To quantitatively determine whether the clinical benefit of mirabegron plus solifenacin for overactive bladder (OAB) reflects pharmacological synergy or independent drug action.
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 (<8/24 h). 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.
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.
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.
Urology. 2026 Jul 15 [Epub ahead of print]
Wei Chen, Soichiro Yoshida, Shugo Yajima, Hiroshi Fukushima, Hiroyuki Sato, Akihiro Hirakawa, Takanobu Yamamoto, Hiroyuki Honda, Tomohiro Matsuo, Naoki Wada, Hitoshi Masuda, Yasuhisa Fujii
Department of Urology, Zigong Fourth People's Hospital, Zigong, Sichuan, China; Department of Urology, Institute of Science Tokyo, Tokyo, Japan. Electronic address: ., Department of Urology, Institute of Science Tokyo, Tokyo, Japan. Electronic address: ., Department of Urology, National Cancer Center Hospital East, Chiba, Japan. Electronic address: ., Department of Urology, Institute of Science Tokyo, Tokyo, Japan. Electronic address: ., Department of Clinical Biostatistics, Institute of Science Tokyo, Tokyo, Japan. Electronic address: ., Department of Clinical Biostatistics, Institute of Science Tokyo, Tokyo, Japan. Electronic address: ., Department of Urology, Tokyo Metropolitan Tama-Nambu Chiiki Hospital, Tokyo, Japan. Electronic address: ., Department of Urology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan. Electronic address: ., Department of Urology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan. Electronic address: ., Department of Renal and Urologic Surgery, Asahikawa Medical University, Asahikawa, Japan. Electronic address: ., Department of Urology, National Cancer Center Hospital East, Chiba, Japan. Electronic address: ., Department of Urology, Institute of Science Tokyo, Tokyo, Japan. Electronic address: .