Treatment of Low-grade Intermediate-risk Nonmuscle-invasive Bladder Cancer With UGN-102 ± Transurethral Resection of Bladder Tumor Compared to Transurethral Resection of Bladder Tumor Monotherapy: A Randomized, Controlled, Phase 3 Trial (ATLAS).

PURPOSE: Low-grade intermediate-risk nonmuscle-invasive bladder cancer is a chronic illness commonly treated by repetitive transurethral resection of bladder tumor. We compared the efficacy and safety of intravesical chemoablation with UGN-102 (a reverse thermal gel containing mitomycin), with or without subsequent transurethral resection of bladder tumor, to transurethral resection of bladder tumor alone in patients with low-grade intermediate-risk nonmuscle-invasive bladder cancer. MATERIALS AND METHODS: This prospective, randomized, phase 3 trial recruited patients with new or recurrent low-grade intermediate-risk nonmuscle-invasive bladder cancer to receive initial treatment with either UGN-102 once weekly for 6 weeks or transurethral resection of bladder tumor. Patients were followed quarterly by endoscopy, cytology, and for-cause biopsy. The primary end point was disease-free survival. All patients were followed for adverse events. RESULTS: Trial enrollment was halted by the sponsor to pursue an alternative development strategy after 282 of a planned 632 patients were randomized to UGN-102 ± subsequent transurethral resection of bladder tumor (n=142) or transurethral resection of bladder tumor monotherapy (n=140), rendering the trial underpowered to perform hypothesis testing. Patients were predominantly male and ≥65 years of age. Tumor-free complete response 3 months after initial treatment was achieved by 92 patients (65%) who received UGN-102 and 89 patients (64%) treated by transurethral resection of bladder tumor. The estimated probability of disease-free survival 15 months after randomization was 72% for UGN-102 ± transurethral resection of bladder tumor and 50% for transurethral resection of bladder tumor (hazard ratio 0.45). The most common adverse events (incidence ≥10%) in the UGN-102 group were dysuria, micturition urgency, nocturia, and pollakiuria. CONCLUSIONS: Primary, nonsurgical chemoablation with UGN-102 for the management of low-grade intermediate-risk nonmuscle-invasive bladder cancer offers a potential therapeutic alternative to immediate transurethral resection of bladder tumor monotherapy and warrants further investigation.

Targeting P21-Activated Kinase-1 for Metastatic Prostate Cancer.

Metastatic prostate cancer (mPCa) has limited therapeutic options and a high mortality rate. The p21-activated kinase (PAK) family of proteins is important in cell survival, proliferation, and motility in physiology, and pathologies such as infectious, inflammatory, vascular, and neurological diseases as well as cancers. Group-I PAKs (PAK1, PAK2, and PAK3) are involved in the regulation of actin dynamics and thus are integral for cell morphology, adhesion to the extracellular matrix, and cell motility. They also play prominent roles in cell survival and proliferation. These properties make group-I PAKs a potentially important target for cancer therapy. In contrast to normal prostate and prostatic epithelial cells, group-I PAKs are highly expressed in mPCA and PCa tissue. Importantly, the expression of group-I PAKs is proportional to the Gleason score of the patients. While several compounds have been identified that target group-I PAKs and these are active in cells and mice, and while some inhibitors have entered human trials, as of yet, none have been FDA-approved. Probable reasons for this lack of translation include issues related to selectivity, specificity, stability, and efficacy resulting in side effects and/or lack of efficacy. In the current review, we describe the pathophysiology and current treatment guidelines of PCa, present group-I PAKs as a potential druggable target to treat mPCa patients, and discuss the various ATP-competitive and allosteric inhibitors of PAKs. We also discuss the development and testing of a nanotechnology-based therapeutic formulation of group-I PAK inhibitors and its significant potential advantages as a novel, selective, stable, and efficacious mPCa therapeutic over other PCa therapeutics in the pipeline.

First-in-human, phase 1 study of PF-06753512, a vaccine-based immunotherapy regimen (VBIR), in non-metastatic hormone-sensitive biochemical recurrence and metastatic castration-resistant prostate cancer (mCRPC).

BACKGROUND: This phase 1 study evaluated PF-06753512, a vaccine-based immunotherapy regimen (PrCa VBIR), in two clinical states of prostate cancer (PC), metastatic castration-resistant PC (mCRPC) and biochemical recurrence (BCR). METHODS: For dose escalation, patients with mCRPC received intramuscular PrCa VBIR (adenovirus vector and plasmid DNA expressing prostate-specific membrane antigen (PSMA), prostate-specific antigen (PSA), and prostate stem cell antigen (PSCA)) with or without immune checkpoint inhibitors (ICIs, tremelimumab 40 or 80 mg with or without sasanlimab 130 or 300 mg, both subcutaneous). For dose expansion, patients with mCRPC received recommended phase 2 dose (RP2D) of PrCa VBIR plus tremelimumab 80 mg and sasanlimab 300 mg; patients with BCR received PrCa VBIR plus tremelimumab 80 mg (Cohort 1B-BCR) or tremelimumab 80 mg plus sasanlimab 130 mg (Cohort 5B-BCR) without androgen deprivation therapy (ADT). The primary endpoint was safety. RESULTS: Ninety-one patients were treated in dose escalation (mCRPC=38) and expansion (BCR=35, mCRPC=18). Overall, treatment-related and immune-related adverse events occurred in 64 (70.3%) and 39 (42.9%) patients, with fatigue (40.7%), influenza-like illness (30.8%), diarrhea (23.1%), and immune-related thyroid dysfunction (19.8%) and rash (15.4%), as the most common. In patients with mCRPC, the objective response rate (ORR, 95% CI) was 5.6% (1.2% to 15.4%) and the median radiographic progression-free survival (rPFS) was 5.6 (3.5 to not estimable) months for all; the ORR was 16.7% (3.6% to 41.4%) and 6-month rPFS rate was 45.5% (24.9% to 64.1%) for those who received RP2D with measurable disease (n=18). 7.4% of patients with mCRPC achieved a ≥50% decline in baseline PSA (PSA-50), with a median duration of 4.6 (1.2-45.2) months. In patients with BCR, 9 (25.7%) achieved PSA-50; the median duration of PSA response was 3.9 (1.9-4.2) and 10.1 (6.9-28.8) months for Cohorts 5B-BCR and 1B-BCR. Overall, antigen specific T-cell response was 88.0% to PSMA, 84.0% to PSA, and 80.0% to PSCA. CONCLUSIONS: PrCa VBIR overall demonstrated safety signals similar to other ICI combination trials; significant side effects were seen in some patients with BCR. It stimulated antigen-specific immunity across all cohorts and resulted in modest antitumor activity in patients with BCR without using ADT. TRIAL REGISTRATION NUMBER: NCT02616185.

Discordance in perceived risk and epidemiological outcomes of prostate cancer among African American men.

As guidelines for prostate cancer screening have changed from an annual screening recommendation starting at age 50 to discussing the benefits and harms of screening with health care providers, it is necessary to examine other types of factors that are important to prostate cancer screening decisions among African American men. Perceived risk of developing cancer has been shown to predict cancer control behaviors and is lower among African Americans. We characterized perceived risk of developing prostate cancer among African American men from November 2009 to 2011 and evaluated the relationship between prostate cancer risk perceptions and sociodemographic characteristics, health care experiences, and knowledge and exposure to health information about cancer. Chi square tests and logistic regression were employed to determine independent associations. Overall, men did not believe they were at increased risk of developing prostate cancer; they believed their risk was equivalent to or lower than men the same age. Perceived risk of prostate cancer was associated with income (OR = 0.59, 95% CI = 0.26, 1.34, p = 0.03), hypertension (OR = 2.68, 95% CI = 1.17, 6.16, p = 0.02), and beliefs about the association between race and cancer risk (OR = 2.54, 95% CI = 1.24, 5.20, p = 0.01). Clinic and community-based approaches to improve prostate cancer risk comprehension among African American men are needed to reduce the discordance between perceived risk and epidemiological data on prostate cancer risk factors. Risk education interventions that are developed for African American men may need to integrate information about susceptibility for multiple diseases as well as address strategies for risk reduction and prevention, and chronic disease management.

Association of Human Development Index with global bladder, kidney, prostate and testis cancer incidence and mortality.

OBJECTIVES: To describe contemporary worldwide age-standardized incidence and mortality rates for bladder, kidney, prostate and testis cancer and their association with development. MATERIALS AND METHODS: We obtained gender-specific, age-standardized incidence and mortality rates for 184 countries and 16 major world regions from the GLOBOCAN 2012 database. We compared the mortality-to-incidence ratios (MIRs) at national and regional levels in males and females, and assessed the association with socio-economic development using the 2014 United Nations Human Development Index (HDI). RESULTS: Age-standardized incidence rates were 2.9 (bladder) to 7.4 (testis) times higher for genitourinary malignancies in more developed countries compared with less developed countries. Age-standardized mortality rates were 1.5-2.2 times higher in more vs less developed countries for prostate, bladder and kidney cancer, with no variation in mortality rates observed in testis cancer. There was a strong inverse relationship between HDI and MIR in testis (regression coefficient 1.65, R2 = 0.78), prostate (regression coefficient -1.56, R2 = 0.85), kidney (regression coefficient -1.34, R2 = 0.74), and bladder cancer (regression coefficient -1.01, R2 = 0.80). CONCLUSION: While incidence and mortality rates for genitourinary cancers vary widely throughout the world, the MIR is highest in less developed countries for all four major genitourinary malignancies. Further research is needed to understand whether differences in comorbidities, exposures, time to diagnosis, access to healthcare, diagnostic techniques or treatment options explain the observed inequalities in genitourinary cancer outcomes.

En Bloc Stapling of the Renal Hilum During Laparoscopic Nephrectomy: A Double-institutional Analysis of Safety and Efficacy.

OBJECTIVE: To explore the safety and efficacy of en bloc stapling of the renal hilum (EBSH) during laparoscopic nephrectomy (LNx) in a large double-institution cohort with an extended follow-up period. METHODS: We performed a retrospective review of patients undergoing LNx with EBSH between 2008 and 2014 at 2 academic medical centers. Data analyzed included tumor size, tumor pathology, operative time, estimated blood loss, and perioperative or postoperative complications. Evaluation of arteriovenous fistula (AVF) formation was assessed by postoperative imaging studies, physical examination, or new-onset diastolic hypertension. RESULTS: A total of 428 patients (mean age: 63 years) underwent LNx, of which there were a total of 433 renal units with EBSH (226 left renal units, 207 right renal units). Mean operative time was 169 minutes (range: 51-489 minutes). Mean estimated blood loss was 155 mL (range: 5 mL-2000 mL). Mean tumor size was 5.6 cm (range: 0.9-14.5 cm). EBSH was performed on 69 patients with chronic infectious and inflammatory benign conditions. Three hundred (70%) patients received post-procedural imaging. No patients developed clinical or radiographic evidence of AVF at a mean follow-up of 51 months. CONCLUSION: EBSH during LNx is efficient, effective, and safe. This large series lends further support that EBSH during LNx may not be associated with any significant risk of AVF formation at extended follow-up. We advocate that this technique is a safe alternative to ligating the renal artery and vein during LNx.

Ever and Annual Use of Prostate Cancer Screening in African American Men.

Since prostate cancer continues to disproportionately affect African American men in terms of incidence, morbidity, and mortality, prostate-specific antigen (PSA) screening plays an important role in early detection, especially when men engage in informed decision making to accept or decline this test. The authors evaluated utilization of PSA testing among African American men based on factors that are important components of making informed decisions. Utilization of PSA testing was evaluated based on whether men had ever had PSA testing and PSA testing during the past year in a community-based sample of African American men ages 50 to 75 ( n = 132). Overall, 64% of men ( n = 85) reported that they had ever had a PSA test; the mean ( SD) age for first use of PSA testing was 47.7 ( SD = 7.4). The likelihood of ever having a PSA test increased significantly with physician communication (odds ratio [OR] = 14.2; 95% confidence interval [CI] = 4.20, 48.10; p = .0001) and with having an annual household income that was greater than $20,000 (OR = 9.80; 95% CI = 3.15, 30.51; p = .0001). The odds of ever having a PSA test were also decreased with each unit increase in future temporal orientation (OR = 0.66; 95% CI = 0.47, 0.93; p = .02). Of the men who had ever had PSA testing, 57% were screened during the past year. Only health insurance status had a significant independent association with having annual PSA testing (OR = 5.10; 95% CI = 1.67, 15.60; p = .004). Different factors were associated significantly with ever having PSA testing and annual testing among African American men. African American men may not be making an informed decision about prostate cancer screening.

Bladder Cancer Mortality in the United States: A Geographic and Temporal Analysis of Socioeconomic and Environmental Factors.

PURPOSE: We assessed the association of temporal, socioeconomic and environmental factors with bladder cancer mortality in the United States. Our hypothesis was that bladder cancer mortality is associated with distinct environmental and socioeconomic factors with effects varying by region, race and gender. MATERIALS AND METHODS: NCI (National Cancer Institute) age adjusted, county level bladder cancer mortality data from 1950 to 2007 were analyzed to identify clusters of increased bladder cancer death using the Getis-Ord Gi* statistic. Socioeconomic, clinical and environmental data were assessed using geographically weighted spatial regression analysis adjusting for spatial autocorrelation. County level socioeconomic, clinical and environmental data were obtained from national databases, including the United States Census, CDC (Centers for Disease Control and Prevention), NCHS (National Center for Health Statistics) and County Health Rankings. RESULTS: Bladder cancer mortality hot spots and risk factors for bladder cancer death differed significantly by gender, race and geographic region. From 1996 to 2007 smoking, unemployment, physically unhealthy days, air pollution ozone days, percent of houses with well water, employment in the mining industry and urban residences were associated with increased rates of bladder cancer mortality (p <0.05). Model fit was significantly improved in hot spots compared to all American counties (R(2) = 0.20 vs 0.05). CONCLUSIONS: Environmental and socioeconomic factors affect bladder cancer mortality and effects appear to vary by gender and race. Additionally there were temporal trends of bladder cancer hot spots which, when persistent, should be the focus of individual level studies of occupational and environmental factors.