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To determine the prevalence and natural history of nmCRPC prior to the adoption of novel androgen receptor axis-targeting therapies(ARAT).This was a retrospective population-based cohort study of men with nmCRPC in Ontario, Canada between January 2007-March 2018. Patients with prostate cancer, castrate level of testosterone(1.7nmol/L) and a PSA2.0ng/mL with a subsequent rise25% from the nadir, and without metastasis were included. Annual prevalence of nmCRPC was calculated. Crude time from nmCRPC to metastasis and all-cause death are presented as medians with interquartile range(IQR). Predictors of time from nmCRPC to death were compared using univariable and multivariable cox proportional hazard models.We identified 2045 patients with nmCRPC. Median age was 79(IQR:72-84). 984 patients(48.1%) received upfront hormonal therapy while 583(28.5%) received initial radiotherapy and 478(23.4%) underwent radical prostatectomy. Median time from primary treatment to nmCRPC was 6 years(IQR:3-10). The average annual prevalence of nmCRPC was 8% among men receiving ADT. Crude median time from nmCRPC to death was 37.6 months(IQR:22.1-55.4). Median time from nmCRPC to metastasis and metastasis to death was 20.0 and 8.3 months, respectively. Patients who had primary surgery experienced longer crude survival. Older patients, patients who had a higher PSA at nmCRPC, and patients with grade group 4 to 5 disease had a shorter time from nmCRPC to death.This is the largest population-level analysis of the prevalence and natural history of nmCRPC. The current study can be used as a historical cohort to compare how novel imaging modalities and ARAT impact prevalence and disease trajectory over time.

Local health leaders and the Director General of the World Health Organization alike have observed that COVID-19 "does not discriminate." Nevertheless, the disproportionate representation of people of low socioeconomic status among those infected resembles discrimination. This population-based retrospective cohort study examined COVID-19 case counts and publicly funded healthcare costs in Ontario, Canada, with a focus on marginalization.Individuals with their first positive severe acute respiratory syndrome coronavirus 2 test from January 1, 2020 to June 30, 2020, were linked to administrative databases and matched to negative/untested controls. Mean net (COVID-19-attributable) costs were estimated for 30 days before and after diagnosis, and differences among strata of age, sex, comorbidity, and measures of marginalization were assessed using analysis of variance tests.We included 28 893 COVID-19 cases (mean age 54 years, 56% female). Most cases remained in the community (20 545, 71.1%) or in long-term care facilities (4478, 15.5%), whereas 944 (3.3%) and 2926 (10.1%) were hospitalized, with and without intensive care unit, respectively. Case counts were skewed across marginalization strata with 2 to 7 times more cases in neighborhoods with low income, high material deprivation, and highest ethnic concentration. Mean net costs after diagnosis were higher for males ($4752 vs $2520 for females) and for cases with higher comorbidity ($1394-$7751) (both P.001) but were similar across levels of most marginalization dimensions (range $3232-$3737, all P ≥ .19).This study suggests that allocating resources unequally to marginalized individuals may improve equality in outcomes. It highlights the importance of reducing risk of COVID-19 infection among marginalized individuals to reduce overall costs and increase system capacity.

COVID-19 imposed substantial health and economic burdens. Comprehensive population-based estimates of health care costs for COVID-19 are essential for planning and policy evaluation. We estimated publicly funded health care costs in 2 Canadian provinces during the pandemic's first wave.In this historical cohort study, we linked patients with their first positive SARS-CoV-2 test result by June 30, 2020, in 2 Canadian provinces (British Columbia and Ontario) to health care administrative databases and matched to negative or untested controls. We stratified patients by highest level of initial care: community, long-term care, hospital (without admission to the intensive care unit [ICU]) and ICU. Mean publicly funded health care costs for patients and controls, mean net (attributable to COVID-19) costs and total costs were estimated from 30 days before to 120 days after the index date, or to July 31, 2020, in 30-day periods for patients still being followed by the start of each period.We identified 2465 matched people with a positive test result for SARS-CoV-2 in BC and 28 893 in Ontario. Mean age was 53.4 (standard deviation [SD] 21.8) years (BC) and 53.7 (SD 22.7) years (Ontario); 55.7% (BC) and 56.1% (Ontario) were female. Net costs in the first 30 days after the index date were $22 010 (95% confidence interval [CI] 19 512 to 24 509) and $15 750 (95% CI 15 354 to 16 147) for patients admitted to hospital, and $65 828 (95% CI 58 535 to 73 122) and $56 088 (95% CI 53 721 to 58 455) for ICU patients in BC and Ontario, respectively. In the community and long-term care settings, net costs were near 0. Total costs for all people, from 30 days before to 30 days after the index date, were $22 128 330 (BC) and $175 778 210 (Ontario).During the first wave, we found that mean costs attributable to COVID-19 were highest for patients with ICU admission and higher in BC than Ontario. Reducing the number of people who acquire COVID-19 and severity of illness are required to mitigate the economic impact of COVID-19.

OBJECTIVES: To quantify the real-world survival benefit of re-resection vs no re-resection in patients diagnosed with T1 bladder cancer (BC) at the population level. PATIENTS AND METHODS: Retrospective population-wide observational cohort study based on pathology reports linked to health administrative data. We identified patients who were diagnosed with T1 BC in the province of Ontario (01/2001-12/2015) and used billing claims to ascertain whether they received re-resection within 2-10 weeks. The time-dependent effect of re-resection on survival outcomes was modelled by Cox proportional hazards regression (unadjusted and adjusted for numerous assumed patient- and surgeon-level confounding variables). Effect measures were presented as hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: We identified 7666 patients of which 2162 (28.7%) underwent re-resection after a median (interquartile range) time of 45 (35-56) days. Patients who received re-resection were less likely to die from any causes (HR 0.68, 95% CI 0.63-0.74, P

Background The hypothesis of a curable oligometastatic prostate cancer (PCa) state remains to be clinically-proven. Conventional imaging often fails to localize early recurrences, hampering the potential for radical approaches. Objective We hypothesize that prostate-specific membrane antigen (PSMA)-targeted PET-MR/CT allows for earlier detection and localization of oligorecurrent-PCa, unveiling a molecularly-defined state amenable to curative-intent metastasis-directed treatment (MDT). Design/setting/participants Single-institution single-arm phase-two study. Patients with rising PSA (0.4-3.0 ng/mL) after maximal local therapy (radical prostatectomy and post-operative radiotherapy), negative conventional staging, and no prior salvage hormonal therapy (HT) were eligible. Interventions All patients underwent [18F]DCFPyL PET-MR/CT. Patients with molecularly-defined oligorecurrent-PCa had MDT (stereotactic ablative body radiotherapy [SABR] or surgery) without HT. Outcome measurements/statistical analysis Primary endpoint was biochemical response (complete, i.e. biochemical ‘no evidence of disease’ [bNED], or partial response [100% or ≥50% PSA decline from baseline, respectively]) after MDT. Simon’s two-stage design was employed (null and alternate hypotheses 20% response rate, respectively), with α and β of 0.1. Results Seventy-two patients were enrolled (May/2017-July/2019). Thirty-eight (53%) had PSMA-detected oligorecurrent-PCa amenable for MDT. Thirty-seven (51%) agreed to MDT: 10 and 27 underwent surgery and SABR, respectively. Median follow-up was 15.9 months (IQR 9.8-19.1). Of patients receiving MDT, the overall response rate was 60%, including 22% rendered bNED. One (2.7%) grade 3 toxicity (intra-operative ureteric injury) was observed. Conclusions PSMA-defined oligorecurrent-PCa can be rendered bNED, a necessary step towards cure, in 1 of 5 patients receiving MDT alone. Randomized trials are justified to determine if MDT +/− systemic agents can expand the curative therapeutic armamentarium for PCa. Patient summary We studied men treated for prostate cancer with rising PSA. We found PSMA imaging detected recurrent cancer in three-quarters of patients, and targeted treatment to these areas significantly decreased PSA in half of patients.

There are conflicting reports regarding radical cystectomy complication risk from obesity subcategories, and a BMI threshold below which complication risk is notably reduced is undefined. A BMI threshold may be helpful in prehabilitation to aid patient counseling and inform weight loss strategies to potentially mitigate obesity-associated complication risk. This study aims to identify such a threshold and further investigate the association between BMI subcategories and perioperative complications from radical cystectomy.Data were extracted from the Canadian Bladder Cancer Information System, a prospective registry across 14 academic centers. Five hundred and eighty-nine patients were analyzed. Perioperative (≤90 days) complications were compared between BMI subcategories. Unconditional multivariable logistic regression and cubic spline analysis were performed to determine the association between BMI and complication risk and identify a BMI threshold.Perioperative complications were reported in 51 (30%), 97 (43%), and 85 (43%) normal, overweight, and obese patients (Complication risk from radical cystectomy is independently associated with BMI. Both overweight and obese patients are at increased risk compared to normal BMI patients. A BMI threshold of 34 kg/m

Objectives To compare toxicity and all-cause mortality for mCRPC patients receiving first line oral systemic therapy prescribed by medical oncologists and urologists. Methods Population-based retrospective cohort study of chemotherapy-naive men aged ≥66 years treated for mCRPC with first-line abiraterone or enzalutamide based on administrative health data (Ontario, Canada, 2012-2017). Primary outcomes were hospitalizations/ER visits for any cause or treatment-related toxicity during first-line mCRPC treatment. Secondary outcome was all-cause mortality. We calculated hazard ratios (HRs) comparing outcomes for different medical specialties using multivariable Cox proportional hazards models. Results Among 3405 mCRPC patients, 2407 (70.7%) received abiraterone and 998 (29.3%) received enzalutamide. 1786 (52.5%) patients visited the ER or were hospitalized. Men treated by medical oncologists had an increased risk of hospitalization/ER visits (HR1.16, 95%CI 1.03-1.31; P = .02), toxicity-related visits (HR1.34, 95%CI 1.08-1.69; P = .01), and mortality (HR1.16, 95%CI 1.02-1.33; P = .02) compared to urologists. Limited information was available, beyond PSA adjustment and prior treatment, on patient disease burden. Conclusion We observed fewer hospital visits overall and for treatment-related toxicity for mCRPC patients who were prescribed first line abiraterone or enzalutamide by urologists compared to medical oncologists. These differences may result from higher prostate cancer disease burden in patients managed by medical oncologists, and/or other unmeasured differences in patient management between specialties.

Summary 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.

The Standardized Reporting of Machine Learning Applications in Urology (STREAM-URO) framework was developed to provide a set of recommendations to help standardize how machine learning studies in urology are reported. This framework serves three purposes: (1) to promote high-quality studies and streamline the peer review process; (2) to enhance reproducibility, comparability, and interpretability of results; and (3) to improve engagement and literacy of machine learning within the urological community.

Background Upper tract urothelial carcinoma (UTUC) is clinically understudied, and there are no definitive recommendations regarding timing of perioperative chemotherapy. The objective of this study was to compare 3 treatment pathways in UTUC: nephroureterectomy (NU) alone, neoadjuvant chemotherapy (NAC), and adjuvant chemotherapy (AC) using a microsimulation model. Patients and Methods An individual-level state transition model was constructed using TreeAgePro software to compare treatment strategies for patients with newly diagnosed UTUC. The base case was that of a 70-year-old patient with a radiographically localized upper tract tumor. Primary outcome was quality-adjusted life expectancy. Secondary outcomes included crude overall survival, rates of adverse events, and bladder cancer diagnoses. Results A total of 100,000 patients were simulated. NAC was preferred, with an estimated quality-adjusted life expectancy of 7.50 years versus 6.79 years with NU alone and 7.23 years with AC. Median crude overall survival was 123 months with NAC, 96 months with NU only, and 111 months with AC. Overall, 40.0% of patients in the AC group with invasive pathology completed chemotherapy. In the NAC group, 83.3% of patients completed chemotherapy. In the NAC group, 37.5% of patients experienced an adverse chemotherapy event compared to 15.1% of patients in the AC group. Bladder cancer recurrence rates were 64.9%, 65.9%, and 67.4% over the patient’s lifetime for the NU, NAC, and AC strategies, respectively. Conclusion This study supports the increased use of NAC in UTUC until robust randomized trials are completed. The ultimate choice should be based on patient and tumor factors.

The aim of this study was to examine the effect of surgeon-anesthesiologist sex discordance on postoperative outcomes.Optimal surgical outcomes depend on teamwork, with surgeons and anesthesiologists forming two key components. There are sex and sex-based differences in interpersonal communication and medical practice which may contribute to patients' perioperative outcomes.We performed a population-based, retrospective cohort study among adult patients undergoing 1 of 25 common elective or emergent surgical procedures from 2007 to 2019 in Ontario, Canada. We assessed the association between differences in sex between surgeon and anesthesiologists (sex discordance) on the primary endpoint of adverse postoperative outcome, defined as death, readmission, or complication within 30 days following surgery using generalized estimating equations.Among 1,165,711 patients treated by 3006 surgeons and 1477 anesthesiologists, 791,819 patients were treated by sex concordant teams (male surgeon/male anesthesiologist: 747,327 and female surgeon/female anesthesiologist: 44,492), whereas 373,892 were sex discordant (male surgeon/female anesthesiologist: 267,330 and female surgeon/male anesthesiologist: 106,562). Overall, 12.3% of patients experienced1 adverse postoperative outcomes of whom 1.3% died. Sex discordance between surgeon and anesthesiologist was not associated with a significant increased likelihood of composite adverse postoperative outcomes (adjusted odds ratio 1.00, 95% confidence interval 0.97-1.03).We did not demonstrate an association between intraoperative surgeon and anesthesiologist sex discordance on adverse postoperative outcomes in a large patient cohort. Patients, clinicians, and administrators may be reassured that physician sex discordance in operating room teams is unlikely to clinically meaningfully affect patient outcomes after surgery.

BACKGROUND The therapeutic role of extended (ePLND) versus nonextended pelvic lymph node dissection (nePLND) to remove occult micrometastases in men undergoing radical prostatectomy for localized prostate cancer (PC) is conflicting. Therefore, our aim was to quantify the direct effect of ePLND versus nePLND (removal of occult micrometastases), which is not mediated through the detection of nodal disease and potential adjuvant therapy (indirect effect). METHODS Retrospective, bi-center cohort study of consecutive patients undergoing radical prostatectomy and PLND for PC (January 2006 and December 2016). Patients were followed until April 2018 for the occurrence of either biochemical recurrence or secondary therapy (composite outcome). ePLND was compared to nePLND by unweighted and weighted survival analysis (total effect) as well as by causal mediation analysis (direct and indirect effect). RESULTS Positive nodal disease was detected in 71 (7%) out of 1008 patients undergoing radical prostatectomy and PLND for PC (ePLND: 368 [36.5%]; nePLND: 640 [63.5%]). Survival analysis demonstrated results in favor of ePLND (unweighted hazard ratio: 0.77 [95% confidence interval: 0.59-1.01], p = .056; weighted hazard ratio: 0.75 [0.56-0.99], p = .044). The causal mediation analysis confirmed the total effect of 0.77 (0.71-0.82). After disentangling this total effect into an indirect effect (via detection of nodal disease and potential adjuvant therapy) and a direct effect (via removal of occult micrometastases), we identified an even more protective direct effect of 0.69 (0.63-0.75). CONCLUSIONS Our results not only indicate the utility of ePLND but also that its impact is not restricted to a staging benefit and probably involves a therapeutic benefit mediated through the removal of occult micrometastases.

AIM Cystoscopic placement of ureteric stents during colorectal surgery (CRS) may aid in the intraoperative identification of the ureters and thus prevent ureteric injury, but may also be associated with prolonged operating time, increased cost and adverse events. No formal recommendations exist regarding the use of ureteric stents prior to CRS. Our aim was to determine the effect of prophylactic ureteric stent insertion on the risk of ureteric injury among adult patients undergoing CRS. METHOD A systematic search using the Ovid platform was completed. The primary outcome was risk of ureteric injury. Secondary outcomes included the risk of acute kidney injury (AKI), urinary tract infection (UTI), sepsis, length of stay (LOS) and mortality. The Paule-Mandel pooling and a random effects model was used to produce odds ratios (ORs) with 95% confidence intervals (CIs) for binary outcomes. Standardized mean differences (MD) were reported for continuous variables. Analyses were completed using R3.5. RESULTS Nine retrospective cohort studies evaluating 98 507 patients were included. The incidence of ureteric injury was 0.6%. Overall, 5.1% of patients underwent ureteric stenting. There was no change in the odds of ureteric injury among stented patients compared with controls (OR 1.30, 95% CI 0.39-4.29, I2 = 25%). Operating time was significantly longer (MD 49.3 min, 95% CI 35.3-63.4, I2 = 96%) in the intervention group. There was no difference in rates of AKI, UTI, sepsis, LOS or mortality between groups. CONCLUSION Given the retrospective nature of the identified studies, the benefit of prophylactic ureteric stenting remains uncertain. Prophylactic ureteric stenting was not associated with increased patient morbidity but did significantly increase operating time.

Penile cancer is a rare condition, which mostly affects men in their sixth decade of life. The most common histology is squamous cell carcinoma (SCC), with about half of the cases linked to human papilloma virus (HPV) infection. The lack of awareness and significant social and psychological stigma associated with penile cancer often leads to delays in presentation, diagnosis and management. Timely multidisciplinary care at experienced centers is therefore critical for improving outcomes. For patients with advanced disease, treatment options are limited and prognosis remains poor. Large international efforts are underway to further define the optimal standards of care. Targeted therapies and immune checkpoint inhibitors could potentially play a role in advanced disease and are under evaluation in clinical trials. In this review, we discuss the current management of penile cancer and future directions.

We determined if the "bag squeeze" technique decreases pain during flexible cystoscopy in men.This single center, prospective, double-blind, randomized controlled trial recruited 200 consenting participants who were ambulatory, outpatient males who had undergone prior cystoscopy and were not expected to require any secondary procedures. Men with prior urethral stricture or bladder neck contracture were excluded from study. Once eligibility was assessed and consent obtained, participants were randomized to undergo cystoscopy with the bag squeeze (group A) or the sham bag squeeze procedure (group B). Following cystoscopy, participants completed a pain questionnaire (visual analogue scale). Differences in mean pain score between groups were evaluated using Students' t-test with a 2-sided alpha of 0.05.A total of 200 patients were randomized and underwent flexible cystoscopy. Ten participants were ineligible because they required secondary procedures. Among the 190 eligible patients 97 were randomized to bag squeeze (group A) and 93 to sham bag squeeze (group B) with mean pain scores of 1.91 and 3.39, respectively (p0.005).This study demonstrated a clinically meaningful decrease in pain for men undergoing flexible cystoscopy when the irrigation bag squeeze technique was used vs placebo bag squeeze. Accordingly, this useful, simple and free method to improve patient comfort during flexible cystoscopy should be adopted by clinicians.

BACKGROUND: Despite recent advances in the management of muscle-invasive bladder cancer (MIBC), treatment outcomes remain suboptimal, and variability exists across current practice patterns. OBJECTIVE: To promote standardization of care for MIBC in Canada by developing a consensus guidelines using a multidisciplinary, evidence-based, patient-centered approach who specialize in bladder cancer. METHODS: A comprehensive literature search of PubMed, Medline, and Embase was performed; and most recent guidelines from national and international organizations were reviewed. Recommendations were made based on best available evidence, and strength of recommendations were graded based on quality of the evidence. RESULTS: Overall, 17 recommendations were made covering a broad range of topics including pathology review, staging investigations, systemic therapy, local definitive therapy and surveillance. Of these, 10 (59% ) were level 1 or 2, 7 (41% ) were level 3 or 4 recommendations. There were 2 recommendations which did not reach full consensus, and were based on majority opinion. This guideline also provides guidance for the management of cisplatin-ineligible patients, variant histologies, and bladder-sparing trimodality therapy. Potential biomarkers, ongoing clinical trials, and future directions are highlighted. CONCLUSIONS: This guideline embodies the collaborative expertise from all disciplines involved, and provides guidance to further optimize and standardize the management of MIBC.

Pathological and oncologic outcomes of delayed radical prostatectomy following prostate cancer active surveillance are not well established. We determined the pathological and oncologic outcomes of favorable risk, Grade Group 1, prostate cancer managed with active surveillance and progressing to radical prostatectomy for clinically significant prostate cancer (Grade Group 2 or greater).Between 1992 and 2015, 170 men with favorable risk prostate cancer underwent delayed radical prostatectomy for clinically significant prostate cancer (ASRP) at the Princess Margaret Cancer Centre. Pathological and oncologic outcomes of the ASRP cohort were compared with a matched cohort treated with up-front radical prostatectomy (405) immediately before surgery. Biochemical recurrence-free survival, overall survival and cancer specific survival were compared. We examined the association between delayed radical prostatectomy and adverse pathology at radical prostatectomy and biochemical recurrence using logistic and Cox regression analyses, respectively.Median time spent on active surveillance before radical prostatectomy was 31.0 months. At radical prostatectomy pT3 (extraprostatic extension, seminal vesicle invasion), positive surgical margin and pN1 rates were comparable between the 2 cohorts. Median followup after radical prostatectomy was 5.6 years. The 5-year biochemical recurrence-free survival rate in the ASRP cohort and up-front radical prostatectomy cohort were 85.8% and 82.4%, respectively (p=0.38). Overall survival and cancer specific survival were comparable between the 2 groups. Delayed radical prostatectomy was not associated with adverse pathological outcomes and biochemical recurrence on regression analyses.Curative intent radical prostatectomy after a period of active surveillance results in excellent pathological and oncologic outcomes at 5 years. A period of active surveillance does not result in inferior outcomes compared to patients with similar risk characteristics undergoing up-front radical prostatectomy.

Background The rate of primary and secondary treatment while on active surveillance (AS) for localized prostate cancer at the general population level is unknown. Our objective was to determine the patterns of secondary treatments after primary surgery or radiation for patients who undergo AS. Methods This was a population‐based retrospective cohort study of men aged 50‐80 years old in Ontario, Canada, between 2008 and 2016. We identified 26 742 patients with prostate cancer, a Gleason grade score ≤7, and an index prostate‐specific antigen ≤10 ng/mL. Patients were categorized as undergoing AS with or without delayed primary treatment (DT; treatment >6 months after diagnosis) versus immediate treatment (IT; treatment ≤6 months). Patients receiving DT and IT were propensity score matched and the rate of secondary treatment (surgery or radiation ± androgen deprivation treatment) was compared using Cox proportional hazards models. Results We identified 10 214 patients who underwent AS and 11 884 patients who underwent IT. Among patients undergoing AS, 3724 (36.5%) eventually underwent DT and among them, 406 (10.9%) underwent secondary treatment. The median time to DT was 1.2 years (IQR 0.5‐8.1 years). The relative rate of undergoing secondary treatment was similar in the DT vs IT group (HR 0.92; 95% CI: 0.79‐1.08). The risk of death in the DT group was higher compared to patients who did not undergo treatment (HR 1.23, 95% CI: 1.01‐1.49). Conclusions Among patients with localized prostate cancer on AS, one third undergo DT. The rate of secondary treatment was similar between the DT and IT groups. Patients in the DT group may experience a higher risk of mortality compared to those who remained on AS., For men with localized prostate cancer who are candidates for active surveillance, one third receive delayed primary treatment. Active surveillance is a safe approach, as there appears to be no adverse risk of progression with similar rates of secondary treatment compared to patients who underwent immediate treatment.

Proton pump inhibitors (PPIs) are commonly prescribed medications that have been shown to have contradicting effects on cancer. We aimed to investigate the effect of pantoprazole and other PPIs on prostate cancer (PCa) specific mortality (PCSM), use of androgen deprivation therapy (ADT), and PCa diagnosis using a large Canadian population-based cohort. We identified 21,512 men aged ≥ 66, with a history of a single negative prostate biopsy and no previous use of any of the analyzed medications between 1994 and 2016. Multivariable Cox regression models with time-dependent covariates were used to assess the associations of PPIs with PCa outcomes. All models included other medications with a putative chemopreventative effect on PCa-outcomes, and were adjusted for age, rurality, comorbidity, and study inclusion year. Over a mean follow-up of 8.06 years (SD 5.44 years), 10,999 patients (51.1%) used a PPI, 5187 patients (24.1%) had PCa, 2043 patients (9.5%) were treated with ADT, and 805 patients (3.7%) died from PCa. For every 6 months of cumulative use, pantoprazole was associated with a 3.0% (95% CI 0.3–6.0%) increased rate of ADT use, while any use of other PPIs was associated with a 39.0% (95% CI 18.0–64.0%) increased risk of PCSM. No association was found with PCa diagnosis. Upon validation of the potentially negative association of PPIs with PCa, PPI use may need to be reassessed in PCa patients.

Background Single‐arm trials are currently an accepted study design to investigate the efficacy of novel therapies (NT) in non‐muscle invasive bladder cancer (NMIBC) unresponsive to intravesical Bacillus Calmette‐Guérin (BCG) immunotherapy as randomized controlled trials are either unfeasible (comparator: early radical cystectomy; ERC), or unethical (comparator: placebo). To guide the design of such single‐arm trials, expert groups published recommendations for clinically meaningful outcomes. The aim of this study was to quantitatively verify the appropriateness of these recommendations. Methods We used a discrete event simulation framework in combination with a supercomputer to find the required efficacy at which a NT can compete with ERC when it comes to quality‐adjusted life expectancy (QALE). In total, 24 different efficacy thresholds (including the recommendations) were investigated. Results After ascertaining face validity with content experts, repeated verification, external validation, and calibration we considered our model valid. Both recommendations rarely showed an incremental benefit of the NT over ERC. In the most optimistic scenario, an increase in the IBCG recommendation by 10% and an increase in the FDA/AUA recommendation by 5% would yield results at which a NT could compete with ERC from a QALE perspective. Conclusions This simulation study demonstrated that the current recommendations regarding clinically meaningful outcomes for single‐arm trials evaluating the efficacy of NT in BCG‐unresponsive NMIBC may be too low. Based on our quantitative approach, we propose increasing these thresholds to at least 45%‐55% at 6 months and 35% at 18‐24 months (complete response rates/recurrence‐free survival) to promote the development of clinically truly meaningful NT., Expert groups published recommendations regarding clinically meaningful outcomes for single‐arm trials evaluating the efficacy of novel therapies in BCG‐unresponsive non‐muscle invasive bladder cancer. In this study, we used a discrete event simulation framework in combination with a supercomputer to demonstrate that these recommendations do probably not reflect clinically meaningful outcomes and should be increased to at least 45%‐55% at 6 months and 35% at 18‐24 months (complete response rates/recurrence‐free survival).

Introduction: Several androgen deprivation therapy (ADT) medications are available for treating advanced prostate cancer with roughly equivalent oncological efficacy and tolerability. We investigated the proportion of physicians who predominantly prescribe one type of ADT drug (“mono-prescriber”) and assessed characteristics associated with prescription behavior. Methods: Ontario men aged ≥65 years who were diagnosed with advanced prostate cancer (1997–2017) and initiated ADT thereafter for ≥3 consecutive months were identified using population-level administrative data. Their first prescription for injectable ADT was linked to a physician, and urologists with ≥10 prescriptions over the study period were included in the analysis (n=282). Urologists were classified as high mono-prescribers if ≥80% of their prescriptions were for one drug type. Multivariable logistic regression was used to examine the association of physician characteristics with the odds of being a high mono-prescriber. Results: Overall, 67 (23.8%) of urologists were classified as high mono-prescribers but the frequency varied across health planning regions. The most commonly prescribed drugs and those used by mono-prescribers were goserelin (41.8% and 56.7%) and leuprolide (44.3% and 43.3%), respectively. In multivariable analysis, the odds of a physician being a high mono-prescriber were higher with more years in practice (odds ratio [OR] 1.06/ year, 95% confidence interval [CI] 1.03–1.09, p

Introduction: This was a secondary analysis aiming to assess whether hydrophilic or hydrophobic statins have a differential effect on urinary retention (UR) and lower urinary tract symptoms (LUTS) in men following a prostate biopsy (PB), who were at risk for prostate cancer development. Methods: This was a population-based cohort study with data incorporated from the Institute for Clinical and Evaluative Sciences database to identify all Ontarian men aged 66 and above with a history of a single negative PB between 1994 and 2016, with no drug prescription history of any of several putative chemopreventative medications (statins, proton pump inhibitors, five-alpha-reductase inhibitors, and alpha-blockers). Multivariable Cox regression models with time-dependent covariates were used to assess the association of hydrophilic and hydrophobic statins with UR and LUTS within 30 days of a PB. All models were adjusted for other known putative chemopreventive medications, age, rurality, pharmacologically treated diabetes, comorbidity score, and study inclusion year. Results: Overall, 21 512 men were included, with a median followup time of 9.4 years (interquartile range [IQR] 5.4–13.4 years). Hydrophobic and hydrophilic statins were initiated by 30.7% and 19.6% of men, respectively, after the first negative PB. UR and LUTS were experienced by 2.2% and 10% of men, respectively. Cox models demonstrated hydrophilic statins were associated with a lower risk of UR (hazard ratio [HR] 0.56, 95% confidence interval [CI] 0.38–0.83, p=0.0038) and LUTS (HR 0.86, 95% CI 0.76–0.98, p=0.022), while no such association was shown for hydrophobic statins. Conclusions: Initiation of hydrophilic statins in men older than 66 appears to be inversely associated with the risk of UR and LUTS within 30 days of a PB.

Nearly all existing direct current (DC) chemical vapor sensing methodologies are based on charge transfer between sensor and adsorbed molecules. However, the high binding energy at the charge-trapped sites, which is critical for high sensitivity, significantly slows sensors' responses and makes the detection of nonpolar molecules difficult. Herein, by exploiting the incomplete screening effect of graphene, we demonstrate a DC graphene electronic sensor for rapid (subsecond) and sensitive (ppb) detection of a broad range of vapor analytes, including polar, nonpolar, organic, and inorganic molecules. Molecular adsorption induced capacitance change in the graphene transistor is revealed to be the main sensing mechanism. A novel sensor design, which integrates a centimeter-scale graphene transistor and a microfabricated flow column, is pioneered to enhance the fringing capacitive gating effect. Our work provides an avenue for a broad spectrum real-time gas sensing technology and serves as an ideal testbed for probing molecular physisorption on graphene.

LBA442 Background: Although most pts with HR NMIBC respond to BCG, pts whose cancer does not respond or who relapse within 12 mo have poor prognosis and require radical cystectomy (RC). The single-arm, multicohort phase 2 KEYNOTE-057 trial (NCT02625961) was designed to investigate the safety and efficacy of pembro monotherapy for pts with BCG-unresponsive HR NMIBC (per FDA) who were ineligible or declined to undergo RC. Results from cohort A (carcinoma in situ [CIS] ± papillary tumors) showed a clinical complete response rate of 41% at 3 mo and led to approval of pembro monotherapy for such pts in the United States. We describe the results from cohort B (papillary tumors without CIS). Methods: Pts were aged ≥18 y with BCG-unresponsive HR NMIBC with papillary tumors only (high-grade Ta or any-grade T1) at baseline and ECOG PS 0-2. Pts received pembro 200 mg every 3 wk (Q3W) for ≤35 cycles (~2 y). Cancer was assessed at 12 wk and Q12W thereafter if no recurrent HR NMIBC or progression was observed; CT urography was done Q24W. Primary end points for cohort B were 12-mo disease-free survival (DFS) rate of HR NMIBC as assessed by central pathology/radiology review and safety, assuming a 12-mo DFS of >20% for HR NMIBC. Secondary efficacy end points were 12-mo DFS rate of any disease; progression-free survival (PFS) to worsening of grade, stage, or death; PFS to muscle invasion, metastasis, or death; and overall survival (OS). Results: Overall, 132 pts received pembro for a median of 9.5 cycles (range, 1.0-35.0). Median age was 72 y (range, 37-87); 57 pts (43.2%) had T1 stage; all pts (100%) had urothelial histology; 104 pts (78.8%) were male; pts received a median of 10 (range, 6-33) prior BCG instillations. Median follow-up was 45.4 mo (range, 14.9-77.1). Efficacy data are shown in Table. Thirty-one pts (23.5%) had RC after stopping pembro. Treatment-related AEs occurred in 97 pts (73.5%); 19 (14.4%) had a grade 3/4 treatment-related AE and 14 pts (10.6%) discontinued due to a treatment-related AE. No deaths from treatment-related AEs occurred. Conclusions: Pembro showed notable antitumor activity in pts with BCG-unresponsive non-CIS papillary HR NMIBC after ~45 mo of follow-up. Toxicity was manageable and consistent with that in cohort A, with no new safety signals. Results suggest pts with non-CIS papillary HR NMIBC unresponsive to BCG who declined or were ineligible to undergo RC may also benefit from pembro monotherapy. Clinical trial information: NCT02625961 . [Table: see text]

TPS582 Background: The majority of patients with bladder cancer present with non-muscle invasive disease (Chang 2016; Woldu 2017; Kates 2020; Li 2020). The standard of care for treatment of high risk NMIBC involves transurethral resection of the bladder tumor (TURBT) followed by intravesical Bacillus Calmette-Guerin (BCG) or chemotherapy. Although the response rate to BCG therapy is high, many patients recur within 1–5 years (Matulay JU 2021). For patients who have BCG unresponsive disease after adequate course of BCG, there are limited options. While radical cystectomy (RC) is still considered the standard of care, most patients are reluctant to undergo RC and their options are limited to intravesical chemotherapy or pembrolizumab. Enfortumab vedotin (EV) is an antibody-drug conjugate directed to Nectin-4, which is highly expressed in bladder tumors. In EV-301, a phase 3 study, EV showed an OS benefit vs chemotherapy in patients with locally advanced or metastatic urothelial carcinoma (la/mUC) who had previously received platinum-based therapy and a PD-1 or PD-L1 inhibitor (Powles NEJM 2021). Based on its demonstrated benefit in la/mUC, EV is currently being evaluated in earlier UC settings. The purpose of this study is to investigate the intravesical administration of EV for patients with NMIBC. Methods: EV-104 (NCT05014139) is a phase 1, open-label, multicenter, dose-escalation and dose-expansion study designed to evaluate the safety, tolerability, PK, and antitumor activity of intravesical EV in adults with high-risk BCG-unresponsive NMIBC (carcinoma in situ with or without papillary disease) who are ineligible for or refuse RC. The dose escalation part of the trial aims to identify the maximum tolerated dose (MTD) and/or recommended dose of intravesical EV. The dose expansion part will evaluate patients at the MTD or recommended dose and further characterize safety and antitumor activity of intravesical EV. The study treatment regimen will include an induction phase, where patients will receive intravesical EV weekly for 6 weeks followed by monthly maintenance for a total of 9 additional EV doses. Patients will be assessed for response every 3 months by cystoscopy and urine cytology, while on study. Safety and antitumor activity endpoints will be summarized using descriptive statistics. The study is currently enrolling in the US with additional sites planned in Canada and the EU. Clinical trial information: NCT05014139 .

TPS591 Background: The PD-1 inhibitor pembro showed antitumor activity in cohort A of the phase 2 KEYNOTE-057 study (NCT02625961), with 41% of pts with HR BCG-unresponsive carcinoma in situ (CIS) of the bladder ± papillary tumors achieving a CR at 3 months with a median DOR of 16.2 months. Based on these results, pembro was approved in the United States for treatment of pts with BCG-unresponsive HR NMIBC with CIS ± papillary tumors who are ineligible for or have elected not to undergo radical cystectomy (RC). However, novel combinations that improve the efficacy of pembro are needed. Immune checkpoints TIGIT and LAG-3 have been shown to contribute to treatment resistance in many cancers, and their inhibition may enhance the activity of pembro. Cohort C of KEYNOTE-057 will evaluate the efficacy and safety of coformulations of pembro and TIGIT inhibitor vibostolimab or LAG-3 inhibitor favezelimab in pts with HR BCG-unresponsive NMIBC with CIS ± papillary tumors. Methods: Key eligibility criteria include adults with histologically confirmed HR NMIBC that is unresponsive to BCG (defined as persistent or recurrent CIS alone or with Ta/T1 ≤12 months of completion of adequate BCG therapy) who are ineligible for or elect not to undergo RC, have CIS ± papillary tumors at baseline (CIS alone, Ta + CIS or T1 + CIS), and have an ECOG score of 0-2. Approximately 60 pts will be randomly assigned 1:1 to Arm 1 (coformulation of pembro 200 mg and vibostolimab 200 mg) or Arm 2 (coformulation of pembro 200 mg and favezelimab 800 mg) IV Q3W (≤35 administrations) until central pathology-confirmed ≥T1 at any time point or persistent or recurrent CIS or high-grade ≥Ta at the 24-week efficacy review or thereafter. Pts with central pathology–confirmed low-grade pTa at any time point may continue treatment following resection of visible tumors. In the absence of disease persistence/recurrence or progression, treatment will continue until unacceptable toxicity, decision to withdraw, or administrative reasons. Tumor evaluations will be performed Q12W until year 2, then Q24W thereafter for up to 5 years. The primary efficacy end point is 12-month CR rate of HR NMIBC as determined by cystoscopy, cytology, biopsy, and radiologic imaging by central pathology and radiology review. Secondary efficacy end points include DOR of HR NMIBC in responders; overall CR rate and CR rate at 3 and 6 months; PFS to worsening of grade, stage, or death; PFS to muscle-invasive or metastatic disease or death; and OS. The safety objective will characterize the safety and tolerability in all pts who received ≥1 dose of study treatment. Efficacy will be evaluated in all pts who received ≥1 dose of study treatment and have a baseline evaluation consisting of pre-enrollment cystoscopy, TURBT/biopsy, urine cytology, and baseline CT urography imaging. Clinical trial information: NCT02625961 .

449 Background: Pelvic lymph node irradiation is still under debate for patients with muscle-invasive bladder cancer (MIBC) planned for curative-intent radiation-based therapy (RT). A previous randomized trial suggested bladder-only (BO)-RT was effective in reducing RT-related toxicity, while associated with non-inferior oncological outcomes – bladder preservation rates, disease-free survival, and overall survival (OS) – compared to whole-pelvis (WP)-RT. In this study, we sought to evaluate the impact of the radiation volume (BO-RT vs. WP-RT) on main oncological outcomes in patients with MIBC. Methods: This nationwide study included patients with urothelial MIBC (cT2-4aN0-2M0) who underwent curative RT at 10 academic centers across Canada. Patients clinically staged with pelvic or abdominal wall invasion (cT4b) or enlarged lymph nodes beyond the common iliac bifurcation (cN3) before RT were excluded. Patients were divided into two groups based on the RT volume: WP-RT vs. BO-RT. Inverse probability of treatment weighting (IPTW) and absolute standardized differences (ASDs) were used to balance baseline covariates across treatment groups. Regression models were used to assess the impact of the RT volume on the rates of complete response (CR) to treatment, cancer-specific survival (CSS), and OS while adjusting for potential confounding variables in the weighted cohorts. Results: A total of 599 patients were analyzed, out of whom 369 (61.6%) underwent WP-RT. Patients in the WP-RT group were younger (mean age 73.2 vs. 77.4; ASD 0.41), and more likely to have an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1 (82.1% vs. 73.5%; ASD 0.21), clinical node-positive disease (12.5% vs. 2.2%; ASD 0.40), and lymphovascular invasion (26.3% vs. 16.1%; ASD 0.25), compared to BO-RT. In addition, WP-RT patients were more commonly treated with neoadjuvant chemotherapy (20.9% vs. 10.4%; ASD 0.29) and concurrent chemotherapy (76.7% vs. 56.5%; ASD 0.44), compared to BO-RT. In the IPTW cohort, age, gender, ECOG PS, clinical staging, the proportion of patients with carcinoma in situ, lymphovascular invasion, variant urothelial histologies, hydronephrosis, and whose tumours were completely resected before RT, treated with NAC, and treated with concurrent chemotherapy were well balanced across groups (all ASDs < 0.10). In multivariable analysis, WP-RT did not impact CR rates post-RT (OR 1.14; p=0.526) but was associated with both CSS (HR 0.66; p=0.016) and OS (HR 0.68; p=0.002), independently of other prognostic factors (Table). Conclusions: Our study demonstrated a significant survival benefit with the use of WP-RT compared to BO-RT in patients with MIBC treated with curative intent. Additional randomized controlled trials are needed to confirm our findings.