In this post hoc analysis of male patients, results were consistent with those of the primary analysis, with a higher frequency of responders observed for most endpoints for the tamsulosin + mirabegron group than for the tamsulosin + placebo group. There were numerical differences in favor of the mirabegron add-on group for micturition endpoints (micturition normalization and ≥ 10% decrease in micturitions/24 h at EoT). In addition, numerical differences in favor of the mirabegron add-on group were observed for two of the urgency endpoints (≥ 50% decrease in urgency episodes/24 h at EoT and fewer than two urgency episodes/24 h at EoT). The MCIC for OABSS was also achieved, and this is likely the most relevant result for clinical practice  because the OABSS is simple and dependable, can provide a quick overall assessment of OAB symptoms, and can indicate symptom severity and bother [15, 16]. Both urgency and incontinence were more affected by increased age. For example, normalization of incontinence episodes in the placebo group ≥ 75 years was 69.2% (versus 66.7% in the mirabegron group).
Differences between the tamsulosin + mirabegron and the tamsulosin + placebo groups were not so pronounced for normalization of urgency, incontinence, urgency urinary incontinence, and nocturia, and for ≥ 50% decrease in incontinence episodes/24 h at EoT. However, in all instances, the tamsulosin + mirabegron group had a higher frequency of responders than the tamsulosin + placebo group. Regarding double responders, there were numerical differences in favor of tamsulosin + mirabegron versus tamsulosin + placebo for micturitions and 50% decrease in urgency, or OABSS and OAB-q (symptom bother or HRQoL). However, there was little numerical difference between the tamsulosin + mirabegron and tamsulosin + placebo groups for urgency normalization and OAB-q (symptom bother or HRQoL).
Another study has similarly found improved responder rates for mirabegron-treated patients, including improvements in micturitions and incontinence. In a post hoc analysis of pooled PRO data in phase 3 studies of mirabegron monotherapy (n = 1324) compared with placebo (n = 1328), mirabegron demonstrated greater improvements from baseline to EoT for responder analyses, whether for individual objective and subjective outcomes or for double and triple responders .
Double responders were patients who were simultaneously responders for either incontinence or micturitions as well as PROs [OAB-q symptom bother scale, OAB-q total HRQoL, or patient perception of bladder condition (PPBC) scale]. Triple responders were patients who were simultaneously responders for either incontinence or micturitions as well as PPBC and the OAB-q symptom bother scale, or PPBC and OAB-q total HRQoL. Improvements over placebo were statistically significant for all double- and triple-responder analyses and for all single-responder analyses except for PPBC.
A recent study also reported improved symptoms for mirabegron in combination with a phosphodiesterase 5 inhibitor, tadalafil 5 mg (n = 89), compared with tadalafil monotherapy (n = 87) in male patients aged ≥ 50 years with residual OAB symptoms . The primary endpoint, change from baseline in total OABSS, was statistically significantly decreased by 1.78 (95% CI 1.05–2.50) points in the combination group compared with the monotherapy group (P < 0.001). Changes in OABSS nighttime voiding score, urgency score, urgency urinary incontinence score, IPSS storage subscores, and micturition chart variables (number of voids, nighttime voids, and urgency episodes/24 h) were also significantly reduced in the combination group (all P < 0.001).
It is possible that antimuscarinics have a more pronounced effect than mirabegron on incontinence and also that antimuscarinics have a more pronounced effect on urgency than on micturitions. The latter certainly seemed to be the case in the ASSIST and SOFIA studies, although it should be noted that these studies had a different primary endpoint than that of MATCH, so cannot be directly compared.
ASSIST was a randomized, double-blind study, in which 638 men aged ≥ 50 years with residual OAB symptoms despite tamsulosin monotherapy were randomized to 12 weeks of add-on therapy with solifenacin (2.5 mg or 5 mg) or placebo . The primary endpoint, mean change in urgency episodes, was reduced by 2.2 episodes in the tamsulosin + solifenacin 2.5 mg group and 2.4 episodes in the tamsulosin + solifenacin 5 mg group, with differences achieving statistical significance compared with tamsulosin + placebo. The number of micturitions/24 h was reduced by 1.27 episodes in the tamsulosin + solifenacin 2.5 mg group and 1.06 episodes in the tamsulosin + solifenacin 5 mg group, once again with statistically significant differences compared with tamsulosin + placebo. The number of nocturia episodes and urgency urinary incontinence episodes were numerically reduced in both tamsulosin + solifenacin groups versus tamsulosin + placebo; however, these differences did not reach statistical significance. Although responder rates were not reported, a statistically significant reduction of OABSS urgency score and number of micturitions/24 h was shown in both solifenacin add-on groups compared with the placebo group, whereas a significant reduction of urgency episodes from bladder diary entries was demonstrated in only the tamsulosin + solifenacin 5 mg group.
Results from a 12-week randomized, placebo-controlled trial (SOFIA) in 794 patients showed that fesoterodine was associated with statistically significantly and clinically greater improvements in urgency episodes (primary endpoint), micturition frequency, incontinence pad use, nocturia, and PROs than placebo in adults ≥ 65 years with OAB, but not in urgency urinary incontinence episodes . Mean number of urgency episodes/24 h decreased from 8.5 at baseline to 4.6 at week 12 in the fesoterodine group and from 8.8 to 6.3 in the placebo group. Mean number of micturitions/24 h decreased from 11.9 to 9.8 in the fesoterodine group and 12.1 to 10.9 in the placebo group. Mean number of incontinence pads used/24 h decreased from 2.8 to 1.8 in the fesoterodine group and 3.3 to 2.7 in the placebo group. Mean number of nocturia episodes decreased from 2.8 to 2.2 in the fesoterodine group and 2.9 to 2.6 in the placebo group. Responder rates on the treatment benefit scale, PPBC, urgency perception scale, and OAB-q satisfaction were also statistically significantly higher with fesoterodine.
However, in a noninferiority study comparing efficacy and safety of mirabegron and solifenacin in 1887 OAB patients dissatisfied with previous antimuscarinic treatment due to lack of efficacy (the BEYOND study), both mirabegron and solifenacin improved responder rates . Micturition normalization at EoT was achieved in 43.6% and 47.2% of mirabegron and solifenacin patients, respectively, with a corresponding odds ratio (OR) versus mirabegron (95% CI) of 1.14 (0.93–1.39); 85.1% and 88.1% of patients, respectively, achieved a ≥ 50% decrease in incontinence episodes/24 h at EoT with a corresponding OR (95% CI) versus mirabegron of 1.25 (0.82–1.90), and 67.3% and 68.5% of patients, respectively, achieved zero incontinence episodes at EoT, OR (95% CI) versus mirabegron 1.02 (0.73–1.42). None of the treatment differences were statistically significant.
The proportion of responders in the mirabegron add-on group in the current MATCH study is similar to the single-responder rates from the BESIDE study, in which mirabegron was used as add-on treatment to the antimuscarinic solifenacin in 2174 patients (male and female) with OAB wet and an inadequate response to solifenacin monotherapy . Compared with solifenacin 5 mg and 10 mg monotherapy, patients receiving mirabegron add-on treatment were 47% and 28% more likely to achieve zero incontinence and 51% and 25% more likely to achieve ≥ 50% decrease in incontinence episodes/24 h. They were also 29% and 12% more likely, respectively, to achieve normalization of micturition frequency. There was statistical significance in favor of the combination compared with solifenacin 5 and 10 mg in the proportion of responders with a ≥ 10-point improvement in OAB-q symptom bother score or OAB-q total HRQoL and a major (≥ 2 point) improvement in PPBC . At EoT, statistically significant improvements were demonstrated for all five exploratory variables (three double- and two triple-responder analyses) in favor of the combination group compared with solifenacin 5 mg.
SYNERGY was a study comparing solifenacin 5 mg + mirabegron 25 mg and solifenacin 5 mg + mirabegron 50 mg with monotherapy and placebo in both treatment-naive and previously treated patients (male and female) with OAB wet (n = 3398). In this study, odds ratios in favor of both combined therapies were shown for the proportion of patients achieving incontinence and micturition frequency normalization compared with monotherapies . In addition, OAB-q symptom bother score responder rates (≥ 10-point improvement from baseline to EoT) were statistically significantly higher than for mirabegron monotherapy for both combination groups, and the combination 5 + 50 mg was significantly better than solifenacin monotherapy . The highest proportion of double responders (50% decrease in incontinence and ≥ 10-point improvement in OAB-q symptom bother) was observed in the combination groups.
The PREFER study, a double-blind, randomized, crossover study in which 358 patients of both sexes received mirabegron and tolterodine, included responder rates for OAB-q subscales and OAB Satisfaction (OAB-S) Medication Tolerability score ≥ 90 . The percentage of responders at EoT for mirabegron and tolterodine extended release was 71.7% versus 65.5% for OAB-q symptom bother and 59.3% versus 54.2% for OAB-q total HRQoL. For the OAB-S medication tolerability score, the percentage of responders (score ≥ 90) at EoT was 52.5% for mirabegron and 48.5% for tolterodine extended release.
In a postmarketing study of mirabegron in 9795 patients aged ≥ 75 years with OAB, mean total OABSS decreased significantly from baseline and exceeded the MCIC in 61.0% and 65.9% of patients aged ≥ 75 and < 75 years, respectively . However, it should be noted that the BESIDE, SYNERGY, and PREFER studies and the postmarketing study all enrolled more female patients than male patients with OAB.
Responder analyses provide a tool to translate changes in subjective or objective measures into clinically meaningful binary outcomes—responders or nonresponders. In this study, responder analyses confirmed that the patients with OAB who achieved significant reductions in symptoms also experienced significant benefits in HRQoL. Higher proportions of patients in the mirabegron add-on group versus the placebo group reported clinically meaningful improvements in the MCIC for OABSS and the MID for the OAB-q subscales, illustrating that add-on therapy has the potential to lead to higher treatment success.
Limitations, due to the post hoc nature of this analysis, are that differences between groups were not analyzed statistically and the PPBC not measured. Further limitations are the omission of severe urgency (PPIUS grade 3 or 4) as an inclusion criterion and the unbalanced ratio of patients by country. In addition, future studies might benefit from including a tamsulosin plus antimuscarinic comparative arm.