Retrospective Study of Claudin 18 Isoform 2 Prevalence and Prognostic Association in Gastric and Gastroesophageal Junction Adenocarcinoma.

PURPOSE: Claudin 18 isoform 2 (CLDN18.2) is an emerging biomarker and therapeutic target in gastric and gastroesophageal junction (G/GEJ) adenocarcinoma. This study aimed to obtain deeper understanding of CLDN18.2 positivity patterns, prognostic implications, and associations with various demographic, clinical, and molecular characteristics in G/GEJ adenocarcinoma. METHODS: Archived tumor tissue samples from 304 patients with G/GEJ adenocarcinoma in the United States were assessed for CLDN18.2 positivity by immunohistochemistry. CLDN18.2 positivity was defined as ≥50% or ≥75% of tumor cells with CLDN18 staining intensity ≥2+. CLDN18.2 positivity patterns were analyzed for association with prognosis and clinicopathologic/demographic characteristics. Where possible, CLDN18.2 positivity was analyzed for matched tissue samples to assess concordance between primary and metastatic tumors and concordance before and after chemotherapy. RESULTS: The overall prevalence of CLDN18.2-positive tumors (with ≥75% cutoff) was 44.4% (n = 135 of 304). CLDN18.2-positive tumors had a prevalence of 51.4% (n = 91 of 177) in gastric and 34.6% (n = 44 of 127) in GEJ adenocarcinoma. With a ≥50% cutoff, the prevalence of CLDN18.2-positive tumors was 64.4% (n = 114 of 177) in gastric adenocarcinoma and 44.9% (n = 57 of 127) in GEJ adenocarcinoma. There was no association between overall survival and CLDN18.2 positivity using either threshold. Statistically significant associations were noted between CLDN18.2 positivity and sex, histologic type of G/GEJ adenocarcinoma, and adenocarcinoma subtype (≥75% cutoff), and metastasis site and tumor grade (≥50% cutoff). The overall concordance of CLDN18.2 positivity (≥75% cutoff) was 73% (27 of 37) for matched primary versus metastatic tumor samples and 74% (29 of 39) for matched samples before and after chemotherapy. CONCLUSION: This study demonstrated that CLDN18.2 positivity did not correlate with survival in G/GEJ adenocarcinoma, consistent with published data. On the basis of matched sample analysis, CLDN18.2 appears to demonstrate >70% concordance as a biomarker. Observed correlations with certain patient/tumor characteristics warrant further study.

Transcriptome-Based Prognostic and Predictive Biomarker Analysis of ENACT: A Randomized Controlled Trial of Enzalutamide in Men Undergoing Active Surveillance.

PURPOSE: Few studies have explored the potential for pharmacological interventions to delay disease progression in patients undergoing active surveillance (AS). This preplanned transcriptomic analysis of patient samples from the ENACT trial aims to identify biomarkers in patients on AS who are at increased risk for disease progression or who may derive the greatest benefit from enzalutamide treatment. PATIENTS AND METHODS: In the phase II ENACT (ClinicalTrials.gov identifier: NCT02799745) trial, patients on AS were randomly assigned 1:1 to 160 mg orally once daily enzalutamide monotherapy or continued AS for 1 year. Transcriptional analyses were conducted on biopsies collected at trial screening, year 1, and year 2. Three gene expression signatures were evaluated in samples collected at screening and in available samples from patients on AS at any time during surveillance (expanded cohort): Decipher genomic classifier, androgen receptor activity (AR-A) score, and Prediction Analysis of Microarray 50 (PAM50) cell subtype signature. RESULTS: The Decipher genomic classifier score was prognostic; higher scores were associated with disease progression in the expanded cohort and AS arm of the expanded cohort. Patients with higher Decipher scores had greater positive treatment effect from enzalutamide as measured by time to secondary rise in prostate-specific antigen >25% above baseline. In patients treated with enzalutamide, higher AR-A scores and PAM50 luminal subtypes were associated with a greater likelihood of negative biopsy incidence at year 2. CONCLUSION: This analysis suggests that the Decipher genomic classifier may be prognostic for disease progression in AS patients with low- to intermediate-risk prostate cancer. Higher Decipher and AR-A scores, as well as PAM50 luminal subtypes, may also serve as biomarkers for treatment response.

Real-world use, dose intensity, and adherence to enfortumab vedotin in locally advanced or metastatic urothelial cancer.

BACKGROUND: Enfortumab vedotin (EV) monotherapy is approved for the treatment of advanced urothelial cancer as later-line therapy (post-immunotherapy and -platinum-chemotherapy) and as earlier-line therapy (cisplatin-ineligible, at least 1 prior therapy). We examined real-world EV monotherapy use, dose intensity and adherence across 280 US cancer clinics. METHODS: This postmarketing study used data from a nationwide (United States) deidentified patient-level electronic health record-derived database. Included were patients with advanced urothelial cancer initiating EV on or after December 19, 2019 (date of accelerated approval). We summarized characteristics of EV users using descriptive statistics and computed metrics of EV use, EV dose intensity, and EV treatment adherence. RESULTS: We identified 416 advanced urothelial cancer patients initiating EV monotherapy. More than half of patients (55.3%) received EV as later-line therapy (3L+), and nearly half (44.7%) received EV as earlier line therapy (1 or 2L). Dosing frequency (mean [SD] 2.4 [0.5] treatments per 28 day cycle) and dose (1.1 [0.2] mg/kg) were lower than label indication guidelines (1.25 mg/kg, Day 1, 8, 15 of a 28 day cycle). Only 58.8% of patients received an average of >2 treatments per 28-day cycle. CONCLUSIONS: Among patients with advanced urothelial cancer treated with EV monotherapy in contemporary practice, EV dosing frequency, and dosage was lower in clinical practice than recommended in the product labeling. Further research is required to understand clinical factors and outcomes associated with the differences observed.

An observational, patient-reported outcome study of sleep quality and depression among individuals with overactive bladder syndrome.

INTRODUCTION: Overactive bladder (OAB) can adversely affect health-related quality-of-life (HRQoL) and adherence to treatments; however, the extent of their association is unknown. This study sought to characterize Sleep Disturbance, Depression, Fatigue, and patient-reported medication adherence among adults with OAB in the United States. MATERIALS AND METHODS: In this descriptive, observational study, patients completed patient-reported outcome (PRO) measures of urinary symptoms, anxiety, depression, fatigue, sleep quality, and medication adherence. PRO scores were compared across age, sex, body mass index, and sleep and antidepressant medication-taking subgroups. Exploratory analyses compared PRO scores between groups and estimated the effect size of differences. RESULTS: Of 1013 patients contacted, 159 completed the assessments (female: 67.3%; ≥65 years of age: 53.5%; most severe OAB symptom: nocturia). Scale scores for Sleep Disturbance, Fatigue, and Depression were consistent with US population norms. No correlations of moderate or greater magnitude were observed between the severity of lower urinary tract symptoms and Sleep Disturbance, Fatigue, or Depression. When comparing individuals receiving antidepressants with those who were not, almost all outcomes including urinary symptoms, anxiety, and depression were significantly worse. Patients taking antidepressants also had poorer adherence to their OAB medications. CONCLUSION: In this cohort of individuals with OAB, Sleep Disturbance, Fatigue, and Depression scores were in line with general population reference values; however, among the subgroups analyzed, patients on antidepressants had worse HRQoL and more substantial impacts on medication adherence, highlighting the importance of the assessment and management of depression in this population.

Enzalutamide Monotherapy vs Active Surveillance in Patients With Low-risk or Intermediate-risk Localized Prostate Cancer: The ENACT Randomized Clinical Trial.

Importance: There are few published studies prospectively assessing pharmacological interventions that may delay prostate cancer progression in patients undergoing active surveillance (AS). Objective: To compare the efficacy and safety of enzalutamide monotherapy plus AS vs AS alone in patients with low-risk or intermediate-risk prostate cancer. Design, Setting, and Participants: The ENACT study was a phase 2, open-label, randomized clinical trial conducted from June 2016 to August 2020 at 66 US and Canadian sites. Eligible patients were 18 years or older, had received a diagnosis of histologically proven low-risk or intermediate-risk localized prostate cancer within 6 months of screening, and were undergoing AS. Patients were monitored during 1 year of treatment and up to 2 years of follow-up. Data analysis was conducted in February 2021. Interventions: Randomized 1:1 to enzalutamide, 160 mg, monotherapy for 1 year or continued AS, as stratified by cancer risk and follow-up biopsy type. Main Outcomes and Measures: The primary end point was time to pathological or therapeutic prostate cancer progression (pathological, ≥1 increase in primary or secondary Gleason pattern or ≥15% increased cancer-positive cores; therapeutic, earliest occurrence of primary therapy for prostate cancer). Secondary end points included incidence of a negative biopsy result, percentage of cancer-positive cores, and incidence of a secondary rise in serum prostate-specific antigen (PSA) levels at 1 and 2 years, as well as time to PSA progression. Adverse events were monitored to assess safety. Results: A total of 114 patients were randomized to treatment with enzalutamide plus AS and 113 to AS alone; baseline characteristics were similar between treatment arms (mean [SD] age, 66.1 [7.8] years; 1 Asian individual [0.4%], 21 Black or African American individuals [9.3%], 1 Hispanic individual [0.4%], and 204 White individuals [89.9%]). Enzalutamide significantly reduced the risk of prostate cancer progression by 46% vs AS (hazard ratio, 0.54; 95% CI, 0.33-0.89; P = .02). Compared with AS, odds of a negative biopsy result were 3.5 times higher; there was a significant reduction in the percentage of cancer-positive cores and the odds of a secondary rise in serum PSA levels at 1 year with treatment with enzalutamide; no significant difference was observed at 2 years. Treatment with enzalutamide also significantly delayed PSA progression by 6 months vs AS (hazard ratio, 0.71; 95% CI, 0.53-0.97; P = .03). The most commonly reported adverse events during enzalutamide treatment were fatigue (62 [55.4%]) and gynecomastia (41 [36.6%]). Three patients in the enzalutamide arm died; none were receiving the study drug at the time of death. No deaths were considered treatment-related. Conclusions and Relevance: The results of this randomized clinical trial suggest that enzalutamide monotherapy was well-tolerated and demonstrated a significant treatment response in patients with low-risk or intermediate-risk localized prostate cancer. Enzalutamide may provide an alternative treatment option for patients undergoing AS. Trial Registration: ClinicalTrials.gov Identifier: NCT02799745.

Effect of mirabegron on cognitive function in elderly patients with overactive bladder: MoCA results from a phase 4 randomized, placebo-controlled study (PILLAR).

BACKGROUND: Antimuscarinics are often used for treatment of overactive bladder (OAB), but exposure to medications such as antimuscarinics that have anticholinergic properties has been linked to adverse cognitive effects. A phase 4 placebo-controlled study (PILLAR; NCT02216214) described the efficacy and safety of mirabegron, a ß3-adrenoreceptor agonist, for treatment of wet OAB in patients aged ≥65 years. This pre-planned analysis aimed to measure differences in cognitive function between mirabegron and placebo, using a rapid screening instrument for mild cognitive impairment: the Montreal Cognitive Assessment (MoCA). METHODS: Outpatients aged ≥65 years with wet OAB were randomized 1:1 to mirabegron or placebo, stratified by age (<75/≥75 years). There were no exclusion criteria regarding cognitive status. Patients randomized to mirabegron initially received 25 mg/day with an optional increase to 50 mg/day after week 4/8 based on patient/investigator discretion. The MoCA was administered at baseline and end of treatment (EoT, week 12). The study protocol was Independent Ethics Committee/Institutional Review Board-approved. RESULTS: Of the 887 randomized patients who received ≥1 dose of study drug, 72.3% were female, 79.5% were white, and 28.1% were aged ≥75 years. All patients had ≥1 comorbidity and 94.3% were receiving ≥1 concomitant medication. One third of patients had a history of psychiatric disorders, the most common being depression (17.2%), insomnia (15.7%), and anxiety (11.4%). Baseline mean (standard error, SE) MoCA total scores were 26.9 (0.1) and 26.8 (0.1) in the mirabegron and placebo groups, respectively. Among patients with MoCA data available at baseline/EoT, 27.1% (115/425) and 25.8% (106/411) of mirabegron and placebo group patients, respectively, had impaired cognitive function at baseline (MoCA total score <26). There was no statistically significant change in adjusted mean (SE) MoCA total score from baseline to EoT in the mirabegron group (-0.2 [0.1]) or the placebo group (-0.1 [0.1]). CONCLUSIONS: Treatment with mirabegron for 12 weeks did not contribute to drug-related cognitive side effects in patients aged ≥65 years, as measured by the MoCA. Furthermore, the pattern of change in cognition over time in an older OAB trial population does not appear to differ from that of subjects receiving placebo. TRIAL REGISTRATION: NCT02216214 (prospectively registered August 13, 2014).