Contributors NMC and LCH were responsible for study design, study coordination, cumulative data collection, data interpretation, and primary manuscript writing. WX did the statistical analyses and participated in the manuscript drafting.

Purpose: To date, there has not been a large, systematic evaluation of the prevalence of germline risk variants in urothelial carcinoma (UC). Methods:We evaluated the frequency of germline pathogenic and likely pathogenic variants in 1038 patients with high-risk UC who underwent targeted clinical germline testing. Case-control enrichment analysis was performed to screen for pathogenic variant enrichment in 17 DNA repair genes in 1038 UC patients relative to cancer-free individuals.Results: Among 1038 patients with UC, the cumulative frequency of patients with pathogenic variants was 24%; 18.6% of patients harbored ≥1 actionable germline variant with preventive or therapeutic utility. MSH2 (34/969, 3.5%) and BRCA1/2 (38/867, 4.4%) germline variants had the highest frequency. Germline variants in DNA damage repair genes accounted for 78% of pathogenic germline variants. Compared to the cancer-free cohort, UC patients had significant variant enrichment in MSH2 (odds ratio [OR]: 15.4, 95% confidence interval [CI]: 7.1-32.7, p < 0.0001), MLH1 (OR: 15.9, 95% CI: 4.4-67.7, p < 0.0001), BRCA2 (OR: 5.7, 95% CI: 3.2-9.6, p < 0.0001), and ATM (OR: 3.8, 95% CI: 1.8-8.3, p = 0.02). Conclusion:In this study, 24% of UC patients harbored pathogenic germline variants and 18.6% had clinically actionable variants. MLH1 and MSH2 were validated as UC risk genes while ATM and BRCA2 were highlighted as potential UC predisposition genes. This work emphasizes the utility of germline testing in selected high-risk UC cohorts. (2020) 22:709-718; https://doi. Genetics in Medicine

Key Points Question Is there a role for platinum-based treatment in molecularly selected patients with advanced prostate cancer? Findings In a case series of 508 patients, platinum-based therapy was associated with antitumor activity, especially among patients with known DNA repair gene aberrations. In patients with DNA repair gene aberrations, nearly half had a decrease in prostate-specific antigen levels of at least 50% and experienced soft tissue responses. Meaning In patients with prostate cancer and DNA repair gene aberrations, platinum-based therapy may be considered a treatment option.

IMPORTANCEPatients with brain metastases from renal cell carcinoma (RCC) have been underrepresented in clinical trials, and effective systemic therapy is lacking. Cabozantinib shows robust clinical activity in metastatic RCC, but its effect on brain metastases remains unclear.OBJECTIVE To assess the clinical activity and toxic effects of cabozantinib to treat brain metastases in patients with metastatic RCC. DESIGN, SETTING, AND PARTICIPANTSThis retrospective cohort study included patients with metastatic RCC and brain metastases treated in 15 international institutions (US, Belgium, France, and Spain) between January 2014 and October 2020. Cohort A comprised patients with progressing brain metastases without concomitant brain-directed local therapy, and cohort B comprised patients with stable or progressing brain metastases concomitantly treated by brain-directed local therapy.EXPOSURES Receipt of cabozantinib monotherapy at any line of treatment. MAIN OUTCOMES AND MEASURES Intracranial radiological response rate by modifiedResponse Evaluation Criteria in Solid Tumors, version 1.1, and toxic effects of cabozantinib. RESULTSOf the 88 patients with brain metastases from RCC included in the study, 33 (38%) were in cohort A and 55 (62%) were in cohort B; the majority of patients were men (n = 69; 78%), and the median age at cabozantinib initiation was 61 years (range, 34-81 years). Median follow-up was 17 months (range, 2-74 months). The intracranial response rate was 55% (95% CI, 36%-73%) and 47% (95% CI, 33%-61%) in cohorts A and B, respectively. In cohort A, the extracranial response rate was 48% (95% CI, 31%-66%), median time to treatment failure was 8.9 months (95% CI, 5.9-12.3 months), and median overall survival was 15 months (95% CI, 9.0-30.0 months). In cohort B, the extracranial response rate was 38% (95% CI, 25%-52%), time to treatment failure was 9.7 months (95% CI, 6.0-13.2 months), and median overall survival was 16 months (95% CI, 12.0-21.9 months). Cabozantinib was well tolerated, with no unexpected toxic effects or neurological adverse events reported. No treatment-related deaths were observed. CONCLUSIONS AND RELEVANCEIn this cohort study, cabozantinib showed considerable intracranial activity and an acceptable safety profile in patients with RCC and brain metastases. Support of prospective studies evaluating the efficacy of cabozantinib for brain metastases in patients with RCC is critical.

Immune checkpoint inhibitors (ICIs) are soluble antibodies that have dramatically changed the outcomes including overall survival in a subset of kidney tumors, specifically in renal cell carcinoma (RCC). To date, there is no a single predictive biomarker approved to be used to select the patients that achieve benefit from ICIs targeting. It seems reasonable to analyze whether the programmed death-ligand 1 (PD-L1) expression could be useful. To assess the role of PD-L1 expression as a potential predictive biomarker for benefit of ICIs in RCC patients, we performed a search of randomized clinical trials (RCTs) comparing ICIs (monotherapy or in combination with other therapies) to standard of care in metastatic RCC patients according to PRISMA guidelines. Trials must have included subgroup analyses evaluating the selected outcomes (progression-free survival (PFS) and overall survival (OS)) in different subsets of patients according to PD-L1 expression on tumor samples. Hazard ratios with confidence intervals were used as the measure of efficacy between groups. A total of 4635 patients (six studies) were included (ICIs arm: 2367 patients; standard of care arm: 2268 patients). Globally, PFS and OS results favored ICIs. Differential expression of PD-L1 on tumor samples could select a subset of patients who could benefit more in terms of PFS (those with higher levels; p-value for difference between subgroups: <0.0001) but it did not seem to impact in OS results (p-value for difference: 0.63). As different methods to assess PD-L1 positivity were used among trials, this heterogeneity could have an influence on the results. PD-L1 could represent a biomarker to test PFS in clinical trials but its value for OS is less clear. In this meta-analysis, the usefulness of PD-L1 expression as a predictive biomarker to select treatment in metastatic RCC patients was not clearly shown.

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Background: Patients with residual muscle-invasive urinary tract cancer after neoadjuvant chemotherapy (NAC) have a high risk of recurrence.Objective: To retrospectively evaluate whether additional adjuvant chemotherapy (AC) improves outcomes compared with surveillance in patients with significant residual disease despite NAC.Design, setting, and participants: We identified 474 patients who received NAC from the Retrospective International Study of Cancers of the Urothelium database, of whom 129 had adverse residual disease (≥ypT3 and/or ypN + ).Outcome measurements and statistical analysis: Time to relapse (TTR) was the primary endpoint assessed starting from 2 mo after surgery to minimize immortal time bias. Secondary endpoints included overall survival (OS), incidence of AC use, and chemotherapy patterns. Kaplan-Meier and Cox regression models estimated TTR, OS, and associations with AC, adjusting for the type of NAC, age, and pathological stage in multivariable analyses. Results and limitations:A total of 106 patients underwent surveillance, while 23 received AC. Gemcitabine-cisplatin was the most frequent regimen employed in both settings (30.4%), and the majority (82.6%) of the patients switched to a different regimen. Median follow-up was 30 mo. Over 50% of patients developed a recurrence. Median TTR was 16 mo (range: <1-108 mo). Longer median TTR was observed with AC compared with surveillance (18 vs 10 mo, p = 0.06). Risk of relapse significantly decreased with AC when adjusted in multivariable analyses (p = 0.01). The subgroup analyses of ypT4b/ypN + patients (AC: 19; surveillance: 50) who received AC had significantly greater median TTR (20 vs 9 mo; hazard ratio 0.43; 95% confidence interval: 0.21-0.89). No difference in OS was found. Limitations include the retrospective design. Conclusions:The utilization of AC after NAC in patients with high-risk residual disease is not frequent in clinical practice but might reduce the risk of recurrence. Further investigation is needed in this high-risk population to identify optimal therapy and to improve clinical outcomes such as the ongoing adjuvant immunotherapy trials.

BackgroundThere is limited experience regarding the safety and efficacy of checkpoint inhibitors (CPI) in patients with autoimmune disorders (AD) and advanced urological cancers as they are generally excluded from clinical trials due to risk of exacerbations.MethodsThis multicenter retrospective cohort analysis of patients with advanced renal cell cancer (RCC) and urothelial cancer (UC) with pre-existing AD treated with CPI catalogued the incidence of AD exacerbations, new immune-related adverse events (irAEs) and clinical outcomes. Competing risk models estimated cumulative incidences of exacerbations and new irAEs at 3 and 6 months.ResultsOf 106 patients with AD (58 RCC, 48 UC) from 10 centers, 35 (33%) had grade 1/2 clinically active AD of whom 10 (9%) required corticosteroids or immunomodulators at baseline. Exacerbations of pre-existing AD occurred in 38 (36%) patients with 17 (45%) requiring corticosteroids and 6 (16%) discontinuing CPI. New onset irAEs occurred in 40 (38%) patients with 22 (55%) requiring corticosteroids and 8 (20%) discontinuing CPI. Grade 3/4 events occurred in 6 (16%) of exacerbations and 13 (33%) of new irAEs. No treatment-related deaths occurred. Median follow-up was 15 months. For RCC, objective response rate (ORR) was 31% (95% CI 20% to 45%), median time to treatment failure (TTF) was 7 months (95% CI 4 to 10) and 12-month overall survival (OS) was 78% (95% CI 63% to 87%). For UC, ORR was 40% (95% CI 26% to 55%), median TTF was 5.0 months (95% CI 2.3 to 9.0) and 12-month OS was 63% (95% CI 47% to 76%).ConclusionsPatients with RCC and UC with well-controlled AD can benefit from CPI with manageable toxicities that are consistent with what is expected of a non-AD population. Prospective study is warranted to comprehensively evaluate the benefits and safety of CPI in patients with AD.