Vibegron for overactive bladder in men with benign prostatic hyperplasia/obstruction: insights from the COURAGE trial

Overactive bladder (OAB) is a prevalent condition affecting a significant proportion of men and women, particularly with advancing age (1). Various treatment options are available for managing OAB, including behavioral and bladder training, biofeedback, pharmacotherapy, botulinum toxin injections, neuromodulation, or other surgical options (2-4).

Oral anticholinergics and β3-adrenergic receptor agonists have long been the mainstay of medical management for OAB (1). However, anticholinergics often result in low adherence and poor tolerance due to bothersome side effects, including dry mouth, constipation, blurred vision, and an elevated risk of dementia (1,5). Furthermore, polypharmacy is common among older adults, especially those aged ≥75 years with OAB, who often require multiple medications. This has contributed to the growing popularity of β3-adrenergic receptor agonists (1). Mirabegron, a β3-adrenoceptor agonist, has shown comparable efficacy to antimuscarinics in phase 3 trials while offering better tolerability and adherence (5,6). This improved profile is due to its reduced incidence of side effects, such as dry mouth and constipation, compared to antimuscarinics (5,6). The association between mirabegron and hypertension has not been definitively proven or disproven in published data. However, uncontrolled hypertension remains a contraindication. Furthermore, there is a potential interaction with medications metabolized by CYP2D6 inhibitors (7,8).

Vibegron is a newer selective β3-adrenoceptor agonist, with a favorable safety profile, which received the Food and Drug Administration (FDA) approval for management of adults with OAB in 2020 (4,9). The FDA supplement for Efficacy-New Indication, December 2024, has listed OAB symptoms of urinary frequency, urgency, and urinary incontinence in adult males on pharmacological therapy for benign prostatic hyperplasia (BPH) as further indications for vibegron with recommended dose of 75 mg daily (10). Vibegron does not inhibit CYP2D6, a critical metabolic pathway for drugs commonly prescribed to older adults, such as donepezil, tramadol, and venlafaxine (1). The randomized international phase 3 EMPOWUR study, which included three arms—placebo, vibegron 75 mg, and tolterodine 4 mg extended-release—demonstrated that vibegron 75 mg significantly improved OAB symptoms. These improvements included a reduction in daily micturitions and episodes of urgency urinary incontinence at 12 weeks, along with a decrease in daily urgency episodes, increase in voided volume per micturition, and at least 75% reduction in urgency incontinence episodes per day, compared to placebo (11). Statistically significant improvements were observed as early as week 2 and sustained through week 12 (11). In terms of efficacy endpoints, vibegron showed numerically better results compared to tolterodine, but the difference was not statistically significant (11). In this study, vibegron was well-tolerated, with adverse event rates including hypertension, comparable to those of placebo (11). In the 40-week extension of the EMPOWUR study, which included two arms—vibegron and extended-release tolterodine—the sustained efficacy of vibegron was demonstrated. Statistical significance in favor of vibegron, as opposed to tolterodine, was shown with regard to incontinence. While there was no placebo group for comparison, vibegron and tolterodine had comparable rates of hypertension (8.8% vs. 8.6%) and urinary tract infection (6.6% vs. 7.3%). Vibegron had a lower incidence of dry mouth (1.8% vs. 5.2%); however, it was associated with higher rates of constipation (3.7% vs. 2.6%) and headache (5.5% vs. 3.9%). Nausea rate was 3.7% with vibegron and 3% with tolterodine. Overall, the authors noted that, aside from dry mouth, the incidence of common adverse events was similar between the two medications (12).

A double-blind placebo-controlled trial by Weber et al. did not show a clinically relevant or statistically significant negative impact from a daily dose of vibegron on ambulatory blood pressure (13).

Both mirabegron and vibegron have been shown to significantly improve mean voided volume per micturition compared to placebo in separate trials. A systematic review and meta-analysis by He et al. indicates that vibegron achieved notably higher values than mirabegron at week 12 (14). They also demonstrated that, while mirabegron was associated with a higher risk of cardiovascular events and nasopharyngitis, vibegron did not increase these risks compared to placebo (14). Another systematic literature review, however, found that when looking at long-term trials, hypertension to be the most common adverse event with vibegron (8.8%), mirabegron 50 mg (9.2%), and tolterodine (8.6–9.6%) (15).

One possible explanation for the association between hypertension and certain beta-3 agonists could be their effect on the kidneys. It has been established that beta-3 adrenergic receptors are present in the kidneys and play a role in water and solute reabsorption (16). However, different beta-3 agonists exhibit varying efficacy and may, therefore, have different side effect profiles. For example, ritobegron failed to meet its primary endpoints in a phase 3 study (16).

While the safety and efficacy of vibegron have been studied in various patient subgroups, including women, older adults, and those who underwent laser vaporization of the prostate (1,17,18), it had not been specifically evaluated in patients receiving pharmacologic treatment for BPH until recently. This gap was addressed by Staskin et al. in the COURAGE trial, published in the Journal of Urology (19).

This phase 3 multicenter, randomized, double-blind, placebo-controlled study evaluated the efficacy and safety of vibegron 75 mg daily. A total of 965 men aged ≥45 years with OAB symptoms (>8 micturitions and >3 urgency episodes per day for >2 months) and BPH completed the trial. All participants were on alpha-blocker therapy (initiated ≥3 months before screening), with or without 5α-reductase inhibitors (initiated ≥6 months before screening). At baseline, participants were required to have an International Prostate Symptom Score (IPSS) of ≥8 and a minimum of two nocturia episodes. They were randomly assigned in a 1:1 ratio to receive either vibegron or placebo for 24 weeks (19). The authors looked at daily frequency and urgency episodes at 12 weeks as primary endpoints for efficacy; while nocturia, daily urgency incontinence, IPSS storage score and volume voided per micturition at 12 weeks were set as secondary endpoints for efficacy. The duration of the study was 24 weeks.

Improvements in all endpoints were reported as early as week 1. The improvements seem to have continued to week 8 and then were generally maintained or improved through the study, indicating rapid and sustained symptom relief. At week 12, vibegron demonstrated a statistically significant reduction compared to placebo in mean daily micturitions and urgency episodes. A greater percentage of participants on vibegron achieved a ≥50% reduction in urgency episodes at all time points. At week 12, there was also a significant reduction in nocturia and urgency urinary incontinence episodes. Vibegron was associated with a higher percentage of participants experiencing ≥75% reductions in urgency episodes and significant improvements in IPSS storage scores and volume voided per micturition (19).

Dropout rate due to adverse events was 3% (17 patients) in the treatment group and 2.7% (15 patients) in the placebo arm. Treatment emergent adverse event rates were similar between vibegron (45.0%) and placebo (39.0%), with hypertension, coronavirus disease 2019 (COVID-19), urinary tract infection, and hematuria being the most common events in both groups (19). No treatment-related serious adverse events were reported. Although the majority of participants in the COURAGE trial had preexisting hypertension, the incidence of treatment-emergent hypertension was reported to be similar between the vibegron and placebo groups. This aligns with the EMPOWUR study, which also found no significant increase in blood pressure with vibegron, despite including patients with preexisting hypertension (11,19).

The significance of this well-designed study lies in its specific focus on addressing storage symptoms in men while being medically treated for benign prostatic obstruction (BPO). Treatments for BPO, like alpha-blockers and 5α-reductase inhibitors, may not address OAB symptoms, and only a small percentage of men with OAB receive OAB-specific medications (19,20). The 2021 American Urological Association guidelines and 2023 amendment recommend offering β3-adrenergic receptor agonists in combination with alpha-blockers for patients with moderate to severe predominant storage lower urinary tract symptoms, while highlighting the need for further large studies to strengthen the evidence supporting these recommendations (2,3). The fact that vibegron had a risk of hypertension comparable to placebo (9% vs. 8.3%) makes it an attractive medication in this setting. The 24-week duration of this study is another point of strength, while many of prior trials were only 12 weeks in duration.

A limitation of this study is the exclusion of a broad range of patients typically encountered in routine practice, such as those with a maximum urinary flow rate of <5.0 mL/s or a history of urinary retention. Additionally, the study does not include men with BPO and OAB symptoms who are not receiving pharmacologic treatment. Based on the IPSS and the aforementioned criteria, the results appear to be primarily applicable to patients exhibiting BPO symptoms of moderate severity.

Although urinary retention rates are reported (0.9% in treatment and 0.5% in placebo arm), this study does not report IPSS voiding score. Therefore, the potential negative impacts of vibegron on lower urinary tract symptoms cannot be assessed, leaving questions about vibegron’s effects on symptoms such as straining, urinary stream, and the sensation of incomplete bladder emptying unanswered.

Furthermore, prostate volume and baseline post-void residual volume (PVR) were not included in the reported inclusion criteria or results. Only about 23% of patients were on 5α-reductase inhibitors. It is unclear whether this was due to the majority having smaller prostates, concerns about side effects, or other factors. Given concerns about urinary retention associated with the use of β3-adrenoceptor agonists (21), a future study specifically examining the efficacy and safety of this medication in patients with larger prostate volumes and potentially higher PVR levels could have a significant impact on clinicians’ daily decision-making. Additionally, it may influence FDA warnings and precautions (10) regarding urinary retention in patients with bladder outlet obstruction.

Another limitation of this study lies in some unclarity regarding the definition, assessment, and reporting of adverse events. For instance, it is uncertain whether patient-reported cases of high blood pressure were included during the trial. The published inclusion criteria and study protocol do not clearly define high blood pressure, specify what constitutes significant changes in blood pressure, or outline the need for adjustments in blood pressure medications. It is also unclear if these factors were considered in the analysis. Having said that, the authors provided well-defined criteria and thorough assessments regarding hypertension in their prior publication on the extension of the EMPOWUR trial.

Another ambiguity lies in the timeframe for observing/recording adverse events. It is unclear whether there was a correlation between the duration of use and the occurrence of more adverse events toward the end of the 24-week trial.

Studies of longer duration and direct comparisons between vibegron and mirabegron could serve as the next step in managing lower urinary tract symptoms across various patient subgroups.

Finally, it should be noted that this study was not designed to address the simultaneous initiation of vibegron with alpha-blockers and/or 5α-reductase inhibitors. Further studies are warranted to explore expanded indications in the following patients:

• Patients with BPH who are not taking alpha-blockers and/or 5α-reductase inhibitors;
• Patients with different IPSS categories;
• Patients with maximum urinary flow rate <5.0 mL/s (by uro-flowmetry);
• Patients with history of urinary retention;
• Patient taking other β2- and β3-adrenergic agonists, anticholinergics, antidiuretics, or long-acting erectile dysfunction medications.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Andrology and Urology. The article has undergone external peer review.

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-2024-759/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2024-759/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Varano S, Staskin D, Frankel J, et al. Efficacy and Safety of Once-Daily Vibegron for Treatment of Overactive Bladder in Patients Aged ≥65 and ≥75 Years: Subpopulation Analysis from the EMPOWUR Randomized, International, Phase III Study. Drugs Aging 2021;38:137-46. [Crossref] [PubMed]
2. Lerner LB, McVary KT, Barry MJ, et al. Management of Lower Urinary Tract Symptoms Attributed to Benign Prostatic Hyperplasia: AUA GUIDELINE PART I-Initial Work-up and Medical Management. J Urol 2021;206:806-17. [Crossref] [PubMed]
3. Sandhu JS, Bixler BR, Dahm P, et al. Management of Lower Urinary Tract Symptoms Attributed to Benign Prostatic Hyperplasia (BPH): AUA Guideline Amendment 2023. J Urol 2024;211:11-9. [Crossref] [PubMed]
4. Shi H, Chen H, Zhang Y, et al. The efficacy and safety of Vibegron in treating overactive bladder: A systematic review and pooled analysis of randomized controlled trials. Neurourol Urodyn 2020;39:1255-63. [Crossref] [PubMed]
5. Yamanishi T, Kamasasko T, Kaga K, et al. Editorial commentary on "Safety and Efficacy of Mirabegron: Analysis of a Large Integrated Clinical Trial Database of Patients with Overactive Bladder Receiving Mirabegron, Antimuscarinics, or Placebo". Transl Androl Urol 2020;9:1009-12. [Crossref] [PubMed]
6. Tubaro A, Batista JE, Nitti VW, et al. Efficacy and safety of daily mirabegron 50 mg in male patients with overactive bladder: a critical analysis of five phase III studies. Ther Adv Urol 2017;9:137-54. [Crossref] [PubMed]
7. Fontaine C, Papworth E, Pascoe J, et al. Update on the management of overactive bladder. Ther Adv Urol 2021;13:17562872211039034. [Crossref] [PubMed]
8. Staskin D. Comment on: update on the management of overactive bladder. Ther Adv Urol 2022;14:17562872211070645. [Crossref] [PubMed]
9. Urovant Sciences Announces U.S. FDA Approval of GEMTESA® (vibegron) 75 mg Tablets for the Treatment of Patients with Overactive Bladder (OAB). 2020. Accessed December 23, 2020. Available online: https://www.us.sumitomo-pharma.com/newsroom/press-releases/Urovant-Sciences-Announces-US-Commercial-Launch-of-GEMTESA-vibegron-75mg-Tablets-for-Patients-with-Overactive-Bladder/
10. Sumitomo Pharma America, Inc. GEMTESA (vibegron) tablets, for oral use. Accessed Dec 20, 2024. Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/213006s011lbl.pdf
11. Staskin D, Frankel J, Varano S, et al. International Phase III, Randomized, Double-Blind, Placebo and Active Controlled Study to Evaluate the Safety and Efficacy of Vibegron in Patients with Symptoms of Overactive Bladder: EMPOWUR. J Urol 2020;204:316-24. [Crossref] [PubMed]
12. Staskin D, Frankel J, Varano S, et al. Once-Daily Vibegron 75 mg for Overactive Bladder: Long-Term Safety and Efficacy from a Double-Blind Extension Study of the International Phase 3 Trial (EMPOWUR). J Urol 2021;205:1421-9. [Crossref] [PubMed]
13. Weber MA, Haag-Molkenteller C, King J, et al. Effects of vibegron on ambulatory blood pressure in patients with overactive bladder: results from a double-blind, placebo-controlled trial. Blood Press Monit 2022;27:128-34. [Crossref] [PubMed]
14. He W, Zhang Y, Huang G, et al. Efficacy and safety of vibegron compared with mirabegron for overactive bladder: A systematic review and network meta-analysis. Low Urin Tract Symptoms 2023;15:80-8. [Crossref] [PubMed]
15. Kennelly MJ, Rhodes T, Girman CJ, et al. Efficacy of Vibegron and Mirabegron for Overactive Bladder: A Systematic Literature Review and Indirect Treatment Comparison. Adv Ther 2021;38:5452-64. [Crossref] [PubMed]
16. Schena G, Caplan MJ. Everything You Always Wanted to Know about β3-AR * (* But Were Afraid to Ask). Cells 2019;8:357. [Crossref] [PubMed]
17. Newman DK, Thomas E, Greene H, et al. Efficacy and Safety of Vibegron for the Treatment of Overactive Bladder in Women: A Subgroup Analysis From the Double-Blind, Randomized, Controlled EMPOWUR Trial. Urogynecology (Phila) 2023;29:48-57. [Crossref] [PubMed]
18. Seki N, Masaoka H, Song Y, et al. Efficacy and safety of Vibegron for the treatment of residual overactive bladder symptoms after laser vaporization of the prostate: A single-center prospective randomized controlled trial (VAPOR TRIAL). Low Urin Tract Symptoms 2024;16:e12529. [Crossref] [PubMed]
19. Staskin D, Owens-Grillo J, Thomas E, et al. Efficacy and safety of vibegron for persistent symptoms of overactive bladder in men being pharmacologically treated for benign prostatic hyperplasia: results from the phase 3 randomized controlled COURAGE trial. J Urol 2024;212:256-66. [Crossref] [PubMed]
20. Burnett AL, Walker DR, Feng Q, et al. Undertreatment of overactive bladder among men with lower urinary tract symptoms in the United States: A retrospective observational study. Neurourol Urodyn 2020;39:1378-86. [Crossref] [PubMed]
21. Kawazoe T, Ishida T, Jobu K, et al. Analysis of Urinary Retention Caused by Selective β 3-adrenoceptor Agonists Using the Japanese Adverse Drug Event Report Database (JADER). Pharmazie 2023;78:56-62. [PubMed]