EUROPEAN UROLOGY 64 (2013)

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1 EUROPEAN UROLOGY 64 (2013) available at journal homepage: Platinum Priority Benign Prostatic Hyperplasia Editorial by Apostolos Apostolidis on pp of this issue Efficacy and Safety of Solifenacin Plus Tamsulosin OCAS in Men with Voiding and Storage Lower Urinary Tract Symptoms: Results from a Phase 2, Dose-finding Study (SATURN) Philip Van Kerrebroeck a, *, François Haab b, Javier C. Angulo c, Viktor Vik d, Ferenc Katona e, Alberto Garcia-Hernandez f, Monique Klaver f, Klaudia Traudtner f, Matthias Oelke g a Maastricht University Medical Centre, Maastricht, The Netherlands; b Hôpital Tenon, Paris, France; c Hospital Universitario de Getafe, Madrid, Spain; d Thomayer Hospital, Prague, Czech Republic; e Josa Andras Hospital, Nyiregyhaza, Hungary; f Astellas Pharma Europe B.V., Leiden, The Netherlands; g Hannover Medical School, Hannover, Germany Article info Article history: Accepted March 8, 2013 Published online ahead of print on March 19, 2013 Keywords: Lower urinary tract symptoms Overactive bladder Tamsulosin OCAS Solifenacin Storage symptoms Voiding symptoms Please visit europeanurology to read and answer questions on-line. The EU-ACME credits will then be attributed automatically. Abstract Background: Storage symptoms are often undertreated in men with lower urinary tract symptoms (LUTS). Objective: To evaluate the combination of an antimuscarinic (solifenacin) with an a-blocker (tamsulosin) versus tamsulosin alone in the treatment of men with LUTS. Design, setting, and participants: A double-blind, 12-wk, phase 2 study in 937 men with LUTS (3 mo, total International Prostate Symptom Score [IPSS] 13, and maximum urinary flow rate ml/s). Intervention: Eight treatment groups: tamsulosin oral controlled absorption system (OCAS) 0.4 mg; solifenacin 3, 6, or 9 mg; solifenacin 3, 6 or 9 mg plus tamsulosin OCAS 0.4 mg; or placebo. Outcome measurements and statistical analysis: The primary efficacy end point was change from baseline in total IPSS. Secondary end points included micturition diary and quality-oflife (QoL) parameters. Post hoc subgroup analyses were performed by severity of baseline storage symptoms, with statistical comparisons presented only for tamsulosin OCAS alone versus combination therapy, due to the small sample size of the solifenacin monotherapy and placebo subgroups. Results and limitations: Combination therapy was associated with significant improvements in micturition frequency and voided volume versus tamsulosin OCAS alone in the total study population; improvements in total IPSS were not significant. Statistically significant improvements in urgency episodes, micturition frequency, total urgency score, voided volume, IPSS storage subscore, IPSS-QoL index, and Patient Perception of Bladder Condition were observed in a subpopulation of men with two or more urgency episodes per 24 h (Patient Perception of Intensity of Urgency Scale grade 3 or 4) and eight or more micturitions per 24 h at baseline (storage symptoms subgroup) with combination therapy versus tamsulosin OCAS alone ( p 0.05 for the dose response slope, all variables). Combination therapy was well tolerated, and adverse events were consistent with the safety profiles of both compounds. Conclusions: Solifenacin plus tamsulosin OCAS did not significantly improve IPSS in the total study population but offered significant efficacy and QoL benefits over tamsulosin OCAS monotherapy in men with both voiding and storage symptoms at baseline. Combination therapy was well tolerated. ClinicalTrials.gov identifier: NCT # 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Department of Urology, Maastricht University Medical Centre, PO Box 5800, 6202 AZ Maastricht, The Netherlands. Tel ; Fax: address: p.vankerrebroeck@mumc.nl (P. Van Kerrebroeck) /$ see back matter # 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.

2 EUROPEAN UROLOGY 64 (2013) Introduction Lower urinary tract symptoms (LUTS) include voiding, storage, and postmicturition symptoms. In men, these are conventionally associated with benign prostatic hyperplasia (BPH) or benign prostatic obstruction; however, they often cannot be attributed to physiologic changes to the prostate, thus treatment guidelines focus on symptom management [1]. Despite a high prevalence of storage symptoms in studies in men with LUTS, the symptoms are commonly undertreated [2,3]. Moreover, under- or inappropriate treatment for storage LUTS is more common in men than in women: In an analysis of claims data from >7.2 million US patients aged >45 yr with overactive bladder (OAB), pharmacologic therapy was prescribed to 17.1% of men versus 28.6% of women ( p < 0.001) [4]. a-blocker monotherapy (eg, tamsulosin) is usually considered the first-line therapy for moderate to severe male LUTS [1]. However, symptom control with these agents may be variable, especially in men with predominant storage symptoms. Current European Association of Urology treatment guidelines suggest that antimuscarinics (eg, solifenacin) can be added to a-blockers to manage storage symptoms that persist after a-blocker monotherapy [1], and a number of studies support the benefit of a-blocker plus antimuscarinic combination treatment [5]. We report the results of a phase 2 study, Solifenacin and Tamsulosin in Males with Lower Urinary Tract Symptoms Associated with Benign Prostatic Hyperplasia (SATURN), that evaluated the efficacy and safety of different doses of an antimuscarinic (solifenacin) in combination with an a-blocker (tamsulosin in an oral controlled absorption system [OCAS] formulation) in men with LUTS. The results of this study were expected to establish the most useful clinical dose of combination therapy for further evaluation in the phase 3 Study of Solifenacin Succinate and Tamsulosin Hydrochloride OCAS in males with moderate to severe storage lower urinary tract symptoms (NEPTUNE). 2. Patients and methods SATURN was a double-blind, parallel-group, placebo-controlled, multicentre, dose-ranging study. The study included a single-blind, 2-wk, placebo run-in period followed by a randomised, double-blind, placebocontrolled, 12-wk treatment period. The study was conducted at 102 centres in 17 European countries, in accordance with the International Conference on Harmonisation Good Clinical Practice guidelines and the principles of the Declaration of Helsinki. All study materials were reviewed and approved by local independent ethics committees, and all patients provided written informed consent before screening Patients The study enrolled men aged 45 yr who were diagnosed with LUTS with both voiding and storage symptoms. Inclusion criteria included total International Prostate Symptom Score (IPSS) 13, a maximum urinary flow rate (Q max ) of ml/s, with a volume voided during free flow 120 ml. Presence of storage symptoms was determined by the investigator, but there were no specific inclusion criteria regarding the level of storage symptoms. All patients underwent ultrasound evaluation of prostate size (transrectal preferred), although no minimum or maximum prostate size was specified for inclusion in the study. Patients were excluded if they had a postvoid residual (PVR) volume >200 ml, evidence of a symptomatic urinary tract infection, a known history or diagnosis of specific urinary conditions (including urinary retention), previous surgery of the bladder neck or prostate, or any other relevant medical history as determined by the investigator Treatments After a 2-wk placebo run-in period, patients were randomised to placebo, tamsulosin OCAS 0.4 mg monotherapy, solifenacin 3, 6, or 9 mg plus tamsulosin OCAS 0.4 mg, or dose-matched solifenacin monotherapy (2:4:4:4:4:1:1:1 randomisation ratio) (Fig. 1). As it was expected that the optimal dose of solifenacin in men with LUTS would be lower than in OAB, the 3- and 6-mg doses were selected from a safety perspective. The 9-mg dose was included to provide information about the dose response curve at the higher end of the dose range. The approved dose of tamsulosin OCAS for LUTS was used End points The primary end point was change in total IPSS from baseline to end of treatment. Secondary end points included change from baseline to end of treatment in IPSS voiding and storage subscores, micturition diary variables (micturition frequency, urgency episodes of Patient Perception of Intensity of Urgency Scale [PPIUS] grade 3 or 4, urgency incontinence episodes, and mean volume voided per micturition), and quality-of-life (QoL) assessments (IPSS-QoL index and Patient Perception of Bladder Condition [PPBC]). Micturition diaries were completed by patients 3 d prior to the baseline and assessment visits. The PPIUS is a 5-point, validated questionnaire used for the judgement of urgency preceding every void, with episodes being rated from 0 to 4 (0, no urgency; 1, mild urgency; 2, moderate urgency; 3, severe urgency; 4, urge incontinence) [6]. The PPBC is a 6-point validated instrument used to judge the general bladder condition, with patients being asked to rate their symptoms from 1 ( does not cause me any problems ) to 6 ( causes me many severe problems ) [7]. Safety parameters included patient-reported adverse events and PVR volume determined by ultrasound. As solifenacin is expected to treat storage symptoms specifically, the total urgency and frequency score (TUFS) was evaluated as a post hoc secondary end point to assess improvements in both frequency and urgency using a single parameter, calculated as the mean of daily totals for all recorded PPIUS urgency grading (0 4) for each diary day. The TUFS (previously known as total urgency score) has been validated in patients with OAB and LUTS [8,9] Statistics Efficacy analyses were carried out in the full analysis set, defined as all patients who received at least one dose of study medication and who had a total IPSS at baseline and at least one postrandomisation total IPSS value. Baseline characteristics and safety analyses were reported for the safety set, defined as all patients who received at least one dose of study medication and for whom any data were reported after the first dose of study drug. The primary efficacy analysis was based on a general linear model, including solifenacin dose and baseline total IPSS as covariates and country as a fixed factor. The dose response relationship was tested by using parametric statistical modelling to calculate the slope resulting from the addition of increasing solifenacin doses to tamsulosin OCAS. The slope represents the expected increase in change from baseline for each increase of 1 mg in the dose of solifenacin (given in combination

3 400 [(Fig._1)TD$FIG] EUROPEAN UROLOGY 64 (2013) Fig. 1 Patient flow in the SATURN study. Soli = solifenacin; TOCAS = tamsulosin oral controlled absorption system. with tamsulosin OCAS), with a significant difference from 0 demonstrating a benefit from increasing the dose of solifenacin added to tamsulosin OCAS. Additional post hoc efficacy analyses are presented for tamsulosin OCAS alone versus combination therapy in a subpopulation with two or more urgency episodes per 24 h (PPIUS grade 3 or 4) and eight or more micturitions per 24 h at baseline, averaged over the 3-d micturition diary documentation (storage symptoms subgroup). All statistical comparisons used two-sided tests at the a = 0.05 significance level. Due to low patient numbers in the subgroup in the solifenacin monotherapy and placebo arms, the test power of the post hoc analysis was reduced. Thus, statistical comparisons are presented only for tamsulosin OCAS alone versus combination therapy. 3. Results 3.1. Patients and baseline characteristics voiding symptoms to the overall population but had a higher level of storage symptoms, demonstrated by greater frequency and urgency (Table 2) Efficacy Primary efficacy end point Reductions in total IPSS were small in all randomised groups and similar to placebo, with no significant difference between combination groups and tamsulosin OCAS alone (Table 3). Parametric statistical modelling found no additional benefit from increasing solifenacin doses in combination with tamsulosin OCAS on the primary end point, total IPSS in the total study population (dose response slope: 0.09; p = ). Of 1163 men with LUTS who were screened, 1079 were enrolled and 937 were randomised (Fig. 1). Baseline characteristics were similar in all groups (Table 1). Men included in the post hoc analyses had similar baseline Secondary efficacy end points Numeric improvements in micturition diary variables were observed for solifenacin monotherapy versus placebo and for combinations of solifenacin with tamsulosin OCAS

4 EUROPEAN UROLOGY 64 (2013) Table 1 Baseline characteristics for all men participating in the SATURN study (total population; safety set) Variable Placebo (n = 92) Soli 3 mg Soli 6 mg Soli 9 mg TOCAS 0.4 mg (n = 177) Soli 3 mg + (n = 179) Soli 6 mg + (n = 178) Soli 9 mg + (n = 175) Age, yr 65.0 (7.9) 65.4 (8.2) 65.7 (8.0) 66.0 (6.5) 65.0 (8.3) 65.2 (8.0) 65.2 (8.1) 65.3 (7.7) Ethnicity, no. (%) White 92 (100) 43 (100) 43 (100) 41 (95.3) 176 (99.4) 178 (99.4) 178 (100) 175 (100) Black (0.6) 0 0 Other (4.7) 1 (0.6) Weight, kg 82.9 (14.7) 88.3 (12.9) 82.7 (13.4) 81.1 (14.4) 82.6 (14.4) 84.4 (13.6) 85.6 (13.0) 85.0 (13.5) Height, m 1.73 (0.08) 1.76 (0.06) 1.73 (0.06) 1.72 (0.06) 1.74 (0.07) 1.74 (0.07) 1.75 (0.07) 1.75 (0.08) BMI, kg/m (5.0) 28.6 (3.3) 27.5 (4.0) 27.4 (4.0) 27.2 (4.1) 27.8 (3.9) 28.0 (3.7) 27.9 (4.2) Estimated prostate 41.8 (21.3) 39.4 (16.5) 40.3 (15.0) 37.2 (11.8) 40.0 (19.1) 37.9 (15.2) 39.2 (14.7) 40.1 (16.6) weight, g PVR volume, ml 34.0 (32.8) 52.2 (45.4) 45.3 (39.4) 43.0 (34.3) 35.7 (38.2) 43.2 (44.7) 38.6 (37.7) 43.4 (42.5) BMI = body mass index; PVR = postvoid residual; Soli = solifenacin; TOCAS = tamsulosin oral controlled absorption system. All values are given as mean (standard deviation) unless otherwise indicated. Table 2 Baseline efficacy parameters for all men participating in the SATURN study and for the subgroup of patients with voiding and storage symptoms (full analysis set) Efficacy measure versus placebo and tamsulosin OCAS alone in the total study population (Table 3). Decreases from baseline to end of treatment in micturition frequency and TUFS, and increases in voided volume per micturition were significantly greater with increasing solifenacin dose plus tamsulosin OCAS versus tamsulosin OCAS monotherapy (dose response slopes: 0.07, p = ; 0.15, p = 0.044; and 2.84, p < , respectively) Post hoc efficacy analyses Total study population (n = 919) Storage symptoms subgroup z (n = 282) Total IPSS 18.3 (4.1) 19.2 (4.1) IPSS voiding 10.3 (3.2) 10.4 (3.3) IPSS storage 7.9 (2.5) 8.8 (2.4) Urgency episodes per 24 h 2.56 (3.06) 5.24 (2.72) (PPIUS grade 3 or 4) Micturitions per 24 h (2.69) (2.37) TUFS per 24 h (9.59) (7.13) IPSS QoL 3.8 (1.1) 4.1 (1.1) Q max, ml/s (2.20) (2.10) IPSS = International Prostate Symptom Score; PPIUS = Patient Perception of Intensity of Urgency Scale; QoL = quality of life; Q max = maximum urinary flow rate; TUFS = total urgency and frequency score. All values are given as mean (standard deviation). z Patients in the tamsulosin oral controlled absorption system monotherapy or combination therapy groups with two or more urgency episodes per 24 h (PPIUS grade 3 or 4) and eight or more micturitions per 24 h at baseline. As improvements in storage symptoms were observed in the total population, a post hoc subgroup analysis was based on the extent of storage symptoms at baseline in patients receiving tamsulosin OCAS alone or in combination with solifenacin. The study had strict inclusion criteria for voiding symptoms, but not for storage symptoms, and half of these patients had only minor storage symptoms (fewer than one urgency episode per 24 h [PPIUS grade 3 or 4] or fewer than eight micturitions per 24 h). These patients experienced little or no additional benefit from combination therapy compared with tamsulosin OCAS monotherapy, but patients in the storage symptoms subgroup with two or more urgency episodes per 24 h (PPIUS grade 3 or 4) and eight or more micturitions per 24 h at baseline showed clear improvements in storage parameters with solifenacin plus tamsulosin OCAS over tamsulosin OCAS alone. In this latter subgroup, there were significant improvements in IPSS storage subscore (Fig. 2c), number of urgency episodes (PPIUS 3 and 4), micturition frequency, voided volume, and TUFS (Fig. 2d) (Table 4). Compared with tamsulosin OCAS monotherapy, combination treatment was associated with numeric improvements in total IPSS (Fig. 2a), but there were no improvements in IPSS voiding subscore (Fig. 2b) Quality of life In the study population as a whole, addition of solifenacin to tamsulosin OCAS did not produce additional improvements in IPSS-QoL index or PPBC. However, the post hoc subanalysis showed additional improvements with combination therapy versus tamsulosin OCAS monotherapy in QoL variables in men in the storage symptoms subgroup (Fig. 3a and 3b) Safety Combination therapy was well tolerated, and most adverse events were of mild or moderate intensity (Table 5). The types of adverse events were in line with the known safety profiles of each individual drug. The most common adverse events in all treatment groups containing solifenacin with or without tamsulosin OCAS were dry mouth and constipation. Treatment-related dry mouth was reported in a total of 47 (8.8%) patients in the combination-therapy groups, compared with 4 (2.3%) with tamsulosin OCAS monotherapy, 8 (6.2%) with solifenacin monotherapy, and none with placebo (Table 5).

5 402 EUROPEAN UROLOGY 64 (2013) Table 3 Changes from baseline to end of treatment in International Prostate Symptom Score and micturition diary variables for the total study population (full analysis set) Variable Placebo Soli 3mg Soli 6mg Soli 9mg TOCAS 0.4 mg Soli 3 mg + Soli 6 mg + Soli 9 mg + Total IPSS Patients, no Baseline value 17.4 (3.5) 19.5 (4.9) 18.1 (4.0) 20.2 (5.2) 18.0 (3.8) 18.7 (4.0) 18.1 (4.0) 17.9 (4.0) Change 6.3 (5.9) 7.4 (5.9) 6.0 (5.4) 6.3 (7.5) 7.7 (5.6) 7.8 (5.7) 7.7 (5.2) 6.6 (6.1) Urgency episodes per 24 h (PPIUS grade 3 or 4) z Patients, no Baseline value 3.61 (2.97) 4.73 (3.90) 3.48 (3.15) 4.67 (3.28) 3.88 (3.38) 3.58 (2.72) 3.47 (3.10) 3.56 (2.76) Change 1.34 (2.58) 1.68 (2.96) 1.21 (2.45) 1.61 (2.77) 1.59 (2.92) 1.52 (2.38) 2.14 (2.75) 1.61 (3.08) Micturitions per 24 h Patients, no Baseline value 9.72 (2.68) (2.69) 9.83 (2.17) (3.14) (2.60) (2.80) (2.73) (2.59) Change 0.93 (2.31) 1.01 (2.01) 1.09 (2.28) 1.33 (2.20) 1.04 (1.79) 1.67 (2.27) 1.74 (2.11) 1.70 (2.05) Urgency incontinence episodes per 24 h z Patients, no Baseline value 1.75 (2.07) 1.38 (1.25) 1.31 (1.61) 1.05 (1.47) 1.34 (1.74) 1.29 (1.06) 1.62 (1.91) 0.91 (0.81) Change 0.96 (1.03) 1.38 (1.25) 0.83 (1.16) 0.76 (1.42) 0.67 (1.77) 0.86 (1.00) 1.46 (1.89) 0.48 (1.16) TUFS per 24 h Patients, no Baseline value (9.06) (12.12) (8.87) (10.64) (9.46) (9.09) (9.67) (8.92) Change 3.13 (7.67) 4.37 (8.62) 3.54 (6.66) 4.44 (7.50) 3.68 (7.29) 5.05 (7.24) 5.37 (7.51) 4.69 (7.99) Volume voided per micturition, ml Patients, no Baseline value (65.65) (60.99) (55.51) (67.58) (54.96) (51.96) (60.88) (53.84) Change 6.36 (42.79) (38.92) (31.65) 6.54 (52.42) (44.64) (42.80) (40.42) (47.78) IPSS = International Prostate Symptom Score; PPIUS = Patient Perception of Intensity of Urgency Scale; Soli = solifenacin; TOCAS = tamsulosin oral controlled absorption system; TUFS = total urgency and frequency score. All values are given as mean (standard deviation). z Only subjects with at least one episode at baseline were included. [(Fig._2)TD$FIG] Fig. 2 Adjusted (least square) mean changes from baseline to end of treatment in (a) total International Prostate Symptom Score (IPSS) (n = 282), (b) IPSS voiding subscore (n = 282), (c) IPSS storage subscore (n = 282), and (d) total urgency and frequency score (TUFS) per 24 h (n = 280) in the storage symptoms subgroup* (full analysis set). P values are for combination therapy versus tamsulosin oral controlled absorption system (TOCAS). Soli = solifenacin; NS = not statistically significant. * IPSS I13, maximum urinary flow rate ml/s, two or more urgency episodes per 24 h (Patient Perception of Intensity of Urgency Scale grade 3 or 4), and eight or more micturitions per 24 h at baseline.

6 EUROPEAN UROLOGY 64 (2013) Table 4 Changes from baseline to end of treatment in International Prostate Symptom Score and micturition diary variables for the storage symptoms subgroup (full analysis set) Soli 3 mg + Soli 6 mg + Soli 9 mg + Slope Total IPSS (n = 282) Mean (SD) baseline 19.1 (4.2) 19.6 (4.3) 19.0 (3.9) 19.0 (4.0) Adjusted mean change from baseline Estimated difference vs TOCAS (95% CI) 0.81 ( 2.52, 0.91) 1.13 ( 2.90, 0.64) 1.72 ( 3.48, 0.04) ( 0.36, 0.00) p Urgency episodes per 24 h (PPIUS grade 3 or 4) * (n = 280) Mean (SD) baseline 5.81 (3.13) 4.84 (2.43) 5.29 (2.95) 5.13 (2.36) Adjusted mean change from baseline Estimated difference vs TOCAS (95% CI) 0.06 ( 0.94, 0.82) 1.14 ( 2.04, 0.23) 0.81 ( 1.71, 0.09) ( 0.21, 0.03) p Micturitions per 24 h (n = 280) Mean (SD) baseline (2.24) (2.25) (2.53) (2.51) Adjusted mean change from baseline Estimated difference vs TOCAS (95% CI) 0.90 ( 1.59, 0.21) 0.96 ( 1.68, 0.25) 1.40 ( 2.11, 0.68) ( 0.21, 0.06) p Urgency incontinence episodes per 24 h * (n = 92) Mean (SD) baseline 0.44 (1.22) 0.42 (0.86) 0.62 (1.45) 0.34 (0.70) Adjusted mean change from baseline Estimated difference vs TOCAS (95% CI) 0.24 ( 0.81, 0.33) 0.68 ( 1.28, 0.09) 0.41 ( 1.01, 0.19) ( 0.12, 0.01) p TUFS per 24 h (n = 280) Mean (SD) baseline (7.39) (6.32) (8.04) (6.88) Adjusted mean change from baseline Estimated difference vs TOCAS (95% CI) 1.79 ( 4.24, 0.67) 3.93 ( 6.47, 1.39) 4.08 ( 6.61, 1.54) ( 0.74, 0.21) p Volume voided per micturition, ml (n = 280) Mean (SD) baseline (47.22) (42.72) (44.72) (44.59) Adjusted mean change from baseline Estimated difference vs TOCAS (95% CI) 6.46 ( 7.85, 20.78) ( 4.64, 25.01) (6.61, 36.41) (0.72, 3.81) p CI = confidence interval; IPSS = International Prostate Symptom Score; PPIUS = Patient Perception of Intensity of Urgency Scale; SD = standard deviation; Soli = solifenacin; TOCAS = tamsulosin oral controlled absorption system; TUFS = total urgency and frequency score. Patients in the TOCAS monotherapy or combination therapy groups with two or more urgency episodes per 24 h (PPIUS grade 3 or 4) and eight or more micturitions per 24 h at baseline. * Only subjects with at least one episode at baseline were included Postvoid residual volume Mean PVR volume increased with increasing solifenacin dose, both when given alone and in combination with tamsulosin OCAS. However, differences between solifenacin doses were less pronounced for the combination-therapy groups than for the solifenacin monotherapy groups (Table 6). Increases in PVR volume were not considered to be clinically relevant and were not accompanied by an increase in the incidence of acute urinary retention (AUR) Urinary retention The incidence of AUR was low in all groups and showed no apparent relationship with increasing solifenacin dose. There were six cases of AUR (Table 5). Five occurred within the first 32 d of treatment and four required catheterisation: one each with solifenacin 9 mg, tamsulosin OCAS monotherapy, solifenacin 3 mg plus tamsulosin OCAS, and solifenacin 9 mg plus tamsulosin OCAS. 4. Discussion This large phase 2 study evaluated the efficacy and safety of three doses of the antimuscarinic solifenacin (3, 6, and 9 mg) with the standard dose of the a-blocker tamsulosin OCAS (0.4 mg) in the treatment of men with LUTS with both voiding and storage symptoms. This description is in line with current terminology [1]. Historically, patients meeting the inclusion criteria used in this study have been referred to as having LUTS associated with BPH, based on their age, prostate size, and reduced Q max, although BPH was not confirmed histologically. In this study, patients were not selected on the basis of prostate pathology or prostate size; however, prostate size was enlarged (mean [SD]: 39.5 g [16.0]; median: 37.0 g), as expected in this population [10]. In this study, combination therapy was not associated with significant additional benefits in total IPSS in the overall study cohort when compared with tamsulosin OCAS alone, while improvements were observed for specific diary variables, particularly micturition frequency and voided volume. All three solifenacin plus tamsulosin OCAS combination-therapy doses were well tolerated, including the highest solifenacin dose, with side-effect profiles consistent with those expected for each individual product [11,12]. There were no clinically meaningful increases in PVR volume, and the rate of AUR requiring catheterisation was low in all groups. The most interesting results from this study are seen in the post hoc subgroup analysis in patients with two or more

7 404 [(Fig._3)TD$FIG] EUROPEAN UROLOGY 64 (2013) Fig. 3 Adjusted (least square) mean changes from baseline to end of treatment in (a) International Prostate Symptom Score (IPSS) quality of life (QoL) (n = 281) and (b) Patient Perception of Bladder Condition (PPBC) (n = 280) in the storage symptoms subgroup * (full analysis set). P values are for combination therapy versus tamsulosin oral controlled absorption system (TOCAS). Soli = solifenacin. * IPSS I13, maximum urinary flow rate ml/s, two or more urgency episodes per 24 h (Patient Perception of Intensity of UrgencyScalegrade3or4),andeightormoremicturitionsper 24 h at baseline. urgency episodes per 24 h (PPIUS grade 3 or 4) and eight or more micturitions per 24 h at baseline. Despite an inclusion criterion specifying that patients should have both voiding and storage LUTS at baseline, only 40% of the men included in the tamsulosin OCAS monotherapy and combinationtherapy arms had storage symptoms severe enough to warrant the addition of an antimuscarinic to a-blocker monotherapy, probably because no specific inclusion criteria were given for storage symptoms. This subgroup analysis showed numerically greater improvements in total IPSS with combination therapy, particularly the two highest solifenacin doses, than with tamsulosin OCAS alone. In addition, combination therapy was associated with significant improvements in IPSS storage subscore, urgency episodes, micturition frequency, TUFS, voided volume, IPSS-QoL index, and PPBC compared with tamsulosin OCAS alone. The phase 3 NEPTUNE study of solifenacin/ tamsulosin combination therapy was initiated to confirm treatment effects in male LUTS, with patients required to demonstrate voiding and storage symptoms to qualify for inclusion; TUFS was a primary efficacy end point. Other studies have evaluated the relatively new approach of adding an antimuscarinic to a-blocker therapy in men with OAB [13], but variability in their designs makes them difficult to compare. For example, in the Tolterodine and Tamsulosin in Men with LUTS Including OAB: Evaluation of Efficacy and Safety (TIMES) study, neither tamsulosin nor tolterodine given as monotherapy demonstrated significant improvements in patient perception of treatment benefit [14], whereas significant improvements were demonstrated with tolterodine plus tamsulosin combination versus placebo in micturition diary variables, total IPSS, and IPSS-QoL. No comparison between combination therapy and tamsulosin was made. The study had no specific inclusion criteria for voiding symptoms and a criterion of three or more urgency episodes per 24 h (grades 3 5 on the urinary sensation scale) compared with two or more episodes per 24 h (PPIUS grade 3 and 4) in the storage symptoms subgroup of the SATURN study, resulting in higher baseline Q max values, more severe storage symptoms, and worse IPSS-QoL scores at baseline, and, consequently, greater differences from baseline, than in SATURN [14]. Urgency, micturition frequency, and IPSS storage subscale were significantly improved in the 12-wk ADAM (tolterodine) [15] and ASSIST (solifenacin) [16] trials, in which patients were taking a stable dose of an a-blocker, usually tamsulosin, for a minimum of 4 wk before the study, whereas only urgency was significantly improved in the VESIcare In Combination with Tamsulosin in OAB Residual Symptoms (VICTOR) trial [17]. In contrast, the addition of fesoterodine to a-blocker therapy was shown to significantly improve micturition frequency and symptom bother, but not urgency episodes [18]. Differences in efficacy results may be a reflection of differences in the study designs; however, these studies indicate that antimuscarinics appear to be efficacious and well tolerated in this patient group, with low AUR rates [6], consistent with our findings from the SATURN study. The SATURN study has several limitations. For this dosefinding study, the three solifenacin doses (3, 6, and 9 mg) selected for evaluation are lower than the currently approved doses for OAB (5 and 10 mg). This decision was made to reflect the potentially different safety profile in patients with voiding and storage LUTS, a population that, atthetimeofstudydesign,wasperceivedtobemoreatrisk of adverse events associated with antimuscarinics (ie, urinary retention). In the meantime, a number of large studies have been performed using antimuscarinics and a- blockers in male patients with LUTS, and they do not support an increased risk of AUR associated with antimuscarinics [6]. This should allay physicians concerns about an increased risk of AUR with antimuscarinics in men. For regulatory reasons, a placebo arm and dose-matched solifenacin monotherapy arms were included, increasing the number of treatment groups beyond the scope of a typical phase 2 study. However, solifenacin monotherapy is not an adequate treatment for these patients, as it does not address the prostate-related symptoms experienced by this population. Results for these arms for the post hoc subgroup analysis are not shown, as the objective of the study was to compare combination therapy with tamsulosin, and low patient numbers in these subgroups prevented statistical comparisons.

8 EUROPEAN UROLOGY 64 (2013) Table 5 Summary of treatment-related adverse events occurring in I1% patients overall and two or more patients in any one group (total population; safety set) Adverse events Placebo (n = 92) Soli 3 mg Soli 6 mg Soli 9 mg (n = 177) Soli 3 mg + (n = 179) Soli 6 mg + (n = 178) Soli 9 mg + (n = 175) Any event 12 (13.0) 6 (14.0) 7 (16.3) 7 (16.3) 33 (18.6) 26 (14.5) 35 (19.7) 43 (24.6) Cardiac disorders (2.3) 5 (2.8) 3 (1.7) 2 (1.1) 2 (1.1) Ear and labyrinth disorders 1 (1.1) (1.7) 1 (0.6) 2 (1.1) 0 Vertigo 1 (1.1) (1.7) 1 (0.6) 2 (1.1) 0 Eye disorders 1 (1.1) 0 2 (4.7) (3.4) 1 (0.6) Blurred vision (4.7) (1.7) 0 Gastrointestinal disorders 2 (2.2) 3 (7.0) 5 (11.6) 5 (11.6) 8 (4.5) 12 (6.7) 21 (11.8) 28 (16.0) Dry mouth 0 2 (4.7) 4 (9.3) 2 (4.7) 4 (2.3) 6 (3.4) 18 (10.1) 23 (13.1) Constipation 1 (1.1) (9.3) 2 (1.1) 4 (2.2) 5 (2.8) 5 (2.9) Dyspepsia (1.7) 2 (1.1) 3 (1.7) Nausea 0 1 (2.3) (1.1) General disorders and (2.3) 1 (2.3) 3 (1.7) 2 (1.1) 0 4 (2.3) administration site conditions Fatigue (1.1) (0.6) Chest pain (1.1) Investigations 3 (3.3) (1.1) 1 (0.6) 3 (1.7) 2 (1.1) Nervous system disorders 2 (2.2) 1 (2.3) 2 (4.7) 0 7 (4.0) 3 (1.7) 3 (1.7) 4 (2.3) Dizziness 0 1 (2.3) (1.7) 1 (0.6) 2 (1.1) 1 (0.6) Headache 2 (2.2) (1.1) 1 (0.6) 1 (0.6) 2 (1.1) Dizziness postural (4.7) 0 1 (0.6) Renal and urinary disorders (7.0) 2 (1.1) 4 (2.2) 1 (0.6) 4 (2.3) Dysuria (4.7) 0 2 (1.1) 1 (0.6) 1 (0.6) Urinary retention (2.3) 1 (0.6) 2 (1.1) 0 2 (1.1) AUR requiring catheterisation z (2.3) 1 (0.6) 1 (0.6) 0 1 (0.6) Reproductive system and breast 2 (2.2) 1 (2.3) 0 1 (2.3) 4 (2.3) 4 (2.2) 6 (3.4) 4 (2.3) disorders Retrograde ejaculation 1 (1.1) (1.1) 5 (2.8) 1 (0.6) Erectile dysfunction 1 (1.1) (2.3) 2 (1.1) (1.1) AUR = acute urinary retention; Soli = solifenacin; TOCAS = tamsulosin oral controlled absorption system. Data given as number (percentage). Medical Dictionary for Regulatory Activities (MedDRA) system organ classes are shown in bold, MedDRA preferred terms are in non-bold. z Not a MedDRA-preferred term. Table 6 Mean change in postvoid residual volume from baseline to end of treatment (total population; safety set) Placebo (n = 92) Soli 3 mg Soli 6 mg Soli 9 mg (n = 176) Soli 3 mg + (n = 179) Soli 6 mg + (n = 178) Soli 9 mg + (n = 175) Baseline, ml 34.0 (32.8) 52.2 (45.4) 45.3 (39.4) 43.0 (34.3) 35.7 (38.2) 43.2 (44.7) 38.6 (37.7) 43.4 (42.5) End of treatment, ml 38.7 (47.4) 57.9 (53.0) 68.3 (83.9) 74.5 (84.4) 31.9 (34.9) 49.3 (59.3) 54.9 (71.3) 59.2 (70.8) Change from baseline, ml 4.6 (41.4) 8.1 (39.7) 26.8 (71.5) 31.8 (83.0) 4.0 (30.2) 6.4 (53.4) 16.9 (59.3) 16.5 (60.0) Soli = solifenacin; TOCAS = tamsulosin oral controlled absorption system. Data are given as mean (standard deviation). We recognise that the results of the subgroup analysis, which provide the most relevant results of the SATURN study, should be interpreted cautiously, owing to their post hoc nature in addition to the smaller sample size in the subgroups, and will need to be confirmed in a preplanned study in a population of patients with both voiding and storage symptoms. 5. Conclusions Previous studies have suggested benefits from using a combination-therapy approach to manage male LUTS. Our study shows that the combination of solifenacin plus tamsulosin OCAS was not associated with benefit on IPSS in the total population of patients with male LUTS when compared with tamsulosin OCAS, while improvements were observed for specific diary variables, particularly micturition frequency and voided volume. However, this combination offered significant efficacy and QoL benefits versus tamsulosin and was well tolerated in the subgroup of men with LUTS who had both voiding and moderate to severe storage symptoms, as shown in a post hoc analysis. Combination therapy with solifenacin 6 or 9 mg and tamsulosin OCAS seemed to have the best efficacy and safety profiles, and these doses have been further assessed in the phase 3 NEPTUNE study.

9 406 EUROPEAN UROLOGY 64 (2013) Author contributions: Philip Van Kerrebroeck had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Van Kerrebroeck, Garcia-Hernandez, Klaver. Acquisition of data: Van Kerrebroeck, Angulo, Oelke. Analysis and interpretation of data: Van Kerrebroeck, Angulo, Garcia- Hernandez, Klaver, Traudtner, Oelke. Drafting of the manuscript: Van Kerrebroeck, Haab, Angulo, Vik, Katona, Garcia-Hernandez, Klaver, Traudtner, Oelke. Critical revision of the manuscript for important intellectual content: Van Kerrebroeck, Haab, Angulo, Vik, Katona, Garcia-Hernandez, Klaver, Traudtner, Oelke. Statistical analysis: Garcia-Hernandez. Obtaining funding: None. Administrative, technical, or material support: None. Supervision: Van Kerrebroeck, Klaver. Other (specify): None. Financial disclosures: Philip Van Kerrebroeck certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Philip van Kerrebroeck is a lecturer for Astellas, Ferring, and Medtronic, and member of an advisory board for Allergan, Astellas, and Ferring. Francois Haab is a consultant, investigator, and lecturer for Allergan, Astellas, and Pfizer. Javier Angulo has received educational grants for research from Astellas and Pfizer and is a lecturer for Astellas, GlaxoSmithKline, and Pfizer. Matthias Oelke has received lecturer and/or consultant honoraria from Apogepha, Astellas, GlaxoSmithKline, Eli Lilly and Company, Ethicon, Ferring, Pfizer, Recordati, and Sophiris and received a research grant from Astellas. Alberto-Garcia Hernandez, Monique Klaver, and Klaudia Traudtner are employees of Astellas. Viktor Vik and Ferenc Katona have nothing to disclose. Funding/Support and role of the sponsor: The SATURN study was conceived and funded by Astellas Pharma Europe B.V. Astellas was involved in study design, data collection and analysis, and manuscript preparation, and approved the final version of the manuscript. Acknowledgment statement: Medical writing and editing assistance for the preparation of this manuscript was provided by Sophie Berry and David Hallett at Darwin Healthcare Communications, UK, and funded by Astellas. The authors would like to acknowledge their colleagues who recruited patients into the SATURN study: Belgium: Dr. F. Ameye, Dr. J. Braeckman, Dr. P. Van Erps, Prof. W. Oosterlinck, Prof. Dr. B. Tombal, Dr. B. van Cleynenbreugel, Dr. J. Vanderkerken, Dr. N. Verleyen, Prof. J.J. Wyndale; Czech Republic: Dr. J. Klecka, Dr. J. Krhut, Dr. J. Liehne, Dr. I. Pavlik, Dr. V. Viktor, Dr. P. Zhanel; Denmark: Dr. M. Borre, Dr. A. Holm- Nielsen, Dr. K. Kroyer, Dr. M. Nohr; Finland: Dr. P. Hellstrom, Dr. K. Lehtoranta, Dr. J. Sairanen, Dr. T. Tammela; France: Dr. J.P. Ansieau, Dr. T. Billebaud, Dr. R. Claude, Prof. P. Costa, Dr. E. Ghazarossian-Ragni, Prof. E. Haab, Dr. J.L. Jung, Dr. S. Mallick, Dr. N. Morin, Dr. B. Rabut; Germany:Dr. T. Benusch, Dr. R. Eckert, Dr. H.P. Fischer, Dr. U. Gerhardt, Dr. W. Grohmann, Dr. M. Hentschel, Dr. W. Hechelmann, Dr. M. Indig, Dr. W. Jorger, Dr. T. Kottig, Dr. A. Kublanck, Dr. M. Markov, Dr. B. Mertins, Dr. M. Voss, Dr. W. Warnack, Dr. J. Willgerodt, Dr. A. Wirger; Great Britain: Mr. P. Bose, Dr. P. Malone, Dr. R. Pawa, Dr. H. Thomas; Hungary: Dr. F. Katona, Dr. G. Nagy, Prof. Dr. L. Pajor, Dr. G. 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