CTLA4 blockade abrogates KEAP1/STK11-related resistance to PD-(L)1 inhibitors.

For patients with advanced non-small-cell lung cancer (NSCLC), dual immune checkpoint blockade (ICB) with CTLA4 inhibitors and PD-1 or PD-L1 inhibitors (hereafter, PD-(L)1 inhibitors) is associated with higher rates of anti-tumour activity and immune-related toxicities, when compared with treatment with PD-(L)1 inhibitors alone. However, there are currently no validated biomarkers to identify which patients will benefit from dual ICB1,2. Here we show that patients with NSCLC who have mutations in the STK11 and/or KEAP1 tumour suppressor genes derived clinical benefit from dual ICB with the PD-L1 inhibitor durvalumab and the CTLA4 inhibitor tremelimumab, but not from durvalumab alone, when added to chemotherapy in the randomized phase III POSEIDON trial3. Unbiased genetic screens identified loss of both of these tumour suppressor genes as independent drivers of resistance to PD-(L)1 inhibition, and showed that loss of Keap1 was the strongest genomic predictor of dual ICB efficacy-a finding that was confirmed in several mouse models of Kras-driven NSCLC. In both mouse models and patients, KEAP1 and STK11 alterations were associated with an adverse tumour microenvironment, which was characterized by a preponderance of suppressive myeloid cells and the depletion of CD8+ cytotoxic T cells, but relative sparing of CD4+ effector subsets. Dual ICB potently engaged CD4+ effector cells and reprogrammed the tumour myeloid cell compartment towards inducible nitric oxide synthase (iNOS)-expressing tumoricidal phenotypes that-together with CD4+ and CD8+ T cells-contributed to anti-tumour efficacy. These data support the use of chemo-immunotherapy with dual ICB to mitigate resistance to PD-(L)1 inhibition in patients with NSCLC who have STK11 and/or KEAP1 alterations.

Association of Tumor Mutational Burden and Microsatellite Instability With Response and Outcomes in Patients With Urothelial Carcinoma Treated With Immune Checkpoint Inhibitor.

BACKGROUND: Microsatellite Instability (MSI) and Tumor Mutational Burden (TMB) are associated with immune checkpoint inhibitor (ICI) efficacy. We examined the association between TMB and MSI status with survival in patients with urothelial carcinoma (UC) treated with ICI. METHODS: Patients from 15 institutions were treated with ICI monotherapy. Primary endpoint was overall survival and secondary endpoints included observed response rate (ORR), and progression-free (PFS) calculated from ICI initiation. TMB was analyzed as dichotomous (≥10 vs. <10 mut/Mb) and continuous variable. RESULTS: We identified 411 patients: 203 were treated with ICI 1L/upfront; 104 with 2 + L. For the 1L/upfront: median [m] OS was numerically longer in patients with TMB ≥10 versus TMB <10: mOS 35 versus 26 months (HR = 0.6) and with MSI-H and MSI-S (mOS NR vs. 22 months), though neither association was statistically significant. A statistically significant association was found between TMB (continuous variable) and OS (HR = 0.96, P = .01). For 2 + L: mOS was numerically longer in patients with TMB ≥10 versus TMB <10: (20 vs. 12 months; HR = 0.9); mOS was 12 and 17 months for patients with MSI-H and MSI-S, respectively. Eighty-nine patients received maintenance avelumab (mAV): mOS was longer in patients with TMB ≥10 versus TMB <10: 61 versus 17 months; (HR = 0.2, P = .02) and with MSI-H and MSI-S (NR vs. 24 months). CONCLUSIONS: Although not reaching statistical significance in several subsets, patients with high TMB and MSI-H had numerically longer OS with ICI, especially with mAV. Further validation is needed.

Oncological and Survival Outcomes of Pelvic Lymph Node Dissection in Patients with Nonmuscle Invasive Bladder Cancer Undergoing Radical Cystectomy Using the National Cancer Database.

OBJECTIVE: To evaluate the role of pelvic lymph node dissection (PLND) in patients diagnosed with high-risk nonmuscle-invasive bladder cancer (NMIBC) undergoing radical cystectomy (RC) using a national cohort of NMIBC patients. METHODS: A cohort of patients diagnosed with NMIBC cancer with urothelial carcinoma from the National Cancer Database (NCDB) between 2004 and 2019 was utilized. The cohort consists of patients who have not received BCG and underwent upfront radical cystectomy or pelvic exenteration. Kaplan-Meier analysis was utilized to assess overall survival (OS) outcomes. Cox regression was also utilized to identify independent predictors of OS. RESULTS: The cohort of 9399 patients was stratified by clinical T stage and then subdivided by pathological outcome. For patients with cTa, a majority received a lymph node dissection 97.74% (941/1019), amongst the entire cohort, a minority had node positive disease 3.3% (34/1019). For cTis, most patients received a lymph node dissection 94.08% (482/507), and a minority had node positive disease 5.1% (26/507). For cT1, most patients had a lymph node dissection 95.62% (6,060/6,337), and a 13.1% (832/6337) of patients had a positive lymph node. Amongst patients with cT1 disease who underwent PLND, KMA demonstrated better OS compared to patients who did not undergo PLND (P < .001). CONCLUSION: The data suggests an OS benefit in patients with later stage (cT1) NMIBC. Thus, our findings support the existing clinical guidelines of pelvic lymph node dissection in patients with high-risk nonmuscle invasive bladder cancer.

Association of Tumor-informed Circulating Tumor DNA Detectability Before and After Radical Cystectomy with Disease-free Survival in Patients with Bladder Cancer.

BACKGROUND AND OBJECTIVE: Despite curative-intent radical cystectomy (RC), patients with muscle-invasive bladder cancer (MIBC) are at high risk of recurrence. Biomarkers are urgently needed to refine prognostication and selection of appropriate perioperative systemic therapies. Our aim was to evaluate the prognostic and predictive value of tumor-informed circulating tumor DNA (ctDNA) results in a multicenter cohort of patients with bladder cancer who underwent RC. METHODS: We performed a retrospective analysis of real-world data for a commercial ctDNA test (Signatera; Natera, Austin, TX, USA) performed in 167 patients (852 plasma samples) before RC and during molecular residual disease (MRD; adjuvant decision) and surveillance windows. We assessed the correlation between recurrence and ctDNA status before and after RC using Cox regression analysis. RESULTS AND LIMITATIONS: During study-defined postoperative MRD and surveillance windows, detectable ctDNA was associated with shorter disease-free survival (DFS) when compared to undetectable ctDNA (MRD: hazard ratio 6.93; p < 0.001; surveillance: hazard ratio 23.02; p < 0.001). Of note, patients with undetectable ctDNA did not appear to benefit from adjuvant therapy (p = 0.34). Detectable ctDNA in the pre-RC (p = 0.045), MRD (p = 0.002), and surveillance (p < 0.001) windows was the only risk factor independently associated with shorter DFS. Limitations include the retrospective and nonrandomized nature of the study. CONCLUSIONS: ctDNA testing in patients with bladder cancer undergoing RC was prognostic and potentially predictive. Identification of patients at high risk of recurrence may aid in patient counseling and decision-making. PATIENT SUMMARY: We found that outcomes for patients with muscle-invasive bladder cancer are strongly linked to detection of tumor DNA in blood samples. The results show the value of tumor-informed testing for tumor DNA in blood for decisions on the best treatment for each individual patient.

Oncolytic adenoviral therapy plus pembrolizumab in BCG-unresponsive non-muscle-invasive bladder cancer: the phase 2 CORE-001 trial.

Cretostimogene grenadenorepvec is a serotype-5 oncolytic adenovirus designed to selectively replicate in cancer cells with retinoblastoma pathway alterations, previously tested as monotherapy in bacillus Calmette-Guérin (BCG)-experienced non-muscle-invasive bladder cancer. In this phase 2 study, we assessed the potential synergistic efficacy between intravesical cretostimogene and systemic pembrolizumab in patients with BCG-unresponsive non-muscle-invasive bladder cancer with carcinoma in situ (CIS). Thirty-five patients were treated with intravesical cretostimogene with systemic pembrolizumab. Induction cretostimogene was administered weekly for 6 weeks followed by three weekly maintenance infusions at months 3, 6, 9, 12 and 18 in patients maintaining complete response (CR). Patients with persistent CIS/high-grade Ta at the 3-month assessment were eligible for re-induction. Pembrolizumab was administered for up to 24 months. The primary endpoint was CR at 12 months as assessed by cystoscopy, urine cytology, cross-sectional imaging and mandatory bladder mapping biopsies. Secondary endpoints included CR at any time, duration of response, progression-free survival and safety. The CR rate in the intention-to-treat population at 12 months was 57.1% (20 out of 35, 95% confidence interval (CI) 40.7-73.5%), meeting the primary endpoint. A total of 29 out of 35 patients (82.9%, 95% CI 70.4-95.3%) derived a CR at 3 months. With a median follow-up of 26.5 months, the median duration of response has not been reached (95% CI 15.7 to not reached). The CR rate at 24 months was 51.4% (18 out of 35) (95% CI 34.9-68.0%). No patient progressed to muscle-invasive bladder cancer in this trial. Adverse events attributed to cretostimogene were low grade, self-limiting and predominantly limited to bladder-related symptoms. A total of 5 out of 35 patients (14.3%) developed grade 3 treatment-related adverse effects. There was no evidence of overlapping or synergistic toxicities. Combination intravesical cretostimogene and systemic pembrolizumab demonstrated enduring efficacy. With a toxicity profile similar to its monotherapy components, this combination may shift the benefit-to-risk ratio for patients with BCG-unresponsive CIS. ClinicalTrials.gov Identifier: NCT04387461 .

NCCN Guidelines® Insights: Bladder Cancer, Version 3.2024.

Bladder cancer, the sixth most common cancer in the United States, is most commonly of the urothelial carcinoma histologic subtype. The clinical spectrum of bladder cancer is divided into 3 categories that differ in prognosis, management, and therapeutic aims: (1) non-muscle-invasive bladder cancer (NMIBC); (2) muscle invasive, nonmetastatic disease; and (3) metastatic bladder cancer. These NCCN Guidelines Insights detail recent updates to the NCCN Guidelines for Bladder Cancer, including changes in the fifth edition of the WHO Classification of Tumours: Urinary and Male Genital Tumours and how the NCCN Guidelines aligned with these updates; new and emerging treatment options for bacillus Calmette-Guérin (BCG)-unresponsive NMIBC; and updates to systemic therapy recommendations for advanced or metastatic disease.

Characterization and impact of non-canonical WNT signaling on outcomes of urothelial carcinoma.

BACKGROUND: Non-canonical WNT family (WNT5A pathway) signaling via WNT5A through ROR1 and its partner, ROR2, or Frizzled2 (FZD2) is linked to processes driving tumorigenesis and therapy resistance. We utilized a large dataset of urothelial carcinoma (UC) tumors to characterize non-canonical WNT signaling through WNT5A, ROR1, ROR2, or FZD2 expression. METHODS: NextGen Sequencing of DNA (592 genes or WES)/RNA (WTS) was performed for 4125 UC tumors submitted to Caris Life Sciences. High and low expression of WNT5A, ROR1, ROR2, and FZD2 was defined as ≥ top and

The Role of Radical Cystectomy in Clinically Node Positive Bladder Cancer: A US Veterans Health Administration Study.

INTRODUCTION: The role of local definitive therapy in addition to systemic treatment in clinically positive regional lymph node (cN+) bladder cancer is yet to be determined. Herein, we sought to investigate the role of radical cystectomy (RC) in management of patients with cN+ bladder cancer at US Veterans Health Administration Facilities. METHODS: We identified patients diagnosed with cN+ bladder cancer between 2000-2017 using the Department of Veterans Affairs (VA) Informatics and Computing Infrastructure (VINCI). We employed a combination of database/registry coded values and chart review for data collection. To minimize mortality bias, we excluded patients who died within 90 days of diagnosis. We divided the patients into cystectomy (C) versus "no cystectomy" (NOC) cohorts. Propensity score matching was performed based on predictors of undergoing RC. Multivariable Cox models and Kaplan-Meier survival curves were used to estimate overall survival (OS) and cancer specific survival (CCS). RESULT: After matching, 158 patients were included in the C and NOC groups. In the C-group, 85(54%) patients received pre-cystectomy chemotherapy, and 73(46%) patients underwent post-cystectomy chemotherapy. In the C-group, 65(41%) patients and in the NOC-group, 66(42%) patients had clinical N1 disease (P = .77). In multivariable Cox model, undergoing RC was associated with improved OS (HR0.62; 95%CI 0.47-0.81), P < .001) and CSS (HR0.58; 95%CI 0.42-0.80; P < .001). CONCLUSION: As part of multimodal treatment, undergoing RC was associated with improved OS and CSS in subset of patients with cN+ bladder cancer. Prospective randomized trials are warranted to further investigate the role of local definitive therapy in this specific patient population.

Treatment Landscape for Metastatic Castrate-Sensitive Prostate Cancer: A Review.

With the advent of new therapeutic modalities, management of metastatic castrate-sensitive prostate cancer (mCSPC) has been in flux. From androgen-deprivation therapy to docetaxel to androgen receptor-signaling inhibitors, each agent has heralded a new treatment paradigm. As such, the optimal first-line therapy for mCSPC remains incompletely defined. This review provides a narrative of recent advances to systemic therapy within the mCSPC treatment space, particularly with regard to expansion to triplet therapy.

Response and Outcomes of Maintenance Avelumab After Platinum-Based Chemotherapy (PBC) in Patients With Advanced Urothelial Carcinoma (aUC): "Real World" Experience.

BACKGROUND: Platinum-based chemotherapy (PBC) followed by avelumab switch maintenance in nonprogressors is standard first line (1L) treatment for advanced urothelial carcinoma (aUC). We describe clinical features and outcomes in a "real-world' cohort treated with avelumab maintenance for aUC. MATERIALS AND METHODS: This was a retrospective cohort study of patients (pts) who received 1L switch maintenance avelumab after no progression on PBC for aUC. We calculated progression-free survival (PFS) and overall survival (OS) from initiation of maintenance avelumab. We also described OS and PFS for specific subsets using Cox regression and observed response rate (ORR). RESULTS: A total of 108 pts with aUC from 14 sites treated with maintenance avelumab were included. There was a median of 6 weeks1-30 from end of PBC to avelumab initiation; median follow-up time from avelumab initiation was 8.8 months (1-42.7). Median [m]PFS was 9.6 months (95%CI 7.5-12.1) and estimated 1-year OS was 72.5%. CR/PR (vs. SD) to 1L PBC (HR = 0.33, 95% CI 0.13-0.87) and ECOG PS 0 (vs. ≥1), (HR = 0.15, 95% CI 0.05-0.47) were associated with longer OS. The presence of liver metastases was associated with shorter PFS (HR = 2.32, 95% CI 1.17-4.59). ORR with avelumab maintenance was 28.7% (complete response 17.6%, partial response 11.1%), 29.6% stable disease, 26.9% progressive disease as best response (14.8% best response unknown). CONCLUSIONS: Results seem relatively consistent with findings from JAVELIN Bladder100 trial and recent "real world" studies. Prior response to platinum-based chemotherapy, ECOG PS 0, and absence of liver metastases were favorable prognostic factors. Limitations include the retrospective design, lack of randomization and central scan review, and possible selection/confounding biases.

Association Between Primary Care Use Prior to Cancer Diagnosis and Subsequent Cancer Mortality in the Veterans Affairs Health System.

Importance: Primary care physicians (PCPs) are significant contributors of early cancer detection, yet few studies have investigated whether consistent primary care translates to improved downstream outcomes. Objective: To evaluate the association of prediagnostic primary care use with metastatic disease at diagnosis and cancer-specific mortality (CSM). Design, Setting, and Participants: This cohort study used databases with primary care and referral linkage from multiple Veterans' Affairs centers from 2004 to 2017 and had a 68-month median follow-up. Analysis was completed between July 2021 and September 2022. Participants included veterans older than 39 years who had been diagnosed with 1 of 12 cancers. Inclusion criteria included known clinical staging, survival follow-up, cause of death, and receiving care at the Veterans Affairs health system (VA). Exposures: Prediagnostic PCP use, measured in the 5 years prior to diagnosis. PCP visits were binned into none (0 visits), some (1-4 visits), and annual (5 visits). Main Outcomes and Measures: Metastatic disease at diagnosis, cancer-specific mortality (CSM) for entire cohort and stratified by tumor subtype. Results: Among 245 425 patients representing 12 tumor subtypes, mean age was 65.8 (9.3) years, and the cohort skewed male (97.6%), and White (76.1%), with higher levels of comorbidity (58.6% with Charlson Comorbidity Index scores ≥2). Compared with no prior visit, some PCP use was associated with 26% decreased odds of metastatic disease at diagnosis (odds ratio [OR], 0.74; 95% CI, 0.71-0.76; P < .001) and 12% reduced risk of CSM (subdistribution hazard ratio [SHR], 0.88; 95% CI, 0.86-0.89; P < .001). Annual PCP use was associated with 39% decreased odds of metastatic disease (OR, 0.61; 95% CI, 0.59-0.63; P < .001) and 21% reduced risk of CSM (SHR, 0.79; 95% CI, 0.77-0.81; P < .001). Among tumor subtypes, prostate cancer had the largest effect size for prior PCP use on metastatic disease at diagnosis (OR for annual use, 0.32; 95% CI, 0.30-0.35; P < .001) and CSM (SHRfor annual use, 0.51; 95% CI, 0.48-0.55; P < .001). Conclusions and Relevance: In this cohort study, increased primary care use before cancer diagnosis was associated with significant decreases in metastatic disease at diagnosis and cancer-related death, with potentially the greatest difference from annual use. PCPs play a vital role in cancer prevention, and additional resources should be allocated to assist these physicians.

Association of the Time to Immune Checkpoint Inhibitor (ICI) Initiation and Outcomes With Second Line ICI in Patients With Advanced Urothelial Carcinoma.

BACKGROUND: Early progression on first-line (1L) platinum-based therapy or between therapy lines may be a surrogate of more aggressive disease and poor outcomes in advanced urothelial carcinoma (aUC), but its prognostic role regarding immune checkpoint inhibitor (ICI) response and survival is unclear. We hypothesized that shorter time until start of second-line (2L) ICI would be associated with worse outcomes in aUC. PATIENTS AND METHODS: We performed a retrospective multi-institution cohort study in patients with aUC treated with 1L platinum-based chemotherapy, who received 2L ICI. Patients receiving switch maintenance ICI were excluded. We defined time to 2L ICI therapy as the time between the start of 1L platinum-based chemotherapy to the start of 2L ICI and categorized patients a priori into 1 of 3 groups: less than 3 months versus 3-6 months versus more than 6 months. We calculated overall response rate (ORR) with 2L ICI, progression-free survival (PFS) and overall survival (OS) from the start of 2L ICI. ORR was compared among the 3 groups using multivariable logistic regression, and PFS, OS using cox regression. Multivariable models were adjusted for known prognostic factors. RESULTS: We included 215, 215, and 219 patients in the ORR, PFS, and OS analyses, respectively, after exclusions. ORR difference did not reach statistical significance between patients with less than 3 months versus 3-6 months versus more than 6 months to 2L ICI. However, PFS (HR 1.64; 95% CI 1.02-2.63) and OS (HR 1.77; 95% CI 1.10-2.84) was shorter among those with time to 2L ICI less than 3 months compared to those who initiated 2L ICI more than 6 months. CONCLUSION: Among patients with aUC treated with 2L ICI, time to 2L ICI less than 3 months was associated with lower, but not significantly different ORR, but shorter PFS and OS compared to 2L ICI more than 6 months. This highlights potential cross resistance mechanisms between ICI and platinum-based chemotherapy.

The Prognostic Significance of Homologous Recombination Repair Pathway Alterations in Metastatic Hormone Sensitive Prostate Cancer.

INTRODUCTION: The homologous recombination repair (HRR) pathway is a frequently mutated pathway in advanced prostate cancer. The clinical course of patients with HRR gene alterations who have metastatic hormone sensitive prostate cancer (mHSPC) has not been fully characterized. Here, we examine the outcomes of men with mHSPC with HRR alterations. METHODS: We conducted a single-center retrospective analysis of men with mHSPC who underwent next generation sequencing. The primary objective was to assess the time from diagnosis of mHSPC to metastatic castrate resistance prostate cancer (mCRPC) in patients with pathogenic HRR alterations compared to individuals lacking these alterations. Key secondary objectives included time to mCRPC in prespecified cohorts, PSA response, and overall survival. RESULTS: 151 men with mHSPC were identified for the study. 24% (N = 37) had pathogenic HRR gene alterations detected with the most common alterations found in BRCA2 (n = 15), ATM (n = 10), and CDK12 (n = 7). Time to mCRPC was significantly decreased in patients with HRR gene alterations versus those without such alterations (12.7 vs. 16.1 months, HR 1.95, P = .02). In multivariate analysis, the effect of HRR gene alterations on time to CRPC remained significant when adjusting for age, mHSPC therapy, the volume of disease, the presence of visceral metastases, and PSA (adjusted HR 1.69, P = .02). Stratified by specific HRR gene alteration, patients with BRCA2 or CDK12 had significantly decreased time to mCRPC compared to other HRR alterations. CONCLUSION: HRR gene alterations are associated with the worse outcomes in mHSPC with significantly shorter time to mCRPC. Given the established role of Poly (ADP-ribose) Polymerase (PARP) inhibitors in mCRPC, these data highlight an opportunity to examine PARP inhibitors earlier in the clinical course for prostate cancer patients. Ongoing prospective studies will further validate the role of PARP inhibitors in mHSPC patients.

Association Between Sites of Metastasis and Outcomes With Immune Checkpoint Inhibitors in Advanced Urothelial Carcinoma.

BACKGROUND: Sites of metastasis have prognostic significance in advanced urothelial carcinoma (aUC), but more information is needed regarding outcomes based on metastatic sites in patients treated with immune checkpoint inhibitors (ICI). We hypothesized that presence of liver/bone metastases would be associated with worse outcomes with ICI. METHODS: We identified a retrospective cohort of patients with aUC across 26 institutions, collecting demographics, clinicopathological, treatment, and outcomes information. Outcomes were compared with logistic (observed response rate; ORR) and Cox (progression-free survival; PFS, overall survival; OS) regression between patients with/without metastasis beyond lymph nodes (LN) and those with/without bone/liver/lung metastasis. Analysis was stratified by 1st or 2nd+ line. RESULTS: We identified 917 ICI-treated patients: in the 1st line, bone/liver metastases were associated with shorter PFS (Hazard ratio; HR: 1.65 and 2.54), OS (HR: 1.60 and 2.35, respectively) and lower ORR (OR: 0.48 and 0.31). In the 2nd+ line, bone/liver metastases were associated with shorter PFS (HR: 1.71 and 1.62), OS (HR: 1.76 and 1.56) and, for bone-only metastases, lower ORR (OR: 0.29). In the 1st line, LN-confined metastasis was associated with longer PFS (HR: 0.53), OS (HR:0.49) and higher ORR (OR: 2.97). In the 2nd+ line, LN-confined metastasis was associated with longer PFS (HR: 0.47), OS (HR: 0.54), and higher ORR (OR: 2.79); all associations were significant. CONCLUSION: Bone and/or liver metastases were associated with worse, while LN-confined metastases were associated with better outcomes in patients with aUC receiving ICI. These findings in a large population treated outside clinical trials corroborate data from trial subset analyses.

Impact of renin-angiotensin system inhibitors on outcomes in patients with metastatic renal cell carcinoma treated with immune-checkpoint inhibitors.

BACKGROUND: Renin-angiotensin system inhibitors (RASi) have been shown to improve outcomes in studies of multiple malignancies by effects on the tumor microenvironment to enhance the immune repertoire and improve drug delivery. Repurposing RASi to treat metastatic renal cell carcinoma (mRCC) in combination with immune-checkpoint inhibitors (ICI) may improve survival coupled with tolerability and cost efficacy. We evaluated the impact of RASi on outcomes in mRCC patients receiving ICI. METHODS: This multicenter, retrospective cohort study included mRCC patients treated with ICI with or without RASi. The patients from Dana-Farber Cancer Institute (DFCI) were used as a discovery cohort, and the patients from University of California San Diego (UCSD) were used for validation. Receipt of an ICI (PD1/L1 and/or CTLA-4 inhibitors) was required. RASi use was defined as receipt of a RASi at baseline and for a minimum of 30 days after ICI initiation. For both the discovery and validation cohorts, the primary outcome assessed was overall survival (OS) and the secondary endpoints were time-to-treatment failure (TTF), and objective response rate (ORR). RESULTS: Overall, 229 patients who received an ICI were included: 100 patients from DFCI and 129 patients from UCSD. Concomitant RASi were administered in 30 patients (30%) in the DFCI cohort and 59 (45%) in the UCSD cohort. Median age at ICI initiation was 62.5 years in both cohorts. Median follow-up was 3.8 [IQR 3-5.3] years in the DFCI cohort, and 2.3 [IQR 1.4-3.6] years in the UCSD cohort. In the DFCI cohort, RASi was significantly associated with longer OS (adjusted-HR 0.35 [95% CI, 0.17-0.70], P = .003) and TTF (adjusted-HR 0.57 [0.36-0.92], P = .02). In the validation cohort, RASi was associated with TTF (adjusted HR, 0.60 [0.39-0.92], P = .02) and not statistically associated with OS (adjusted-HR 0.60 [0.34-1.06], P = .07). The propensity analysis, matching 83 patients from both cohorts receiving RASi while on ICI with 83 who did not, showed that RASi significantly improved OS (HR 0.59 [0.37-0.95], P = .03) and TTF (HR 0.60 [0.43-0.85], P = .0034). CONCLUSIONS: RASi was associated with improved OS and TTF in mRCC patients receiving ICI. This provides a rationale for prospective randomized studies combining ICI and RASi in mRCC patients.

An evaluation of trends in the representation of patients by age, sex, and diverse race/ethnic groups in bladder and kidney cancer clinical trials.

OBJECTIVES: To determine the representation of women, minorities, and the elderly groups in clinical trials and whether participation has changed over time. METHODS: Retrospective study in the National Cancer Institute (NCI) Clinical Data Update System and Center for Disease Control and Prevention United States Cancer Statistics 2000 to 2019. We compared cancer incidence proportion to proportion of patients enrolled in an NCI trial when stratified by race/ethnicity, sex, and age. We performed multivariable analysis to determine the odds of participating in a clinical trial in 2015 to 2019 when compared to 2000 to 2004. RESULTS: This study included 14,094 patients, 12,169 (86.3%) non-Hispanic White patients, 662 (4.7%) Black patients, and 660 (4.7%) Hispanic patients. There were 3,701 (26.3%) female patients and 10,393 (73.7%) male patients. For bladder cancer clinical trials, Black patients and Hispanic patients were underrepresented in clinical trials compared to Non-Hispanic White patients (odds ratio [OR] 0.71, 95% confidence interval [CI] 0.57-0.88, P = 0.002) and (OR 0.69, 95%CI 0.54-0.88, P = 0.003), respectively. For kidney cancer trials, Black and Hispanic patients were underrepresented in clinical trials compared to Non-Hispanic White patients (OR 0.42, OR 0.33-0.54, P < 0.001) and (OR 0.68, 95% CI 0.55-0.83, P < 0.001), respectively. Women were underrepresented in kidney cancer trials compared to men (OR 0.80, 95% CI 0.72-0.89) and similarly for bladder cancer trials (OR 0.72, 95% CI 0.64-0.81, P < 0.001). For bladder cancer trials, the participation of Black patients over time (OR 1.04, P = 0.814) and female patients over time (OR 1.03, P = 0.741) were unchanged. For kidney cancer trials, the participation of Black patients over time (OR 1.17, P = 0.293) and female patients over time (OR 1.03, P = 0.663) participation was also unchanged. CONCLUSION: In this study of clinical trials in bladder and kidney cancer, we identified that Blacks, Hispanics, and females were underrepresented. Additionally, Black and female participation was unchanged over the span of 20 years.

Outcomes by time to definitive chemoradiation treatment for patients with muscle-invasive bladder cancer.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has raised concerns about delaying treatment for localized cancer and its impact on long-term outcomes. OBJECTIVE: We aimed to investigate the impact of time to chemoradiation (CRT) on recurrence and survival outcomes for patients with muscle-invasive bladder cancer (MIBC). METHODS: In the national Veterans Affairs' database, we identified patients with urothelial histology, MIBC (T2-4a/N0-3/M0) diagnosed between 2000 to 2018 and treated with definitive CRT. Time to treatment was defined as the number of days between date of diagnosis and start date of CRT. The cohort was stratified into < 90 (early) or ≥ 90 days (delayed) groups. Endpoints of locoregional failure (LRF), distant failure (DF), overall survival (OS), and bladder cancer-specific survival (BCS) were evaluated in multivariable Cox and Fine-Gray models. RESULTS: 305 patients with MIBC underwent CRT - 190 (62.3%) received early CRT, 115 (37.7%) received delayed CRT. Multivariable analysis (including success of transurethral resection of bladder tumor and type of chemotherapy) revealed no difference in recurrence between groups - LRF HR 1.12 (95%CI 0.76-1.67, P = 0.56) and DF HR 1.03 (95%CI 0.70-1.53, P = 0.88). Similarly, there were no differences in survival outcomes. The lack of association was maintained at both earlier and later time cutoffs (60-120 days). CONCLUSIONS: Our findings suggest that a short-term delay in definitive therapy may not affect long-term outcomes for patients with MIBC undergoing CRT. This study does not endorse delays in therapy, but rather provides information to aid patients and clinicians navigate the unique challenges of MIBC care in both pandemic and non-pandemic times.

Metastasis and Mortality in Men With Low- and Intermediate-Risk Prostate Cancer on Active Surveillance.

BACKGROUND: Active surveillance (AS) is a safe treatment option for men with low-risk, localized prostate cancer. However, the safety of AS for patients with intermediate-risk prostate cancer remains unclear. PATIENTS AND METHODS: We identified men with NCCN-classified low-risk and favorable and unfavorable intermediate-risk prostate cancer diagnosed between 2001 and 2015 and initially managed with AS in the Veterans Health Administration. We analyzed progression to definitive treatment, metastasis, prostate cancer-specific mortality (PCSM), and all-cause mortality using cumulative incidences and multivariable competing-risks regression. RESULTS: The cohort included 9,733 men, of whom 1,007 (10.3%) had intermediate-risk disease (773 [76.8%] favorable, 234 [23.2%] unfavorable), followed for a median of 7.6 years. The 10-year cumulative incidence of metastasis was significantly higher for patients with favorable (9.6%; 95% CI, 7.1%-12.5%; P<.001) and unfavorable intermediate-risk disease (19.2%; 95% CI, 13.4%-25.9%; P<.001) than for those with low-risk disease (1.5%; 95% CI, 1.2%-1.9%). The 10-year cumulative incidence of PCSM was also significantly higher for patients with favorable (3.7%; 95% CI, 2.3%-5.7%; P<.001) and unfavorable intermediate-risk disease (11.8%; 95% CI, 6.8%-18.4%; P<.001) than for those with low-risk disease (1.1%; 95% CI, 0.8%-1.4%). In multivariable competing-risks regression, favorable and unfavorable intermediate-risk patients had significantly increased risks of metastasis and PCSM compared with low-risk patients (all P<.001). CONCLUSIONS: Compared with low-risk patients, those with favorable and unfavorable intermediate-risk prostate cancer managed with AS are at increased risk of metastasis and PCSM. AS may be an appropriate option for carefully selected patients with favorable intermediate-risk prostate cancer, though identification of appropriate candidates and AS protocols should be tested in future prospective studies.