, et al. Long-term risk of retreatment of patients using alpha-blockers for lower urinary tract symptoms. J Urol 2002;167:1734 9. [9] Jaffe JS, Ginsberg PC, Harkaway RC. Prostate size and PSA predict failure in patients undergoing alpha blocker monotherapy. Abstract presented at the American Urological Association 2001. [10] Baldwin KC, Ginsberg PC, Harkaway RC. Discontinuation of alphablockade after initial treatment with finasteride and doxazosin for bladder outlet obstruction. Urol Int 2001;66:84 8. [11] Barry MJ, Williford WO, Chang Y, et al. Benign prostatic hyperplasia specific health status measures in clinical research: how much change in the American Urological Association symptom index and the benign prostatic hyperplasia impact index is perceptible to patients? J Urol 1995;154:1770 4.