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Purpose: Immune checkpoint inhibitors (ICI) have revolutionized the treatment of patients with clear-cell renal cell carcinomas (ccRCC). Although analyses of transcriptome, genetic alterations, and the tumor microenvironment (TME) have shed light into mechanisms of response and resistance to these agents, the role of epigenetic alterations in this process remains fully unknown. Experimental Design: We investigated the methylome of six ccRCC cohorts as well as one cell line dataset. Of note, we took advantage of the BIONIKK trial aiming to tailor treatments according to Paris Descartes 4-gene expression subgroups, and performed Illumina EPIC profiling for 46 samples related to patients treated with ipilimumab plus nivolumab, and 17 samples related to patients treated with sunitinib. Results: A group of tumors associated with enhancer demethylation was discovered, namely TED. TED was associated with tumors with sarcomatoid differentiation and poor clinical outcome. TED harbored TET1 promoter demethylation, activated the gene expression signature of epithelial–mesenchymal transition and IL6/JAK/STAT3 pathways, and displayed a TME characterized by both immune activation and suppressive populations, fibroblast infiltration, and endothelial depletion. In addition, TED was a predictive factor of resistance to the combination of first-line ipilimumab-nivolumab in the BIONIKK clinical trial. Finally, TED was associated with activation of specific regulons, which we also found to be predictive of resistance to immunotherapy in an independent cohort. Conclusions: We report on the discovery of a novel epigenetic phenotype associated with resistance to ICIs that may pave the way to better personalizing patients’ treatments. See related commentary by Zhou and Kim, p. 1170

Purpose:Immune checkpoint inhibitors (ICI) have revolutionized the treatment of patients with clear-cell renal cell carcinomas (ccRCC). Although analyses of transcriptome, genetic alterations, and the tumor microenvironment (TME) have shed light into mechanisms of response and resistance to these agents, the role of epigenetic alterations in this process remains fully unknown.Experimental Design:We investigated the methylome of six ccRCC cohorts as well as one cell line dataset. Of note, we took advantage of the BIONIKK trial aiming to tailor treatments according to Paris Descartes 4-gene expression subgroups, and performed Illumina EPIC profiling for 46 samples related to patients treated with ipilimumab plus nivolumab, and 17 samples related to patients treated with sunitinib.Results:A group of tumors associated with enhancer demethylation was discovered, namely TED. TED was associated with tumors with sarcomatoid differentiation and poor clinical outcome. TED harbored TET1 promoter demethylation, activated the gene expression signature of epithelial–mesenchymal transition and IL6/JAK/STAT3 pathways, and displayed a TME characterized by both immune activation and suppressive populations, fibroblast infiltration, and endothelial depletion. In addition, TED was a predictive factor of resistance to the combination of first-line ipilimumab-nivolumab in the BIONIKK clinical trial. Finally, TED was associated with activation of specific regulons, which we also found to be predictive of resistance to immunotherapy in an independent cohort.Conclusions:We report on the discovery of a novel epigenetic phenotype associated with resistance to ICIs that may pave the way to better personalizing patients’ treatments.See related commentary by Zhou and Kim, p. 1170

Figure S2. Focal copy number deletion identified by the GISTIC algorithm for a) 𝑇𝐸𝐷+ and b) 𝑇𝐸𝐷−, respectively, in the TCGA-KIRC cohort.

Figure S4. Focal copy number deletion identified by the GISTIC algorithm for a) 𝑇𝐸𝐷+ and b) 𝑇𝐸𝐷−, respectively, in the immunotherapy arm of the BIONIKK cohort.

Figure S7. a) Heatmap showing the methylation profiles of two 𝑇𝐸𝐷 phenotypes by unsupervised clustering of enhancer probes in the Beuselinck cohort in which 102 patients developed metastatic ccRCC and were treated with the first-line TKI of sunitinib. Kaplan-Meier survival curves showing the survival rate of two 𝑇𝐸𝐷 phenotypes in view of b) OS and c) PFS.

Supplementary Figure from Plasma CD27, a Surrogate of the Intratumoral CD27–CD70 Interaction, Correlates with Immunotherapy Resistance in Renal Cell Carcinoma

Purpose:CD70 is a costimulatory molecule known to activate CD27-expressing T cells. CD27–CD70 interaction leads to the release of soluble CD27 (sCD27). Clear-cell renal cell carcinoma (ccRCC) expresses the highest levels of CD70 among all solid tumors; however, the clinical consequences of CD70 expression remain unclear.Experimental Design:Tumor tissue from 25 patients with ccRCC was assessed for the expression of CD27 and CD70 in situ using multiplex immunofluorescence. CD27+ T-cell phenotypes in tumors were analyzed by flow cytometry and their gene expression profile were analyzed by single-cell RNA sequencing then confirmed with public data. Baseline sCD27 was measured in 81 patients with renal cell carcinoma (RCC) treated with immunotherapy (35 for training cohort and 46 for validation cohort).Results:In the tumor microenvironment, CD27+ T cells interacted with CD70-expressing tumor cells. Compared with CD27− T cells, CD27+ T cells exhibited an apoptotic and dysfunctional signature. In patients with RCC, the intratumoral CD27–CD70 interaction was significantly correlated with the plasma sCD27 concentration. High sCD27 levels predicted poor overall survival in patients with RCC treated with anti–programmed cell death protein 1 in both the training and validation cohorts but not in patients treated with antiangiogenic therapy.Conclusions:In conclusion, we demonstrated that sCD27, a surrogate marker of T-cell dysfunction, is a predictive biomarker of resistance to immunotherapy in RCC. Given the frequent expression of CD70 and CD27 in solid tumors, our findings may be extended to other tumors.

Figure S6. a) Heatmap showing the methylation profiles of two 𝑇𝐸𝐷 phenotypes by unsupervised clustering of enhancer probes in the BIONIKK cohort; samples were combined from both immunotherapy and target therapy arms. Kaplan-Meier survival curves showing the survival rate of two 𝑇𝐸𝐷 phenotypes in view of b) OS, c) PFS, and d) TST.

Figure S5. Box violin plots showing the distribution of the methylation level of the TET1 associated promoter probe (i.e., cg23602092) in four cohorts and one cell line dataset with DNA methylation profiles where three of them had available normal samples.

Supplementary Table from Plasma CD27, a Surrogate of the Intratumoral CD27–CD70 Interaction, Correlates with Immunotherapy Resistance in Renal Cell Carcinoma

Figure S1. Flow chart of the study. A total of six ccRCC cohorts and one cell line dataset were used in this study.

Supplementary Data from Plasma CD27, a Surrogate of the Intratumoral CD27–CD70 Interaction, Correlates with Immunotherapy Resistance in Renal Cell Carcinoma

Supplemental Table 4-6. Table S4: Detail for each sample of the PBRM1 and VHL-mutation status. NA stands for Not Available. Table S5: For each data type, clinical, transcriptome, methylome or SNP array, sensitity and specificity of the two predictors: PD vs (PR+SD) and PR vs (PD+SD) in the training and validation sets. The 'N()' columns indicate the numbers of each responder type. Table S6: List of the 27 genes firstly used by the classifier to predict the subtypes ccrcc2, ccrcc3 and the joint subtype ccrcc14 and list of the 8 genes used by the second classifier to assign the ccrcc14 samples to the two subtypes ccrcc1 and ccrcc4.

Supplemental Figure 7-10. Figure S7: Summary of the results obtained on the TCGA data; Figure S8: Survival analysis of the patients included in the TCGA according to our classification ccrcc 1 to 4; Figure S9: Illustration of the gradient assumption defined by subtype order

PDF file - 83K, Baseline characteristics of 52 patients with RCC lung metastasis. * determined by Heng et al.

PDF file - 90K, Baseline characteristics of 140 patients with CRC lung metastasis. The stage was determined by pathological examination at the time of diagnosis.

Purpose:In the placebo-controlled SPARTAN study, apalutamide added to androgen-deprivation therapy (ADT) improved metastasis-free survival, second progression-free survival (PFS2), and overall survival (OS) in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC). Mechanisms of resistance to apalutamide in nmCRPC require evaluation.Patients and Methods:In a subset of patients from SPARTAN, aberrations were assessed at baseline and end of study treatment (EOST) using targeted next-generation sequencing or qRT-PCR. Circulating-tumor DNA (ctDNA) levels were assessed qualitatively. Select aberrations in androgen receptor (AR) and other common PC-driving genes were detected and summarized by the treatment group; genomic aberrations were summarized in ctDNA-positive samples. Association between detection of aberrations in all patients and outcomes was assessed using Cox proportional-hazards models and multivariate analysis.Results:In 247 patients, the overall prevalence of ctDNA, AR aberrations, and TP53 inactivation increased from baseline (40.6%, 13.6%, and 22.2%) to EOST (57.1%, 25.4%, and 35.0%) and was comparable between treatment groups at EOST. In patients who received subsequent androgen signaling inhibition after study treatment, detectable biomarkers at EOST were significantly associated with poor outcomes: ctDNA with PFS2 or OS (HR, 2.01 or 2.17, respectively; P < 0.0001 for both), any AR aberration with PFS2 (1.74; P = 0.024), and TP53 or BRCA2 inactivation with OS (2.06; P = 0.003; or 3.1; P < 0.0001).Conclusions:Apalutamide plus ADT did not increase detectable AR/non-AR aberrations over ADT alone. Detectable ctDNA, AR aberrations, and TP53/BRCA2 inactivation at EOST were associated with poor outcomes in patients treated with first subsequent androgen signaling inhibitor.

Purpose: The PREINSUT study characterized factors predictive of response to sunitinib given before planned nephrectomy in patients with metastatic renal cell carcinoma (mRCC).Patients and Methods: This French multicenter, prospective, open-label, phase II trial (NCT00930345) included treatment-naïve patients with clear-cell mRCC. Patients received two cycles of sunitinib before nephrectomy. The primary objective was to evaluate the potential of circulating angiogenesis-related biomarkers measured before and on treatment for identifying responders based on primary renal tumor (PRT) size change. Secondary objectives were to evaluate the ability of biomarkers to predict progression-free survival (PFS) and overall survival (OS).Results: Thirty-two patients were enrolled. The median PFS was 4.5 months, and the median OS was 12.4 months. OS was significantly longer in responding patients (28.8 vs. 11.1 months; P = 0.03). Of 27 patients evaluable for PRT response, nine (33.3%) had a ≥10% decrease in PRT size. Baseline biomarkers significantly associated with outcome were endothelial progenitor cells (PRT response); vascular endothelial growth factor (VEGF)-A, stromal cell–derived factor-1 (SDF-1), soluble VEGF receptors (sVEGFR)1 and 2 (PFS); and SDF-1 and sVEGFR1 (OS). During treatment, changes in biomarkers associated with outcome were SDF-1 and platelet-derived growth factor (PDGF)-BB (PRT response), sVEGFR2 (PFS), and SDF-1 and sVEGFR1 (OS). There was no correlation between plasma sunitinib or its active metabolite steady-state trough concentrations and clinical outcome.Conclusions: Angiogenesis-related parameters that could reflect hypoxia seem to be associated with worse outcome in mRCC. As blood biomarkers are not subjected to tumor heterogeneity and allow longitudinal follow-up, circulating angiogenesis profile has a promising place in antiangiogenic therapy guidance. Clin Cancer Res; 24(22); 5534–42. ©2018 AACR.

Purpose: Selecting patients with metastatic clear-cell renal cell carcinoma (m-ccRCC) who might benefit from treatment with targeted tyrosine kinase inhibitors (TKI) is a challenge. Our aim was to identify molecular markers associated with outcome in patients with m-ccRCC treated with sunitinib.Experimental Design: We performed global transcriptome analyses on 53 primary resected ccRCC tumors from patients who developed metastatic disease and were treated with first-line sunitinib. We also determined chromosome copy-number aberrations, methylation status, and gene mutations in von Hippel–Lindau and PBRM1. Molecular data were analyzed in relation with response rate (RR), progression-free survival (PFS), and overall survival (OS). Validation was performed in 47 additional ccRCC samples treated in first-line metastatic setting with sunitinib.Results: Unsupervised transcriptome analysis identified 4 robust ccRCC subtypes (ccrcc1 to 4) related to previous molecular classifications that were associated with different responses to sunitinib treatment. ccrcc1/ccrcc4 tumors had a lower RR (P = 0.005) and a shorter PFS and OS than ccrcc2/ccrcc3 tumors (P = 0.001 and 0.0003, respectively). These subtypes were the only significant covariate in the multivariate Cox model for PFS and OS (P = 0.017 and 0.006, respectively). ccrcc1/ccrcc4 tumors were characterized by a stem-cell polycomb signature and CpG hypermethylation, whereas ccrcc3 tumors, sensitive to sunitinib, did not exhibit cellular response to hypoxia. Moreover, ccrcc4 tumors exhibited sarcomatoid differentiation with a strong inflammatory, Th1-oriented but suppressive immune microenvironment, with high expression of PDCD1 (PD-1) and its ligands.Conclusions: ccRCC molecular subtypes are predictive of sunitinib response in metastatic patients, and could be used for personalized mRCC treatment with TKIs, demethylating or immunomodulatory drugs. Clin Cancer Res; 21(6); 1329–39. ©2015 AACR.

Purpose: If immune cells are involved in tumor surveillance and have a prognostic impact in most primary tumors, little is known about their significance in metastases. Because patients' survival is heterogeneous, even at metastatic stages, we hypothesized that immune cells may be involved in the control of metastases. We therefore characterized the tumor immune microenvironment and its prognostic value in colorectal and renal cell carcinoma (RCC) metastases, and compared it to primary tumors.Experimental Design: We analyzed by immunohistochemistry (n = 192) and qPCR (n = 32) the immune environments of colorectal carcinoma and RCC lung metastases.Results: Metastases from colorectal carcinoma and RCC have different immune infiltrates. Higher densities of DC-LAMP+ mature dendritic cells (P < 0.0001) and lower densities of NKp46+ NK cells (P < 0.0001) were observed in colorectal carcinoma as compared to RCC metastases, whereas densities of T cells were similar. High densities of CD8+ and DC-LAMP+ cells correlated with longer overall survival (OS) in colorectal carcinoma (P = 0.008) and shorter OS in RCC (P < 0.0001). High NK-cell densities were associated with improved survival in RCC (P = 0.002) but not in colorectal carcinoma. Densities of immune cells correlated significantly from primary to relapsing metastases for the same patient. A TH1 orientation was found in colorectal carcinoma metastases, whereas a heterogeneous immune gene expression was found in RCC metastases.Conclusions: Our results show a major prognostic value of the immune pattern (CD8+/DC-LAMP+ cell densities) in colorectal carcinoma and RCC, reproducible from primary to metastatic tumors, although with opposite clinical impacts, and highlight the role of the tumor cell in shaping its immune environment. Clin Cancer Res; 19(15); 4079–91. ©2013 AACR.

PDF file - 101K, Influence of pre-operative patient treatments on the distribution of CD8+, DC-LAMP+ and NKp46+ immune cells in CRC (a, b and c) and RCC lung metastases (d, e and f). 63/140 patients with CRC lung metastases have been treated with neo-adjuvant chemotherapy and 9/52 patients with RCC lung metastases have been treated with IL2/IFN. Whiskers length represents 10-90 percentile. ns, not significant (Mann-Whitney test).

Supplementary Data for Smith et al SPARTAN AR Aberrations

Supplemental Figure 1-3. Figure S1: Expression of immune modulators among the 4 molecular subgroups and normal Samples; Figure S2: Expression of cell-type specific metagenes among the different subgroups and normal samples; Figure S3: CD8+ cell infiltration according to the molecular ccRCC subtype classification.

Summary of currently available data looking at biomarkers during antiantiogenic therapy

Kaplan-Meier analysis of progression-free survival (PFS; A-D) and overall survival (OS; E-F) according to baseline biomarker levels. HR, hazard ratio; CI, confidence interval.

PDF file - 88K, Gene expression in lung metastases from CRC and RCC. Expression of genes related to (a) immune cell populations, (b) Th1/Th2 orientations, (c) inflammation and angiogenesis, (d) immunosuppression, (e) cytotoxicity, (f) chemokines/chemokine receptors in lung metastases from CRC (grey bars) and RCC (white bars). Expression levels of genes were determined using threshold cycle (Ct) values normalized to actin B ACTB (ΔCt). Whiskers length represents 10-90 percentile. ns, not significant; *P

PDF file - 107K, Kaplan-Meier curves for the duration of OS according to the presence of CD8+ T cells in the center of the tumor (CT) (a), in the invasive margin (IM) (b) and in combined regions (CT+IM) (c) of CRC lung metastases. Statistical comparison was performed by the log-rank test.

Supplementary Figure and Table Legends. Legends of all supplemental Figures and Tables

Supplemental Table 7-10. Table S7: Area under the ROC curve or c-index for the predictive and prognostic markers presented in Table 1 and Figures 3A, 3B and 3C. Table S8: P-values of the pathway enrichment analysis for the genes differentially expressed, the genes differentially methylated and the genes differentially methylated and anti-correlated to expression data in the four unsupervised subgroups. Table S9: List of the recurrent chromosomal aberrations characterizing ccrcc4-samples with a sensitivity and a specificity greater than 0.65. Table S10: Correlation of the centroids of our classification in four subtypes with the Brannon classification in three subgroups ccA, ccB and cluster_3 and the subtypes predicted in the TCGA cohort

PDF file - 148K, Kaplan-Meier curves for the duration of OS according to the presence of CD8+ T cells in the center of the tumor (CT) (a), in the invasive margin (IM) (b) and in combined regions (CT+IM) (c) of RCC lung metastases. Representation of the Kaplan-Meier curves for the duration of OS according to the presence of NKp46+ cells in the CT (d), in the IM (e) and in combined region (CT+IM) (f) of RCC lung metastases. Statistical comparison was performed by the log-rank test.

Kaplan-Meier analysis of median (m) overall survival (A) and progression-free survival (A) according to response. HR, hazard ratio; CI, confidence interval.

Kaplan-Meier analysis of progression-free survival (PFS) and overall survival (OS) according to relative changes in biomarkers during cycle 1 (A-B) and cycle 2 (C). HR, hazard ratio; CI, confidence interval.

Table S1: Baseline clinical characteristics of the 87 primary clear cell RCC patient selected for multiparametric immunofluorescence in situ analysis Table S2: Baseline clinical characteristics of the 42 primary RCC patient with analysis of fresh tumor TIL Table S3 : List of antibodies used for cytometry and in situ immunofluorescence Table S4: Correlation between the total number (Nb) of CD8+T cells and those expressing Tim-3 and/or PD-1 and the Fuhrman grade and UISS. Table S5 : RCC patients characteristics in the prospective cohorts Table S6 : RCC patients characteristics in the retrospective cohorts

Inhibitory receptors expressed by T cells mediate tolerance to tumor antigens, with coexpression of these receptors exacerbating this dysfunctional state. Using the VectraR automated multiparametric immunofluorescence technique, we quantified intratumoral CD8+ T cells coexpressing the inhibitory receptors PD-1 and Tim-3 from patients with renal cell carcinoma (RCC). A second validation cohort measured the same parameters by cytometry. The percentage of tumor-infiltrating CD8+ T cells coexpressing PD-1 and Tim-3 correlated with an aggressive phenotype and a larger tumor size at diagnosis. Coexpression of PD-1 and Tim-3 above the median conferred a higher risk of relapse and a poorer 36-month overall survival. Notably, other CD8+T-cell subsets did not exert a similar effect on overall survival. Moreover, only the PD-1+Tim-3+ subset of CD8+ T cells exhibited impaired function after stimulation. Our findings establish intratumoral Tim-3+PD1+CD8+ T cells as critical mediators of an aggressive phenotype in RCC. Use of the Vectra tool may be useful to identify similarly critical prognostic and predictive biomarkers in other tumor types and their response to immunotherapy. Cancer Res; 77(5); 1075–82. ©2016 AACR.

PDF file - 81K

Primary renal tumor response on sunitinib according to MSKCC risk group

BACKGROUND: Patients with von Hippel–Lindau (VHL) disease have a high incidence of renal cell carcinoma owing to VHL gene inactivation and constitutive activation of the transcription factor hypoxia-inducible factor 2α (HIF-2α). METHODS: In this phase 2, open-label, single-group trial, we investigated the efficacy and safety of the HIF-2α inhibitor belzutifan (MK-6482, previously called PT2977), administered orally at a dose of 120 mg daily, in patients with renal cell carcinoma associated with VHL disease. The primary end point was objective response (complete or partial response) as measured according to the Response Evaluation Criteria in Solid Tumors, version 1.1, by an independent central radiology review committee. We also assessed responses to belzutifan in patients with non–renal cell carcinoma neoplasms and the safety of belzutifan. RESULTS: After a median follow-up of 21.8 months (range, 20.2 to 30.1), the percentage of patients with renal cell carcinoma who had an objective response was 49% (95% confidence interval, 36 to 62). Responses were also observed in patients with pancreatic lesions (47 of 61 patients [77%]) and central nervous system hemangioblastomas (15 of 50 patients [30%]). Among the 16 eyes that could be evaluated in 12 patients with retinal hemangioblastomas at baseline, all (100%) were graded as showing improvement. The most common adverse events were anemia (in 90% of the patients) and fatigue (in 66%). Seven patients discontinued treatment: four patients voluntarily discontinued, one discontinued owing to a treatment-related adverse event (grade 1 dizziness), one discontinued because of disease progression as assessed by the investigator, and one patient died (of acute toxic effects of fentanyl). CONCLUSIONS: Belzutifan was associated with predominantly grade 1 and 2 adverse events and showed activity in patients with renal cell carcinomas and non–renal cell carcinoma neoplasms associated with VHL disease. (Funded by Merck Sharp and Dohme and others; MK-6482-004 ClinicalTrials.gov number, NCT03401788.)

INTRODUCTION: Apalutamide and darolutamide are next-generation androgen receptor inhibitors that have demonstrated superior efficacy compared to placebo in men with non-metastatic castration-resistant prostate cancer (nmCRPC) receiving androgen deprivation therapy (ADT). In the absence of head-to-head studies, the present study sought to indirectly compare the efficacy and tolerability between these two treatments. METHODS: This anchored matching-adjusted indirect comparison (MAIC) used patient-level data from the phase 3, randomized, controlled SPARTAN study (apalutamide + ADT), weighted to match aggregate published data from the ARAMIS study (darolutamide + ADT) for clinically relevant baseline measures. Hazard ratios (HR) and 95% credible intervals (CrI) were estimated for efficacy endpoints: metastasis-free survival (MFS), prostate-specific antigen (PSA) progression, progression-free survival (PFS), and overall survival (OS). Odds ratios were estimated for tolerability outcomes: adverse events and serious adverse events. RESULTS: Before weighting, baseline characteristics from SPARTAN versus ARAMIS were different for median PSA (7.8 vs. 9.2 ng/mL), Eastern Cooperative Oncology Group performance status of 1 (23% vs. 31%), use of bone-targeted agents (10% vs. 4%), median time from initial diagnosis (94.9 vs. 85.4 months), and proportion of patients from North America (35% vs. 12%) and Europe (50% vs. 64%). After matching (n = 455), our analysis demonstrated that apalutamide + ADT had a Bayesian probability of being more effective than darolutamide + ADT for MFS [98.3%; HR 0.70 (95% CrI 0.51, 0.98)], PSA progression [~ 100%; HR 0.46 (95% CrI 0.33, 0.64)], and PFS [93.2%; HR 0.79 (95% CrI 0.59, 1.08)]. Results for OS and tolerability were similar between apalutamide + ADT and darolutamide + ADT. CONCLUSION: This anchored MAIC analysis of pivotal phase 3 studies in patients with nmCRPC suggests that apalutamide + ADT is more effective than darolutamide + ADT for MFS, progression-free survival (PFS), and prostate-specific antigen (PSA) progression, with a similar OS benefit and tolerability profile. TRIAL REGISTRATION: ARAMIS ClinicalTrials.gov number: NCT02200614; SPARTAN ClinicalTrials.gov number: NCT01946204. ispartof: ADVANCES IN THERAPY vol:39 issue:1 pages:518-531 ispartof: location:United States status: published

Summary Background The majority of patients with metastatic castration-resistant prostate cancer (mCRPC) will have disease progression of a uniformly fatal disease. mCRPC is driven by both activated androgen receptors and elevated intratumoural androgens; however, the current standard of care is therapy that targets a single androgen signalling mechanism. We aimed to investigate the combination treatment using apalutamide plus abiraterone acetate, each of which suppresses the androgen signalling axis in a different way, versus standard care in mCRPC. Methods ACIS was a randomised, placebo-controlled, double-blind, phase 3 study done at 167 hospitals in 17 countries in the USA, Canada, Mexico, Europe, the Asia-Pacific region, Africa, and South America. We included chemotherapy-naive men (aged ≥18 years) with mCRPC who had not been previously treated with androgen biosynthesis signalling inhibitors and were receiving ongoing androgen deprivation therapy, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and a Brief Pain Inventory-Short Form question 3 (ie, worst pain in the past 24 h) score of 3 or lower. Patients were randomly assigned (1:1) via a centralised interactive web response system with a permuted block randomisation scheme (block size 4) to oral apalutamide 240 mg once daily plus oral abiraterone acetate 1000 mg once daily and oral prednisone 5 mg twice daily (apalutamide plus abiraterone–prednisone group) or placebo plus abiraterone acetate and prednisone (abiraterone–prednisone group), in 28-day treatment cycles. Randomisation was stratified by presence or absence of visceral metastases, ECOG performance status, and geographical region. Patients, the investigators, study team, and the sponsor were masked to group assignments. An independent data-monitoring committee continually monitored data to ensure ongoing patient safety, and reviewed efficacy data. The primary endpoint was radiographic progression-free survival assessed in the intention-to-treat population. Safety was reported for all patients who received at least one dose of study drug. This study is completed and no longer recruiting and is registered with ClinicalTrials.gov , number NCT02257736 . Findings 982 men were enrolled and randomly assigned from Dec 10, 2014 to Aug 30, 2016 (492 to apalutamide plus abiraterone–prednisone; 490 to abiraterone–prednisone). At the primary analysis (median follow-up 25·7 months [IQR 23·0–28·9]), median radiographic progression-free survival was 22·6 months (95% CI 19·4–27·4) in the apalutamide plus abiraterone–prednisone group versus 16·6 months (13·9–19·3) in the abiraterone–prednisone group (hazard ratio [HR] 0·69, 95% CI 0·58–0·83; p Interpretation Despite the use of an active and established therapy as the comparator, apalutamide plus abiraterone–prednisone improved radiographic progression-free survival. Additional studies to identify subgroups of patients who might benefit the most from combination therapy are needed to further refine the treatment of mCRPC. Funding Janssen Research & Development.

Background The optimal therapeutic strategies for patients with metastatic hormone-sensitive prostate cancer (mHSPC) followed by metastatic castrate-resistant prostate cancer (mCRPC), in terms of cost and effectiveness remains unknown. This study aims to compare the cost-effectiveness of various potential strategies, from the start of first-line treatment in mHSPC to the death of the patients. Methods Two Markov decision-analysis models were developed, one for cohort A “asymptomatic/mildly symptomatic patients in mCRPC” and one for cohort B “symptomatic patients in mCRPC”. Each strategy reflects daily practice for mHSPC until progression in mCRPC from the start of first treatment regimen with either docetaxel or abiraterone acetate plus prednisone (AA) in mHSPC to the death of the patient. The cost-effectiveness analysis was performed from the French public healthcare system perspective. Only direct medical costs were included. Survival data were extracted from results of published randomized clinical trials. Results For cohort A, docetaxel followed by AA is the most cost-effective therapeutic strategy (€96,925 for 4.24 life-years). For cohort B, docetaxel followed by docetaxel is the most cost-effective therapeutic strategy (€81,463 for 4.05 life-years). Sensitivity analyses confirmed the robustness of our results except for a price reduction of 70% for AA or enzalutamide. Conclusions Our approach is innovative to the extent that our analysis takes into account various potential strategies for mPC. Our economic evaluation suggests that a price reduction of AA or enzalutamide impacts on the results. This approach must continue, including new drugs for patients with mPC. MICRO-ABSTRACT This study aims to define optimal sequencing for patients moving from mHSPC to mCRPC based on their cost and effectiveness through literature publications. The results add useful information to clinician and patients facing treatment decisions in the real world.

Background The CARMENA trial in patients with metastatic renal cell carcinoma (mRCC) demonstrated that treatment with sunitinib alone was noninferior to cytoreductive nephrectomy (CN) followed by sunitinib (nephrectomy⬜sunitinib). Objective The objective of this study was to provide updated overall survival (OS) outcomes of CARMENA and assess whether some subgroups may still benefit from upfront CN. Design, setting, and participants CARMENA was a phase III trial in 450 patients with mRCC enrolled from 2009 to 2017. Intervention Patients in the intention-to-treat population received nephrectomy⬜sunitinib (standard of care [SOC]; n = 226) or sunitinib alone (n = 224). Outcome measurements and statistical analysis Primary endpoint was OS, assessed using an updated data cut-off (October 2018; median OS event-free follow-up, 36.6 mo). Patients were reclassified by risk using International Metastatic RCC Database Consortium (IMDC) criteria. Results and limitations Sunitinib alone was noninferior to nephrectomy⬜sunitinib (hazard ratio [HR], 0.97; 95% confidence interval, 0.79⬜1.19; p = 0.8) and demonstrated longer median OS (19.8 mo vs 15.6 mo, respectively). For patients with two or more IMDC risk factors, OS was significantly longer with sunitinib alone than with nephrectomy⬜sunitinib (31.2 mo vs 17.6 mo, respectively; HR, 0.65; p = 0.03). For patients with one IMDC risk factor, OS was longer for nephrectomy⬜sunitinib versus sunitinib alone although not significantly (31.4 mo vs 25.2 mo; HR, 1.30; p = 0.2). The post hoc nature of the subgroup analyses may limit their interpretation. Conclusions Sunitinib alone was noninferior compared with nephrectomy⬜sunitinib, suggesting that CN should not be considered SOC in patients with mRCC requiring systemic treatment. Certain subgroups, including patients with one IMDC risk factor, may still benefit from upfront CN. Patient summary We assessed the survival of patients with metastatic kidney cancer in a clinical trial. Patients treated with sunitinib on its own had the same survival as patients who had surgery before sunitinib treatment. We conclude that surgery may not be necessary for some patients with metastatic kidney cancer.

Introduction Cabazitaxel multiple rechallenges may be a treatment option in heavily pretreated patients with metastatic castration‐resistant prostate cancer (mCRPC) who had a good initial response to cabazitaxel and who are still fit to receive it. Our objective was to assess the efficacy and toxicity of multiple rechallenges. Patients and methods We retrospectively identified 22 mCRPC patients previously treated with docetaxel and/or androgen receptor‐targeted agents who received multiple cabazitaxel rechallenges in 9 French centers. Cabazitaxel was initiated at a dose of 25 mg/m2 q3week. A reduced dose (20 mg/m2 q3w) or an alternative schedule (mainly 16 mg/m2 q2w) was increasingly used for subsequent rechallenges. Progression‐free survival, prostate‐specific antigen (PSA) response, best clinical response, and grade ≥3 toxicities were collected. Overall survival was calculated from various time points. Results Twenty‐two patients with an initial response to cabazitaxel were rechallenged at least twice. The median number of cabazitaxel cycles was 7 at first cabazitaxel treatment, 6 at first rechallenge, and 5 at subsequent rechallenges. Median progression‐free survival at first rechallenge was 9.6 months and 5.6 months at second rechallenge. Median overall survival was 50.9 months from the first cabazitaxel dose, 114.9 months from first life‐extending therapy initiation in mCRPC, and 105 months from mCRPC diagnosis. There was no cumulative grade ≥3 neuropathy or nail disorder and one case of febrile neutropenia. Conclusion Cabazitaxel multiple rechallenges may be a treatment option without cumulative toxicity in heavily pretreated patients having a good response to first cabazitaxel use and still fit to receive it. Novelty & Impact Statements Patients with metastatic castration‐resistant prostate cancer can be treated with Cabazitaxel after docetaxel and androgen receptor‐targeted agent. This chemotherapy can be used multiple times with efficacy and manageable toxicity., We assessed the efficacy and toxicity of multiple rechallenges with cabazitaxel for 22 patients with metastatic castration‐resistant prostate cancer (mCRPC). Median overall survival was 50.9 months from the first cabazitaxel dose, 114.9 months from first life‐extending therapy initiation in mCRPC, and 105 months from mCRPC diagnosis. Cabazitaxel rechallenge may be an effective option in heavily pretreated mCRPC patients with a good initial response to cabazitaxel and still fit to receive it, without cumulative grade ≥3 toxicity.

Bladder cancer detection and follow-up is based on cystoscopy and/or cytology, but it remains imperfect and invasive. Current research focuses on diagnostic biomarkers that could improve bladder cancer detection and follow-up by discriminating patients at risk of aggressive cancer who need confirmatory TURBT (Transurethral Resection of Bladder Tumour) from patients at no risk of aggressive cancer who could be spared from useless explorations.To perform a systematic review of data on the clinical validity and clinical utility of eleven urinary biomarkers (VisioCytAll available studies on the 11 biomarkers published between May 2010 and March 2021 and present in MEDLINEMost studies on urinary biomarkers had a prospective design and high level of evidence. However, their results should be interpreted with caution given the heterogeneity among studies. Most of the biomarkers under study displayed higher detection sensitivity compared with cytology, but lower specificity. Some biomarkers may have clinical utility for NMIBC surveillance in patients with negative or equivocal cystoscopy or negative or atypical urinary cytology findings, and also for recurrence prediction.Urinary biomarkers might have a complementary place in bladder cancer diagnosis and NMIBC surveillance. However, their clinical benefit remains to be confirmed.