Erdafitinib or Chemotherapy in Advanced or Metastatic Urothelial Carcinoma.

BACKGROUND: Erdafitinib is a pan-fibroblast growth factor receptor (FGFR) inhibitor approved for the treatment of locally advanced or metastatic urothelial carcinoma in adults with susceptible FGFR3/2 alterations who have progression after platinum-containing chemotherapy. The effects of erdafitinib in patients with FGFR-altered metastatic urothelial carcinoma who have progression during or after treatment with checkpoint inhibitors (anti-programmed cell death protein 1 [PD-1] or anti-programmed death ligand 1 [PD-L1] agents) are unclear. METHODS: We conducted a global phase 3 trial of erdafitinib as compared with chemotherapy in patients with metastatic urothelial carcinoma with susceptible FGFR3/2 alterations who had progression after one or two previous treatments that included an anti-PD-1 or anti-PD-L1. Patients were randomly assigned in a 1:1 ratio to receive erdafitinib or the investigator's choice of chemotherapy (docetaxel or vinflunine). The primary end point was overall survival. RESULTS: A total of 266 patients underwent randomization: 136 to the erdafitinib group and 130 to the chemotherapy group. The median follow-up was 15.9 months. The median overall survival was significantly longer with erdafitinib than with chemotherapy (12.1 months vs. 7.8 months; hazard ratio for death, 0.64; 95% confidence interval [CI], 0.47 to 0.88; P = 0.005). The median progression-free survival was also longer with erdafitinib than with chemotherapy (5.6 months vs. 2.7 months; hazard ratio for progression or death, 0.58; 95% CI, 0.44 to 0.78; P<0.001). The incidence of grade 3 or 4 treatment-related adverse events was similar in the two groups (45.9% in the erdafitinib group and 46.4% in the chemotherapy group). Treatment-related adverse events that led to death were less common with erdafitinib than with chemotherapy (in 0.7% vs. 5.4% of patients). CONCLUSIONS: Erdafitinib therapy resulted in significantly longer overall survival than chemotherapy among patients with metastatic urothelial carcinoma and FGFR alterations after previous anti-PD-1 or anti-PD-L1 treatment. (Funded by Janssen Research and Development; THOR ClinicalTrials.gov number, NCT03390504.).

Management of Fibroblast Growth Factor Inhibitor Treatment-emergent Adverse Events of Interest in Patients with Locally Advanced or Metastatic Urothelial Carcinoma.

Background: Erdafitinib is indicated for the treatment of adults with locally advanced/metastatic urothelial carcinoma and susceptible FGFR3/2 alterations progressing on/after one or more lines of prior platinum-based chemotherapy. Objective: To better understand the frequency and management of select treatment-emergent adverse events (TEAEs) to enable optimal fibroblast growth factor receptor inhibitor (FGFRi) treatment. Design setting and participants: Longer-term efficacy and safety results of the BLC2001 (NCT02365597) trial in patients with locally advanced and unresectable or metastatic urothelial carcinoma were studied. Intervention: Erdafitinib schedule of 8 mg/d continuous in 28-d cycles, with uptitration to 9 mg/d if serum phosphate level was <5.5 mg/dl and no significant TEAEs occurred. Outcome measurements and statistical analysis: Adverse events were graded using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. The Kaplan-Meier methodology was used for the cumulative incidence of the first onset of TEAEs by grade. Time to resolution of TEAEs was summarized descriptively. Results and limitations: At data cutoff, the median treatment duration was 5.4 mo among 101 patients receiving erdafitinib. Select TEAEs (total; grade 3) were hyperphosphatemia (78%; 2.0%), stomatitis (59%; 14%), nail events (59%; 15%), non-central serous retinopathy (non-CSR) eye disorders (56%; 5.0%), skin events (55%; 7.9%), diarrhea (55%; 4.0%), and CSR (27%; 4.0%). Select TEAEs were mostly of grade 1 or 2, and were managed effectively with dose modifications, including dose reductions or interruptions, and/or supportive concomitant therapies, resulting in few events leading to treatment discontinuation. Further work is needed to determine whether management is generalizable to the nonprotocol/general population. Conclusions: Identification of select TEAEs and appropriate management with dose modification and/or concomitant therapies resulted in improvement or resolution of most TEAEs in patients, allowing for continuation of FGFRi treatment to ensure maximum benefit. Patient summary: Early identification and proactive management are warranted to mitigate or possibly prevent erdafitinib side effects to allow for maximum drug benefit in patients with locally advanced or metastatic bladder cancer.

Efficacy and safety of erdafitinib in patients with locally advanced or metastatic urothelial carcinoma: long-term follow-up of a phase 2 study.

BACKGROUND: Erdafitinib, a pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, was shown to be clinically active and tolerable in patients with advanced urothelial carcinoma and prespecified FGFR alterations in the primary analysis of the BLC2001 study at median 11 months of follow-up. We aimed to assess the long-term efficacy and safety of the selected regimen of erdafitinib determined in the initial part of the study. METHODS: The open-label, non-comparator, phase 2, BLC2001 study was done at 126 medical centres in 14 countries across Asia, Europe, and North America. Eligible patients were aged 18 years or older with locally advanced and unresectable or metastatic urothelial carcinoma, at least one prespecified FGFR alteration, an Eastern Cooperative Oncology Group performance status of 0-2, and progressive disease after receiving at least one systemic chemotherapy or within 12 months of neoadjuvant or adjuvant chemotherapy or were ineligible for cisplatin. The selected regimen determined in the initial part of the study was continuous once daily 8 mg/day oral erdafitinib in 28-day cycles, with provision for pharmacodynamically guided uptitration to 9 mg/day (8 mg/day UpT). The primary endpoint was investigator-assessed confirmed objective response rate according to Response Evaluation Criteria In Solid Tumors version 1.1. Efficacy and safety were analysed in all treated patients who received at least one dose of erdafitinib. This is the final analysis of this study. This study is registered with ClinicalTrials.gov, NCT02365597. FINDINGS: Between May 25, 2015, and Aug 9, 2018, 2328 patients were screened, of whom 212 were enrolled and 101 were treated with the selected erdafitinib 8 mg/day UpT regimen. The data cutoff date for this analysis was Aug 9, 2019. Median efficacy follow-up was 24·0 months (IQR 22·7-26·6). The investigator-assessed objective response rate for patients treated with the selected erdafitinib regimen was 40 (40%; 95% CI 30-49) of 101 patients. The safety profile remained similar to that in the primary analysis, with no new safety signals reported with longer follow-up. Grade 3-4 treatment-emergent adverse events of any causality occurred in 72 (71%) of 101 patients. The most common grade 3-4 treatment-emergent adverse events of any cause were stomatitis (in 14 [14%] of 101 patients) and hyponatraemia (in 11 [11%]). There were no treatment-related deaths. INTERPRETATION: With longer follow-up, treatment with the selected regimen of erdafitinib showed consistent activity and a manageable safety profile in patients with locally advanced or metastatic urothelial carcinoma and prespecified FGFR alterations. FUNDING: Janssen Research & Development.

Outcomes after Robotic-assisted Pyeloplasty in Patients Presenting with Pain Versus Nonpain Presenting Symptoms.

OBJECTIVE: To assess the impact of presenting symptom or incidental finding on symptomatic and radiographic outcomes after robotic-assisted pyeloplasty (RAP). METHODS: We retrospectively reviewed the records of 143 patients at our institution who received pyeloplasty from 2001-2017. Patients without both pre- and postoperative radiographic data were excluded. Patients were grouped by primary presenting symptom into either pain at presentation (pain) or nonpain primary presenting symptom, including incidental findings (nonpain). Primary outcomes were persistence of postoperative symptoms and improvement in diuretic renogram half-times. RESULTS: The study inclusion criteria was met by 105 patients. Pain was the most common presenting symptom (70.0%), followed by incidental finding (10.5%), infection (7.6%), hematuria (4.8%), hypertension (2.8%), elevated creatinine (2.8%), and nausea (1.0%). Patients with nonpain presentations were significantly more likely to have postoperative symptoms (P = .04), and less likely to improve on diuretic renogram (P = .03). Incidental presentation was found to be associated with greater likelihood of persistent postoperative symptoms compared with other presentations (36.3% vs 8.5%, P = .02). CONCLUSION: Ureteropelvic junction obstruction (UPJO) patients presenting with pain, experience better symptom and radiographic improvement following RAP compared with patients presenting without pain. Incidental UPJO was the most common nonpain presentation and is associated with less symptomatic and radiographic benefit after RAP. These findings will help reconstructive urologists counsel patients with UPJO regarding outcomes of RAP.

Robotic Pyeloplasty in Patients with Equivocal Diuretic Renogram.

INTRODUCTION: Previous studies examining patients with equivocal renal scans performed before robotic assisted pyeloplasty for ureteropelvic junction obstruction have shown conflicting results regarding outcomes. To address these conflicting reports we compared rates of symptom resolution and improvement in postoperative radiographic scans between patients at our institution presenting with equivocal vs obstructed preoperative diuretic renograms. METHODS: We conducted a retrospective review of 143 patients who underwent robotic assisted pyeloplasty by a single surgeon at our institution from 2001 to 2017. Patients with preoperative and postoperative diuretic renograms available were included in study. Patients were analyzed in equivocal preoperative imaging or obstructed preoperative imaging groups. RESULTS: A total of 102 patients were included in this study, 16 with equivocal diuretic renograms and 86 with obstructed diuretic renograms. Mean preoperative differential function was 34.9% in the obstructed group and 43.2% in the equivocal group (p=0.07). Postoperative symptom resolution was equivalent between equivocal and obstructed groups (87.5% vs 89.4%, p=0.69). However, improvement in diuretic renogram obstruction was significantly greater in obstructed compared with equivocal cases (84.7% vs 56.3%, p=0.01). CONCLUSIONS: Surgical management of patients with equivocal obstruction can be challenging. Patients with preoperative equivocal diuretic renograms are less likely to have radiographic improvement after robotic assisted pyeloplasty but do experience equivalent symptom resolution compared to patients with obstructed preoperative diuretic renograms. Symptom improvement rather than improvement in radiographic obstruction should be the primary focus when offering robotic assisted pyeloplasty to patients presenting with equivocal diuretic renograms.

Relations of GlycA and lipoprotein particle subspecies with cardiovascular events and mortality: A post hoc analysis of the AIM-HIGH trial.

BACKGROUND: The Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcomes trial showed no incremental benefit of extended-release niacin (ERN) therapy added to simvastatin in subjects with cardiovascular disease (CVD). OBJECTIVES: To examine the effects of ERN treatment on lipoprotein particles and GlycA, a new marker of systemic inflammation, and their relations with incident CVD events including mortality. METHODS: GlycA and very low-density lipoprotein, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) particle subclasses were quantified by nuclear magnetic resonance spectroscopy using available stored baseline (n = 2754) and 1-year in-trial (n = 2581) samples. Associations with CVD events and all-cause mortality were assessed using multivariable Cox proportional hazards regression adjusted for age, sex, diabetes, treatment assignment, and lipoproteins. RESULTS: Compared to placebo, ERN treatment lowered very low-density lipoprotein and LDL and increased HDL particle concentrations, increased LDL and HDL particle sizes (all P < .0001), but did not affect GlycA. Baseline and in-trial GlycA levels were associated with increased risk of CVD events: hazard ratio (HR) per SD increment, 1.17 (95% confidence interval [CI], 1.06-1.28) and 1.13 (1.02-1.26), respectively. However, none of the lipoprotein particle classes or subclasses was associated with incident CVD. By contrast, all-cause mortality was significantly associated with both GlycA (baseline HR: 1.46 [1.22-1.75]; in-trial HR: 1.41 [1.24-1.60]) and low levels of small HDL particles (baseline HR: 0.69 [0.56-0.86]; in-trial HR: 0.69 [0.56-0.86]). CONCLUSIONS: This Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcomes trial post hoc substudy indicates that inflammation, as indexed by GlycA, is unaffected by ERN treatment but is significantly associated with the residual risk of CVD and death in patients treated to low levels of LDL cholesterol.

Impact of Canagliflozin Treatment on Health-Related Quality of Life among People with Type 2 Diabetes Mellitus: A Pooled Analysis of Patient-Reported Outcomes from Randomized Controlled Trials.

BACKGROUND: Evidence from patient-reported outcomes in clinical trials may explain health-related behaviors observed in the real world. OBJECTIVE: The purpose of this analysis was to evaluate the effect of treatment with canagliflozin, a sodium glucose co-transporter 2 inhibitor, compared with placebo or sitagliptin on health-related quality-of-life outcomes in participants with type 2 diabetes mellitus from the clinical development program. METHODS: Patient-reported outcomes data from four randomized controlled trials of canagliflozin (n = 2536) were pooled and analyzed to evaluate participants' interest in continuing study medication; satisfaction with weight; and physical, mental, and emotional health after 26-52 weeks of treatment with canagliflozin vs. placebo or sitagliptin. RESULTS: Upon trial completion, participants treated with canagliflozin were more likely to express interest in continuing study medication than participants treated with placebo or sitagliptin [odds ratio (95% confidence interval) of 1.54 (1.19-1.99); p = 0.001]. Those treated with canagliflozin were also more likely to be satisfied with their weight and report favorable outcomes (score improvement or maintenance of good scores) related to physical and emotional health. CONCLUSIONS: The results of this pooled analysis suggest that people with type 2 diabetes mellitus treated with canagliflozin generally had positive experiences with treatment and improvements in health-related quality of life. Future research is needed to determine if these improvements result in improved type 2 diabetes mellitus management and treatment adherence. CLINICALTRIALS. GOV IDENTIFIERS: NCT01106625, NCT01106677, NCT01137812, NCT02025907.

Increasing Adherence to an AUA Guideline: A Durable Impact on Immediate Postoperative Mitomycin C Use.

INTRODUCTION: In this quality initiative we assessed whether providing surgeons with the American Urological Association guideline regarding intravesical mitomycin C at the time of surgery scheduling impacts compliance. Furthermore, we examined the durability of the intervention and the influence of surgeon volume on guideline adherence. METHODS: All patients (105) undergoing transurethral bladder tumor resection from July 2015 to February 2016 at Virginia Mason Medical Center were included prospectively. At the scheduling of surgery urologists were provided with a preoperative tool that included the relevant guideline. Mitomycin C use during the study period was compared to historical and subsequent year's use. Additionally, we stratified results by high and low volume resectionists. RESULTS: Before this study mitomycin C was used in 17.1% (25 of 146) of all resections. During the intervention period its use nearly tripled to 43% (28 of 65), an increase of 25.9%. The year after the intervention its use decreased to 32.7% (36 of 110). Durability was strongest for high volume surgeons and trended toward significance for low volume surgeons. CONCLUSIONS: Providing surgeons with a copy of the guideline at the time of surgery scheduling resulted in a threefold increase in guideline compliance. This change is durable and most impactful for higher volume surgeons. We believe this model can be used to ensure adherence and consideration for many guidelines.

A decision aid versus shared decision making for prostate cancer screening: results of a randomized, controlled trial.

INTRODUCTION: Shared decision making (SDM) is widely encouraged by both the American Urological Association and Choosing Wisely for prostate cancer screening. Implementation of SDM is challenging secondary to time constraints and competing patient priorities. One strategy to mitigate the difficulties in implementing SDM is to utilize a decision aid (DA). Here we evaluate whether a DA improves a patient's prostate cancer knowledge and affects prostate-specific antigen (PSA) screening rates. MATERIALS AND METHODS: Patients were randomized to usual care (UC), DA, or DA + SDM. Perception of quality of care was measured using the Consumer Assessment of Healthcare Providers and Systems (CAHPS) survey. Outcomes were stratified by long term provider relationship (LTPR, > 3 years) versus short term provider relationship (STPR, < 3 years). Knowledge of prostate cancer screening and the decision regarding screening were assessed. Groups were compared using ANOVA and logistic regression models. RESULTS: A total of 329 patients were randomized. Patients in the DA + SDM arm were significantly more likely to report discussing the implication of screening (33% DA + SDM, 22% UC, 16% DA, p = 0.0292) and answered significantly more knowledge questions correctly compared to the UC arm (5.03 versus 4.46, p = 0.046). However, those in the DA arm were significantly less likely to report that they always felt encouraged to discuss all health concerns (72% DA, 78% DA + SDM, 87% UC, p = 0.0285). Interestingly, STPR patients in the DA arm were significantly more likely to undergo PSA-based prostate cancer screening (41%) than the UC arm (8%, p = 0.019). This effect was not observed in the LTPR group. CONCLUSIONS: Providing patients a DA without a personal interaction resulted in a greater chance of undergoing PSA-based screening without improving knowledge about screening or understanding of the consequences of this decision. This effect was exacerbated by a shorter term provider relationship. With complex issues such as the decision to pursue PSA-based prostate cancer screening, tools cannot substitute for direct interaction with a trusted provider.