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PURPOSE In this phase II response-adaptive trial, we investigated the rational application of immune checkpoint blockade in renal cell carcinoma (RCC; ClinicalTrials.gov identifier: NCT03203473 ). METHODS We enrolled patients with metastatic RCC with no prior checkpoint inhibitor exposure. All patients received nivolumab alone with subsequent arm allocation based on response. Patients with a confirmed partial response (PR) or complete response (CR) within 6 months discontinued nivolumab and were observed (arm A). Patients with stable disease or progressive disease (PD) after no more than 6 months of nivolumab received two doses of ipilimumab (arm B). The primary endpoints were the proportion of patients with PR/CR at 1 year after nivolumab discontinuation (arm A) and proportion of nivolumab nonresponders who converted to PR/CR after ipilimumab (arm B). RESULTS Overall, 83 patients initiated treatment, of whom 96% had clear-cell histology, 51% were treatment naïve, and 67% had intermediate/poor-risk disease. Median follow-up was 19.5 months. Within 6 months, induction nivolumab resulted in a confirmed PR in 12% of patients (n = 10). Fourteen patients were not allocated to a study arm (seven because of toxicity, seven because of PD). Twelve patients (14%) were allocated to arm A and discontinued nivolumab, of whom five (42%; 90% CI, 18% to 68%) remained off nivolumab at ≥ 1 year. Of 57 patients (69%) allocated to arm B, two patients converted to a confirmed PR (4%; 90% CI, 1% to 11%), and no CRs were observed. CONCLUSION In this study, nivolumab followed by two doses of ipilimumab resulted in no CRs and a low PR/CR conversion. The number of patients evaluated for nivolumab discontinuation was too small to assess the value of this approach. Currently, our data do not support a response-adaptive strategy for checkpoint blockade in advanced RCC.

The immunosuppressive cytokine interleukin- 8 (IL-8), produced by tumor cells and some myeloid cells, promotes inflammation, angiogenesis, and metastasis. In our discovery work, elevated serum IL-8 at androgen deprivation therapy (ADT) initiation portended worse overall survival (OS). Leveraging serum samples from the phase 3 CHAARTED trial of patients treated with ADT +/- docetaxel for metastatic hormone-sensitive prostate cancer (mHSPC), we validated these findings.Two hundred and thirty-three patients had serum samples drawn within 28 days of ADT initiation. The samples were assayed using the same Mesoscale Multiplex ELISA platform employed in the discovery cohort. After adjusting for performance status, disease volume, and de novo/metachronous metastases, multivariable Cox proportional hazards models assessed associations between IL-8 as continuous and binary variables on OS and time to castration-resistant prostate cancer (CRPC). The median IL-8 level (9.3 pg/ml) was the a priori binary cutpoint. Fixed-effects meta-analyses of the discovery and validation sets were performed.Higher IL-8 levels were prognostic for shorter OS (continuous: hazard ratio [HR] 2.2, 95% confidence interval [CI]: 1.4-3.6, p = .001; binary9.3: HR 1.7, 95% CI: 1.2-2.4, p = .007) and time to CRPC (continuous: HR 2.3, 95% CI: 1.6-3.3, p .001; binary: HR 1.8, 95% CI: 1.3-2.5, p .001) and independent of docetaxel use, disease burden, and time of metastases. Meta-analysis including the discovery cohort, also showed that binary IL-8 levels9.3 pg/ml from patients treated with ADT alone was prognostic for poorer OS (HR 1.8, 95% CI: 1.2-2.7, p = .007) and shorter time to CRPC (HR 1.4, 95% CI: 0.99-1.9, p = .057).In the phase 3 CHAARTED study of men with mHSPC at ADT initiation, elevated IL-8 portended worse survival and shorter time to castration-resistant prostate cancer independent of docetaxel administration, metastatic burden, and metachronous versus de novo metastatic presentation. These findings support targeting IL-8 as a strategy to improve mHSPC outcomes.

Background Cabozantinib is approved for the first and subsequent line treatment of metastatic clear-cell renal cell carcinoma (ccRCC) based on trials in which most patients were immune checkpoint blockade (ICB) naive. With an expanding role of ICB in earlier lines of therapy, we assessed activity of cabozantinib in patients with metastatic ccRCC after progressing on anti-PD-1/PD-L1–based ICBs. Methods We retrospectively analysed the clinical outcomes of 86 patients from 2 academic centres who received cabozantinib after progression on ICB alone, ICB in combination with vascular endothelial growth factor inhibitors (VEGFis) or ICB in combination with other therapies. Overall response rate (ORR, investigator assessed), time to treatment failure (TTF), overall survival (OS) and toxicities leading to dose reductions or cessation were evaluated. Results Eighty-six patients were included in the analysis; the median age was 63 years (range 33–84) and the median number of prior therapies was 2 (range 1–10). The type of prior ICB therapy was ICBs alone (64%), an ICB in combination with a VEGFi (29%) or ICBs in combination with other therapies (7%). At the time of cabozantinib treatment, 71% of patients were in the International Metastatic RCC Database Consortium good- or intermediate-risk groups. Approximately half of patients (52%) were started on cabozantinib at the full 60 mg daily dose. The ORR was 36% (95% confidence interval [CI] = 26–47%) with no complete response and 43% achieving stable disease; 21% had primary progressive disease. The median TTF was 6.5 months (95% CI = 5.3–8.5.). The median OS was 13.1 months (95% CI = 8.7-NR) with 55% (95% CI = 41–66%) OS rate at 12 months. Most common reasons for dose reductions were fatigue (27%), palmar-plantar erythrodysesthesia (16%) and diarrhoea (10%). Conclusions Cabozantinib is active in patients treated with prior ICB-based therapies, with no new safety signals. This study supports the use of cabozantinib after ICB-based therapies.

Background In metastatic urothelial carcinoma (mUC), predictive biomarkers that correlate with response to immune checkpoint inhibitors (ICIs) are lacking. Here, we interrogated genomic and clinical features associated with response to ICIs in mUC. Methods Sixty two mUC patients treated with ICI who had targeted tumour sequencing were studied. We examined associations between candidate biomarkers and clinical benefit (CB, any objective reduction in tumour size) versus no clinical benefit (NCB, no change or objective increase in tumour size). Both univariable and multivariable analyses for associations were conducted. A comparator cohort of 39 mUC patients treated with taxanes was analysed by using the same methodology. Results Nine clinical and seven genomic factors correlated with clinical outcomes in univariable analysis in the ICI cohort. Among the 16 factors, neutrophil-to-lymphocyte ratio (NLR) ≥5 (OR = 0.12, 95% CI, 0.01–1.15), visceral metastasis (OR = 0.05, 95% CI, 0.01–0.43) and single-nucleotide variant (SNV) count Conclusions This three-factor model includes genomic (SNV count >9) and clinical (NLR

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

Cytoreductive nephrectomy (CN) was established as the standard of care for the management of metastatic renal cell carcinoma (mRCC) in the early 2000s. Since that time, systemic therapeutic options for mRCC have rapidly expanded and progressed. The CARMENA trial was a phase III prospective, randomized clinical trial that accrued patient from 2009 to 2017, and the results show that treatment with sunitinib is noninferior to treatment with CN followed by sunitinib. Because the findings of CARMENA suggest that systemic therapy should be considered alongside CN as frontline therapy for mRCC, it is therefore important to define the clear indications for CN in the management of mRCC which include palliation, nonclear cell histology, consolidative therapy after systemic therapy, and oligometastic disease. Furthermore, CN may become increasingly important as immunotherapeutic options become widely adopted in the future. Given the heterogeneous nature of mRCC, a multidisciplinary approach should be taken to tailor the use of systemic therapy and CN for each individual patient.

BACKGROUND Achieving a pathologic complete response (pCR) with neoadjuvant chemotherapy (NAC) in patients with muscle-invasive bladder cancer (MIBC) has been associated with improved overall survival (OS). This study was aimed at evaluating the impact of pathologic downstaging (pDS; ie, a pT stage at least 1 stage lower than the pre-NAC cT stage) on the OS of patients with MIBC treated with NAC. METHODS The Retrospective International Study of Cancers of the Urothelial Tract (RISC) and the National Cancer Database (NCDB) were queried for cT2-4N0M0 patients treated with NAC. A multivariable Cox model including either pDS or pCR was generated. A nested model was built to evaluate the added value of pDS (excluding patients achieving a pCR) to a model including pCR alone. C indices were computed to assess discrimination. NCDB was used for validation. The treatment effect of NAC versus cystectomy alone in achieving pDS was estimated through an inverse probability-weighted regression adjustment. RESULTS Overall, 189 and 2010 patients from the RISC and NCDB cohorts, respectively, were included; pDS and pCR were achieved by 33% and 35% and by 20% and 15% in RISC and NCDB, respectively. In both data sets, pDS and pCR were associated with better OS and C indices. Adding pDS excluding pCR to the model with pCR fit the data better (likelihood ratio, P = .019 for RISC and P

Safe use of immune checkpoint blockade in patients with cancer and autoimmune disorders requires a better understanding of the pathophysiology of immunologic activation. We describe the immune correlates of reactivation of granulomatosis with polyangiitis (GPA)—an antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis—in a patient with metastatic urothelial carcinoma treated with pembrolizumab. After PD-1 blockade, an inflammatory pulmonary nodule demonstrated a granulomatous, CD4+ T-cell infiltrate, correlating with increased CD4+ and CD8+ naïve memory cells in the peripheral blood without changes in other immune checkpoint receptors. Placed within the context of the existing literature on GPA and disease control, our findings suggest a key role for PD-1 in GPA self-tolerance and that selective strategies for immunotherapy may be needed in patients with certain autoimmune disorders. We further summarize the current literature regarding reactivation of autoimmune disorders in patients undergoing immune checkpoint blockade, as well as potential immunosuppressive strategies to minimize the risks of further vasculitic reactivation upon rechallenge with anti-PD-1 blockade. Key Points Nonspecific imaging findings in patients with cancer and rheumatological disorders may require biopsy to distinguish underlying pathology. Patients with rheumatologic disorders have increased risk of reactivation with PD-(L)1 immune checkpoint blockade, requiring assessment of disease status before starting treatment. Further study is needed to evaluate the efficacy of treatment regimens in preventing and controlling disease reactivation.

Purpose: The purpose of this study is to characterize the mutational landscape across the spectrum of urothelial carcinoma (UC) to identify mutational features and potential therapeutic targets. Experimental Design: Using targeted exome sequencing (n = 237 genes), we analyzed the mutation spectra of 82 low-grade nonmuscle-invasive bladder cancers (LG-NMIBC), 126 high-grade (HG) NMIBC, 199 muscle-invasive bladder cancers (MIBC), 10 LG-upper tract urothelial cancers (LG-UTUC), and 55 HG-UTUC. Results: FGFR3 and KDM6A mutations were significantly more common in LG-NMIBC (72% and 44%, respectively) versus other bladder subtypes. FGFR3 alterations were also enriched in LG-UTUC versus HG-UTUC tumors (80% vs. 16%). In contrast, TP53 and RB1 mutations were significantly more frequent in all 3 HG urothelial carcinoma subtypes than in LG-NIMBC (45%–58% vs. 4%; 9%–22% vs. 0; respectively). Among LG-NMIBC tumors, KDM6A mutations were more common in women than in men (71% vs. 38%). HG-NMIBC and MIBC had higher tumor mutational burden (TMB) than LG-NMIBC (P = 0.001 and P < 0.01, respectively). DNA-damage repair (DDR) alterations were associated with a higher TMB in HG-NMIBC and MIBC tumors, and these two tumor types were also enriched for an APOBEC mutational signature compared with LG-NMIBC and HG-UTUC. Alterations in FGFR3, PIK3CA, and EP300 correlated with worse overall survival in HG-UTUC and occurred concurrently. Conclusions: Our analysis suggests that a fraction of MIBCs likely arise from precursor lesions other than LG-NMIBC. KDM6A mutations are twice as common in women with LG-NIMBC than those in men. DDR gene mutations and APOBEC mutagenesis drive mutations in HG-NMIBC and MIBC. UTUC has a distinct mutation profile from bladder cancer.

Summary Background Cabozantinib is approved for patients with metastatic renal cell carcinoma on the basis of studies done in clear-cell histology. The activity of cabozantinib in patients with non-clear-cell renal cell carcinoma is poorly characterised. We sought to analyse the antitumour activity and toxicity of cabozantinib in advanced non-clear-cell renal cell carcinoma. Methods We did a multicentre, international, retrospective cohort study of patients with metastatic non-clear-cell renal cell carcinoma treated with oral cabozantinib during any treatment line at 22 centres: 21 in the USA and one in Belgium. Eligibility required patients with histologically confirmed non-clear-cell renal cell carcinoma who received cabozantinib for metastatic disease during any treatment line roughly between 2015 and 2018. Mixed tumours with a clear-cell histology component were excluded. No other restrictive inclusion criteria were applied. Data were obtained from retrospective chart review by investigators at each institution. Demographic, surgical, pathological, and systemic therapy data were captured with uniform database templates to ensure consistent data collection. The main objectives were to estimate the proportion of patients who achieved an objective response, time to treatment failure, and overall survival after treatment. Findings Of 112 identified patients with non-clear-cell renal cell carcinoma treated at the participating centres, 66 (59%) had papillary histology, 17 (15%) had Xp11.2 translocation histology, 15 (13%) had unclassified histology, ten (9%) had chromophobe histology, and four (4%) had collecting duct histology. The proportion of patients who achieved an objective response across all histologies was 30 (27%, 95% CI 19–36) of 112 patients. At a median follow-up of 11 months (IQR 6–18), median time to treatment failure was 6·7 months (95% CI 5·5–8·6), median progression-free survival was 7·0 months (5·7–9·0), and median overall survival was 12·0 months (9·2–17·0). The most common adverse events of any grade were fatigue (58 [52%]), and diarrhoea (38 [34%]). The most common grade 3 events were skin toxicity (rash and palmar-plantar erythrodysesthesia; five [4%]) and hypertension (four [4%]). No treatment-related deaths were observed. Across 54 patients with available next-generation sequencing data, the most frequently altered somatic genes were CDKN2A (12 [22%]) and MET (11 [20%]) with responses seen irrespective of mutational status. Interpretation While we await results from prospective studies, this real-world study provides evidence supporting the antitumour activity and safety of cabozantinib across non-clear-cell renal cell carcinomas. Continued support of international collaborations and prospective ongoing studies targeting non-clear-cell renal cell carcinoma subtypes and specific molecular alterations are warranted to improve outcomes across these rare diseases with few evidence-based treatment options. Funding None.

Background Inflammation and infections have been associated with prostate cancer progression. We assessed whether elevated serum cytokines or T. vaginalis seropositivity at the time of diagnosis was associated with higher grade or lethal prostate cancer. Patients and Methods Men with localized or metastatic prostate cancer were included in this study. Cytokine serum levels including interleukin (IL)-1α, IL-1β, IL-2, IL-6, IL-8, monocyte chemotactic protein 1 (CCL-2), tumor necrosis factor α, and growth-regulated oncogene α (CXCL-1) using a multiplex enzyme-linked immunosorbent assay and T. vaginalis serology were measured in blood samples at diagnosis. Results A total of 324 patients were identified at time of localized disease and 118 at time of metastatic disease. Of the 189 patients with localized disease and clinical follow-up data (median, 73 months), 28 developed lethal disease. There was no association between circulating cytokine levels above median concentrations nor T. vaginalis seropositivity and risk of intermediate- to high-risk or lethal prostate cancer. Conclusion Higher levels of serum cytokine levels and T. vaginalis seropositivity at diagnosis are not associated with high-grade or lethal prostate cancer and do not aid risk stratification of localized prostate cancer.

Sarcomatoid and rhabdoid (S/R) renal cell carcinoma (RCC) are highly aggressive tumors with limited molecular and clinical characterization. Emerging evidence suggests immune checkpoint inhibitors (ICI) are particularly effective for these tumors, although the biological basis for this property is largely unknown. Here, we evaluate multiple clinical trial and real-world cohorts of S/R RCC to characterize their molecular features, clinical outcomes, and immunologic characteristics. We find that S/R RCC tumors harbor distinctive molecular features that may account for their aggressive behavior, including BAP1 mutations, CDKN2A deletions, and increased expression of MYC transcriptional programs. We show that these tumors are highly responsive to ICI and that they exhibit an immune-inflamed phenotype characterized by immune activation, increased cytotoxic immune infiltration, upregulation of antigen presentation machinery genes, and PD-L1 expression. Our findings build on prior work and shed light on the molecular drivers of aggressivity and responsiveness to ICI of S/R RCC., Sarcomatoid and rhabdoid tumours are highly aggressive forms of renal cell carcinoma that are also responsive to immunotherapy. In this study, the authors perform a comprehensive molecular characterization of these tumours discovering an enrichment of specific alterations and an inflamed phenotype.

BackgroundCD73–adenosine signaling in the tumor microenvironment is immunosuppressive and may be associated with aggressive renal cell carcinoma (RCC). We investigated the prognostic significance of CD73 protein expression in RCC leveraging nephrectomy samples. We also performed a complementary analysis using The Cancer Genome Atlas (TCGA) dataset to evaluate the correlation of CD73 (ecto-5′-nucleotidase (NT5E), CD39 (ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1)) and A2 adenosine receptor (A2AR;ADORA2A) transcript levels with markers of angiogenesis and antitumor immune response.MethodsPatients with RCC with available archived nephrectomy samples were eligible for inclusion. Tumor CD73 protein expression was assessed by immunohistochemistry and quantified using a combined score (CS: % positive cells×intensity). Samples were categorized as CD73negative(CS=0), CD73lowor CD73high(< and ≥median CS, respectively). Multivariable Cox regression analysis compared disease-free survival (DFS) and overall survival (OS) between CD73 expression groups. In the TCGA dataset, samples were categorized as low, intermediate and highNT5E,ENTPD1andADORA2Agene expression groups. Gene expression signatures for infiltrating immune cells, angiogenesis, myeloid inflammation, and effector T-cell response were compared betweenNT5E,ENTPD1andADORA2Aexpression groups.ResultsAmong the 138 patients eligible for inclusion, ‘any’ CD73 expression was observed in 30% of primary tumor samples. High CD73 expression was more frequent in patients with M1 RCC (29% vs 12% M0), grade 4 tumors (27% vs 13% grade 3 vs 15% grades 1 and 2), advanced T-stage (≥T3: 22% vs T2: 19% vs T1: 12%) and tumors with sarcomatoid histology (50% vs 12%). In the M0 cohort (n=107), patients with CD73hightumor expression had significantly worse 5-year DFS (42%) and 10-year OS (22%) compared with those in the CD73negativegroup (DFS: 75%, adjusted HR: 2.7, 95% CI 1.3 to 5.9, p=0.01; OS: 64%, adjusted HR: 2.6, 95% CI 1.2 to 5.8, p=0.02) independent of tumor stage and grade. In the TCGA analysis, highNT5Eexpression was associated with significantly worse 5-year OS (p=0.008).NT5EandENTPD1expression correlated with higher regulatory T cell (Treg) signature, whileADORA2Aexpression was associated with increased Treg and angiogenesis signatures.ConclusionsHigh CD73 expression portends significantly worse survival outcomes independent of stage and grade. Our findings provide compelling support for targeting the immunosuppressive and proangiogenic CD73–adenosine pathway in RCC.

Purpose: Androgen receptor (AR) inhibition can upregulate c-MET expression, which may be a resistance mechanism driving progression of castration-resistant prostate cancer (CRPC). We conducted a phase I trial investigating the safety and pharmacokinetics of a potent c-MET inhibitor, crizotinib, with the AR antagonist, enzalutamide, in CRPC. Patients and Methods: Employing a 3+3 dose-escalation design, we tested three dose levels of crizotinib (250 mg daily, 200 mg twice a day, and 250 mg twice a day) with standard-dose enzalutamide (160 mg daily). The primary endpoint was rate of dose-limiting toxicities (DLTs). Tolerability and pharmacokinetics profile were secondary endpoints. Results: Twenty-four patients were enrolled in the dose-escalation (n = 16) and dose-expansion (n = 8) phases. Two DLTs occurred in dose escalation (grade 3 alanine aminotransferase elevation). The MTD of crizotinib was 250 mg twice a day. Most frequent treatment-related adverse events were fatigue (50%), transaminitis (38%), nausea (33%), and vomiting, constipation, and diarrhea (21% each). Grade ≥3 events (25%) included transaminitis (n = 2), fatigue (n = 1), hypertension (n = 1), pulmonary embolism (n = 1), and a cardiac event encompassing QTc prolongation/ventricular arrhythmia/cardiac arrest. Median progression-free survival was 5.5 months (95% confidence interval, 2.8–21.2). Pharmacokinetics analysis at the MTD (n = 12) revealed a mean Cmaxss of 104 ± 45 ng/mL and AUCτss of 1,000 ± 476 ng•h/mL, representing a 74% decrease in crizotinib systemic exposure relative to historical data (Cmaxss, 315 ng/mL and AUCτss, 3,817 ng•h/mL). Conclusions: Concurrent administration of enzalutamide and crizotinib resulted in a clinically significant 74% decrease in systemic crizotinib exposure. Further investigation of this combination in CRPC is not planned. Our results highlight the importance of evaluating pharmacokinetics interactions when evaluating novel combination strategies in CRPC.

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 2mo 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 30mo. Over 50% of patients developed a recurrence. Median TTR was 16mo (range: 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.PATIENT SUMMARY: We found that administering additional chemotherapy in patients who had significant residual disease despite preoperative chemotherapy is not frequent in clinical practice. While it might reduce the risk of recurrence, it did not clearly increase overall survival. We encourage participation in the ongoing immunotherapy trials to see whether we can improve outcomes using a different type of therapy that stimulates the immune system.

Background: There 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. Methods: This 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. Results: Of 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%). Conclusions: Patients 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., SCOPUS: ar.j, info:eu-repo/semantics/published

Background: Optimal chemotherapy for patients who received cisplatin for localized urothelial carcinoma (UC) and develop metastatic disease is unclear. We compared the efficacy of platinum-based (PBC) versus non–platinum-based (NPBC) first-line chemotherapy for metastasis. Patients and Methods: Data were collected from the Retrospective International Study of Cancers of the Urothelial Tract (RISC), a database of 3024 patients from 28 international academic centers from 2005 to 2012. Patient inclusion criteria included: (1) predominant UC; (2) any primary tumor site; (3) cT2-4, cN0-N2, cM0; (4) prior receipt of perioperative/radiation cisplatin-containing chemotherapy; and (5) receipt of cytotoxic chemotherapy in the first-line metastatic setting. Multivariate Cox proportional hazards models were used to show progression-free survival (PFS) and overall survival (OS) from the first day of chemotherapy for metastatic disease to date of censor. Results: Eligibility criteria was met by 132 patients (n = 74 PBC; n = 58 NPBC). The median OS was 8.13 months (interquartile range, 4.87-16.64 months) and 8.77 months (interquartile range, 4.01-13.49 months) for PBC and NPBC, respectively. Neither OS (hazard ratio [HR], 1.04; 95% confidence interval [CI], 0.64-1.69; P =. 87) nor PFS (HR, 0.86; 95% CI, 0.56-1.31; P =. 48) differed for PBC versus NPBC. However, for patients who received chemotherapy more than a year after perioperative/radiation chemotherapy, OS was superior for PBC over NPBC (HR, 0.31; 95% CI, 0.10-0.92; P = .03). Conclusions: There is no significant outcome difference between PBC and NPBC in patients with metastatic UC who previously received cisplatin-based chemotherapy for localized disease. However, if over a year has elapsed, return to PBC is associated with superior OS. The optimal chemotherapy regimen for metastatic urothelial carcinoma following previous cisplatin-based chemotherapy, administered for localized disease, remains unclear. We found benefit of platinum-based over non–platinum-based first-line chemotherapy for patients with metastatic disease treated at least 1 year from completion of prior perioperative and/or peri-radiation cisplatin-based chemotherapy. These findings support return to platinum chemotherapy in this clinical scenario.

BACKGROUND: Metastatic urothelial carcinoma (mUC) is a genomically diverse disease with known alterations in the mTOR pathway and tyrosine kinases including FGFR. We investigated the efficacy and safety of combination treatment with everolimus and pazopanib (E/P) in genomically profiled patients with mUC. METHODS: mUC patients enrolled on a Phase I dose escalation study and an expansion cohort treated with E/P were included. The primary end point was objective response rate (ORR); secondary end points were safety, duration of response (DOR), progression-free survival (PFS) and overall survival (OS). Patients were assessed for mutations and copy number alterations in 300 relevant cancer-associated genes using next-generation sequencing and findings were correlated with outcomes. Time-to-event data were estimated with Kaplan-Meier methods. RESULTS: Of the 23 patients enrolled overall, 19 had mUC. ORR was 21% (one complete response (CR), three partial responses (PR), eight with stable disease (SD). DOR, PFS and OS were 6.5, 3.6, and 9.1 months, respectively. Four patients with clinical benefit (one CR, two PR, one SD) had mutations in TSC1/TSC2 or mTOR and a 5th patient with PR had a FGFR3-TACC3 fusion. CONCLUSIONS: Combination therapy with E/P is safe in mUC and select patients with alterations in mTOR or FGFR pathways derive significant clinical benefit.

Background Cabozantinib can enhance the effect of abiraterone in preclinical prostate cancer models. This study aimed to define the recommended phase 2 dose (RP2D) and preliminary efficacy of abiraterone + cabozantinib in mCRPC. Methods Patients with progressive mCRPC with 0-2 prior chemotherapy regimens but no prior CYP17A1 or MET inhibitor received abiraterone acetate at 1000 mg daily with prednisone 5 mg BID in combination with cabozantinib at 20, 40, or 60 mg daily in a dose-escalation 3 + 3 open-label phase 1 design (Part A). After tolerable doses were defined, cohorts were expanded to better define toxicity and efficacy (Part B). Results There were no dose-limiting toxicities (DLTs) in the first 4 weeks at any of the three dose levels in Part A. Two of the three patients at the 60 mg dose level required dose reductions beyond cycle 2 due to fatigue. In Part B, nine more patients were accrued to each of the 20 and 40 mg doses. Of the 12 patients treated at the 40 mg dose, only one DLT (grade 3 Lipase elevation) was observed in cycle 1. The median time to radiographic progression was 12.88 months (95% CI:5.42- not estimated [NE]) in the 20 mg cohort and 22.01 months (95% CI:15.44-NE) in the 40 mg cohort. Median overall survival was 23.29 months (95% CI:19.06-NE) in the 20 mg cohort and 39.08 months (95% CI:17.38-NE) in the 40 mg cohort. Conclusions Based on tolerability and preliminary efficacy, 40 mg cabozantinib plus 1000 mg abiraterone daily is the RP2D.

Background Overall survival (OS) is a critical endpoint in adjuvant trials but requires long durations to events and significant patient resources. In the current study, the authors assessed whether disease-free survival (DFS) can be an early clinical surrogate for OS in the adjuvant setting for localized renal cell carcinoma (RCC). Methods Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, the authors performed a systematic literature review of PubMed and the American Society of Clinical Oncology, European Society for Medical Oncology, and ClinicalTrial.gov Web sites (1996-2016). Inclusion in the current study required randomized controlled trials (RCTs) of adjuvant systemic therapy for localized RCC after nephrectomy with ≥3 years of outcomes data. Data regarding hazard ratios (HRs) and 5-year event-free rates from Kaplan-Meier estimates were extracted. A trial-level meta-analysis correlated estimates of 5-year DFS and 5-year OS as well as treatment effects (HRs) on these endpoints, weighted by the number of DFS events. R-squared ≥ 0.7 was prespecified as being indicative of a strong correlation and the potential for surrogacy. Results Thirteen RCTs encompassing 6473 patients who were treated with a variety of systemic therapies met eligibility. Only a modest correlation was observed between 5-year DFS and 5-year OS rates (R-squared, 0.48; 95% confidence interval, 0.14-0.67) and between treatment effects as measured by DFS and OS HRs (R-squared, 0.44; 95% confidence interval, 0.00-0.69). Conclusions Across RCTs of adjuvant systemic therapy for localized RCC, there was no strong correlation noted between 5-year DFS and 5-year OS rates or between treatment effects on these endpoints. These results highlight the need to identify alternative and more rapid clinical or biologic endpoints to hasten drug development and improve clinical outcomes. Cancer 2018;124:925-33. © 2017 American Cancer Society.

Whole-exome sequencing of cell-free DNA (cfDNA) could enable comprehensive profiling of tumors from blood but the genome-wide concordance between cfDNA and tumor biopsies is uncertain. Here we report ichorCNA, software that quantifies tumor content in cfDNA from 0.1× coverage whole-genome sequencing data without prior knowledge of tumor mutations. We apply ichorCNA to 1439 blood samples from 520 patients with metastatic prostate or breast cancers. In the earliest tested sample for each patient, 34% of patients have ≥10% tumor-derived cfDNA, sufficient for standard coverage whole-exome sequencing. Using whole-exome sequencing, we validate the concordance of clonal somatic mutations (88%), copy number alterations (80%), mutational signatures, and neoantigens between cfDNA and matched tumor biopsies from 41 patients with ≥10% cfDNA tumor content. In summary, we provide methods to identify patients eligible for comprehensive cfDNA profiling, revealing its applicability to many patients, and demonstrate high concordance of cfDNA and metastatic tumor whole-exome sequencing., Identifying the mutational landscape of tumours from cell-free DNA in the blood could help diagnostics in cancer. Here, the authors present ichorCNA, software that quantifies tumour content in cell free DNA, and they demonstrate that cell-free DNA whole-exome sequencing is concordant with metastatic tumour whole-exome sequencing.

In preclinical models, c-Met promotes survival of renal cancer cells through the regulation of programmed death-ligand 1 (PD-L1). However, this relationship in human clear cell renal cell carcinoma (ccRCC) is not well characterized. We evaluated c-Met expression in ccRCC patients using paired primary and metastatic samples and assessed the association with PD-L1 expression and other clinical features. Areas with predominant and highest Fuhrman nuclear grade (FNG) were selected. c-Met expression was evaluated by IHC using an anti-Met monoclonal antibody (MET4 Ab) and calculated by a combined score (CS, 0–300): intensity of c-Met staining (0–3) x % of positive cells (0–100). PD-L1 expression in tumor cells was previously assessed by IHC and PD-L1+ was defined as PD-L1 > 0% positive cells. Our cohort consisted of 45 pairs of primary and metastatic ccRCC samples. Overall, c-Met expression was higher in metastatic sites compared to primary sites (average c-Met CS: 55 vs. 28, p = 0.0003). Higher c-Met expression was associated with higher FNG (4 vs. 3) in primary tumors (average c-Met CS: 52 vs. 20, p = 0.04). c-Met expression was numerically greater in PD-L1+ vs. PD-L1- tumors. Higher c-Met expression in metastatic sites compared to primary tumors suggests that testing for biomarkers of response to c-Met inhibitors should be conducted in metastases. While higher c-Met expression in PD-L1+ tumors requires further investigation, it supports exploring these targets in combination clinical trials.

Given the lack of randomized evidence comparing trimodal therapy (TMT) to radical cystectomy (RC) for muscle-invasive urothelial carcinoma of the bladder (UCB), we performed an observational cohort study to examine the comparative effectiveness of these two definitive treatments. Within the National Cancer Data Base (2004-2011),we identified 1257 (9.8%) and 11 586 (90.2%) patients who received TMT and RC, respectively. Inverse probability of treatment weighting (IPTW)-adjusted Kaplan-Meier analysis showed that median overall survival (OS) was similar between the TMT (40 mo, 95% confidence interval [CI] 34-46) and RC groups (43 mo 95% CI 41-45; p=0.3). In IPTW-adjusted Cox regression analysis with a time-varying covariate, TMT was associated with a significant adverse impact on long-term OS (hazard ratio 1.37, 95% CI 1.16-1.59; p0.001). Interaction terms indicated that the adverse treatment effect of TMT versus RC decreased with age (p=0.004), while there was no significant interaction with gender (p=0.6), Charlson comorbidity index (p=0.09) or cT stage (p=0.8). In conclusion, we found that TMT was generally associated with worse long-term OS compared to RC for muscle-invasive UCB. However, the survival benefit of RC should be weighed against the risks of surgery, especially in older patients. These results are preliminary and emphasize the need for a randomized controlled trial to compare TMT versus RC.We examined the comparative effectiveness of trimodal therapy versus radical cystectomy for muscle-invasive urothelial carcinoma of the bladder. We found that trimodal therapy was generally associated with worse long-term overall survival, although there may be no difference with radical cystectomy in older individuals.

Introduction The 2017 Coffey-Holden Prostate Cancer Academy (CHPCA) Meeting, “Beyond the Androgen Receptor II: New Approaches to Understanding and Treating Metastatic Prostate Cancer,” was held in Carlsbad, California from June 14-17, 2017. Methods The CHPCA is an annual scientific conference hosted by the Prostate Cancer Foundation (PCF) that is uniquely designed to produce extensive and constructive discussions on the most urgent and impactful topics concerning research into the biology and treatment of metastatic prostate cancer. The 2017 CHPCA Meeting was the 5th meeting in this annual series and was attended by 71 investigators focused on prostate cancer and a variety of other fields including breast and ovarian cancer. Results The discussions at the meeting were concentrated on topics areas including: mechanisms and therapeutic approaches for molecular subclasses of castrate resistant prostate cancer (CRPC), the epigenetic landscape of prostate cancer, the role of DNA repair gene mutations, advancing the use of germline genetics in clinical practice, radionuclides for imaging and therapy, advances in molecular imaging, and therapeutic strategies for successful use of immunotherapy in advanced prostate cancer. Discussion This article reviews the presentations and discussions from the 2017 CHPCA Meeting in order to disseminate this knowledge and accelerate new biological understandings and advances in the treatment of patients with metastatic prostate cancer.

In 2017, there is no adjuvant systemic therapy proven to increase overall survival in non-metastatic renal cell carcinoma (RCC). The anti-PD-1 antibody nivolumab improves overall survival in metastatic treatment refractory RCC and is generally tolerable. Mouse solid tumor models have revealed a benefit with a short course of neoadjuvant PD-1 blockade compared to adjuvant therapy. Two ongoing phase 2 studies of perioperative nivolumab in RCC patients have shown preliminary feasibility and safety with no surgical delays or complications. The recently opened PROSPER RCC trial (A Phase 3 RandOmized Study Comparing PERioperative Nivolumab vs. Observation in Patients with Localized Renal Cell Carcinoma Undergoing Nephrectomy; EA8143) will examine if the addition of perioperative nivolumab to radical or partial nephrectomy can improve clinical outcomes in patients with high risk localized and locally advanced RCC. With the goal of increasing cure and recurrence-free survival (RFS) rates in non-metastatic RCC, we are executing a three-pronged, multidisciplinary approach of presurgical priming with nivolumab followed by resection and adjuvant PD-1 blockade. We plan to enroll 766 patients with clinical stage ≥T2 or node positive M0 RCC of any histology in this global, randomized, unblinded, phase 3 National Clinical Trials Network study. The investigational arm will receive two doses of nivolumab 240 mg IV prior to surgery followed by adjuvant nivolumab for 9 months. The control arm will undergo the current standard of care: surgical resection followed by observation. Patients are stratified by clinical T stage, node positivity, and histology. The trial is powered to detect a 14.4% absolute benefit in the primary endpoint of RFS from the ASSURE historical control of 55.8% to 70.2% at 5 years (HR = 0.70). The study is also powered to detect a significant overall survival benefit (HR 0.67). Key safety, feasibility, and quality of life endpoints are incorporated. PROSPER RCC exemplifies team science with a host of planned correlative work to investigate the impact of the baseline immune milieu and changes after neoadjuvant priming on clinical outcomes.

Background Statins compete with DHEAS for influx through the SLCO2B1 transporter, which may prolong time to progression (TTP) on androgen deprivation therapy. Abiraterone acetate (AA) may also undergo SLCO-mediated transport. Based on preclinical findings showing antagonism, we hypothesized that statins may compete with AA for influx via SLCO2B1 and could negatively impact drug efficacy. Methods We queried two institutional clinical databases (Dana-Farber Cancer Institute [DFCI], Johns Hopkins University [JHU]) for CRPC patients treated with AA. Treatment duration was a surrogate for TTP. Associations between statin use and AA duration were estimated using the Kaplan-Meier method. Multivariable Cox regression modeling adjusted for known prognostic factors. Results Of the 224 DFCI and 270 JHU patients included, the majority (96%) had metastatic disease. Nearly half (41% and 45%) were statin users. In the DFCI cohort, there was a trend toward longer AA duration in statin users: 14.2 versus 9.2 months (HR 0.79, 95%CI: 0.57-1.09, P = 0.14). There was no association between statin use and AA duration in the JHU cohort: 8.3 versus 8.0 months (HR 0.89, 95%CI: 0.69-1.16, P = 0.38) in the statin users versus non-users, except for a trend in patients that had not previously received docetaxel or enzalutamide (HR 0.79; 95%CI: 0.57-1.10). Conclusions Contrary to our initial hypothesis, there was a trend toward longer (rather than shorter) AA duration in statin users in the entire DFCI cohort and in the enzalutamide- and docetaxel-naive JHU patients. Together, these results do not support the hypothesis that statins interfere with AA efficacy.

Purpose: The use of large-field external beam reirradiation (re-RT) after pelvic radiation therapy (RT) for genitourinary (GU) cancers has not been reported. We report the results of such treatment in patients with either symptomatic GU second malignant neoplasms or locally recurrent pelvic tumors after initial RT for whom surgery or further systemic therapy was not an option. Methods and materials: The records of 28 consecutive patients with advanced, bulky GU malignancies treated with high-dose, large-field re-RT with palliative intent between 2008 and 2014 were retrospectively reviewed. Descriptive outcome analyses focused on toxicities and symptom control, and responses were evaluated by 2 independent observers. Results: Twenty-seven male patients (96%) were included. Median initial external beam RT dose was 64 Gy (range, 30-75.6 Gy). The median time between initial RT and re-RT was 9.5 years (range, 0.2-32 years). At the time of re-RT, there were 16 local recurrences and 12 second malignant neoplasms together comprising 16 bladder, 10 prostate, 1 ureteral, and 1 penile cancer. Indications for re-RT were pain and bleeding/hemorrhage. The median equivalent sphere diameter planning target volume for re-RT was 8.6 cm (range, 4.7-16.3 cm). Given the severity of the symptoms and the bulk of the disease at the time of re-RT, a higher dose of RT was administered. The median re-RT dose was 50 Gy (range, 27.5-66 Gy). For patients who received

PURPOSE In this multicenter phase II trial, we evaluated atezolizumab combined with bevacizumab in patients with advanced renal cell carcinoma (RCC) with variant histology or any RCC histology with ≥ 20% sarcomatoid differentiation. PATIENTS AND METHODS Eligible patients may have received previous systemic therapy, excluding prior bevacizumab or checkpoint inhibitors. Patients underwent a baseline biopsy and received atezolizumab 1,200 mg and bevacizumab 15 mg/kg intravenously every 3 weeks. The primary end point was overall response rate (ORR) by RECIST version 1.1. Additional end points were progression-free survival (PFS), toxicity, biomarkers of response as determined by programmed death-ligand 1 (PD-L1) status, and on-therapy quality-of-life (QOL) metrics using the Functional Assessment of Cancer Therapy Kidney Symptom Index-19 and the Brief Fatigue Inventory. RESULTS Sixty patients received at least 1 dose of either study agent; the majority (65%) were treatment naïve. The ORR for the overall population was 33% and 50% in patients with clear cell RCC with sarcomatoid differentiation and 26% in patients with variant histology RCC. Median PFS was 8.3 months (95% CI, 5.7 to 10.9 months). PD-L1 status was available for 36 patients; 15 (42%) had ≥ 1% expression on tumor cells. ORR in PD-L1–positive patients was 60% (n = 9) v 19% (n = 4) in PD-L1–negative patients. Eight patients (13%) developed treatment-related grade 3 toxicities. There were no treatment-related grade 4-5 toxicities. QOL was maintained throughout therapy. CONCLUSION In this study, atezolizumab and bevacizumab demonstrated safety and resulted in objective responses in patients with variant histology RCC or RCC with ≥ 20% sarcomatoid differentiation. This regimen warrants additional exploration in patients with rare RCC, particularly those with PD-L1–positive tumors.

PURPOSE Patients with locally advanced prostate cancer have an increased risk of cancer recurrence and mortality. In this phase II trial, we evaluate neoadjuvant enzalutamide and leuprolide (EL) with or without abiraterone and prednisone (ELAP) before radical prostatectomy (RP) in men with locally advanced prostate cancer. PATIENTS AND METHODS Eligible patients had a biopsy Gleason score of 4 + 3 = 7 or greater, prostate-specific antigen (PSA) greater than 20 ng/mL, or T3 disease (by prostate magnetic resonance imaging). Lymph nodes were required to be smaller than 20 mm. Patients were randomly assigned 2:1 to ELAP or EL for 24 weeks followed by RP. All specimens underwent central pathology review. The primary end point was pathologic complete response or minimal residual disease (residual tumor ≤ 5 mm). Secondary end points were PSA, surgical staging, positive margins, and safety. Biomarkers associated with pathologic outcomes were explored. RESULTS Seventy-five patients were enrolled at four centers. Most patients had high-risk disease by National Comprehensive Cancer Network criteria (n = 65; 87%). The pathologic complete response or minimal residual disease rate was 30% (n = 15 of 50) in ELAP-treated patients and 16% (n = four of 25) in EL-treated patients (two-sided P = .263). Rates of ypT3 disease, positive margins, and positive lymph nodes were similar between arms. Treatment was well-tolerated. Residual tumors in the two arms showed comparable levels of ERG, PTEN, androgen receptor PSA, and glucocorticoid receptor expression. Tumor ERG positivity and PTEN loss were associated with more extensive residual tumors at RP. CONCLUSION Neoadjuvant hormone therapy followed by RP in locally advanced prostate cancer resulted in favorable pathologic responses in some patients, with a trend toward improved pathologic outcomes with ELAP. Longer follow-up is necessary to evaluate the impact of therapy on recurrence rates. The potential association of ERG and PTEN alterations with worse outcomes warrants additional investigation.

The availability of new potent systemic therapies for urothelial carcinoma may change the way we use standard chemotherapy perioperatively. In particular, identifying which patients with muscle-invasive bladder cancer (MIBC) would benefit from adjuvant chemotherapy (AC) is compelling. From a multicenter database we selected 950 patients with cT2–4N0M0 MIBC treated with radical cystectomy (RC), with or without neoadjuvant chemotherapy (NAC), and AC. We used Kaplan-Meier analyses to test 1-yr recurrence-free survival (RFS) rates according to AC use. Nomogram-derived probabilities of 1-yr recurrence after RC were plotted against actual recurrence rates according to AC use. Overall, we did not see evidence of an AC effect on the 1-yr RFS rate (p = 0.6). Conversely, the 1-yr RFS rate was higher among patients with pT3–4 or pN1 disease who received AC (75% vs 54%; p < 0.001). We were unable to demonstrate a difference between AC and no AC among patients who received prior NAC (1-yr RFS 57% vs 76%; p = 0.057). As the most important finding, AC was associated with incremental RFS benefits only for patients with a nomogram-derived 1-yr recurrence probability of >40%. Patient summary: Maximizing disease control with adjuvant chemotherapy was beneficial for patients with muscle-invasive bladder cancer who had a calculated recurrence risk of >40% and did not impact cancer recurrence in lower-risk disease. Therefore, patient stratification using the nomogram available for predicting recurrence is advisable pending external validation.

Background Antibiotic use alters commensal gut microbiota, which is a key regulator of immune homeostasis. Objective To investigate the impact of antibiotic use on clinical outcomes in metastatic renal cell carcinoma (mRCC) patients treated with systemic agents. Design, setting, and participants We analyzed two cohorts: an institutional cohort (n = 146) receiving programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1)-based immune checkpoint inhibitors (ICIs) and a trial-database cohort (n = 4144) receiving interferon-α (n = 510), mammalian target of rapamycin (mTOR) inhibitors (n = 660), and vascular endothelial growth factor targeted therapies (VEGF-TT; n = 2974) on phase II/III clinical trials. Outcomes measurements and statistical analysis The association of antibiotic use (defined as use from 8 wk before to 4 wk after the initiation of anticancer therapy) with progression-free survival (PFS) and overall survival (OS) was evaluated using Cox regression, adjusted for known prognostic factors including International Metastatic RCC Database Consortium risk factors. Results and limitations Most patients were male, had clear cell histology, and were at an intermediate risk. Overall, in the institutional cohort, objective response rate (ORR) was 30%, PFS was 7.2 mo, and 1-yr OS was 77%. Antibiotic users (n = 31, 21%) had a lower ORR (12.9% vs 34.8%, p = 0.026) and shorter PFS (adjusted hazard ratio [HR] = 1.96, 95% confidence interval [CI] 1.20–3.20, p = 0.007) than antibiotic nonusers. In the trial-database cohort, antibiotic use (n = 709, 17%) adversely impacted OS in patients treated with interferon (HR = 1.62, 95% CI 1.13–2.31, p = 0.008) or with VEGF-TT and prior cytokines (HR = 1.65, 95% CI 1.04–2.62, p = 0.033), but not patients treated with mTOR inhibitors or VEGF-TT without prior cytokines. Limitations include retrospective design, and limited details regarding concomitant medications and antibiotic indication/duration. Conclusions Antibiotic use appears to reduce the efficacy of immunotherapy-based regimens in mRCC. The modulation of gut microbiota may play an important role in optimizing outcomes of patients treated with ICIs. Patient summary We evaluated metastatic renal cell carcinoma patients and found that those who were treated with immunotherapy had worse outcomes if they also received antibiotics at the start of treatment. This study highlights the importance of judicious antibiotic use.

Adjuvant therapy for non-metastatic renal cell carcinoma (RCC) remains controversial. Of the four reported randomized controlled trials evaluating adjuvant vascular endothelial growth factor (VEGF) inhibition, only one met its primary endpoint. The S-TRAC study demonstrated a statistically significant improvement in disease-free survival (DFS) of greater than 1 year with adjuvant sunitinib compared to placebo in patients with high-risk localized RCC and earned it FDA approval. However, the larger ASSURE study which reported first did not find a difference in DFS or overall survival between 1 year of adjuvant sunitinib or sorafenib compared to placebo. Given the discordant results of the two sunitinib studies, two other negative studies of adjuvant targeted therapy with pazopanib and axitinib, the lack of definite overall survival benefit in any study, and the high incidence of treatment-related adverse events with sunitinib, we do not recommend the routine use of adjuvant sunitinib. The decision to offer adjuvant sunitinib should be considered on an individual basis after an informed discussion of the potential toxicities and the risk/benefit ratio. Despite numerous efforts and recently published works, there is a paucity of prognostic and predictive molecular biomarkers in RCC. Further investigation is needed to discover new tools that can enhance the identification of patients who are most likely to benefit from adjuvant treatment beyond pathologic stage. Immune checkpoint inhibitors have great potential to significantly improve outcomes in high-risk localized RCC. Building on their established efficacy in the metastatic setting, several ongoing clinical trials are evaluating their value as single agents or in combination in the neoadjuvant and adjuvant settings. At this time, we recommend participation in clinical trials as the preferred therapeutic option for patients with high-risk, non-metastatic RCC planned for nephrectomy.

Patients with high-risk renal cell carcinoma (RCC) experience high rates of recurrence despite definitive surgical resection. Recent trials of adjuvant tyrosine kinase inhibitor therapy have provided conflicting efficacy results at the cost of significant adverse events. PD-1 blockade via monoclonal antibodies has emerged as an effective disease-modifying treatment for metastatic RCC. There is emerging data across other solid tumors of the potential efficacy of neoadjuvant PD-1 blockade, and preclinical evidence supporting a neoadjuvant over adjuvant approach. PROSPER RCC is a Phase III, randomized trial evaluating whether perioperative nivolumab increases recurrence-free survival in patients with high-risk RCC undergoing nephrectomy. The neoadjuvant component, intended to prime the immune system for enhanced efficacy, distinguishes PROSPER from other purely adjuvant studies and permits highly clinically relevant translational studies.

Background: Limited data is available on the role, and extent of, postchemotherapy lymphadenectomy (PC-LND) in patients with clinical evidence of pelvic (cN1-3) or retroperitoneal (RP) lymph node spread from urothelial bladder carcinoma. Objective: To compare the outcomes of operated versus nonoperated patients after first-line chemotherapy. Design, setting, and participants: Data from 34 centers was collected, totaling 522 patients, treated between January 2000 and June 2015. Criteria for patient selection were the following: bladder primary tumor, lymph node metastases (pelvic. ±. RP) only, first-line platinum-based chemotherapy given. Intervention: LND (with cystectomy) versus observation after first-line chemotherapy for metastatic urothelial bladder carcinoma. Outcome measures and statistical analysis: Overall survival (OS) was the primary endpoint. Multiple propensity score techniques were adopted, including 1:1 propensity score matching and inverse probability of treatment weighting. Additionally, the inverse probability of treatment weighting analysis was performed with the inclusion of the covariates, that is, with doubly robust estimation. Results and limitations: Overall, 242 (46.4%) patients received PC-LND and 280 (53.6%) observation after chemotherapy. There were 177 (33.9%) and 345 (66.1%) patients with either RP or pelvic LND only, respectively. Doubly robust estimation-adjusted comparison was not significant for improved OS for PC-LND (hazard ratio [HR]: 0.86, 95% confidence interval [CI]: 0.56-1.31, p = 0.479), confirmed by matched analysis (HR: 0.91, 95% CI: 0.60-1.36, p = 0.628). This was also observed in the RP subgroup (HR: 1.12, 95% CI: 0.68-1.84). The retrospective nature of the data and the heterogeneous patient population were the major limitations. Conclusions: Although there were substantial differences between the two groups, after accounting for major confounders we report a nonsignificant OS difference with PC-LND compared with observation only. These findings may be hypothesis-generating for future prospective trials. Patient summary: We found no differences in survival by adding postchemotherapy lymphadenectomy in patients with pelvic or retroperitoneal lymph node metastatic bladder cancer. The indication to perform postchemotherapy lymphadenectomy in the most suitable patients requires additional studies. In contemporary cohorts of patients with metastatic pelvic or retroperitoneal lymph nodes from bladder cancer, we found no survival benefit from postchemotherapy surgery versus observation in a retrospective study. Performing postchemotherapy lymphadenectomy remains investigational in patients with metastatic bladder cancer.

Background The impact of cisplatin use on long-term survival of unselected patients with advanced urinary tract cancer (aUTC) has not been adequately investigated. We used a multinational database to study long-term survival and the impact of treatment type in unselected patients with aUTC. Materials and Methods A total of 1,333 patients with aUTC (cT4bN0M0, cTanyN+M0, cTanyNanyM+), transitional-cell, squamous, or adenocarcinoma histology who received systemic chemotherapy and had available survival data were selected. Long-term survival was defined as alive at 3 years following initiation of first-line chemotherapy. Conditional overall survival (COS) analysis was employed to study change in prognosis given time survived from initiation of first-line chemotherapy. Results Median follow-up was 31.7 months. The combination of cisplatin use and cisplatin eligibility accurately predicted long-term survival. Eligible patients treated with cisplatin conferred a 31.6% probability of 3-year survival (95% confidence interval [CI]: 25.1–38.3), and 2-year COS for patients surviving 3 years after initiation of cisplatin-based chemotherapy was 83% (95% CI: 59.7–93.5). The respective probabilities for patients who were ineligible for cisplatin or not treated with cisplatin despite eligibility were 14% (95% CI: 10.8–17.6) and 49.3% (95% CI: 28.2–67.4). Two-year COS remained significantly different between these two groups up to 3 years after chemotherapy initiation. Conclusion Cisplatin-based therapy was associated with the highest likelihood of long-term survival in patients with aUTC and should be used in patients who fulfill the established eligibility criteria. Novel therapies are necessary to increase long-term survival in cisplatin-ineligible patients. Implications for Practice Long-term, disease-free survival is possible in one in four eligible-for-cisplatin patients with advanced urinary tract cancer (aUTC) treated with cisplatin-based combination chemotherapy. Therefore, deviations from eligibility criteria should be avoided. Consolidation surgery should be considered in responders. These data provide benchmarks for the study of novel therapies in aUTC.

Background: Little is known about the outcomes of robot-assisted radical cystectomy (RARC) compared to open radical cystectomy (ORC) combined with perioperative chemotherapy for muscle-invasive urothelial bladder cancer (UBC). Objective: To evaluate surgical and oncological outcomes for RARC and ORC in multimodal treatment. Design, setting, and participants: Data from 28 centres were collected for cystectomies performed between January 2000 and July 2013. Intervention: RARC or ORC combined with perioperative chemotherapy for UBC. Outcome measures and statistical analysis: Fisher's exact tests, χ2 tests, and Wilcoxon rank-sum tests were used to compare the RARC and ORC groups. Logistic and Cox regression analyses were performed to evaluate potential prognostic factors. Results and limitations: A total of 688 patients (n = 603 ORC and n = 85 RARC) were analysed; 60.6% received neoadjuvant chemotherapy, and 45.1% adjuvant chemotherapy. No significant differences in baseline characteristics were found between the groups. The median time from surgery to adjuvant chemotherapy was 1.9 mo for both RARC and ORC groups. The median number of lymph nodes removed was 21 (interquartile range [IQR] 14-35) for RARC and 13 (IQR 8-21) for ORC (p< 0.001); the results were confirmed in subgroup analyses. Multivariable analyses revealed no difference in the rate of positive surgical margins (p = 0.54 and p = 0.78), rate of neobladder diversion (p = 0.33 and p = 0.51), relapse-free survival (p = 0.31 and p = 0.23), and overall survival (p = 0.63 and p = 0.69). The retrospective nature of the data is the major limitation. Conclusions: In this study, no differences in efficacy outcomes or ability to deliver adjuvant chemotherapy were observed between RARC and ORC. The increasing use of RARC is justifiable from an oncological viewpoint. Patient summary: In a retrospective study of patients who received perioperative chemotherapy for urothelial bladder cancer, we found no difference in key outcomes between robot-assisted radical cystectomy (RARC) and open radical cystectomy. Performing RARC seems to be justifiable in the multidisciplinary setting. In contemporary cohorts of patients who have received perioperative chemotherapy for muscle-invasive bladder cancer, no substantial differences were found between robot-assited radical cystectomy (RARC) and open radical cystectomy, and the number of lymph nodes removed was higher with RARC.

310 Background: Cabo shows robust clinical activity in mRCC. Patients (pts) with BM have been underrepresented in clinical trials and effective systemic therapy is lacking. We retrospectively characterized the clinical activity and toxicity of cabo in pts with BM from RCC. Methods: Consecutive medical records from mRCC pts with BM treated with cabo monotherapy across 15 institutions were reviewed. Pts were grouped by radiologic presence (cohort 1) or absence (cohort 2) of progressing intracranial metastases. Brain-directed local therapy was allowed but radiological confirmation of intracranial progression at cabo start was required in cohort 1. Radiological response rate was investigator-assessed by modified RECIST 1.1 for intracranial and RECIST 1.1 for extracranial responses. Time to treatment failure (TTF) and overall survival (OS) were estimated by Kaplan-Meier. Results: We identified 69 pts with BM from RCC, 25 (36%) in cohort 1 and 44 (64%) in cohort 2. Majority were IMDC intermediate/poor (87%) and received cabo as ≥2nd line (75%). Median time from mRCC diagnosis to BM was 19.1 months (mos) (IQR 4.4-39.5). Overall, median number of BM was 3 (range 1-27) and median size of largest lesion was 1.2 cm (range 0.2-6.6) with frontal (62%) and parietal (48%) as the most frequent localizations. Prior brain directed therapy was used in 65% and 93% of pts in cohort 1 and 2 respectively. Median follow-up after cabo initiation was 11 mos (range 4-72). Twenty three percent of pts remained on therapy while 52% discontinued for progression and 9% for toxicity. Intracranial response rate was 61% (95%CI 39%-80%), with 3 complete responses, for cohort 1 and 57% (95%CI 41%-72%) for cohort 2. Only 10% (n = 7) had intracranial progression as best response. For cohort 1, extracranial response was 52% (95%CI 31%-72%), median TTF was 9.9 mos (95%CI 5.9-14.0) and OS was 14.7 mos (95%CI 7.7-23.0). For cohort 2, extracranial response was 41% (95%CI 26%-57%), TTF was 9.0 mos (95%CI 4.6-11.4) and OS was 14.1 mos (95%CI 11.0-22.0). Most common adverse events were fatigue (77%) and diarrhea (46%). Eight pts received concomitant brain-directed treatment during cabo therapy without neurological toxicities. Conclusions: Cabo shows significant intracranial activity and acceptable safety profile in pts with BM from RCC. [Table: see text]

BACKGROUND: Trials of adjuvant chemotherapy following radical cystectomy generally require chemotherapy to start within 90 days postoperatively. However, it is unclear, whether the interval between surgery and start of adjuvant therapy (S-AC-interval) impacts the oncological outcome.METHODS: Using the Retrospective International Study of Invasive/Advanced Cancer of the Urothelium (RISC) data base, we identified patients who underwent radical cystectomy for muscle invasive bladder cancer and subsequent adjuvant chemotherapy. Univariate analysis of patient characteristics, surgical factors and tumor characteristics regarding their impact on S-AC-interval was performed using Kruskal-Wallis testing and Fisher's exact test. Analysis of progression-free (PFS) and overall survival (OS) (follow-up time beginning with the start date of adjuvant chemotherapy) was analyzed in relation to S-AC-interval (continuous and dichotomous with a cut-off at 90 days) using Kaplan-Meier method and COX regression analysis.RESULTS: We identified 238 eligible patients (83.5% male, mean age: 63.4 years, 76.1% T3/T4, 66.4% pN+, 14.7% R+, 70.6% urothelial carcinoma, 71% cisplatin-based adjuvant chemotherapy). The majority of patients (n = 207, 87%) started chemotherapy within 90 days after surgery. Median S-AC-interval was 57 days (interquartile range 32.8). S-AC-interval did not have consistent association with any patient/tumor characteristics or surgery related factors (type of surgery, urinary diversion). Survival analysis using continuous S-AC-interval revealed a trend toward an impact of S-AC-interval on OS (hazard ratio 1.004, 95% confidence ratio 0.9997-1.0084, P = 0.071). With regards to PFS, that impact was shown to be statistically significant (hazard ratio 1.004, 95% confidence ratio 1.0003-1.0075, P = 0.032). In multivariate analysis, however, S-AC-interval was negated by tumor and patient related factors (pathological T-stage, N-stage, ECOG performance status). Accounting for eligibility criteria defined in some clinical trials, we extended our analysis dividing S-AC-interval in ≤90 and >90 days. Although we could confirm the trend toward better outcome in patients with a shorter S-AC interval in dichotomous analysis, neither differences in OS nor in PFS reached statistical significance (P = 0.438 and P = 0.056).CONCLUSIONS: In a large multi-institutional experience, 87% of patients who received adjuvant chemotherapy received it within the guideline recommended window of 90 days. While it was not possible to determine whether this is the optimal cut-off, early start of adjuvant chemotherapy seems to be reasonable. Regarding prognosis, tumor-related pathological factors abrogated the importance of the S-AC-interval in our analysis.

Background: Trimodality bladder preservation therapy (BPT) in muscle invasive bladder cancer (MIBC) includes a maximal transurethral resection followed by concurrent chemoradiotherapy as an alternative to radical cystectomy (RC) in appropriately selected patients, or as a treatment option in non-cystectomy candidates. Several chemotherapy regimens can be used in BPT, but little is known about current practice patterns. Objective: To describe utilization patterns of BPT and associated survival outcomes in MIBC. Methods: Data were collected from the Retrospective International Study of Cancers of the Urothelial Tract (RISC), a database of 3,024 consecutive patients from 29 international academic centers from 2005 to 2013. Patients with clinical T2-T4aN0M0 urothelial cancer of the bladder were included. Results: 265 patients received BPT. Compared with the 1,447 patients who received RC, BPT patients were older, had poorer performance status, and had more comorbidities (p

We evaluated the incidence and predictors of the use of long-term (2-3 years) versus shorter term androgen deprivation therapy (ADT) in radiation-managed men with high-risk prostate cancer.We identified 302 patients from the Dana-Farber Cancer Institute patient registry who had been diagnosed with high-risk prostate cancer (T3a or prostate-specific antigen [PSA]20 ng/mL or Gleason score 8-10) from 1993 to 2015. We assessed the intended duration of ADT and used multivariable Cox regression to evaluate the predictors of receiving a shorter course of ADT than recommended by the guidelines (2 years).The course of ADT intended by physicians increased after the 2008/2009 publication of trials showing the superiority of long-term versus short-term ADT, with 43.5% intending ≥ 2 years before versus 61.4% after (P = .014). Starting in 2010, 49.4% of patients actually received 2 years of ADT. The most common reasons for receipt of shorter course ADT were intolerance of ADT side effects, patient comorbidity/age, the presence of T3a on magnetic resonance imaging only as the sole high-risk feature, or participation in a clinical trial. Moderate to severe comorbidity assessed using the Adult Comorbidity Evaluation-27 (adjusted hazard ratio [AHR] = 2.94), Gleason score 8 (AHR = 5.66), and PSA 20 ng/mL (AHR = 4.19) all predicted for receipt of shorter course ADT (P .05 for all).In a tertiary-care setting, the rates of long-course ADT for high-risk disease have increased since the 2008/2009 trials supporting its use. However, approximately one half of patients continued to receive shorter course ADT, often because of intolerance of side effects, underlying comorbidity, or physician judgment about the aggressiveness of the disease.

Background The phosphatidylinositol-3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is dysregulated in patients with metastatic renal cell carcinoma (mRCC). Buparlisib is a pan-PI3K inhibitor with activity in advanced solid tumors. The primary objective of the current study was to determine the maximum tolerated dose (MTD) and dose-limiting toxicities of buparlisib and bevacizumab in patients with mRCC. Secondary objectives included efficacy, biomarker discovery, and additional toxicity. Methods This was a standard 3 + 3 dose escalation study of buparlisib (at a dose of 60-100 mg/day) and bevacizumab (at a dose of 10 mg/kg every 2 weeks). After the MTD was defined, 15 patients were accrued to the expansion cohort. Results Thirty-two patients were accrued (3 were treated at 60 mg/day, 21 were treated at 80 mg/day, 6 were treated at 100 mg/day, and 2 patients never received therapy). The majority of patients had clear cell histology (87%) and 50% had received ≥2 prior lines of therapy. The MTD of buparlisib was 80 mg/day and that of bevacizumab was 10 mg/kg every 2 weeks. A total of 28 patients discontinued therapy: 17 because of disease progression, 7 because of toxicity, and 4 for other reasons. Dose-limiting toxicities included rash/pruritis, elevated lipase/amylase, anorexia, and psychiatric disorders (suicidal ideation, depression, and cognitive disturbances). Of the 30 patients who received at least 1 dose, 13% achieved a partial response (95% confidence interval, 4%-31%). Two patients harboring activating PI3KA mutations achieved 42% and 16% maximal tumor shrinkage, respectively. Conclusions Buparlisib at a dose of 80 mg/day with bevacizumab was found to be a tolerable regimen with preliminary activity in vascular endothelial growth factor-refractory mRCC. The benefit of this combination may be of interest for future mRCC trials, possibly in a selected patient population. Cancer 2016;122:2389-2398. © 2016 American Cancer Society.

5005 Background: Nivo + Ipi is an established first-line treatment (tx) for advanced RCC. We hypothesized that the addition of CTLA-4 blockade may not be required for all patients (pts). Furthermore, the optimal duration of Nivo maintenance in responding pts is unknown. In this phase II response-adaptive trial, we investigate the sequential addition of 2 doses of Ipi to induce response in Nivo non-responders (NR) and duration of Nivo in responding pts (NCT03203473). Methods: We enrolled pts with advanced RCC with no prior checkpoint inhibitor exposure. All pts received Nivo alone with subsequent arm allocation based on RECISTv1.1 response within 6 months (mos) of tx. Pts with a confirmed partial response (PR) or complete response (CR) within 6 months (mos) discontinued Nivo and were observed (Arm A). Arm A pts reinitiated Nivo if they developed progressive disease (PD); Ipi was added to Nivo if PD persisted or recurred. Pts with stable disease (SD) or PD after no more than 6 mos of Nivo alone received 2 doses of Ipi (Arm B). The primary endpoints were the proportion with PR/CR at 1-year (yr) after Nivo discontinuation (Arm A) and proportion of Nivo NR who convert to PR/CR after adding Ipi (Arm B). Results: 83 pts initiated tx of whom 99% had ECOG 0-1, 96% clear cell RCC, 51% tx-naïve, and 69% IMDC intermediate/poor risk. Median follow-up was 17.0 mos. 15 pts were not allocated to an arm [7 withdrew for PD, 7 withdrew for toxicity, 1 still on tx with unconfirmed PR (uPR)]. At 6 mos, induction Nivo resulted in a confirmed PR in 11% of pts (n=9/83): 12% (n=5/42) tx-naïve, 10% (4/41) prior tx, 8% (n=1/13) favorable risk, 11% (n=8/70) intermediate/poor risk (Table). 11 pts (13%: 9 PR, 1 uPR, 1 SD) were allocated to Arm A, of whom 5 (45%, 90% CI 20-73%) remained off Nivo at ≥ 1 yr. Of 57 pts (69%) allocated to Arm B, 2 pts converted to a PR (4%, 90% CI 1-11%), both of whom had prior tx and PD as best response to Nivo alone. Grade 3-4 treatment related adverse events (TrAE) occurred in 7% (n=6/83) on induction Nivo and in 23% (n=13/57) on Arm B (Nivo + Ipi). Conclusions: We cannot currently recommend a strategy of Nivo followed by response-based addition of Ipi due to the absence of CR and low PR/CR conversion rate (4%). Though a subset of pts treated with Nivo alone can maintain durable responses off tx at 1-yr, early Nivo discontinuation in the absence of toxicity cannot currently be recommended. Investigation into biomarkers to guide tx is ongoing. Clinical trial information: NCT03203473 . [Table: see text]

BackgroundImmune checkpoint inhibitors (ICIs) are associated with immune-related adverse events (irAEs). Although the incidence and prevalence of irAEs have been well characterized in the literature, less is known about the cumulative incidence rate of irAEs. We studied the cumulative incidence of irAEs, defined as the probability of irAE occurrence over time and the risk factors for irAE development in metastatic urothelial carcinoma (mUC) and renal cell carcinoma (mRCC) patients treated with ICIs.MethodsWe identified a cohort of patients who received ICIs for mUC and mRCC. irAEs were classified using Common Terminology Criteria for Adverse Event (CTCAE) V.5.0 guidelines. The monthly incidence of irAEs over time was reported after landmark duration of therapy. Cumulative incidence of irAEs was calculated to evaluate the time to the first occurrence of an irAE accounting for the competing risk of death. Prognostic factors for irAE were assessed using the Fine and Gray method.ResultsA total of 470 patients were treated with ICIs between July 2013 and October 2018 (mUC: 199 (42.3%); mRCC: 271 (57.7%)). 341 (72.6%) patients received monotherapy, 86 (18.3%) received ICIs in combination with targeted therapies, and 43 (9.2%) received dual ICI therapy. Overall, 186 patients (39.5%) experienced an irAE at any time point. Common irAEs included hypothyroidism (n=42, 22.6%), rush and pruritus (n=36, 19.4%), diarrhea/colitis (n=35, 18.8%), transaminitis (n=32, 17.2%), and pneumonitis (n=14, 7.5%). Monthly incidence rates decreased over time; however, 17 of 109 (15.6%, 95% CI: 9.4% to 23.8%) experienced their first irAE at least 1 year after treatment initiation. No differences in cumulative incidence were observed based on cancer type, agent, or irAE grade. On multivariable analysis, combined ICI therapy with another ICI or with targeted therapy (pConclusionsThis study quantitates the incidence of developing irAEs due to ICI conditioned on time elapsed without irAE development. Although the monthly incidence of irAEs decreased over time on therapy, patients can still develop delayed irAEs beyond ICI discontinuation, and thus, continuous vigilant monitoring is warranted.

171 Background: IL-8 (CXCL-8) is a cytokine produced by leukocytes and tumor cells, which promotes inflammation, angiogenesis, anti-apoptosis, and metastasis. Our published training set identified serum IL-8 levels drawn within 28 days of androgen deprivation therapy (ADT) initiation as prognostic for shorter overall survival (OS). We sought to validate this finding using samples from CHAARTED patients treated with ADT +/- docetaxel for mHSPC. Methods: We assayed serum samples drawn ≤28 days from ADT initiation from 233 patients using the same Mesoscale multiplex ELISA assay as the training set. Multivariable Cox proportional hazards models adjusted for ECOG performance status, disease volume, and prior local therapy (radiation/prostatectomy vs. none) with IL-8 as continuous and binary variables. The training median 9.3 pg/mL was the a priori binary cutpoint. Fixed-effects meta-analysis of the training and validation sets was performed. Results: Higher IL-8 levels were prognostic for shorter OS and time to CRPC for ADT alone and ADT + docetaxel (Table) and were independent of disease volume or docetaxel use. Meta-analysis of binary IL-8 levels >9.3pg/mL from patients treated with ADT alone (training + validation cohorts) was prognostic for poorer OS (HR 1.8, 95% CI: 1.2-2.7, p= 0.007) and shorter time to CRPC (HR: 1.4, 95%CI: 0.99-1.9, p=0.057). The validation cohort’s baseline median IL-8 level was similar at 10 pg/mL. Conclusions: Higher IL-8 is prognostic for shorter time to CRPC and OS independent of docetaxel use, disease volume and presentation with metachronous or de novo metastatic disease. These findings support targeting IL-8 as a strategy to improve mHSPC outcomes.[Table: see text]

Tumor content in circulating cell-free DNA (cfDNA) is a promising biomarker, but longitudinal dynamics of tumor-derived and non-tumor-derived cfDNA through multiple courses of therapy have not been well described.CfDNA from 663 plasma samples from 140 patients with castration-resistant prostate cancer (CRPC) was subject to sparse whole genome sequencing. Tumor fraction (TFx) estimated using the computational tool ichorCNA was correlated with clinical features and responses to therapy.TFx associated with the number of bone metastases (median TFx = 0.014 with no bone metastases, 0.047 with 1-3 bone metastases, 0.190 for 4+ bone metastases; P0.0001) and with visceral metastases (P0.0001). In multivariable analysis, TFx remained associated with metastasis location (P = 0.042); TFx was positively correlated with alkaline phosphatase (P = 0.0227) and negatively correlated with hemoglobin (Hgb) (P0.001), but it was not correlated with prostate specific antigen (PSA) (P = 0.75). Tumor-derived and non-tumor-derived cfDNA track together and do not increase with generalized tissue damage from chemotherapy or radiation at the time scales examined. All new treatments that led to ≥30% PSA decline at 6 weeks were associated with TFx decline when baseline TFx was7%; however, TFx in patients being subsequently maintained on secondary hormonal therapy was quite dynamic.TFx correlates with clinical features associated with overall survival in CRPC, and TFx decline is a promising biomarker for initial therapeutic response.Dana-Farber/Harvard Cancer Center (DF/HCC) protocol no. 18-135.Wong Family Award in Translational Oncology, Dana Farber Cancer Institute Medical Oncology grant, Gerstner Family Foundation, Janssen Pharmaceuticals Inc., and Koch Institute Support (core) grant P30-CA14051 from the National Cancer Institute (NCI).

Purpose Data revealed the benefit of high-volume care in many complex disease processes. Among patients undergoing nephrectomy, those receiving cytoreductive nephrectomy (CN) for metastatic renal cell cancer (mRCC) constitute a unique subset. They often have a greater medical and surgical complexity. Against this backdrop, we sought to investigate the effect of hospital volume on overall survival among patients undergoing CN for mRCC. Material and methods We identified 11,089 patients who received CN for mRCC in the National Cancer Database from 1998 to 2012. We ranked hospitals based on annual CN volume. Patients who received surgery in hospitals in the top vs. bottom deciles were compared. Inverse Probability of Treatment Weighting (IPTW)-adjusted Kaplan-Meier and Cox regression analyses were used to compare the primary endpoint of overall survival between balanced cohorts of patients. Secondary endpoints were 30-day mortality, 30-day readmissions, and receipt of subsequent systemic therapy. Results Median follow-up was 60.39 months (interquartile range [IQR] 35.09–95.95). Median overall survival was 17.61 months (IQR 7.16–44.58). Following propensity score weighting, surgery at a high-volume hospital was associated with a decreased risk of mortality (IPTW-adjusted Cox proportional Hazard Ratio = 0.91; 95% confidence interval: 0.86–0.96). On our IPTW-adjusted Kaplan-Meier analysis, the median survival was 19.94 months (IQR 7.98–50.27) at high-volume hospitals vs. 15.97 months (IQR 6.6–41.56) at low-volume hospitals. With regard to secondary endpoints, the data did not reveal a significant advantage for treatment at a high-volume hospital. Conclusion We found a significant association between receipt of CN at high-volume hospitals and prolonged overall survival, demonstrated by a nearly 4 month survival benefit.

Background: Currently, there is no universally accepted prognostic classification for patients (pts) with metastatic hormone sensitive prostate cancer (mHSPC) treated with androgen deprivation therapy (ADT). Subgroup analyses demonstrated that pts with low volume (LV), per CHAARTED trial definition, mHSPC, and those who relapse after prior local therapy (PLT) have longer overall survival (OS) compared to high volume (HV) and de-novo (DN), respectively. Using a hospital-based registry, we aimed to assess whether a classification based on time of metastatic disease (PLT vs DN) and disease volume (LV vs HV) are prognostic for mHSPC pts treated with ADT. Methods: A retrospective cohort of consecutive patients with mHSPC treated with ADT between 1990 and 2013 was selected from the prospectively collected Dana-Farber Cancer Institute database and categorized as DN or PLT and HV or LV, at time of ADT start. Primary and secondary endpoints were OS and time to castration-resistant prostate cancer (CRPC), respectively, which were measured from date of ADT start using Kaplan-Meier method. Multivariable Cox proportional hazards models using known prognostic factors was used. Results: The analytical cohort consisted of 436 patients. The median OS and time to CRPC for PLT/LV were 92.4 (95%CI: 80.4-127.2) and 25.6 (95%CI: 21-35.7) months and 43.2 (95%CI: 37.2-56.4) and 12.2 (95%CI: 9.8-14.8) months for DN/HV, respectively, whereas intermediate values were observed for PLT/HV and DN/LV. A robust gradient for both outcomes was observed (Trend test P < 0.0001) in the four groups. In a multivariable analysis, DN presentation, HV, and cancer-related pain were independent prognostic factors. Conclusions: In our hospital-based registry, time of metastatic presentation and disease volume were prognostic for mHSPC pts treated with ADT. This simple prognostic classification system can aid patient counseling and future trial design.