Efficacy and safety evaluation of imidafenacin administered twice daily for continency recovery following radical prostatectomy in prostate cancer patients: Prospective open-label case-controlled randomized trial

According to data from the Korea Central Cancer Registry released in 2023, 277,523 new cases of cancer were reported in South Korea in 2021. Among them, prostate cancer (C61) accounted for 18,697 cases, ranking sixth with 6.7% of all cancer cases and fourth among cancers occurring in men. Over the past 20 years, as medical robot technology has been applied to the treatment of prostate cancer, tremendous technological progress has been made in prostate cancer surgery, and the number of surgeries has increased significantly. Robot-assisted radical prostatectomy (RARP) has shown excellent functional and oncological outcomes [1, 2]. However, as the number of RARP cases increases, urinary incontinence and voiding dysfunction that occur after prostatectomy are also increasing, but this problem remains unresolved. There have been various developments in surgical techniques to address these problems, and surgical treatments such as inserting a sling or artificial urethral sphincter, as well as drug treatment and behavioral therapy, are being implemented; however, urinary incontinence remains a problem in some people. Urinary incontinence after RARP has a significant impact on the patient's quality of life and causes social inconvenience. The incidence rate has been reported to be approximately 4%–69% [3, 4].

After RARP, anticholinergics are commonly used for treating urinary incontinence. These act on the muscarinic receptors of the bladder to inhibit bladder overactivity and potentially facilitated recovery from incontinence. However, their efficacy remains controversial.

This study aims to prospectively analyze the effects of anticholinergic therapy using imidafenacin on detrusor overactivity occurring after RARP and its impact on improving voiding dysfunction and urinary incontinence through questionnaire surveys.

We analyzed the effects of anticholinergics on urinary incontinence after RARP in patients diagnosed with prostate cancer at Dong-A University College of Medicine between July 2019 and June 2023. This study was approved by the Institutional Review Board of Dong-A University Hospital (approval number: DAUHIRB-18-217), and the written informed consent was obtained from all patients. And this study protocol was designed and conducted in accordance with CONSORT (Consolidated Standards of Reporting Trials) guidelines for randomized controlled trials.

A total of 60 patients were randomly assigned to participate in the study, resulting in a final participation of 49 patients (25 in the treatment group and 24 in the control group), 11 patients excluded due to patient refusal and lost to follow-up (Fig. 1). No differences were observed between groups in terms of age, comorbidities, prostate size, or pathological staging (Table 1). No serious adverse reactions related to the drug were identified, and mild dry mouth symptoms were reported by 5 patients (10.2%).

Fig. 1
Flow diagram of the prospective open-label case-controlled randomized trial.

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Table 1
Patients demographics

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Recovery of continence was observed in the treatment group, with recovery rates of 68.0%, 84.0%, and 96.0% at 1, 3, and 6 months postoperatively, respectively, whereas continence recovery rates in the control group were 66.7%, 79.2%, and 87.5%, respectively. However, there was no statistically significant difference between the groups (p=0.282) (Fig. 2).

Fig. 2
Continence recovery rate. V2, visit 2 (2–4 weeks post–robot-assisted radical prostatectomy [RARP]); V3, visit 3 (1 month post-RARP); V4, visit 4 (3 months post-RARP); V5, visit 5 (6 months post-RARP).

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According to the IPSS questionnaire results, there was no statistically significant difference between the treatment and control groups at 6 months post-surgery, with scores of 8.08±4.30 and 10.46±7.11, respectively (p=0.161), also. However, when comparing storage and voiding symptoms separately, a statistically significant improvement in storage symptoms was observed in the treatment group compared to the control group, starting from 3 months post-surgery (p=0.012) (Table 2).

Table 2
IPSS and OABSS questionnaire scores and difference

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Analysis of the OABSS between the treatment and control groups also revealed a statistically significant improvement in symptoms from 3 months postoperatively (p=0.005), which persisted until 6 months postoperatively (IPSS storage, p=0.023; OABSS, p=0.013) (Table 2, Fig. 3).

Fig. 3
Flow chart of International Prostate Symptom Score (IPSS) and Overactive Bladder Symptom Score (OABSS) scores. V2, visit 2 (2–4 weeks post–robot-assisted radical prostatectomy [RARP]); V3, visit 3 (1 month post-RARP); V4, visit 4 (3 months post-RARP); V5, visit 5 (6 months post-RARP).

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The frequency of urinary incontinence after RARP varies widely from 1% to 87%, depending on the definition of incontinence, timing of assessment, surgical techniques, and evaluators [5, 6, 7, 8]. Generally, urinary continence is defined as the ability to control urination without the use of pads after radical prostatectomy. Most patients experience temporary urinary incontinence after RARP, with continence recovery typically occurring 2–3 months post-RARP. At 12 months post-RARP prostatectomy, continence recovery rates ranged from 68% to 97%, with gradual improvement observed for up to 2 years postoperation [9, 10, 11, 12, 13, 14].

Various factors contribute to post-RARP urinary incontinence, including intrinsic sphincter deficiency and prominent bladder dysfunction. Intrinsic sphincter deficiency is often confirmed through urodynamic testing with reported frequencies ranging from 67% to 92.4%. This deficiency is typically induced by damage to the rhabdosphincter during apical dissection of the prostate. Techniques such as bladder neck preservation, posterior reconstruction, and Reziussparing have been developed to address this issue.

In this study, bladder neck preservation was performed in all the patients. This technique can preserve a sufficient length of the urethra through precise bladder neck dissection, and recovery of urinary function can be expected. The results of a recent meta-analysis based on 13 published papers also confirmed that the bladder neck preservation procedure was significantly helpful not only in the early recovery of urinary continence, but also in the recovery of long-term urinary continence (6 months: odds ratio [OR] 1.66, 95% confidence interval [CI] 1.21–2.27; p=0.001) (>12 months: OR 3.99, 95% CI 1.94–8.21; p=0.0002) [15].

Similarly, the preservation or restoration of the membranous urethral supporting structure and Rezius-sparing techniques have shown significant improvements in continence recovery [16, 17]. However, even with well-preserved sphincters, urinary incontinence may persist due to bladder abnormalities or an overactive bladder. Post-RARP overactive bladder or bladder dysfunction occurs in 33%–61% of cases, although it rarely serves as the sole cause of urinary incontinence and often co-occurs with intrinsic sphincter deficiency [18, 19, 20, 21, 22].

Bladder dysfunction is presumed to arise from partial somatic and autonomic nerve damage, inflammation, or infection resulting from bladder dissection during surgery. Additionally, factors such as urethral stricture at the bladder neck or preexisting conditions such as prostate enlargement or bladder neck obstruction can contribute to urinary incontinence [23, 24, 25, 26].

Recently, anticholinergics have been commonly used to treat bladder overactivity following RARP. Porena et al. [25] reported that 50% of patients develop urination problems after prostatectomy due to decreased bladder compliance; for this reason, they explained that treatment using anticholinergics is helpful in recovering from urinary incontinence. Bianco et al. [27] reported a urinary continence rate of 29% versus 21% in a 12-week observational study of 640 patients in the solifenacin 5 mg daily group and the placebo group in a multicenter, randomized, double-blind study. It has been reported that solifenacin is helpful in the recovery from incontinence. Shim et al. [28] reported the effectiveness of solifenacin 5 mg once daily in reducing the amount of urinary incontinence and improving lower urinary tract symptom through a prospective randomized trial study.

In this study, the use of imidafenacin 0.1 mg twice daily was prospectively analyzed and compared to a control group. Although a slight difference was observed between the medication and control groups three and six months after radical prostatectomy, the difference was not statistically significant. However, significant improvements were observed in the IPSS and OABSS, suggesting that imidafenacin may enhance bladder stability and improve storage symptoms (Table 2, Fig. 3).

This study is a prospective open-label case-controlled randomized trial, but it has limitations due to the small number of subjects and the relatively short duration of the study (only 6 months). However, currently, there is a lack of research confirming the clinical efficacy of anticholinergic drugs other than solifenacin. The significance of this study lies in demonstrating the effectiveness of an imidafenacin 0.1 mg twice twice-daily regimen in improving storage symptoms associated with urinary incontinence caused by bladder dysfunction after radical prostatectomy. Therefore, further multi-center studies of various medications are necessary.

In this study, it was found that even with successful preservation of the internal urethral sphincter, bladder overactivity can still lead to urinary incontinence. It was confirmed that administering imidafenacin twice daily helps improve bladder overactivity, thereby addressing urinary incontinence.