Cheryl Guttman Krader, BS, Pharm

Findings from a double-blind extension study of the vibegron EMPOWUR phase 3 trial demonstrated that once-daily vibegron maintained a favorable safety profile and had durable benefit for improving symptoms of overactive bladder (OAB) over the 52 weeks of the study, exceeding that of the comparator anticholinergic agent, tolterodine extended release.

The data were presented by David Staskin, MD, during the 2020 American Urological Association Virtual Experience.

“Long-term efficacy and safety were investigated as key outcome measures in the extension 

study, and the long-term safety profile demonstrated for vibegron is consistent with the findings in the 12-week placebo-controlled phase 3 study,” said Staskin, associate professor of urology at Tufts University School of Medicine in Boston, Massachusetts.

“The efficacy data from the extension study showed that the benefits of vibegron for reducing average number of daily micturitions, episodes of urge urinary incontinence [UUI], urgency, and total incontinence that were observed at the end of the 12-week pivotal trial were maintained with treatment for up to 52 weeks,” Staskin said. “Furthermore, in post hoc analyses of data from the extension study, vibegron had statistically significant superiority to tolterodine extended-release for reducing UUI and total incontinence episodes.”

Vibegron is a novel ß3-adrenergic receptor agonist. A once-daily dose of vibegron 75 mg was administered in the EMPOWUR phase 3 study (NCT03492281) and the extension study. Notably, vibegron does not inhibit the cytochrome P450 2D6 enzyme (CYP2D6), the hepatic enzyme that is involved in the metabolism of approximately 25% of all drugs. Approximately 43% of patients with OAB take a drug metabolized by CYP2D6.

“Avoiding the potential for drug interactions is especially important in this population, as many OAB patients have comorbidities and take multiple medications,” Staskin said.

Reductions in average daily micturitions seen

Significant reductions in average daily micturitions were seen at week 2 among those taking vibegron, and there was even greater benefit at week 52 in the extension trial, when the mean change from baseline was –2.4. A similar pattern was observed in the analysis of reduction in UUI episodes over time among patients treated with vibegron.

The analysis of change in daily urgency episodes from baseline to week 52 showed a reduction of 3.4 in the vibegron group and 3.2 for tolterodine. At 52 weeks compared with baseline, patients treated with vibegron had 2.5 fewer incontinence episodes daily; daily episodes were reduced by an average of 1.9 in the tolterodine group.

“Post hoc analyses evaluating the difference in week 52 change from baseline between vibegron and tolterodine using the mixed model for repeated measures specified in the statistical analysis plan showed vibegron was statistically superior to tolterodine for reducing both UUI and total incontinence episodes from baseline to week 52,” Staskin said.

Results of a UUI responder analysis of UUI episodes recorded in a 7-day diary showed that 61% of vibegron-treated patients achieved at least a 75% reduction at week 52 and 41% of patients had a 100% reduction: They were dry with no incontinence episodes over the study’s final 7 days.

The phase 3, 12-week, placebo- and active-controlled, double-blind EMPOWUR study randomized 1518 adults with wet or dry OAB to once-daily treatment with vibegron 75 mg, placebo, or tolterodine extended-release 4 mg. EMPOWUR met both coprimary end points, demonstrating statistically significant greater improvement in average number of daily micturitions and UUI episodes with vibegron compared with placebo.

“There was no preplanned statistical comparison between vibegron and tolterodine in EMPOWUR, but numerical differences favoring vibegron were noted in all evaluable efficacy measures,” Staskin said.

In the double-blind extension study, patients originally randomized to vibegron or tolterodine continued the same treatment, and patients in the placebo group were randomized to receive vibegron or tolterodine. The extension study had a target participation of 500 patients. It enrolled 506 patients, and 505 received at least 1 dose of study medication, including 273 who received vibegron and 232 who got tolterodine. The completion rate of patients in the extension trial was approximately 85% and similar across all treatment groups.

Baseline characteristics of participants in the extension trial were similar to those of the EMPOWUR study. They had a median age of 64 years, 78% were women, and 78% had wet OAB.

Adverse events (AEs) were reported by 62.6% of patients receiving vibegron and 54.3% of patients in the tolterodine group. Rates of AE-related discontinuation in the vibegron and tolterodine groups were 1.5% and 3.4%, respectively; rates of treatment-emergent serious AEs were 3.3% and 4.3%, respectively.

AEs reported by more than 5% of patients treated with vibegron included hypertension (8.8%), urinary tract infection (6.6%), and headache (5.5%). The rates of these AEs, including that of hypertension, were similar in the tolterodine group, Staskin reported.

“First demonstrated in the 12-week EMPOWUR study, data from the extension study now confirm efficacy and a very good safety and tolerability profile for vibegron over the 52 weeks of treatment,” Staskin said.

Disclosures: Urovant Sciences provided funding for the study. Staskin is an investigator and consultant for Urovant Sciences and a consultant to Astellas Pharma, Ferring Pharmaceuticals, and New Uro BV.

1. Staskin D, Frankel J, Varano S, Shortino D, Jankowich R, Mudd P. Once-daily vibegron 75 mg for overactive bladder (OAB): double-blind 52-week results from an extension study of the international phase 3 trial (EMPOWUR). Paper presented at: 2020 American Urological Association Virtual Experience; June 27-28, 2020.

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Beta 3-adrenergic receptor agonist’s benefits observed at 52 weeks, investigators report.

Overactive bladder treatment maintains favorable long-term safety profile

Positron emission tomography (PET) imaging with fluorine 18 (18F)–rhPSMA-7.3 is superior to morphological imaging with computerized tomography (CT) for lymph node (LN) staging in patients with primary intermediate- and high-risk prostate cancer, according to the findings of a retrospective study presented at the 2020 American Urological Association Virtual Experience.

The data from an initial clinical evaluation of the diagnostic efficacy of the investigational radiohybrid 18F-labeled PSMA-7.3 ligand was reported by Tobias Maurer, MD, a urology specialist at the Martini-Klinik prostate cancer center at the University of Hamburg-Eppendorf in Germany.

“68Ga-PSMA PET imaging has become a common method for primary staging of prostate cancer in Europe,” Maurer said. “Although our evaluation of 18F-rhPSMA-7.3 PET imaging is a retrospective analysis, the findings demonstrating its performance are consistent with evidence from studies reporting increased LN detection rates using 68GA-PSMA PET imaging compared with CT.”

Radiohybrid PSMA ligands are a new class of diagnostic/therapeutic PSMA-targeting agents that can be efficiently labeled with 18F. Compared with Ga-labeled PSMA tracers, the 18F-radiohybrid PSMA ligand has several advantages, according to Maurer.

“18F labeled PSMA ligands have a longer half-life, larger batch production, and lower positron range that results in a higher PET image resolution,” he explained. “In addition, radiohybrids have negligible urinary excretion that allows evaluation of the small pelvis without urinary background.”

The first rhPSMA agent evaluated in the clinic, 18F-rhPSMA-7, comprises 4 isomers, and 18F-rhPSMA-7.3 was chosen for clinical development based on findings from preclinical studies. The clinical study investigating the efficacy of 18F-rhPSMA-7.3 PET imaging included 56 consecutive patients with intermediate- or high-risk prostate cancer as defined by the D’Amico risk classification system. All the men underwent the PET imaging and conventional cross-section morphological imaging prior to undergoing radical prostatectomy with a template-based extended LN dissection.

The median injected activity of the tracer was 349 MBq. The median uptake time was 72 minutes, which indicates that the procedure could be nicely integrated in the clinical workflow, Maurer told 

The median number of LNs removed per patient was 21. On pathology, 18 patients (32%) had metastases, of whom 15 had pelvic LN metastases and 3 had bone metastases. The number of pelvic LN metastases present per patient ranged up to 19, and the metastases were located in 33 of 319 templates (10.3%).

The presence of LN metastases on imaging was done by an experienced reader independently for the PET and morphological data sets. The diagnostic accuracy of the 2 imaging techniques was determined by comparing their results to histological findings in template-based, patient-based, and side-based (right/left) analyses.

In all 3 analyses, 18F-rhPSMA-7.3 PET imaging demonstrated statistically significant superiority to conventional CT imaging for detecting LN metastases. The values for area under the receiver operating characteristic curve for 18F-rhPSMA-7.3 PET imaging and CT were 0.842 and 0.697, respectively, for the patient-based analysis (

 < .05); 0.843 and 0.631, respectively, for the right/left-based analysis (

 < .001); and 0.801 and 0.639, respectively, for the template-based analysis (

Disclosure: Blue Earth Diagnostics Ltd provided funding for the study.

1. Maurer T, Langbein T, Kroenke M, et al. Diagnostic efficacy of 18F-rhPSMA-7.3 imaging for N-staging patients with high-risk prostate cancer. Paper presented at: 2020 American Urological Association Virtual Experience. Abstract MP62-17

Agent shows statistically significant superiority to conventional computed tomography.

PET imaging agent found superior to CT for lymph node staging in prostate cancer

Men on active surveillance for prostate cancer may benefit from adherence to Mediterranean diet principles, according to results of a study conducted by investigators from the University of Texas MD Anderson Cancer Center, Houston.

The research, which was presented during the 2020 European Association of Urology Virtual Congress,1 evaluated Gleason grade group progression in men with newly diagnosed localized prostate cancer enrolled in a prospective active surveillance trial. A Mediterranean diet score (MDS) was calculated for each participant who completed a baseline food frequency questionnaire, and the population was divided into tertiles based on the MDS. A higher MDS reflects greater adherence to the Mediterranean dietary pattern.

During a median follow-up of 36 months, 76 men (18.5%) progressed. Results from a Cox proportional hazards model controlling for clinical characteristics showed that the MDS was modestly associated with time to grade group progression, reported Justin Gregg, MD, assistant professor of urology at The University of Texas MD Anderson Cancer Center.

Compared with the reference group of men in the lowest MDS tertile, there was little difference in risk of progression over time for men with a middle range MDS (hazard ratio [HR] and 95% confidence interval [CI]: 1.02 [0.61-1.70]; 

=0.93). Higher MDS adherence appeared to be associated with lower risk of grade progression (HR and 95% CI for the highest vs lowest tertile: 0.63 [0.33-1.19]; 

-trend=0.06). In analyses stratifying men by clinical factors, the general trend favoring a higher MDS for reducing progression risk was maintained across various subgroups.

The investigators stated that further work is needed to identify subgroups who may benefit from diet interventions based on the Mediterranean diet.

“We are currently evaluating this further in a prospective fashion,” Gregg said.

The study in which the data were collected was started at MD Anderson Cancer Center in 2005. Although it enrolled about 1000 men, the analysis of the association of MDS and prostate cancer progression included only 410 men who had baseline dietary information from the food frequency questionnaire that provided data to determine the MDS.

The MDS, which is calculated across 9 energy-adjusted food groups, has a possible range of 0 to 9. Approximately one-third of the 410 men included in the study had an MDS score in the lowest tertile (MDS 0-3), 41.5% were in the middle tertile (MDS 4-5), and approximately 25% were in the highest tertile (MDS 6-9).

Gabriel Haas, MD, moderated the virtual session. He commented that he was surprised by study results indicating benefit of Mediterranean diet adherence in healthier patients—those who did not have diabetes or hypercholesterolemia—but not in patients who had diabetes or who were statin users.

Offering an explanation for the data, Gregg stated the need to be cautious interpreting the findings for the diabetic cohort because of its relatively small size. Nevertheless, he suggested that the findings are consistent with the idea that a Mediterranean diet can affect prostate cancer progression through lowering of systemic inflammation.

“The possibility that someone who has diabetes already has a high level of inflammation that cannot be counterbalanced by the Mediterranean diet may be a hypothesis worth looking at,” Gregg said.

Addressing the association with statin use, Gregg said, “The Mediterranean diet may have more potential impact among men who are not taking a medication that affects inflammation.”

1. Gregg JR, Zhang X, Zheng J, et al. Association of Mediterranean diet score and disease progression among localized prostate cancer patients on active surveillance. 2020 European Association of Urology Virtual Congress. July 17-26, 2020. Abstract PT157

<<<More from the 2020 EAU Annual Congress

Mediterranean diet score was modestly associated with time to grade group progression.

Men on active surveillance for prostate cancer may benefit from Mediterranean diet

There are currently no validated clinical tools to standardize the frequency of biopsies or clinical assessment for men in active surveillance for prostate cancer. With this in mind, investigators from the University of California San Francisco sought to determine predictors of biopsy reclassification at specific time points over a 10-year period using data from their active surveillance cohort.

The research was presented by Peter Eoin Lonergan, MD, at the 2020 European Association of Urology Virtual Congress.1

“Multi-parametric magnetic resonance imaging and genomic testing have been proposed to aid in tailoring surveillance intensity, but this remains to be determined. With this in mind, we sought to determine predictors of biopsy reclassification at specific time points up to 10 years after enrollment in a cohort of 1031 men at UCSF,” said Lonergan, urologic oncology fellow, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco.

Wrote the investigators, “Our findings suggest that genomic score and PSA density are risk factors for upgrading within 3 years of commencing active surveillance, whereas PSA kinetics is associated with longer-term risk of upgrade. When used in tandem, genomic scores may identify a subset of men who could potentially have less intensive surveillance.”

The study included 1031 men enrolled in the active surveillance cohort at the University of California San Francisco between 2000 and 2016. At diagnosis, the men had a mean age of 62 years, 80% of the men were Caucasian, and 91% were in grade group 1.

Median PSA density was 0.13 ng/mL2. PSA kinetics were calculated using a linear mixed-effects model for log of PSA, adjusted for clinical characteristics. Median slope PSA kinetics at diagnosis was 0.24.

A genomic score was calculated as a composite of results from three commercially available genomic tests: Oncotype DX Genomic Prostate Score, Decipher, and Prolaris. Only 412 men (40% of the total cohort) had data available to calculate a genomic score. A total of 53 men were classified as having a “high” genomic score defined as a composite score greater than the mean plus 1 standard deviation of the cohort.

Only 315 men (30.6%) had a PI-RADS score at diagnosis, of which 126 men had a PI-RADS 1-3 lesion and 189 had a PI-RADS 4-5 lesion.

The primary outcome analyzed was biopsy reclassification to grade group 2 or higher on subsequent biopsy. A multivariable Cox proportional hazards regression model was used to identify factors associated with risk upgrade at first surveillance biopsy and at 3, 5, and 10 years after beginning active surveillance.

In the adjusted analysis, PSA density ≥0.15, percentage biopsy cores positive, and a high genomic score were associated with reclassification at first surveillance biopsy. A high genomic score and PSA density were risk factors for reclassification within 3 years of commencing surveillance. PSA kinetics was associated with a risk of reclassification at 5 and 10 years.

Having a PI-RADS 4-5 lesion was not an independent risk factor for biopsy reclassification on active surveillance at any of the follow-up intervals.

Lonergan noted there may be bias in the study considering that only about 40% of the active surveillance cohort had genomic testing.

“Whether or not a patient gets a genomic test is also at the discretion of the treating provider. Generally speaking, the tests may be done for men with intermediate risk who are trying to delay treatment,” he said.

In a comment submitted during the virtual session, an audience participant complimented the research because of its importance and stated that it should be validated in other active surveillance cohorts.

1. Lonergan PE, Washington SL, Zhao S, et al. Risk factors which predict biopsy upgrading over time in active surveillance for prostate cancer. 2020 European Association of Urology Virtual Congress. July 17-26, 2020. Abstract PT151

“Our findings suggest that genomic score and PSA density are risk factors for upgrading within 3 years of commencing active surveillance,” the investigators wrote.

Author | Cheryl Guttman Krader, BS, Pharm

Articles

Overactive bladder treatment maintains favorable long-term safety profile

PET imaging agent found superior to CT for lymph node staging in prostate cancer

Men on active surveillance for prostate cancer may benefit from Mediterranean diet

Study reveals risk factors for upgrading in active surveillance for prostate cancer