A plain language summary of the TROPHY-U-01 study: sacituzumab govitecan use in people with locally advanced or metastatic urothelial cancer.

WHAT IS THIS SUMMARY ABOUT?: Sacituzumab govitecan (brand name: TRODELVY®) is a new treatment being studied for people with a type of bladder cancer, called urothelial cancer, that has progressed to a locally advanced or metastatic stage. Locally advanced and metastatic urothelial cancer are usually treated with platinum-based chemotherapy. Metastatic urothelial cancer is also treated with immune checkpoint inhibitors. There are few treatment options for people whose cancer gets worse after receiving these treatments. Sacituzumab govitecan is a suitable treatment option for most people with urothelial cancer because it aims to deliver an anti-cancer drug directly to the cancer in an attempt to limit the potential harmful side effects on healthy cells. This is a summary of a clinical study called TROPHY-U-01, focusing on the first group of participants, referred to as Cohort 1. All participants in Cohort 1 received sacituzumab govitecan. WHAT ARE THE KEY TAKEAWAYS?: All participants received previous treatments for their metastatic urothelial cancer, including a platinum-based chemotherapy and a checkpoint inhibitor. The tumor in 31 of 113 participants became significantly smaller or could not be seen on scans after sacituzumab govitecan treatment; an effect that lasted for a median of 7.2 months. Half of the participants were still alive 5.4 months after starting treatment, without their tumor getting bigger or spreading further. Half of them were still alive 10.9 months after starting treatment regardless of tumor size changes. Most participants experienced side effects. These side effects included lower levels of certain types of blood cells, sometimes with a fever, and loose or watery stools (diarrhea). Side effects led 7 of 113 participants to stop taking sacituzumab govitecan. WHAT WERE THE MAIN CONCLUSIONS REPORTED BY THE RESEARCHERS?: The study showed that sacituzumab govitecan had significant anti-cancer activity. Though most participants who received sacituzumab govitecan experienced side effects, these did not usually stop participants from continuing sacituzumab govitecan. Doctors can help control these side effects using treatment guidelines, but these side effects can be serious.Clinical Trial Registration: NCT03547973 (ClinicalTrials.gov) (TROPHY-U-1).

Emerging monoclonal antibody therapies in the treatment of metastatic urothelial carcinoma.

INTRODUCTION: The treatment landscape for advanced-stage, unresectable or metastatic urothelial carcinoma (mUC) has shifted dramatically over a short period of time, with new therapeutic agents available for clinical use. However, despite these recent advances in the field, mUC continues to be a disease with significant morbidity and mortality and remains generally incurable. While platinum-based therapy remains the backbone of therapy, many patients are ineligible for chemotherapy or have failed initial chemotherapy treatment. In post-platinum treated patients, immunotherapy and antibody drug conjugates have provided incremental advances, but agents with better therapeutic index guided by precision medicine are needed. AREAS COVERED: This article covers the available monoclonal antibody therapies in mUC excluding immunotherapy and antibody drug conjugates. Included are a review of data utilizing monoclonal antibodies targeting VEG-F, HER-2, FGFR, and KIR-2 in the setting of mUC. A literature search from 6/2022- 9/2022 was performed utilizing PubMed with key terms including urothelial carcinoma, monoclonal antibody, VEG-F, HER-2, FGFR. EXPERT OPINION: Often used in combination with immunotherapy or other therapeutic agents, monoclonal antibody therapies have exhibited efficacy in mUC in early trials. Upcoming clinical trials will further explore their full clinical utility in treating mUC patients.

Optimal pathological response after neoadjuvant chemotherapy for muscle-invasive bladder cancer: results from a global, multicentre collaboration.

OBJECTIVES: To evaluate outcomes of patients achieving a post-treatment pathological stage of

Correction to: Immunotherapy Advances in Urothelial Carcinoma.

In the original version of this article, which published in Current Treatment Options in Oncology, Volume 20, Issue 12, December 2018, the surname of the third author was captured incorrectly. The name shown above is correct.

Immunotherapy Advances in Urothelial Carcinoma.

OPINION STATEMENT: Checkpoint inhibitors have monumentally transformed the treatment of metastatic urothelial carcinoma. While the efficacy and safety of the different agents are similar in platinum-refractory metastatic urothelial carcinoma, pembrolizumab is the only agent that was superior to chemotherapy in a randomized phase III trial. Pembrolizumab and atezolizumab are also approved as first-line therapies in cisplatin-ineligible metastatic urothelial carcinoma. Several immunotherapy trials are ongoing in non-metastatic setting to maximize responses upfront. Despite the promising responses with immunotherapy, majority of patients do not respond to monotherapy and combination approaches would be the path moving forward to maximize responses. In addition, novel therapies are needed for patients who progress on checkpoint inhibitors. There is still a lot to be done to better understand predictive biomarkers, optimal combination, and sequences to improve clinical outcomes in urothelial carcinoma.

PrECOG PrE0807: A Phase 1b Feasibility Trial of Neoadjuvant Nivolumab Without and with Lirilumab in Patients with Muscle-invasive Bladder Cancer Ineligible for or Refusing Cisplatin-based Neoadjuvant Chemotherapy.

BACKGROUND AND OBJECTIVE: Neoadjuvant cisplatin-based chemotherapy prior to radical cystectomy (RC) improves overall survival (OS) in muscle-invasive bladder cancer (MIBC). However, many patients are cisplatin ineligible; therefore, new treatment options are needed. Nivolumab without/with lirilumab prior to RC was investigated in cisplatin-ineligible patients in this phase 1b trial (NCT03532451) to determine its safety/feasibility. METHODS: Patients with localized MIBC received two doses of nivolumab (480 mg) alone (cohort 1) or with lirilumab (240 mg; cohort 2) prior to RC. Cohorts were enrolled sequentially. The key eligibility criteria were cT2-4aN0-1M0 stage and cisplatin ineligibility/refusal. The primary endpoint was the rate of grade (G) ≥3 treatment-related adverse events (TRAEs) as per Common Terminology Criteria for Adverse Events version 5.0. The key secondary endpoints included the proportion of patients who underwent RC >6 wk after the last dose, CD8+ T-cell density change between pretreatment transurethral resection of bladder tumor (TURBT) and post-treatment RC, ypT0N0, 6 wk. In cohorts 1 and 2, ypT0N0 rates for patients with MIBC and RC were 17% and 21%,

Impact of Angiotensin Converting Enzyme Inhibitors on Pathologic Complete Response With Neoadjuvant Chemotherapy for Muscle Invasive Bladder Cancer.

INTRODUCTION: The renin-angiotensin system (RAS) has been demonstrated to modulate cell proliferation, desmoplasia, angiogenesis and immunosuppression. We examined the association of RAS inhibitors (RASi)-namely angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB)-with neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (MIBC) preceding radical cystectomy (RC). PATIENTS AND METHODS: We retrospectively investigated concurrent RASi use with NAC prior to RC in 302 patients with MIBC from 3 academic institutions. Outcomes included pathologic complete response (pCR) and overall survival (OS). Pathologic features, performance status (PS), clinical stage, type/number of cycles of NAC, and toxicities were collected. RESULTS: Overall pCR rate was 26.2% and 5-year OS was 62%. Concurrent ACEi intake with NAC approached significance for association with pCR (odds ratio [OR] = 1.71; 95% CI, 0.94-3.11; P = .077). Patients with cT3/4N0-N1 disease receiving ACEi had higher pCR rates (30.8% vs. 17.7%, P = .056) than those not on ACEi. Female sex had a statistically significant favorable interaction for pCR with ACEi intake (P = .044). ACEi intake was not associated with OS, while pCR, PS and lower clinical stage were significantly associated with improved OS. CONCLUSION: ACEi intake is potentially associated with increased pCR in patients with MIBC receiving NAC prior to RC, and this association is more pronounced in patients with higher clinical stage of disease at the initiation of therapy and female sex. Our data suggest the potential relevance of the RAS as a therapeutic target in aggressive MIBC.

Inherited Germline Variants in Urinary Tract Cancer: A Multicenter Whole-Exome Sequencing Analysis and Correlation With Clinical Features and Tumor Genomics.

PURPOSE: This study investigates a real-world multicenter cohort of patients with urinary tract cancer (UTC), with primary disease sites including the bladder, urethra, and upper tract, who enrolled for research molecular testing of their germline and tumor. The purpose of this study was to evaluate factors that could affect the likelihood of identifying a clinically actionable germline pathogenic variant (PV). METHODS: Patients with UTC were identified from 10 cancer institutes of the Oncology Research Information Exchange Network consortium. The data set comprised abstracted clinical data with germline and tumor genomic data, and comparative analyses were conducted. RESULTS: Clinically actionable germline PVs in cancer predisposition genes were identified in 16 (4.5%) of 354 patients. A higher proportion of patients with the urethra and the upper tract as the primary sites of disease had PVs with a prevalence of 11% (5/45), compared with only 3.6% (11/308) in those with the bladder as the primary site of disease (P = .04). There were no significant differences in markers of genomic instability (such as tumor mutational burden, microsatellite instability [MSI], and loss of heterozygosity, copy number, and chromosomal instability) between those with PVs and those without (P > .05). Of the PVs identified, 10 (62%) were in homologous recombination repair (HRR) genes, three (19%) in mismatch repair (MMR) genes, and three (19%) in genes associated with other pathways. CONCLUSION: Tissue-based assessment of genomic instability, such as MSI, does not reliably indicate germline PV. A comprehensive clinical germline testing approach that includes HRR genes in addition to MMR genes is likely to yield PVs in approximately one of 10 patients with nonbladder primary disease sites such as the upper tract and the urethra.

Antibody-Drug Conjugates in the Treatment of Urothelial Cancer.

Antibody-drug conjugates (ADCs) have transformed the treatment landscape in oncology and become an essential therapeutic modality. In urothelial carcinoma (UC), the two ADCs that have been especially successful in clinical practice are enfortumab vedotin and sacituzumab govitecan. These drugs are currently approved as monotherapy for later lines of treatment in locally advanced or metastatic UC and have had a significant impact for patients with limited treatment options. Combinational trials, as well as additional ADCs, are currently being investigated in the treatment of UC for subsequent lines of therapy as overall survival rates remain dismal.

A Phase II Study of Durvalumab for Bacillus Calmette-Guerin (BCG) Unresponsive Urothelial Carcinoma In Situ of the Bladder.

PURPOSE: Immune checkpoint blockade holds promise for treating bacillus Calmette-Guerin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC). In this phase II study, we investigated the safety and efficacy of durvalumab, a human IgG1 monoclonal antibody, against BCG-unresponsive carcinoma in situ (CIS). PATIENTS AND METHODS: Patients with BCG-unresponsive CIS-containing NMIBC received durvalumab IV at 1,500 mg every 4 weeks for up to 12 months. The primary endpoint was complete response (CR) rate at month 6, defined by negative cystoscopy, urine cytology, and absence of high-grade recurrence on bladder mapping biopsy. The null hypothesis specified a CR rate of 18% and alternative hypothesis of 40%. According to the Simon two-stage design, if ≤3/13 patients achieved CR during stage 1, the trial is stopped due to futility. RESULTS: Between March 8, 2017, and January 24, 2020, 17 patients were accrued whereas 4 withdrew from study treatment after bladder biopsy at month 3 was positive for CIS. Two of 17 (12%) achieved a CR at month 6, with duration of response of 10 and 18 months, respectively. A single grade 3 lipase elevation was attributed to durvalumab, and immune-related adverse events were observed in 7/17 (41%) patients. Only 1/17 patients had high programmed death-ligand 1 expression pretreatment. On RNA sequencing, complement activation genes were elevated posttreatment, along with enrichment of tumor-associated macrophage signature. CONCLUSIONS: Durvalumab monotherapy conferred minimal efficacy in treating BCG-unresponsive CIS of the bladder, with 6-month CR of 12%. Complement activation is a potential mechanism behind treatment resistance.

Effectiveness of perioperative chemotherapy and radical cystectomy in treating bladder cancer.

BACKGROUND: Despite abundant evidence supporting the use of perioperative chemotherapy from clinical trials, no study to date has comprehensively evaluated its use in the treatment of muscle-invasive bladder cancer (MIBC) in the real-world setting. Little is known regarding the impact of pretreatment disease stage and real-world factors such as patient comorbidities preventing timely completion of therapy on its effectiveness. This study aims to assess the usage of perioperative chemotherapy and examines its impact on pathologic downstaging rates and recurrence free survival in patients undergoing radical cystectomy. METHODS: A retrospective review was conducted in 805 patients with muscle invasive bladder cancer undergoing radical cystectomy with no perioperative chemotherapy, 761 with presurgical chemotherapy followed by radical cystectomy, and 134 radical cystectomy followed by adjuvant chemotherapy. Relevant clinicopathologic features were reviewed. Recurrence-free survival and Overall Survival probability estimates were calculated using the Kaplan-Meier method and compared using the Log-rank or Gehan-Breslow tests. The prognostic effects of presurgical chemotherapy and adjuvant chemotherapy regimens were evaluated by estimating hazard ratio and 95% confidence interval from an adjusted Cox proportional hazards model. Statistical tests were 2-sided, and significance was defined as P-value < 0.05. RESULTS: In this contemporary, real-world cohort, 5-yr RFS was found to be 65.6% in pT0, 59.1%in pT2, and 10.8% in pN+ patients. Presurgical chemotherapy increased pathologic downstaging rates from 27.5% to 41.1% in patients with ≥cT2 BCa. Stratified by clinical T-stage, only cT2 patients derived recurrence-free survival (Median 45.3 months vs. 29.0 months, P < 0.01) and overall survival (Median 62.3 months vs. 41.9 months, P < 0.001) benefits.  In patients with adverse pathologic features (≥pT3 or pN+), adjuvant chemotherapy improved recurrence-free survival (Median 22.8 months vs. 10.0 months, P < 0.0001) and overall survival (Median OS 32.4 months vs. 16.3 months, P < 0.0001). CONCLUSIONS: We report real-world outcomes from a large cohort of muscle-invasive bladder cancer patients undergoing surgical treatment with/out perioperative chemotherapy. Pathologic response rates to pre-surgical chemotherapy were modest and led to clinical benefit only in cT2 patients. Adjuvant chemotherapy provided survival benefit for pathologically advanced MIBC patients irrespective of pT/N staging.

Circulating and urinary tumour DNA in urothelial carcinoma - upper tract, lower tract and metastatic disease.

Precision medicine has transformed the way urothelial carcinoma is managed. However, current practices are limited by the availability of tissue samples for genomic profiling and the spatial and temporal molecular heterogeneity observed in many studies. Among rapidly advancing genomic sequencing technologies, non-invasive liquid biopsy has emerged as a promising diagnostic tool to reproduce tumour genomics, and has shown potential to be integrated in several aspects of clinical care. In urothelial carcinoma, liquid biopsies such as plasma circulating tumour DNA (ctDNA) and urinary tumour DNA (utDNA) have been investigated as a surrogates for tumour biopsies and might bridge many shortfalls currently faced by clinicians. Both ctDNA and utDNA seem really promising in urothelial carcinoma diagnosis, staging and prognosis, response to therapy monitoring, detection of minimal residual disease and surveillance. The use of liquid biopsies in patients with urothelial carcinoma could further advance precision medicine in this population, facilitating personalized patient monitoring through non-invasive assays.

Impact of surgical margin and extent of lymphadenectomy on oncologic outcomes in plasmacytoid urothelial carcinoma.

OBJECTIVE: Guideline recommendations disagree on template boundaries for pelvic lymph node dissection (PLND) in conventional urothelial carcinoma. Less is known about PLND in variant histology. We aimed to analyze the role of LND in plasmacytoid urothelial carcinoma (PUC). METHODS: A retrospective review of patients with cTanyNanyM0 PUC who underwent radical cystectomy (RC) with PLND was performed from 2012 to 2022. Lymph node count (LNC) was a surrogate for extent of lymph node dissection and dichotomized based on maximally selected rank statistics. Multivariable cox hazard regression analysis (MVA) for overall survival (OS) corrected for age, perioperative chemotherapy, soft tissue margin status, and stage ≥pT3 and/or pN+ was performed. Disease free survival (DFS) and OS were estimated using Kaplan-Meier (KM) analysis. RESULTS: Sixty-seven patients with median age of 71, who were 79.1% male were included. Neoadjuvant and adjuvant chemotherapy were administered in 61.2% and 19.4% of patients, respectively. At RC, 70.1% were ≥pT3. Median LNC was 22 (IQR 14-27) with 43.3% of patients being pN+. Calculated optimal-LNC cut point for DFS and OS was 19. Grouping by optimal (≥20) vs. suboptimal-LNC (<20), no significant clinicodemographic differences were found. Optimal-LNC provided improved DFS (P = 0.05) and OS (P = 0.02). Optimal-LNC (HR 0.47, 0.24-0.93 CI 95%, P = 0.03) and negative soft tissue margin (HR 0.38, 0.19-0.76 CI 95%, P = 0.01) was associated with improved OS on MVA. Receipt of perioperative chemotherapy did not improve OS (P = 0.46). CONCLUSION: In PUC, complete surgical extirpation achieving negative soft tissue margins and removing ≥20 lymph should be prioritized if operative intervention is pursued.

Establishment and characterization of a novel cell line derived from human thymoma AB tumor.

Thymomas are low-grade epithelial tumors of the anterior mediastinum. The complexity of the disease and the lack of in vitro and in vivo models hamper the development of better therapeutics. In this study, we report a novel cell line, designated as IU-TAB-1, which was established from a patient with stage II thymoma (World Health Organization-type AB). The IU-TAB-1 cell line was established in vitro and characterized using histological and immunohistochemical staining, fluorescence-activated cell sorting, cytogenetic analyses and functional assays including in vitro and a NOD/SCID xenograft model. A whole-genome gene expression analysis (Illumina) was performed on the IU-TAB-1 cell line and 34 thymomas to determine the clinical relevance of the cell line. The IU-TAB-1 cell line was positive for epithelial markers (pan-cytokeratin and EpCAM/CD326) including thymic epithelial (TE) surface markers (such as CD29, CD9, CD54/ICAM-1, CD58 and CD24) and p63, and negative for B- and T-cell lineage markers. Gene expression profiling demonstrated overlapping and distinct genes between IU-TAB-1 and primary thymomas including the primary tumor (from which the cell line was derived). IU-TAB-1 cells are tumorigenic when implanted in immunodeficient mice with tumors reaching a volume of 1000 mm³ at around 130 days. The established cell line represents a biologically relevant new tool to investigate the molecular pathology of thymic malignancies and to evaluate the efficacy of novel therapeutics both in vitro and in vivo.

FOXA1 is an independent prognostic marker for ER-positive breast cancer.

Forkhead box protein A1 (FOXA1) is a "pioneer factor" that plays a role in controlling nearly 50% of estrogen receptor target genes. FOXA1 expression correlates with estrogen receptor (ER)-positivity especially in luminal subtype A breast cancers. The aim of this study was to investigate the precise role of FOXA1 in breast cancer using a large population-based cohort. Nuclear expression of FOXA1 was analyzed in a tissue microarray of 4,444 invasive breast cancer cases using immunohistochemistry and correlated with clinicopathologic variables using previously described methods and cutoff points. The entire cohort was equally divided into a training and validation set. All survival analyses were performed using a previously defined cutoff (3) for validation. Additional X-tile analysis performed to analyze prognostic effects of low and high FOXA1 levels identified 24 as a cutoff. Bonferroni-Holmes test was used as appropriate. FOXA1 expression significantly correlated positively with markers of good prognosis or ER-positivity, and negatively with tumor size, tumor grade, nodal status, Ki67, HER2 expression, and basal subtype (each P value <0.0001). In both survival analyses, FOXA1 was a significant predictor of breast cancer-specific survival (P < 0.0001) and relapse-free survival (P < 0.0001). FOXA1 was also an independent predictor of breast cancer-specific survival at 10 years using both cutoffs. Among the ER-positive subgroup treated with tamoxifen, FOXA1 was an independent prognostic marker using the 24 cutoff (P = 0.030). FOXA1 is a significant marker of good prognosis in breast cancer; it also identifies a subset of ER-positive tamoxifen treated patients at low risk of recurrence.

Extrathoracic metastases of thymic origin: a review of 35 cases.

Thymic tumors are categorized as types A, AB, B1, B2, B3, and thymic carcinoma under the World Health Organization (WHO) classification. Thymomas are typically slow growing tumors that predominantly involve the surrounding structures through direct invasion, while thymic carcinomas tend to be more aggressive. A significant number of patients are asymptomatic and can present with metastases as the first presentation. The exact incidence of extrathoracic metastases from thymoma is not known. This study describes a series of 35 cases of histologically documented metastatic thymomas and thymic carcinomas at extrathoracic sites. These cases were classified according to the current World Health Organization (WHO) classification criteria, and we present their clinical data as well as discuss the differential diagnoses of these lesions. Our study shows that all types of thymic tumors, regardless of histologic type, can be associated with invasion and metastases to thoracic and extrathoracic sites.

FGFR2/3 genomic alterations and response to Enfortumab Vedotin in metastatic urothelial carcinoma.

Enfortumab Vedotin (EV) is approved for metastatic urothelial carcinoma (mUC) progressing post-platinum and PD1/L1 inhibitor therapy. Erdafitinib is approved for post-platinum mUC with activating somatic genomic alterations (GAs) in FGFR2/3. Information on the activity of EV in mUC with FGFR2/3 alterations will facilitate optimal clinical management. In this multi-center, retrospective analysis, we assessed the overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) to EV in mUC patients with and without FGFR2/3 GAs including mutations and fusions. Multivariable cox-regression and logistic regression analyses with 2-tailed p-values were used to evaluate the association of GAs with outcomes. A majority of the evaluable 60 patients were male (44/60, 78%), exhibited ECOG performance score 0-1 (53/60, 88.3%) and had a median age of 70.5 (range 48 - 88) years when starting EV. GAs in FGFR2/3 did not influence the ORR (p=0.32), OS (p=0.79) or PFS (p = 0.32) with EV. In conclusion, FGFR2/3 GAs did not appear to compromise major outcomes with EV in mUC. Larger studies are required to further evaluate the impact of FGFR2/3 GAs on the activity of EV and the optimal sequencing of EV and erdafitinib in mUC.

Outcomes of metastatic urothelial carcinoma following discontinuation of enfortumab-vedotin.

BACKGROUND: Enfortumab vedotin (EV) is approved to treat metastatic urothelial carcinoma (mUC) following platinum and PD1/L1 inhibitors. Since the outcomes and patterns of therapy of patients following discontinuation of EV are unknown, we conducted a retrospective study to assess this issue. METHODS: Data were retrospectively obtained from patients with mUC following discontinuation of EV after prior platinum-based chemotherapy and PD1/L1 inhibitors. Objective response rate (ORR) was evaluated in those who received therapy post-EV. Statistical analyses were performed to describe the overall survival (OS) and compare patient characteristics and outcomes of those who did or did not receive treatment post-EV. RESULTS: Data were available for 63 patients from 6 institutions: 46 (73%) were male and median age was 68 years (range 43-83). The median OS was 32 weeks. Thirty-two patients (51%) received therapy after EV. The OS of those who did vs. did not receive post-EV therapy was significantly different (median 43.1 vs. 16.9 weeks, P = .015). Longer duration of prior EV therapy was associated with receipt of post-EV therapy (P = .0437) as well as OS in both the treated (P = .045) and untreated groups (P = .012). Objective response was observed in 3 of 32 patients (9.4%) who received therapy post-EV. CONCLUSION: Outcomes of patients with mUC following discontinuation of EV are dismal and only 51% received therapy after discontinuation of EV. This study identifies benchmarks for the interpretation of activity of new agents following EV and raises the hypothesis for duration of EV as a potential prognostic factor following discontinuation of EV.

Survival Outcomes Associated With Cytoreductive Nephrectomy in Patients With Metastatic Clear Cell Renal Cell Carcinoma.

Importance: Level I evidence has failed to demonstrate an overall survival (OS) advantage for cytoreductive nephrectomy in patients with metastatic clear cell renal cell carcinoma (ccRCC) in the modern era, which is at odds with observational studies reporting a marked OS benefit associated with these operations. These observational studies were not designed to adjust for unmeasured confounding. Objective: To assess whether cytoreductive nephrectomy is associated with improved OS in patients with metastatic ccRCC. Design, Setting, and Participants: This cohort study identified patients with metastatic ccRCC in the National Cancer Database from January 1, 2006, to December 31, 2016, who received systemic targeted therapy. The analysis was finalized on July 23, 2021. Exposures: Receipt of cytoreductive nephrectomy. Main Outcomes and Measures: The primary outcome was OS from the date of diagnosis to death or censoring at last follow-up. Distance from the patients' zip code of residence to the treating facility was identified as a valid instrument and was used in a 2-stage residual inclusion instrumental variable analysis. Conventional adjustments for selection bias, multivariable Cox proportional hazards regression, and propensity score matching were performed for comparison. Measured covariates adjusted for in all analyses included age, sex, race, Charlson-Deyo score, facility type, year of diagnosis, clinical T stage, and clinical N stage. Results: The final study population included 12 766 patients (median age, 63 years; IQR, 56-70 years; 8744 [68%] male; 11 206 [88%] White). Cytoreductive nephrectomy was performed in 5005 patients (39%). Conventional adjustments for selection bias demonstrated a significant OS benefit associated with cytoreductive nephrectomy (multivariable Cox proportional hazards regression: hazard ratio [HR], 0.49; 95% CI, 0.47-0.51; propensity score matching: HR, 0.48; 95% CI, 0.46-0.50). Instrumental variable estimates did not demonstrate an association between cytoreductive nephrectomy and OS (HR, 0.92; 95% CI, 0.78-1.09). Conclusions and Relevance: Instrumental variable analysis did not demonstrate a survival advantage associated with cytoreductive nephrectomy for patients with metastatic ccRCC. This discrepancy likely reflects the fact that surgical indication for cytoreductive nephrectomy is primarily driven by factors that are not commonly measured or available in observational data sets.