Quantitative Assessment of Additive Effects of Mirabegron and Solifenacin in Overactive Bladder: Re-analysis of SYNERGY Study.

OBJECTIVE

To quantitatively determine whether the clinical benefit of mirabegron plus solifenacin for overactive bladder (OAB) reflects pharmacological synergy or independent drug action.

METHODS

We conducted a post hoc quantitative reanalysis of the SYNERGY study comparing solifenacin monotherapy, mirabegron monotherapy, and their combinations (S5+M25, S5+M50). A copula-based independent drug action (IDA) framework with a Gaussian copula was applied to model correlated response propensity between monotherapies. Co-primary endpoints were zero urgency urinary incontinence (Zero UI) and normalization of micturition frequency (<8/24hours). Continuous endpoints and patient-reported outcomes (OAB-q, health-related quality of life, PPBC) were also evaluated. Agreement between observed and IDA-predicted effects was assessed using predicted response rate (PRR) and additivity indices across a wide range of correlation assumptions.

RESULTS

For S5+M50, the observed Zero UI responder rate was 50.7%, and PRR was 62.4%, decomposed into 21.1% solifenacin-only, 19.5% mirabegron-only, and 21.8% overlapping responders. Normalized micturition frequency responders reached 52.2% (PRR 65.6%). For S5+M25, Zero UI and normalization responder rates were 51.3% (PRR 64.4%) and 52.6% (PRR 63.3%), respectively. Observed responder rates consistently fell within IDA-predicted ranges across correlation parameters (ρ = 0.79-0.87). Continuous endpoints showed additivity indices close to 1.0 for both dose regimens. Patient-reported outcomes similarly demonstrated additive patterns, with PRRs of 85%-94% across OAB-q, quality-of-life, and PPBC measures. No endpoint exceeded additive expectations.

CONCLUSION

The efficacy of mirabegron-solifenacin combination therapy in OAB seems to be explained by additive IDA. Its clinical value lies in additive symptom control with preserved tolerability rather than synergistic interaction.