Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): an open-label, single-arm, multicentre, phase 2 study.

BACKGROUND: Standard treatment for high-risk non-muscle-invasive bladder cancer is transurethral resection of bladder tumour followed by intravesical BCG immunotherapy. However, despite high initial responses rates, up to 50% of patients have recurrence or become BCG-unresponsive. PD-1 pathway activation is implicated in BCG resistance. In the KEYNOTE-057 study, we evaluated pembrolizumab, a PD-1 inhibitor, in BCG-unresponsive non-muscle-invasive bladder cancer. METHODS: We did this open-label, single-arm, multicentre, phase 2 study in 54 sites (hospitals and cancer centres) in 14 countries. In cohort A of the trial, adults aged 18 years or older with histologically confirmed BCG-unresponsive carcinoma in situ of the bladder, with or without papillary tumours, with an Eastern Cooperative Oncology Group performance status of 0-2, and who were ineligible for or declined radical cystectomy were enrolled. All enrolled patients were assigned to receive pembrolizumab 200 mg intravenously every 3 weeks for up to 24 months or until centrally confirmed disease persistence, recurrence, or progression; unacceptable toxic effects; or withdrawal of consent. The primary endpoint was clinical complete response rate (absence of high-risk non-muscle-invasive bladder cancer or progressive disease), assessed by cystoscopy and urine cytology approximately 3 months after the first dose of study drug. Patient follow-ups were done every 3 months for the first 2 years and every 6 months thereafter for up to 5 years. Efficacy was assessed in all patients who received at least one dose of the study drug and met BCG-unresponsive criteria. Safety was assessed in all patients who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov number, NCT02625961, and is ongoing. FINDINGS: Between Dec 9, 2015, and April 1, 2018, we screened 334 patients for inclusion. 186 patients did not meet inclusion criteria, and 47 patients were assigned to cohort B (patients with BCG-unresponsive high grade Ta or any grade T1 papillary disease without carcinoma in situ; results will be reported separately). 101 eligible patients were enrolled and assigned to receive pembrolizumab. All 101 patients received at least one dose of the study drug and were included in the safety analysis. Five patients had disease that did not meet the US Food and Drug Administration definition of BCG-unresponsive non-muscle-invasive bladder cancer and were therefore not included in the efficacy analysis (n=96). Median follow-up was 36·4 months (IQR 32·0-40·7). 39 (41%; 95% CI 30·7-51·1) of 96 patients with BCG-unresponsive carcinoma in situ of the bladder with or without papillary tumours had a complete response at 3 months. Grade 3 or 4 treatment-related adverse events occurred in 13 (13%) patients; the most common were arthralgia (in two [2%] patients) and hyponatraemia (in three [3%] patients). Serious treatment-related adverse events occurred in eight (8%) patients. There were no deaths that were considered treatment related. INTERPRETATION: Pembrolizumab monotherapy was tolerable and showed promising antitumour activity in patients with BCG-unresponsive non-muscle-invasive bladder cancer who declined or were ineligible for radical cystectomy and should be considered a a clinically active non-surgical treatment option in this difficult-to-treat population. FUNDING: Merck Sharp & Dohme.

KEYNOTE-676: Phase III study of BCG and pembrolizumab for persistent/recurrent high-risk NMIBC.

Background: Nonmuscle-invasive bladder cancer (NMIBC) is the most common form of bladder cancer, with high rates of disease recurrence and progression. Current treatment for high-risk NMIBC involves Bacillus Calmette-Guérin (BCG) therapy, but treatment options are limited for patients with recurrent or BCG-unresponsive disease. Aberrant programmed death 1 signaling has been implicated in BCG resistance and bladder cancer recurrence and progression, and pembrolizumab has shown efficacy in patients with BCG-unresponsive high-risk NMIBC. Aim: To describe the rationale and design for the randomized, comparator-controlled Phase III KEYNOTE-676 study, which will evaluate the efficacy and safety of pembrolizumab in combination with BCG in patients with persistent/recurrent high-risk NMIBC after BCG induction therapy. Trial registration number: NCT03711032.

Pembrolizumab versus chemotherapy in recurrent, advanced urothelial cancer in Japanese patients: a subgroup analysis of the phase 3 KEYNOTE-045 trial.

BACKGROUND: The open-label, randomized, active-controlled KEYNOTE-045 study (NCT02256436) showed that second-line pembrolizumab significantly improved overall survival (OS) of patients with advanced/metastatic urothelial cancer (UC) that progressed after first-line platinum-containing chemotherapy, compared with standard chemotherapy (paclitaxel, docetaxel, or vinflunine). Pembrolizumab is approved for patients with bladder cancer in Japan. PATIENTS AND METHODS: Analysis was performed in the subgroup of Japanese patients enrolled in the KEYNOTE-045 study. Coprimary end points were OS and progression-free survival (PFS). Objective response rate (ORR) and safety were secondary end points. RESULTS: Fifty-two Japanese patients (pembrolizumab, n = 30; chemotherapy, n = 22) were followed up for a median of 26.1 months. Patients who received pembrolizumab compared with chemotherapy had a 19% lower risk for death (hazard ratio [HR] 0.81, 95% CI 0.44-1.50); after adjusting for baseline covariates, the HR for OS was 0.61 (95% CI 0.32-1.15). The 24-month OS rate was higher with pembrolizumab (26.9% vs 14.3%). PFS was 2.0 and 4.9 months for pembrolizumab and chemotherapy, respectively (HR 1.71, 95% CI 0.95-3.08). ORR was similar for pembrolizumab and chemotherapy (20.0% vs 18.2%); durability of response was higher with pembrolizumab: 67% and 33% of patients, respectively, maintained a response for > 12 months. Treatment-related adverse events, including grade 3-5 events, occurred less frequently with pembrolizumab. CONCLUSIONS: Pembrolizumab provided durable antitumor activity in patients with locally advanced/metastatic UC that progressed after platinum-containing chemotherapy in the overall population and in the Japanese subgroup; safety profile was consistent with that previously observed for pembrolizumab.

Phase II dose-finding study on ovulation inhibition and cycle control associated with the use of contraceptive vaginal rings containing 17ß-estradiol and the progestagens etonogestrel or nomegestrol acetate compared to NuvaRing.

PURPOSE: To identify at least one contraceptive vaginal ring that effectively inhibits ovulation and demonstrates cycle control that is non-inferior to NuvaRing® (Merck Sharp & Dohme B.V., The Netherlands) in terms of an unscheduled bleeding incidence, with a non-inferiority margin of 10%. METHODS: This was a randomised, active controlled, parallel group, multicentre, partially blinded trial in healthy women 18-35 years of age. Subjects received one of six contraceptive vaginal rings with an average daily release rate of 300 µg 17ß-estradiol (E2) and various rates of either etonogestrel (ENG; 75, 100, or 125 µg/day) or nomegestrol acetate (NOMAC; 500, 700, or 900 µg/day), or the active control NuvaRing® (ENG/ethinylestradiol 120/15 µg), for three 28-day cycles. RESULTS: Ovulation inhibition was observed in all groups as confirmed by absence of progesterone concentrations compatible with ovulation (>16 nmol/L) and absence of ultrasound evidence of ovulation. All investigational rings provided good cycle control, with the ENG-E2 125/300 µg/day group being associated with the best cycle control based on the numerically lowest incidence of unscheduled bleeding and absence of scheduled bleeding. Non-inferiority to NuvaRing® with respect to the incidence of unscheduled bleeding could not be concluded for any of the investigational ring groups. The safety profile was consistent with the known safety profile of combined estrogen/progestin contraceptives and similar across all groups. CONCLUSIONS: Contraceptive rings releasing 300 µg E2 and 75-125 µg/day of ENG or 500-900 µg/day of NOMAC provided adequate ovulation inhibition and cycle control and are generally well-tolerated. While non-inferiority to NuvaRing® was not met, among the investigational rings, the ENG-E2 125/300 ring provided the best cycle control.

Evaluation of an experimental urodynamic platform to identify treatment effects: a randomized, placebo-controlled, crossover study in patients with overactive bladder.

AIMS: To evaluate a urodynamic platform designed to identify treatment effects in small numbers of patients after a short duration of treatment using a medication with known efficacy in overactive bladder (OAB). METHODS: Twenty women with OAB were randomized in a crossover study with 7-day treatment periods with either tolterodine 4 mg long-acting (LA) or placebo and 7-day washout. Patients underwent urodynamic study (UDS) at baseline, 4-hr post-dose on Day 1 (PD1) and 4 hr post-dose on Day 7 (PD7) in each treatment period. The primary endpoint was the change from baseline in volume at maximum cystometric capacity (MCC) at PD7. As a result of dosing errors, some patients allocated to tolterodine in Period 1 mistakenly received placebo on Day 7. The data from the time points at which patients were dosed incorrectly were excluded from the per protocol (PP) analysis. RESULTS: The PP and intent to treat (ITT) mean increase in volume at MCC on PD7 for tolterodine compared with placebo was 28.9% (P = 0.038, one-sided) and 23.2% (P = 0.008, one-sided), respectively. The PD7 mean increase in volume at first desire to void was 36.5% (P = 0.054, PP) and 40.3% (P = 0.008, ITT). No volume endpoint at PD1 was statistically significant. Of all the endpoints, MCC was the least variable. CONCLUSIONS: This crossover design was able to detect a clinically meaningful and statistically significant treatment effect consistent with the previous reports of tolterodine. Despite multiple urodynamics per patient, the study was able to recruit quickly. This model is valuable for evaluating therapeutic effects for existing and novel treatments for OAB.

Variability of urodynamic parameters in patients with overactive bladder.

AIMS: To report interpatient, intrapatient, and study site variability of urodynamic study (UDS) parameters in patients with overactive bladder (OAB). METHODS: Fifty-eight patients with OAB participated in a randomized, double-blind, placebo-controlled, urodynamic trial of an experimental OAB drug. Patients underwent 3 serial cystometries (CMGs) at three times: screening, pre-dose, and 4-hr postdose. This post hoc analysis describes intrapatient, interpatient, and site variability for the 6 CMGs prior to administration of study drug. Sites were given standard procedures for equipment calibration and UDS technique. Instilled volumes and pressures were recorded at first sensation of filling, first desire to void (FDV), strong desire to void (SDV), and maximum cystometric capacity (MCC). RESULTS: The UDS volume endpoint with the smallest observed within-patient variability based on coefficient of variation (%CV) was MCC (%CV 24). Pressure measurements of all bladder sensations had larger within-patient variability than volume (MCC %CV 105). The between-patient variability was greater than within-patient variability for all bladder sensation volumes. Between-patient MCC variability for the 6 pre-treatment CMGs ranged from %CV of 50 to 58, whereas the within-patient %CV for MCC was 21-23. Excellent reproducibility was observed for bladder volume for MCC (intraclass correlation coefficients, range: 0.80-0.84). The between-site variability was large, as demonstrated by the mean volumes by site for MCC (132-397 ml). CONCLUSIONS: MCC was the most reproducible sensation. Pressure measurements were substantially more variable than volume. Between-patient variability was substantially greater than within-patient variability. The observed intersite variability suggests that despite detailed instructions, sensations may not have been measured in a consistent manner across sites.

A multicenter, double-blind, randomized, placebo controlled trial of a neurokinin-1 receptor antagonist for overactive bladder.

PURPOSE: Neurokinin-1 receptor dependent mechanisms may regulate urinary frequency and urgency. We conducted this study to assess the efficacy and tolerability of the neurokinin-1 receptor antagonist serlopitant vs placebo or tolterodine in patients with overactive bladder. MATERIALS AND METHODS: This randomized, double-blind, 69-center trial enrolled adults with overactive bladder (8 or more average daily micturitions and 1 or more daily urge incontinence episodes). After a 1-week placebo run-in the patients were randomized to 8 weeks of daily 0.25, 1 or 4 mg serlopitant, 4 mg tolterodine extended release or placebo. Patients kept 7-day voiding diaries. The primary end point was change from baseline in micturitions per day. Secondary end points included urgency, total incontinence, urge incontinence episodes and incidence of dry mouth. RESULTS: Of 557 patients randomized 476 completed the trial and had valid efficacy data for analysis. Mean change from baseline in daily micturitions was significantly greater for 0.25 (-1.1) and 4 mg (-1.1) serlopitant, and for tolterodine (-1.5) than for placebo (-0.5), but not for 1 mg serlopitant (-0.8). No serlopitant dose response was demonstrated. Tolterodine was numerically superior to all doses of serlopitant in mean micturitions per day and secondary end points. The incidence of dry mouth on serlopitant (3.3%) was comparable to placebo (4.6%) and lower than tolterodine (8.8%). Serlopitant was generally well tolerated. CONCLUSIONS: Serlopitant (0.25 and 4 mg) significantly decreased the primary end point of daily micturitions but not the secondary end points compared with placebo. Serlopitant was generally well tolerated. Thus, NK-1 receptor antagonists may have a role in the treatment of overactive bladder but this compound does not offer advantages in efficacy compared to tolterodine.

The cost effectiveness of pembrolizumab versus chemotherapy or atezolizumab as second-line therapy for advanced urothelial carcinoma in the United States.

Aims: Pembrolizumab demonstrated significantly prolonged overall survival (OS) vs. chemotherapy in the Phase III KEYNOTE-045 trial, and is approved in the US for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who progressed after platinum-based chemotherapy. Using longer follow-up and individual patient-data from KEYNOTE-045, this study evaluates the cost-effectiveness of pembrolizumab vs. chemotherapy or atezolizumab from a US payer perspective.Materials and methods: A partitioned-survival model was developed over a 20-year time horizon. Progression-free survival (PFS) and OS for pembrolizumab and chemotherapy were extrapolated using a piecewise modelling approach, where patient-level data from KEYNOTE-045 were used for the initial period followed by parametric distributions. OS of atezolizumab was estimated by indirect treatment comparisons based on KEYNOTE-045 and IMvigor211. Different scenarios were explored in the absence of indirect comparisons on PFS and time-on-treatment (ToT) between pembrolizumab and atezolizumab. Drug acquisition/administration, disease management, adverse events, and terminal care costs were considered.Results: Compared with chemotherapy, pembrolizumab resulted in a mean gain of 1.33 life-years and 1.14 quality-adjusted life-years (QALYs) and an incremental cost of $106,299, yielding an incremental cost-effectiveness ratio of $93,481/QALY gained. Pembrolizumab dominated atezolizumab in extending patients' life by 0.89 years and 0.76 QALYs, while reducing costs by $26,458. Key drivers of cost-effectiveness included survival extrapolation, OS hazard ratio of pembrolizumab vs. atezolizumab, and time horizon. Pembrolizumab had a 66% and 100% probability of being cost-effective vs. chemotherapy and atezolizumab, respectively, at a $100,000 willingness-to-pay threshold.Limitations and conclusions: Uncertainties remain with extrapolated PFS and OS for pembrolizumab, OS indirect comparison, and ToT for atezolizumab. Despite these limitations, the model used robust methods to estimate key clinical endpoints with patient-level data from longer follow-up of KEYNOTE-045. Pembrolizumab dominates atezolizumab and is very likely cost-effective vs. chemotherapy in 2 L mUC at a $100,000 willingness-to-pay threshold.

Long-Term Outcomes in KEYNOTE-052: Phase II Study Investigating First-Line Pembrolizumab in Cisplatin-Ineligible Patients With Locally Advanced or Metastatic Urothelial Cancer.

PURPOSE: The phase II single-arm KEYNOTE-052 study evaluated the efficacy and safety of first-line pembrolizumab for patients with locally advanced or metastatic cisplatin-ineligible urothelial carcinoma (UC). PATIENTS AND METHODS: Three hundred seventy patients received pembrolizumab 200 mg intravenously every 3 weeks for up to 24 months. Positive tumor programmed death ligand 1 (PD-L1) expression was defined as combined positive score (CPS) ≥ 10. Response was assessed by independent central review every 9 weeks per RECIST v1.1. The primary end point was objective response rate (ORR). RESULTS: At data cutoff (September 26, 2018), the minimum follow-up was 2 years since the last patient enrolled. ORR was 28.6% (95% CI, 24.1% to 33.5%); 33 patients (8.9%) and 73 patients (19.7%) achieved complete and partial response, respectively. The median duration of response was 30.1 months (95% CI, 18.1 months to not reached [NR]); responses lasted ≥ 12 and ≥ 24 months in 67% and 52% of patients, respectively. Forty patients with complete or partial response completed 2 years of study treatment, and 32 had ongoing response at completion. Median overall survival (OS) was 11.3 months (95% CI, 9.7 to 13.1 months), and 12- and 24-month OS rates were 46.9% and 31.2%, respectively. In patients with CPS ≥ 10, ORR was 47.3% (95% CI, 37.7% to 57.0%) and median OS was 18.5 months (95% CI, 12.2 to 28.5 months). In patients with lymph node-only disease, ORR was 49.0% (95% CI, 34.8% to 63.4%), and median OS was 27.0 months (12.4 months to NR). There were no new safety signals. CONCLUSION: First-line pembrolizumab confers meaningful and durable clinical response in cisplatin-ineligible patients with advanced UC and is associated with prolonged OS, particularly with PD-L1 CPS ≥ 10 and lymph node-only disease.

Pembrolizumab as First-line Therapy in Cisplatin-ineligible Advanced Urothelial Cancer (KEYNOTE-052): Outcomes in Older Patients by Age and Performance Status.

BACKGROUND: Patients with treatment-naive advanced urothelial cancer (UC) ineligible for cisplatin-based chemotherapy are typically older and have comorbidities, representing a difficult-to-treat population. OBJECTIVE: To evaluate the safety and antitumor activity of first-line pembrolizumab in subgroups of cisplatin-ineligible older patients (aged ≥65 and ≥75 yr) with advanced UC in KEYNOTE-052 (NCT02335424), including those with poor performance status (Eastern Cooperative Oncology Group performance status score 2 [ECOG PS2]). DESIGN, SETTING, AND PARTICIPANTS: Patients were cisplatin ineligible, had treatment-naive, histologically/cytologically confirmed, locally advanced/metastatic UC with measurable disease (Response Evaluation Criteria in Solid Tumors version 1.1 [RECIST v1.1]), and had ECOG PS0-2. Patient subgroups analyzed were aged ≥65yr (n = 302), ≥75 yr (n = 179), ≥65yr with ECOG PS2 (≥65yr+ECOG PS2; n = 119), and ≥75 yr+ECOG PS2 (n = 78). INTERVENTION: All patients received pembrolizumab 200mg intravenously every 3 wk until confirmed progression, intolerable toxicity, patient withdrawal, or 24 mo of therapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was objective response rate (ORR) as per RECIST v1.1. The key secondary endpoints were overall survival (OS), duration of response (DOR), and safety. RESULTS AND LIMITATIONS: ORRs for the ≥65yr, ≥75 yr, ≥65yr+ECOG PS2, and ≥75 yr+ECOG PS2 subgroups were 29%, 27%, 29%, and 31%, respectively; rates of complete and partial responses were similar across subgroups (9%, 5%, 6%, and 6%, and 20%, 22%, 23%, and 24%, respectively). Median DOR and OS were also consistent across the ≥65yr and ≥65yr+ECOG PS2 subgroups and the ≥75 yr and ≥75 yr+ECOG PS2 subgroups. Study limitations included open-label design, lack of a comparator group, and nature of post hoc exploratory analysis. CONCLUSIONS: The clinical benefit of pembrolizumab in advanced UC appeared to be consistent regardless of age and/or poor performance status. PATIENT SUMMARY: This study looked at whether older age and poorer performance status affect how well patients with previously untreated advanced urothelial cancer ineligible for standard-of-care treatment respond to pembrolizumab. Outcomes with pembrolizumab were not affected by older age or poorer performance status, making it an effective option.

Systematic Literature Review and Meta-Analysis of Response to First-Line Therapies for Advanced/Metastatic Urothelial Cancer Patients Who Are Cisplatin Ineligible.

OBJECTIVE: The purpose of this systematic literature review (SLR) and meta-analysis was to compile the response of historic treatment options in first-line settings for patient populations who are cisplatin ineligible. MATERIALS AND METHODS: SLR was conducted to compile objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS) of historic therapies for this population based on stringent criteria. Clinical trials published in English from January 1991 to June 2016 were identified by searching the PubMed (Medline), Cochrane, and Embase databases. RESULTS: Eighteen studies (21 arms; N=810) were identified and used for this meta-analysis. For all treatments included in these studies, the pooled ORR was 0.36 (95% confidence interval [CI], 0.30-0.42). The ORR for the carboplatin+gemcitabine arms (6 arms; N=259), which is the National Comprehensive Cancer Network's recommended first-line treatment (before approval of atezolizumab and pembrolizumab) for this population was 0.36 (95% CI, 0.30-0.42), the median DOR (4 arms) was 7.00 months (95% CI, 4.34-11.29), and the median OS was 8.39 months (95% CI, 7.05-9.98). CONCLUSIONS: The results of this SLR clearly demonstrate the paucity of clinical studies that assess therapeutic intervention in truly cisplatin-ineligible advanced/metastatic urothelial carcinoma subjects and highlight the development of novel therapies that can create real improvement in long-term outcomes. The recent approval of 2 checkpoint inhibitors, atezolizumab and pembrolizumab, were added in the National Comprehensive Cancer Network guidance as recommended first-line treatment for cisplatin-ineligible patients with advanced/metastatic urothelial carcinoma and has provided alternatives for this patient population.

A phase 2b multicenter, randomized, double-blind, placebo-controlled clinical trial to evaluate the efficacy and safety of vaginal rings containing nomegestrol acetate or etonogestrel and 17ß-estradiol in the treatment of women with primary dysmenorrhea.

OBJECTIVE: To evaluate the effect of investigational vaginal rings containing nomegestrol acetate (NOMAC) plus 17ß-estradiol (E2) or etonogestrel (ENG) plus E2 in women with moderate to severe primary dysmenorrhea. STUDY DESIGN: This was a Phase 2b randomized, placebo-controlled, multicenter, double-blind study. We randomized participants to one of five treatment groups: four hormonal rings and one placebo ring. The investigational vaginal rings released 300 µg of E2 daily along with 700 µg or 900 µg of NOMAC or 100 µg or 125 µg of ENG. Each participant received 2 identical rings and was to insert each for 21 days followed by a 7-day ring-free period. The primary endpoint, as assessed by a daily electronic diary (e-Diary), was the change in menstrual pain score from baseline to the second in-treatment withdrawal bleeding episode (Cycle 2). The pain score was the mean of the three highest scores for menstrual cramping pain (0-4 point scale) recorded from the day before menses to the third day of bleeding. The primary hypothesis was that at least one investigational vaginal ring would demonstrate a statistically significant larger reduction from baseline in pain score compared to placebo. Secondary endpoints included total mean impact score (which assessed the negative impact on work/school, physical activities, leisure/social activities) and the amount and days of rescue medication (ibuprofen) used. CLINICAL TRIAL REGISTRATION NUMBER: NCT01670656. RESULTS: We randomized 439 participants. The mean pain score decreased from baseline to Cycle 2 in all groups; the decrease in all four treatment groups compared to placebo was statistically significant (p-values ≤0.002). All treatment groups had greater reductions than placebo in ibuprofen intake and greater improvement in impact scores; these differences were statistically significant for both endpoints for the ENG-E2 100/300 µg/day group, while the other groups were not statistically significant for one or both endpoints. CONCLUSION: All four investigational rings produced a statistically significantly larger reduction from baseline in mean menstrual pain score compared to placebo while pain medication use decreased. IMPLICATIONS: This placebo-controlled study provides evidence that vaginal contraceptive rings containing NOMAC-E2 or ENG-E2 improve moderate to severe dysmenorrhea, across all of doses studied. This adds to the evidence that hormonal contraceptives are effective treatments for dysmenorrhea.

Vibegron (RVT-901/MK-4618/KRP-114V) Administered Once Daily as Monotherapy or Concomitantly with Tolterodine in Patients with an Overactive Bladder: A Multicenter, Phase IIb, Randomized, Double-blind, Controlled Trial.

BACKGROUND: Antimuscarinics have shown modest efficacy with unwanted side effects in patients with overactive bladder (OAB). Efficacy of vibegron, a new ß3-adrenergic receptor agonist, for OAB is unknown. OBJECTIVE: To evaluate the efficacy of once-daily oral vibegron in OAB patients (primary), and its safety, tolerability, and efficacy when administered alone or concomitantly with tolterodine (secondary). DESIGN, SETTING, AND PARTICIPANTS: International, phase IIb, randomized, double-blind, placebo- and active comparator-controlled, two-part superiority trial (2011-2013) in OAB-wet or OAB-dry patients aged 18-75 yr (NCT01314872). INTERVENTIONS: Part 1: once-daily oral vibegron monotherapy (3 [V3], 15 [V15], 50 [V50], or 100 [V100] mg), tolterodine extended release 4mg (TER4), or placebo for 8 wk, or combination V50/TER4 for 4 wk and then V50 for 4 wk; part 2: V100/TER4, V100, TER4, or placebo for 4 wk. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Average daily micturitions at week 8 of part 1 (primary); urge incontinence episodes, total incontinence episodes, and urgency episodes (secondary). RESULTS AND LIMITATIONS: Overall, 1395 patients were randomized. From baseline to week 8, V50 and V100 significantly decreased average daily micturitions (least square mean difference [95% confidence interval], -0.64 [-1.11, -0.18]; p=0.007 and -0.91 [-1.37, -0.44]; p<0.001, respectively) and the number of urge incontinence episodes (-0.72 [-1.11, -0.33] and -0.71 [-1.10, -0.32], respectively; both p<0.001) versus placebo. All vibegron doses were well tolerated. The incidence of dry mouth was higher with TER4 than with vibegron monotherapy. Results are limited by the relatively short treatment duration. CONCLUSIONS: Once-daily V50 and V100 improved OAB symptoms; vibegron was well tolerated as monotherapy and concomitantly with tolterodine. Further development is warranted. PATIENT SUMMARY: Antimuscarinics, commonly used to treat overactive bladder, produce modest efficacy and unwanted side effects. In this study, a different type of drug (vibegron) was efficacious and safe, alone or with an antimuscarinic (tolterodine).

Bladder dysfunction in mice with experimental autoimmune encephalomyelitis.

The vast majority of patients with multiple sclerosis (MS) develop bladder control problems including urgency to urinate, urinary incontinence, frequency of urination, and retention of urine. Over 60% of MS patients show detrusor-sphincter dyssynergia, an abnormality characterized by obstruction of urinary outflow as a result of discoordinated contraction of the urethral sphincter muscle and the bladder detrusor muscle. In the current study we examined bladder function in female SWXJ mice with different defined levels of neurological impairment following induction of experimental autoimmune encephalomyelitis (EAE), an animal model of central nervous system inflammation widely used in MS research. We found that EAE mice develop profound bladder dysfunction characterized by significantly increased micturition frequencies and significantly decreased urine output per micturition. Moreover, we found that the severity of bladder abnormalities in EAE mice was directly related to the severity of clinical EAE and neurologic disability. Our study is the first to show and characterize micturition abnormalities in EAE mice thereby providing a most useful model system for understanding and treating neurogenic bladder.

Sexually transmitted infections.

This article addresses the importance of screening for sexually transmitted diseases as a form of secondary prevention. The differential diagnoses of genital ulcers or inflammatory disorders of the genitourinary tract, with a higher index of suspicion for sexually transmitted disease, are discussed, as well as currently recommended treatment options for the same.

Management of iatrogenic foreign bodies of the bladder and urethra following pelvic floor surgery.

OBJECTIVE: Literature regarding the management of iatrogenic foreign body in the bladder and urethra following female pelvic reconstructive surgery, especially mesh erosion, are sparse. We present our recent experience with the removal of iatrogenic foreign bodies from the bladder and urethra and propose a treatment algorithm. METHODS: A retrospective review yielded 22 patients with iatrogenic foreign body in the bladder or urethra between 1/1998 and 12/2005. Presenting complaints, cystoscopic findings, operative techniques, and outcomes were reviewed. RESULTS: Source surgery of the iatrogenic foreign bodies included bladder suspension in 9 patients, synthetic sling in 11 patients, abdominal sacrocolpopexy and porcine dermis sling in 1 patient each. The majority of patients presented with multiple voiding dysfunctions including overactive bladder symptoms (11), incontinence (5), chronic pelvic or urethral pain (7), urinary tract infections (7), obstructive voiding symptoms (5), and gross hematuria (3). Eleven cases were managed endoscopically, 4 using the holmium laser. One patient required subsequent cystorrhaphy. Four patients were managed with urethroplasty, 4 with cystorrhaphy, and the remainder utilizing a combination of techniques. No patients required complex reconstruction with interposition flaps. CONCLUSIONS: The diagnosis of iatrogenic foreign bodies in the lower urinary tract requires a high index of suspicion and a low threshold for performing cystoscopy. From this series, we have found that sutures can most often be managed successfully with endoscopic techniques, whereas mesh is best managed with cystorrhaphy and/or urethroplasty. To our knowledge, our series represents the largest number of reported iatrogenic foreign body removals at a single institution.

Safety and efficacy of the NuvaRing® Applicator in healthy females: a multicenter, open-label, randomized, 2-period crossover study.

INTRODUCTION: We assessed performance and safety of the NuvaRing® Applicator. METHODS: We randomized women (18-45 years) to insert a placebo ring using the applicator or fingers-only and then vice versa. We assessed outcomes post-insertion and then 24-72 h later. RESULTS: Insertion was 100% successful using both methods (applicator, n=163; fingers-only, n=162). A total of 8.6% (applicator) and 4.3% (fingers-only) of subjects reported at least 1 treatment-related adverse event (AE); all were mild. Subjects reported 5 applicator-related AEs (vulvovaginal pain, 4; abdominal cramping, 1). There was no vaginal bleeding within 15 h post-applicator use. Ring expulsions were rare (applicator, 1; fingers-only, 2). CONCLUSION: NuvaRing Applicator is effective and well-tolerated (NCT02275546).

Discovery of Vibegron: A Potent and Selective ß3 Adrenergic Receptor Agonist for the Treatment of Overactive Bladder.

The discovery of vibegron, a potent and selective human ß3-AR agonist for the treatment of overactive bladder (OAB), is described. An early-generation clinical ß3-AR agonist MK-0634 (3) exhibited efficacy in humans for the treatment of OAB, but development was discontinued due to unacceptable structure-based toxicity in preclinical species. Optimization of a series of second-generation pyrrolidine-derived ß3-AR agonists included reducing the risk for phospholipidosis, the risk of formation of disproportionate human metabolites, and the risk of formation of high levels of circulating metabolites in preclinical species. These efforts resulted in the discovery of vibegron, which possesses improved druglike properties and an overall superior preclinical profile compared to MK-0634. Structure-activity relationships leading to the discovery of vibegron and a summary of its preclinical profile are described.

Injectable neuromodulatory agents: botulinum toxin therapy.

Botulinum toxin therapy is a diverse treatment option for various dysfunctions of the lower urinary tract. The limited but growing clinical experience reveals that temporary chemodenervation with reduction or loss of neuronal activity at the target organ may be achieved with minimal risk. This highly favorable risk-benefit ratio in urology is derived from the clinical ability to treat an end-organ condition effectively with controllable site-specific delivery (eg, subcutaneous, intramuscular, or instillation) combined with high affinity for toxin uptake by the peripheral cholinergic nerves. Although many questions remain regarding the optimal use of this minimally invasive option for urologic applications, the opportunity for expanding indications will provide urologists with more options for addressing difficult challenges in voiding dysfunction.

Perioperative use of etoricoxib reduces pain and opioid side-effects after total abdominal hysterectomy: a double-blind, randomized, placebo-controlled phase III study.

OBJECTIVE: To evaluate the effects of two different doses of etoricoxib delivered perioperatively compared with placebo and standard pain management on pain at rest, pain with mobilization, and use of additional morphine/opioids postoperatively. RESEARCH DESIGN AND METHODS: In this double-blind, placebo-controlled, randomized clinical trial, we evaluated postoperative pain following total abdominal hysterectomy over 5 days in patients receiving placebo or etoricoxib administered 90 min prior to surgery and continuing postoperatively. Patients were randomly assigned to receive either placebo (n = 144), etoricoxib 90 mg/day (n = 142), or etoricoxib 120 mg/day (n = 144). Average Pain Intensity at Rest over days 1-3 (0- to 10-point numerical rating scale [NRS]) was the primary efficacy endpoint. Secondary endpoints included Average Pain Intensity upon Sitting, Standing, and Walking over days 1-3 (0- to 10-point NRS) as well as Average Total Daily Dose of Morphine over days 1-3. CLINICAL TRIAL REGISTRATION: This trial is registered on www.clinicaltrials.gov (NCT00788710). RESULTS: The least squares (LS) means (95% CI) for the primary endpoint were 3.26 (2.96, 3.55); 2.46 (2.16, 2.76); and 2.40 (2.11, 2.69) for placebo, etoricoxib 90 mg, and etoricoxib 120 mg, respectively, significantly different for both etoricoxib doses versus placebo (p < 0.001). Patients on etoricoxib 90 mg and 120 mg required ~30% less morphine per day than those on placebo (p < 0.001), which led to more rapid bowel recovery in the active treatment groups by ~10 hours vs. placebo. A greater proportion of patients on etoricoxib (10-30% greater than placebo) achieved mild levels of pain with movement, defined as pain ≤3/10. LIMITATIONS: A key limitation for this study was that movement-evoked pain measurements were not designated as primary endpoints. CONCLUSION: In patients undergoing total abdominal hysterectomy, etoricoxib 90 mg and 120 mg dosed preoperatively and then continued postoperatively significantly reduces both resting and movement-related pain, as well as reduced opioid (morphine) consumption that led to more rapid bowel recovery.