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Recent randomized controlled trials (RCTs) examined the role of adding androgen receptor signaling inhibitors (ARSIs), including abiraterone acetate (ABI), apalutamide, darolutamide (DAR), and enzalutamide (ENZ), to docetaxel (DOC) and androgen deprivation therapy (ADT) in patients with metastatic hormone-sensitive prostate cancer (mHSPC).To analyze the oncologic benefit of triplet combination therapies using ARSI + DOC + ADT, and comparing them with available treatment regimens in patients with mHSPC.Three databases and meetings abstracts were queried in April 2022 for RCTs analyzing patients treated with first-line combination systemic therapy for mHSPC. The primary interests of measure were overall survival (OS) and progression-free survival (PFS). Subgroup analyses were conducted to assess the differential outcomes in patients with low- and high-volume disease as well as de novo and metachronous metastasis.Overall, 11 RCTs were included for meta-analyses and network meta-analyses (NMAs). We found that the triplet combinations outperformed DOC + ADT in terms of OS (pooled hazard ratio [HR]: 0.74, 95% confidence interval [CI]: 0.65-0.84) and PFS (pooled HR: 0.49, 95% CI: 0.42-0.58). There was no statistically significant difference between patients with low- and high-volume disease in terms of an OS benefit from adding an ARSI to DOC +ADT (both HR: 0.79; p = 1). Based on NMAs, triplet therapy also outperformed ARSI + ADT in terms of OS (DAR + DOC + ADT: pooled HR: 0.74, 95% CI: 0.55-0.99) and PFS (ABI + DOC + ADT: HR: 0.68, 95% CI: 0.51-0.91, and ENZ + DOC + ADT: HR: 0.70, 95% CI: 0.53-0.93). An analysis of treatment ranking among de novo mHSPC patients showed that triplet therapy had the highest likelihood of improved OS in patients with high-volume disease; however, doublet therapy using ARSI + ADT had the highest likelihood of improved OS in patients with low-volume disease.We found that the triplet combination therapy improves survival endpoints in mHSPC patients compared with currently available doublet treatment regimens. Our findings need to be confirmed in further head-to-head trials with longer follow-up and among various patient populations.Our study suggests that triplet therapy with androgen receptor signaling inhibitor, docetaxel, androgen deprivation therapy prolongs survival in patients with metastatic hormone-sensitive prostate cancer compared with the current standard doublet therapy.

In the current era of immune checkpoint inhibitors (ICIs), the role and optimal timing of a nephrectomy in patients with metastatic renal cell carcinoma (mRCC) remain unknown.To assess the oncological outcomes of patients who responded to ICI-based treatments and were subsequently treated with a delayed nephrectomy.This national retrospective evaluation included 30 patients with mRCC who underwent a nephrectomy after a complete response (CR) or a major partial response (80%) to ICI treatment at metastatic sites.Partial or radical nephrectomy after a favorable response to ICI treatment.Disease-free survival (DFS), progression-free survival (PFS), overall survival (OS), and potential discontinuation of systemic treatment were assessed.ICI-based treatments included ipilimumab-nivolumab (40%), ICI + tyrosine kinase inhibitor (10%), and nivolumab (50%). A delayed nephrectomy was performed after a median ICI treatment duration of 10 mo. In 19 cases (63.3%), surgeons faced difficulties due to adhesions or inflammatory changes. A complete pathological response was observed in 16.7% of patients. After a median follow-up of 19.5 mo after nephrectomy, 76.7% of patients achieved DFS. At 1 yr, 66.7% of patients were free from systemic treatment. The PFS and OS rates were, respectively, 96.7% and 100% at 1 yr, and 78.3% and 86.1% at 2 yr. Patients with a CR at metastatic sites had a better prognosis than those with a major partial response, in terms of DFS (p = 0.022) and PFS (p = 0.014).Despite potentially challenging surgery, a delayed nephrectomy for patients who responded to ICI treatment provided promising oncological outcomes, and the majority of patients could discontinue systemic treatment.In this study, we evaluated the clinical outcome in patients who responded well to immunotherapy, and subsequently underwent kidney ablation surgery. Three-quarters of patients experienced no recurrence, and in most cases, medical treatment could be discontinued.

Supplementary Figure from Escherichia coli–Specific CXCL13-Producing TFH Are Associated with Clinical Efficacy of Neoadjuvant PD-1 Blockade against Muscle-Invasive Bladder Cancer

Biomarkers guiding the neoadjuvant use of immune-checkpoint blockers (ICB) are needed for patients with localized muscle-invasive bladder cancers (MIBC). Profiling tumor and blood samples, we found that follicular helper CD4+ T cells (TFH) are among the best therapeutic targets of pembrolizumab correlating with progression-free survival. TFH were associated with tumoral CD8 and PD-L1 expression at baseline and the induction of tertiary lymphoid structures after pembrolizumab. Blood central memory TFH accumulated in tumors where they produce CXCL13, a chemokine found in the plasma of responders only. IgG4+CD38+ TFH residing in bladder tissues correlated with clinical benefit. Finally, TFH and IgG directed against urothelium-invasive Escherichia coli dictated clinical responses to pembrolizumab in three independent cohorts. The links between tumor infection and success of ICB immunomodulation should be prospectively assessed at a larger scale.Significance:In patients with bladder cancer treated with neoadjuvant pembrolizumab, E. coli–specific CXCL13 producing TFH and IgG constitute biomarkers that predict clinical benefit. Beyond its role as a biomarker, such immune responses against E. coli might be harnessed for future therapeutic strategies.This article is highlighted in the In This Issue feature, p. 2221

Purpose of review To investigate the features and optimal management of pN+ cM0 prostate cancer (PCa) according to registry-based studies. Recent findings Up to 15% of PCa patients harbor lymph node invasion (pN+) at radical prostatectomy plus lymph node dissection. Nonetheless, the optimal management strategy in this setting is not well characterized. Summary We performed a systematic review including n = 13 studies. Management strategies comprised 13 536 men undergoing observation, 11 149 adjuvant androgen deprivation therapy (aADT), 7,075 adjuvant radiotherapy (aRT) +aADT and 705 aRT. Baseline features showed aggressive PCa in the majority of men. At a median follow-up ranging 48-134months, Cancer-related death was 5% and overall-mortality 16.6%. aADT and aRT alone had no cancer-specific survival or overall survival advantages over observation only and over not performing aRT, respectively. aADT plus aRT yielded a survival benefit compared to observation and aADT, which in one study, were limited to certain intermediate-risk categories. Age, Gleason, Charlson score, positive surgical margins, pathological stage, and positive nodes number, but not prostate specific antigen, were most relevant prognostic factors. Our work further confirmed pN+ PCa is a multifaceted disease and will help future research in defining its optimal management based on different risk categories to maximize survival and patient's quality of life.

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.

Summary Introduction Neoadjuvant chemotherapy (NAC) is now recommended to treat muscle-invasive bladder cancer (MIBC) but is not always executed in real life. This study aims to evaluate the proportion of patients with MIBC who receive an optimal NAC, and to present the predictive factors of its achievement. Methods This monocenter retrospective study included all the patients who underwent radical cystectomy for ≥ pT2NxM0 MIBC between 2013, January and 2018, December. NAC consisted in 4–6 cycles of MVAC (methotrexate, vinblastine, adriamycin, and cisplatin) or 4 cycles of GC (gemcitabin, and carboplatin). Demographic (sex, age, ECOG-PS, glomerular filtration rate [GFR], and cN stage), surgical (urinary derivation, time of surgery, blood loss, and complications), and oncological characteristics were analyzed. Multivariate analysis are made to find predictors of administration of NAC. Results One hundred and twenty-seven patients were included. Thirty received CNA (24%). Patients who underwent CNA were younger, with better ECOG and better GFR. Multivariate analysis showed that cN+ stage and better GFR were significantly associated to administration of NAC. Eight patients (27%) couldn’t receive an optimal treatment due to toxicity. Perioperative complication rates were similar, with or without NAC. Patients who underwent NAC had a worse GFR after treatment (−17 versus +5 mL/min, P Conclusion Due to the risks of toxicity, NAC can only be proposed to selected population, which is not the current patients. Immunotherapy could allow to treat more patients because of better tolerance. Level of evidence 3.

Purpose: Radiation therapy is a possible treatment strategy for patients with testicular seminoma after orchiectomy in clinical stage I or II disease. Little is known about the outcome of patients who experience a relapse after radiation therapy. ----- Methods and materials: Data from 61 patients who relapsed after adjuvant or curative radiation therapy from 17 centers in 11 countries were collected and retrospectively analyzed. Primary outcomes were disease-free and overall survival. Secondary outcomes were time to relapse, stage at relapse, treatment for relapse, and rate of febrile neutropenia during chemotherapy for relapse. ----- Results: With a median follow-up of 9.9 years (95% confidence interval [CI], 7.5-10.9), we found a 5-year disease-free survival of 90% (95% CI, 79-95) and a 5-year overall survival of 98% (95% CI, 89-100). Sixty-six percent of patients had stage III disease at time of relapse and 93% of patients fell into the good prognosis group per the International Germ Cell Cancer Collaborative Group classification. The median time to relapse after radiation therapy was 15.6 months (95% CI, 12-23). Twenty-two (36%) patients relapsed more than 2 years after radiation therapy and 7 (11.5%) patients relapsed more than 5 years after radiation therapy. One-third of relapses was detected owing to patients' symptoms, whereas two-thirds of relapses were detected during routine follow-up. The majority (93%) of cases were treated with cisplatin-based chemotherapy. The rate of febrile neutropenia during chemotherapy was 35%. Five patients experienced a second relapse. At last follow-up, 55 patients (90%) were alive without disease. Only 1 patient died owing to disease progression. ----- Conclusions: Cisplatin-based chemotherapy for patients with seminoma who have relapsed after treatment with radiation therapy alone leads to excellent outcomes. Patients and physicians should be aware of possible late relapses after radiation therapy.

471 Background: In the phase 3 JAVELIN Bladder 100 trial, avelumab 1L maintenance + best supportive care (BSC) significantly prolonged overall survival (OS) vs BSC alone in pts with aUC that had not progressed with 1L platinum-based chemotherapy (CTx). The JAVELIN Bladder regimen is now standard of care with level 1 evidence in international treatment guidelines. The AVENANCE study (NCT04822350), is investigating the efficacy and safety of avelumab 1L maintenance in a real-world population of pts with aUC in France. Data from the full analysis set are reported for the first time. Methods: In this ongoing, noninterventional, ambispective study, eligible pts have locally advanced or metastatic UC that has not progressed with 1L platinum-based CTx and previous, ongoing, or planned avelumab 1L maintenance treatment. The primary endpoint is OS from start of avelumab; secondary endpoints include progression-free survival (PFS), duration of treatment (DOT), and safety. Results: 591 pts received avelumab. At data cutoff (July 31, 2022), median follow-up was 12.0 mo (95% CI, 10.9-12.9). Median age was 73.1 y (IQR, 67.0-78.1). At start of 1L CTx (excluding pts with missing data), disease stage was metastatic in 524 pts (90.5%; visceral metastases in 426 [81.5%]) and locally advanced in 54 (9.3%). ECOG PS was 0-1 in 407 pts (85.3%) and 2-3 in 69 (14.5%). Tumor histology was pure UC in 528 pts (91.8%) and UC with variant or pure variant in 47 (8.2%). 1L CTx was gemcitabine + carboplatin (GemCarbo), gemcitabine + cisplatin (GemCis), dose-dense methotrexate + vinblastine + adriamycin + cisplatin (DD-MVAC), and other in 353 (61.0%), 170 (29.4%), 28 (4.8%), and 28 (4.8%) pts, respectively. Median number of cycles was 5 (range, 1-10). Median DOT with avelumab was 5.8 mo (95% CI, 5.2-7.0); 241 pts (40.8%) remained on treatment at data cutoff. The most common reasons for treatment discontinuation were disease progression (74.1% [n=258]), death (11.5% [n=40]), and adverse events ([AEs] 10.3% [n=36]). Median OS from start of avelumab was 18.4 mo (95% CI, 15.4-not estimable [NE]), the 12-month OS rate was 64.8% (95% CI, 60.0%-69.1%), and median PFS was 5.7 mo (95% CI, 5.3-7.0). In pts who had received GemCarbo, GemCis, or DD-MVAC, median OS (95% CI) was 16.2 mo (13.4-NE), not reached (NR; 18.1-NE), and NR (15.2-NE), respectively. Subgroups analyses will be presented. 218 pts received subsequent 2L, including CTx, antibody-drug conjugates, immunotherapy, and other in 186 (85.3%), 22 (10.1%), 6 (2.8%), and 4 (1.8%) pts, respectively. Any-grade treatment-related AEs (TRAEs) occurred in 217 pts (36.7%), including serious TRAEs in 29 (4.9%). Conclusions: Real-world data for avelumab 1L maintenance in pts with aUC from AVENANCE support the findings of JAVELIN Bladder 100 and confirm the clinical activity and acceptable safety profile of avelumab in a heterogeneous population. Clinical trial information: NCT04822350 .

TPS744 Background: Cabozantinib is a tyrosine kinase inhibitor (TKI) directed against VEGFR, MET and AXL. In the pivotal phase III METEOR study, cabozantinib demonstrated significantly improved progression-free survival (PFS), overall response rate (ORR) and overall survival (OS) versus everolimus in patients with previously treated aRCC with clear-cell component. Thus, cabozantinib received marketing authorization from the European Medicine Agency in September 2016 for the treatment of aRCC in patients previously treated with a VEGF-targeted therapy. Cabozantinib effectiveness and safety have been investigated in several real-world evidence studies such as CABOREAL or CASSIOPE. However, many questions arising during the routine care of patients with aRCC treated by cabozantinib remain unanswered by the current literature. Therefore, the aims of OCTOPUS study are to describe the effectiveness and safety of 2nd line cabozantinib in a real-life setting in France and to address these unanswered questions in certain patients subgroups. Methods: Octopus is a multicenter (25 centers), retrospective, non-comparative, non-interventional study in patients with aRCC initiating cabozantinib in 2nd line in France. The primary endpoint is the duration of treatment (DOT) with cabozantinib: median DOT will be estimated using Kaplan Meier method. Key secondary endpoints to be assessed are: best overall response (BOR), PFS, adverse events (AEs) and subsequent treatment. DOT, BOR, PFS, safety and all baseline characteristics for each of the following subgroups will be described as exploratory endpoints: sequencing post-cabozantinib, long-responders, non-responders, cabozantinib & rechallenge, cabozantinib & therapeutic schedules, cabozantinib & local treatment, cabozantinib & elderly patients. Data will be analyzed descriptively. Due to the observational nature of this study, no formal calculation of sample size and statistical power were performed. With a sample size of 300 participants who started cabozantinib in 2nd line between 1st March 2018 and 1st March 2021 and a median DOT of 7.6 months, the two-sided confidence interval of the median will be estimated with a width equal to 1.7 months (95% Confidence Interval [CI] [6.8; 8.6]) and a censoring probability near 0. All collected data will be in accordance with the daily practice of medical doctors, with a maximum follow-up of 12-months. Data collection started in Q3 2022 and the first patient was included on September 16th 2022. No interim analysis is planned. This study is funded by Ipsen Pharma. Clinical trial information: NCT05444933 .

618 Background: Muscle metastases (MM) are among rare secondary locations in renal cell carcinoma (RCC). Current guidelines do not provide specific advice on the management of these patients. There is a lack of scientific literature on the subject, mainly based on case reports or small retrospective monocentric cohorts. To date, therefore, there remains uncertainty about the clinical history, prognosis, and appropriate management of patients with MM. Methods: ARTEMIS is an ambispective national French multicenter, non-interventional study. It was opened to patients with metastatic RCC who had MM. The study was designed to assess overall survival (OS), progression-free survival (PFS), describe diagnostic and treatment modalities, and treatment-related serious adverse events in case of local treatments (TR-SAEs). Results: Median follow-up was 74.4 months IC95% [38.7-84.1]. The 146 enrolled patients were 73.6% male, with a median age of 57.6 years at diagnosis. They were initially diagnosed with stage IV RCC for 40.4% of them and had a favorable (36.2%), intermediate (45.7%), or poor (18.1%) IMDC risk score at the onset of metastases. Initially, metastases were mainly located in the lungs (55.5%), lymph nodes (26.7%), and bones (24.0%). Patients had a history of partial or total nephrectomy in 78.8% of cases. There were 30.0% of patients with synchronous MM. The median times from initial diagnosis or metastatic status to MM discovery were 25.5 [16.8-35.7] months and 8.4 [5.0-13.5] months, respectively. The majority (69.0%) of MM were discovered on conventional injected CT scans, whereas 8.3% were diagnosed clinically. Survival data are displayed on the table. Thirty-seven (25.3%) patients received local treatment of their MM which consisted of: external radiotherapy (48.6%), surgery (27.0%), cryotherapy (27.0%), stereotactic radiotherapy (5.4%), embolization (2.7%). Among them, local treatments prevented local relapse of MM in 28 patients (75.7%). Local TR-SAEs were seen in two patients (5.4%). Conclusions: ARTEMIS is the largest published cohort describing the disease history of patients with RCC suffering from MM. To our knowledge, this is the first study reporting the diagnostic and treatment modalities, also survival data. Despite its low incidence, the issue of these patients is not so rare in physicians’ practice. This work thus allows a greater understanding of clinical features and treatment of this pathology. [Table: see text]

This letter to the editor remarks on a recently published article about dermatologic events induced by enfortumab vedotin, comparing results from other similar studies.

Collecting duct carcinoma (CDC) and renal medullary carcinoma (RMC) are two rare subtypes of kidney cancer with a poor prognosis in the metastatic setting. Beyond first-line treatment, there are no standard-of-care therapies. This retrospective study assessed the efficacy of treatments after first-line chemotherapy in 57 patients with metastatic (m) CDC (n = 35) or RMC (n = 22) treated between 2010 and 2019 at 11 French centers. The median age was 53 years; overall, 60% (n = 34) of patients were metastatic at diagnosis. After a median follow-up of 13 months, the median overall survival was 12 (95% CI, 11–16) months. All patients received first-line platinum chemotherapy ± bevacizumab, with a median time to progression of 7.27 (95% CI, 7–100 months and an objective response rate (ORR) of 39% (95% CI, 26–52%). Patients received a median of two (1–5) treatment lines. Subsequent treatments included tyrosine kinase inhibitors (n = 12), chemotherapy (n = 34), and checkpoint inhibitors (n = 20), with ORR ranging 10–15% and disease control rates ranging 24–50%. The duration of response for all treatments was ~2 months. Notably, nine patients with CDC were still alive > two years after metastatic diagnosis. Beyond first-line therapy, treatments showed very low antitumor activity in mCDC/RMC. A better understanding of the biology of those rare tumors is urgently needed in order to identify potential targets.

Biomarkers guiding the neoadjuvant use of immune-checkpoint blockers (ICB) are needed for patients with localized muscle-invasive bladder cancers (MIBC). Profiling tumor and blood samples, we found that follicular helper CD4+ T cells (TFH) are among the best therapeutic targets of pembrolizumab correlating with progression-free survival. TFH were associated with tumoral CD8 and PD-L1 expression at baseline and the induction of tertiary lymphoid structures after pembrolizumab. Blood central memory TFH accumulated in tumors where they produce CXCL13, a chemokine found in the plasma of responders only. IgG4+CD38+ TFH residing in bladder tissues correlated with clinical benefit. Finally, TFH and IgG directed against urothelium-invasive Escherichia coli dictated clinical responses to pembrolizumab in three independent cohorts. The links between tumor infection and success of ICB immunomodulation should be prospectively assessed at a larger scale. Significance: In patients with bladder cancer treated with neoadjuvant pembrolizumab, E. coli–specific CXCL13 producing TFH and IgG constitute biomarkers that predict clinical benefit. Beyond its role as a biomarker, such immune responses against E. coli might be harnessed for future therapeutic strategies. This article is highlighted in the In This Issue feature, p. 2221

Until 2014, no new therapeutic agent have been approved by authorities in more than 2 decades for bladder cancer. But the panel of treatments has expended in recent years with the emergence of at least 3 different therapeutic classes. First, the immune checkpoint inhibitors that have demonstrated an overall survival benefit in metastatic patients after failure of platinum based chemotherapy. They are therefore currently evaluated alone or in combination with chemotherapy in multiple studies at earlier stages (localized and meta-static). The second and third therapeutic classes are the targeted therapies (especially FGFR inhibitor) and the antibody-drug conjugates with promising results in early clinical trials. In this article, we review all the current and future studies conducted in urothelial carcinoma of the bladder.

Summary Background: The nivolumab-ipilimumab combination provides an overall response rate of 42% in first-line metastatic treatment of clear cell renal carcinoma (mccRCC). To date, there is no robust predictive biomarker of response to immune checkpoint inhibitor (ICI). In addition, severe autoimmune disorders occur more frequently with ICI combination than with ICI alone. The objective of this study is to compare the efficacy of ICI alone or in combination in patients according to tumor molecular characteristics. Methods: Using a 35-gene expression mRNA signature, patients were divided into 4 molecular groups (1 to 4). Patients in groups 1 and 4 were randomized to receive nivolumab alone (arms 1A and 4A) or nivolumab plus ipilimumab for 4 injections followed by nivolumab alone (arms 1B and 4B). Patients in groups 2 and 3 were randomized to receive nivolumab plus ipilimumab followed by nivolumab alone (arms 2B and 3B) or a tyrosine kinase inhibitor (sunitinib or pazopanib at the investigator’s choice (arms 2C and 3C)). The main objective is the overall response rate by treatment and molecular group. Discussion: BIONIKK is the first trial in mccRCC to study the personalization of treatment with ICI or TKI according to tumor molecular characteristics in mccRCC. This trial is the most appropriate to prospectively identify biomarkers of response to nivolumab used alone or in combination or TKI monotherapy in patients with mccRCC. NCT02960906.

Background Ramucirumab-an IgG1 vascular endothelial growth factor receptor 2 antagonistplus docetaxel was previously reported to improve progression-free survival in platinum-refractory, advanced urothelial carcinoma. Here, we report the secondary endpoint of overall survival results for the RANGE trial.Methods We did a randomised, double-blind, phase 3 trial in patients with advanced or metastatic urothelial carcinoma who progressed during or after platinum-based chemotherapy. Patients were enrolled from 124 investigative sites (hospitals, clinics, and academic centres) in 23 countries. Previous treatment with one immune checkpoint inhibitor was permitted. Patients were randomly assigned (1:1) using an interactive web response system to receive intravenous ramucirumab 10 mg/kg or placebo 10 mg/kg volume equivalent followed by intravenous docetaxel 75 mg/m 2 (60 mg/m 2 in Korea, Taiwan, and Japan) on day 1 of a 21-day cycle. Treatment continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met. Randomisation was stratified by geographical region, Eastern Cooperative Oncology Group performance status at baseline, and visceral metastasis. Progression-free survival (the primary endpoint) and overall survival (a key secondary endpoint) were assessed in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT02426125; patient enrolment is complete and the last patient on treatment is being followed up for safety issues.Findings Between July 20, 2015, and April 4, 2017, 530 patients were randomly allocated to ramucirumab plus docetaxel (n=263) or placebo plus docetaxel (n=267) and comprised the intention-to-treat population. At database lock (March 21, 2018) for the final overall survival analysis, median follow-up was 7.4 months (IQR 3.5-13.9). In our sensitivity analysis of investigator-assessed progression-free survival at the overall survival database lock, median progression-free survival remained significantly improved with ramucirumab compared with placebo (4.1 months [95% CI 3.3-4.8] vs 2.8 months [2.6-2.9]; HR 0.696 [95% CI 0.573-0.845]; p=0.0002). Median overall survival was 9.4 months (95% CI 7.9-11.4) in the ramucirumab group versus 7.9 months (7.0-9.3) in the placebo group (stratified HR 0.887 [95% CI 0.724-1.086]; p=0.25). Grade 3 or worse treatment-related treatment-emergent adverse events in 5% or more of patients and with an incidence more than 2% higher with ramucirumab than with placebo were febrile neutropenia (24 [9%] of 258 patients in the ramucirumab group vs 16 [6%] of 265 patients in the placebo group) and neutropenia (17 [7%] of 258 vs six [2%] of 265). Serious adverse events were similar between groups (112 [43%] of 258 patients in the ramucirumab group vs 107 [40%] of 265 patients in the placebo group). Adverse events related to study treatment and leading to death occurred in eight (3%) patients in the ramucirumab group versus five (2%) patients in the placebo group.Interpretation Additional follow-up supports that ramucirumab plus docetaxel significantly improves progression-free survival, without a significant improvement in overall survival, for patients with platinum-refractory advanced urothelial carcinoma. Clinically meaningful benefit might be restricted in an unselected population. Copyright (C) 2019 Elsevier Ltd. All rights reserved.

With the therapeutic landscape of advanced prostate cancer rapidly evolving and oncological benefits being shown for a plethora of new agents and indications, health-related quality of life (HRQOL)-associated evidence is still subpar. In the current comprehensive review, we discuss the importance of HRQOL for patients with advanced PC (metastatic hormone-sensitive prostate cancer (mHSPC), metastatic castration-resistant prostate cancer (mCRPC) and non-metastatic castrationresistant prostate cancer (nmCRPC)), and present the most frequently used tools to evaluate HRQOL in recent randomized trials. Furthermore, we discuss the ease of use of these validated questionnaires for clinicians and try to focus on the suggested appropriate use in clinical practice, as well as potential strategies for improvement of HRQOL evaluation in these clinical scenarios of advanced prostate cancer., NA

Introduction. Immune checkpoint inhibitors (ICI) have been approved for front-line therapy in metastatic renal cell carcinoma (mRCC). However, progressive disease often occurs and subsequent therapies are needed. ICI rechallenge may be an option, but there is a lack of data regarding efficacy and prognostic factors. We assessed efficacy of ICI rechallenge and factors associated with better outcomes. Patients and Methods. This ambispective multicenter study included 45 mRCC patients rechallenged with nivolumab ± ipilimumab between 2014 and 2020. Primary endpoint was investigator-assessed best objective response rate (ORR) for ICI rechallenge (ICI-2). Factors associated with ICI-2 progression-free survival (PFS) were evaluated with multivariate Cox models. Results. ORR was 51% (n = 23) at first ICI therapy (ICI-1) and 16% (n = 7) for ICI-2. Median PFS was 11.4 months (95% CI, 9.8–23.5) and 3.5 months (95% CI, 2.8–9.7), and median overall survival was not reached (NR) (95% CI, 37.8–NR) and 24 months (95% CI, 9.9–NR) for ICI-1 and ICI-2, respectively. Factors associated with poorer ICI-2 PFS were a high number of metastatic sites, presence of liver metastases, use of an intervening treatment between ICI regimens, Eastern Cooperative Oncology Group performance status ≥2, and poor International Metastatic RCC Database Consortium score at ICI-2 start. Conversely, ICI-1 PFS >6 months was associated with better ICI-2 PFS. In multivariate analysis, there were only statistical trends toward better ICI-2 PFS in patients with ICI-1 PFS >6 months ( p = 0.07 ) and toward poorer ICI-2 PFS in patients who received a treatment between ICI regimens ( p = 0.07 ). Conclusion. Rechallenge with nivolumab-based ICI has some efficacy in mRCC. We identified various prognostic factors in univariate analysis but only statistical trends in multivariate analysis. Our findings bring new evidence on ICI rechallenge and preliminary but unique data that may help clinicians to select patients who will benefit from this strategy.

For the last decade, biology of urothelial tumorigenesis has been widely explored, helping to better understand the molecular pathways in urothelial carcinoma (UC). Until recently, no targeted therapies have been approved in UC. However, several new molecules have shown promising results in metastatic UC: fibroblast growth factor receptor inhibitors, conjugated antibodies, PARP inhibitors, and antiangiogenics. In this article, the authors review the targeted therapies that are being evaluated in bladder UC.

Objective The development of oral chemotherapy (OC) has led to the recent establishment of multidisciplinary programmes involving pharmacists. We evaluated the utility of our local programme for detecting potential interactions with OCs, particularly drug-drug interactions (DDIs) and herbal-drug interactions (HDIs). Methods We performed a single-centre retrospective descriptive study of patients on OC attending a pharmaceutical consultation (PC) during a seven-month period. These consultations included the use of various complementary tools/databases to search for interactions. Results We analysed 308 treatments taken by 42 consecutive patients. Fifty-four potential interactions with OCs were detected in 26% (n = 79) of the treatments taken by patients: 46 DDIs (32 minor, 12 major, 2 contraindicated) and eight HDIs. Five interventions associated with interactions were suggested by pharmacists during the consultations (4 were taken into account by oncologists). The total mean time spent on each PC for an individual patient was 80 minutes (36 minutes of preparation, 44 minutes with the patient). Conclusion This pilot study highlights the importance of studying interactions in such patients, and of the expertise of pharmacists for detecting interactions, which were found in more than one in four treatment lines. The further development of such activities, which already take up considerable amounts of time, is therefore warranted.

The field of clear cell renal cell carcinoma (ccRCC) has undergone major changes in the last decade, both in terms of the understanding of the mechanisms of oncogenesis and the role of the tumor microenvironment in anti-tumor immunity, as well as in therapeutic developments. After the era of tyrosine kinase inhibitors (TKIs) targeting VEGFR and then the era of immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 pathway, we are now entering the era of combination therapy for first-line metastatic cancer (m-ccRCC), such as combinations including a TKI and a PD-1 inhibitor or combinations of PD-1 and CTLA-4 blockers. In this extremely dynamic environment, new molecules with various mechanisms of action will appear in the very near future: immune response modulators (other ICIs, pro-inflammatory cytokines, gut microbiota modulators), new anti-angiogenic agents (new TKIs, anti-HIF-1α antibodies), agents affecting cell metabolism (glutaminase inhibitors, tryptophan regulators or adenosine A2A receptor antagonists) or epigenetic regulators (HDAC inhibitors). In parallel, new strategies are being evaluated that could rapidly change the standards of management of advanced disease, including therapeutic intensification with triple combinations or, conversely, adaptive and/or alternative de-escalation regimens (SURF trial), and biomarker-driven treatments (BIONIKK trial). The main new molecules and strategies currently being evaluated are reviewed in this article.

Resume Les avancees therapeutiques durant les 30 dernieres annees dans les cancers de la vessie ont ete tres limitees. Le XXIe siecle s’annonce plus prometteur avec l’avenement des immunotherapies, avec en tete de liste les inhibiteurs des checkpoints immunologiques Programmed Cell-Death 1 (PD-1)/Programmed Death-Ligand 1 (PD-L1), dont les resultats des essais precoces laissent esperer que ces nouvelles therapies s’inscriront bientot dans l’arsenal therapeutique des carcinomes urotheliaux. Cet article resume les donnees cliniques des essais therapeutiques actuellement en cours des immunotherapies (inhibiteurs des checkpoints immunologiques, vaccin, cytokines), ainsi que les associations avec les chimiotherapies, les antiangiogeniques et la radiotherapie.

Resume Le cancer du rein a cellules claires est un type tumoral dont le developpement et la progression sont diriges par la voie de l’angiogenese HIF/VEGF. Les anti-angiogeniques (AA), en particulier les inhibiteurs de tyrosine kinase (TKI) anti-VEGFR, ont profondement modifie le pronostic des patients au stade metastatique (mRCC) depuis leur enregistrement en 2006. Dans le meme temps, des inhibiteurs de la voie mTOR, ont egalement apporte un benefice non negligeable aux patients. Plus recemment, des traitements restaurant l’immunite adaptative antitumorale, les inhibiteurs de checkpoints (ICP) anti-program death 1 (anti-PD-1), viennent a leur tour revolutionner la prise en charge des mRCC. L’efficacite multitumeurs de ces ICP nous prouve le role crucial de l’immunite antitumorale dans le controle d’un certain nombre de tumeurs dont le cancer du rein. Il est etabli que le microenvironnement (TME) immunitaire des tumeurs du rein a cellules claires (ccRCC) est tres immunosuppressif. Ainsi, les ccRCC sont caracterises par une forte infiltration de lymphocytes T CD8+, exprimant frequemment des molecules de checkpoints immunologiques a leur surface, leur conferant un caractere de mauvais pronostic. Ces caracteristiques du TME expliquent en partie l’efficacite des ICP dans le ccRCC et constituent un rationnel fort pour la poursuite du developpement d’ICP, soit a un stade plus precoce, soit en combinaison, en particulier avec des AAA ou des TKI. Dans cette revue sont compiles les principaux resultats cliniques des molecules de checkpoints immunologiques seuls ou en association, en premiere ligne ou apres echec d’un TKI.

International audience; BACKGROUND: The management of older cancer patients has been highly challenging for clinicians in a health-care system operating at maximum capacity during the COVID-19 pandemic. PATIENTS AND METHODS: We analyzed data from 9 different institutions. The primary endpoint was to assess the prevalence of adapted patient care during the pandemic for elderly cancer patients. The secondary endpoint was to assess the incidence of hospitalization and mortality due to COVID-19. All patients were older than 65years of age. RESULTS: We analyzed data from 332 outpatients’ case files between 9th of March and 30th of April 2020. The median age was 75years (range: 65-101) and 53% were male. Because of the COVID-19 pandemic, more than half of the outpatients received modified patient care, defined as postponement or cancellation of surgery, irradiation scheme adapted, systemic treatment or the use of telemedicine. Among patients with localized cancer, 60% had a change in management strategy due to the pandemic. Changes in management strategy were made for 53% of patients at the metastatic stage. GCSF was used , in 83% of patients, increasing considerably in the context of the pandemic. Sixty-nine percent of physicians used telemedicine. In the final analysis, only one patient was hospitalized for COVID-19 infection. No deaths due to COVID-19 were reported in elderly cancer patients during this time period. CONCLUSION: Our study is the first to assess modification of patient care in elderly cancer outpatients during an epidemic. With this unprecedented crisis, our objective is to protect our patients from infection via protective barrier measures and social distancing, but also to guarantee the continuity of cancer care without overexposing this fragile population. Physicians were able to adapt their practice and used new forms of management, like telemedicine.

International audience; This review details the clinical utility of Immunoscore, measuring the immune response to cancer within the tumor microenvironment, in bladder cancer. Immunoscore was recently introduced into ESMO Clinical Practice Guidelines for gastrointestinal cancer and into the WHO classification of the Digestive System Tumors. In muscle-invasive bladder cancer (MIBC), the standard-of-care treatment is neo-adjuvant chemotherapy and cystectomy. However, only 50% of the patients are still alive at 5 years. The degree of histologic response positively correlated with Immunoscore and patients at lower risk of relapse or death were associated with a high-Immunoscore. Immunoscore is also predicting response to neoadjuvant chemotherapy-based treatment in several indications. This paves the way for the use of Immunoscore in clinical practice not only in gastrointestinal tumors but also in bladder cancer, and beyond.

Purpose Fumarate hydratase–deficient (FHdef) renal cell carcinoma (RCC) is a rare entity associated with the hereditary leiomyomatosis and RCC syndrome with no standard therapy approved. The aim of this retrospective study was to evaluate the efficacy of different systemic treatments in this population. Methods We performed a multicentre retrospective analysis of Fhdef RCC patients to determine the response to systemic treatments. The endpoints were objective response rate (ORR), time-to-treatment failure (TTF), and overall survival (OS). The two latter were estimated using the Kaplan–Meier method. Results Twenty-four Fhdef RCC patients were identified, and 21 under systemic therapy were included in the analysis: ten received cabozantinib, 14 received sunitinib, nine received “other antiangiogenics” (sorafenib, pazopanib, and axitinib), three received erlotinib-bevacizumab (E-B), three received mTOR inhibitors, and 11 received immune checkpoint blockers (ICBs). ORR for treatments were 50% for cabozantinib, 43% for sunitinib, 63% for “other antiangiogenics,” and 30% for E-B, whereas ORR was 0% for mTOR inhibitors and 18% for ICBs. The median TTF (mTTF) was significantly higher with antiangiogenics (11.6 months) than with mTOR inhibitors (4.4 months) or ICBs (2.7 months). In the first-line setting, antiangiogenics presented a higher ORR compared with nivolumab-ipilimumab (64% versus 25%) and a significantly superior mTTF (11.0 months vs 2.5 months; p = 0.0027). The median OS from the start of the first systemic treatment was 44.0 months (95% confidence interval: 13.0–95.0). Conclusions We report the first European retrospective study of Fhdef RCC patients treated with systemic therapy with a remarkably long median OS of 44.0 months. Our results suggest that antiangiogenics may be superior to ICB/mTOR inhibitors in this population.

(1) Background&mdash, The five-year overall survival (OS) of muscle-invasive bladder cancer (MIBC) with neoadjuvant chemotherapy and cystectomy is around 50%. There is no validated biomarker to guide the treatment decision. We investigated whether the Immunoscore (IS) could predict the pathologic response to neoadjuvant chemotherapy and survival outcomes. (2) Methods&mdash, This retrospective study evaluated the IS in 117 patients treated using neoadjuvant chemotherapy for localized MIBC from six centers (France and Greece). Pre-treatment tumor samples were immunostained for CD3+ and CD8+ T cells and quantified to determine the IS. The results were associated with the response to neoadjuvant chemotherapy, time to recurrence (TTR), and OS. (3) Results&mdash, Low (IS-0), intermediate (IS-1&ndash, 2), and high (IS-3&ndash, 4) ISs were observed in 36.5, 43.7, and 19.8% of the cohort, respectively. IS was positively associated with a pathologic complete response (pCR, p-value = 0.0096). A high IS was found in 35.7% of patients with a pCR, whereas it was found in 11.3% of patients without a pCR. A low IS was observed in 48.4% of patients with no pCR and in 21.4% of patients with a pCR. Low-, intermediate-, and high-IS patients had five-year recurrence-free rates of 37.2%, 36.5%, and 72.6%, respectively. In the multivariable analysis, a high IS was associated with a prolonged TTR (high vs. low: p = 0.0134) and OS (high vs. low: p = 0.011). (4) Conclusions&mdash, This study showed the significant prognostic and predictive roles of IS regarding localized MIBC.

Cabazitaxel (25 mg/m2 every 3 weeks) is the standard second-line chemotherapy for patients with metastatic castration-resistant prostate cancer previously treated with docetaxel. It is associated with a risk of neutropenic complications, which may be a barrier to its use in daily clinical practice, particularly in frail elderly patients. Here the authors reviewed key studies conducted with cabazitaxel (TROPIC, PROSELICA, AFFINITY, CARD and the European compassionate use program) and pilot studies with adapted schedules. Based on this review, the use of prophylactic granulocyte colony-stimulating factor from cycle 1 appears crucial to maximize the benefit-risk ratio of cabazitaxel in metastatic castration-resistant prostate cancer. Preliminary data with alternative schedules look promising, especially for frail patients. Results of the ongoing Phase III CABASTY trial (ClinicalTrials.gov: NCT02961257 ) are awaited.

Context The assessment of “soft” endpoints such as health-related quality of life (HRQOL) is increasingly relevant when evaluating the optimal treatment sequence of novel therapeutic options in patients with advanced prostate cancer (PCa). Objective To systematically review contemporary data regarding HRQOL outcomes in patients with advanced PCa. Evidence acquisition A systematic review of the literature published between January 2011 and March 2019 was performed using the PubMed/Medline Database. In total, 873 articles were screened, and 14 articles including 12 661 patients were selected for synthesis and included in the current analysis according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) and European Association of Urology recommendations. Evidence synthesis Regarding HRQOL assessment, the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire was used in 11 of 14 studies, the European Quality of Life 5-Dimensions (EQ-5D) questionnaire in six of 14 studies, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30) in two of 14, and its prostate-specific amendment QLQ-PR25 was used in one of 14 studies. Three studies included patients with metastatic castration-sensitive prostate PCa, and found beneficial HRQOL effects for abiraterone acetate and docetaxel compared with standard androgen deprivation therapy. Two studies included patients with nonmetastatic castration-resistant PCa, and positive HRQOL effects for enzalutamide and apalutamide were observed. Nine studies focused on patients with metastatic castration-resistant PCa. Hereby, beneficial HRQOL outcomes were described for enzalutamide, abiraterone acetate, and radium-223. Evidence synthesis was mostly based on studies with a low risk of bias based on standardized risk of bias assessment. Limitations include hampered comparability between different validated questionnaires, lack of baseline values, and unclear impact of supportive care on HRQOL outcomes. Conclusions There is strong evidence from several phase III trials supporting a beneficial effect of current systemic treatment options on HRQOL outcomes in patients with advanced PCa compared with standard androgen deprivation therapy. Patient summary In this systematic review, we provide an overview of contemporary data from large clinical trials on the effect of current treatment strategies on patients’ health-related quality of life (HRQOL). We summarize the assessment tools that have been used to measure HRQOL and show that there are robust data for positive HRQOL effects of numerous agents in different clinical stages of advanced prostate cancer.

535 Background: Immune checkpoint inhibitors (ICIs), such as anti-PD-1/PD-L1 antibodies, have emerged as a successful immunotherapeutic strategy for advanced and metastatic urothelial cancer (UC). Therapeutic blockade of PD-1 or PD-L1 with monoclonal antibodies leads to durable tumor regressions in up to 25% metastatic muscle invasive UC (MIBC). Neoadjuvant use of ICI also showed remarkable efficacy and represents a unique opportunity to study immunodynamics during PD-1 blockade to decipher functional predictors of response and resistance. Methods: Patients diagnosed with T2-T4aN0M0 MIBC were treated with 3 cycles of neoadjuvant pembrolizumab before cystectomy in the PANDORE trial (NCT03212651). The primary endpoint was pathologic complete response (ypT0N0). Secondary endpoints focused on safety, progression-free survival (PFS) and biomarker analysis. We performed longitudinal analysis of peripheral and tumor infiltrating lymphocytes, tumor microbiome as well as soluble factors using high dimensionnal immune phenotyping by mass cytometry, immuno-fluorescence and -histochemistry and multiplex immunoassays. Humoral and cellular recall immune memory against urinary tract commensals were studied. Results: Thirty-nine patients were enrolled from October 2017 to December 2019. All but 5 (n = 34 patients (87.2%)) proceeded with cystectomy. Ten patients presented with ypT0N0 (29.4%; 95% CI: 15.1 %-47.5 %). Multidimensional biomarkers analysis showed that baseline follicular T helper (Tfh) and post-pembrolizumab tertiary lymphoid structure (TLS) and activated B cells were associated with outcome ( p= 0.005, p= 0.01 and p= 0.04, respectively). Plasma CXCL13 (the prototypic chemokine secreted by Tfh and involved in TLS functions) increased after 1 cycle of PD-1 blockade in responders and patients without progression at 24 months ( p= 0.002 and p= 0.0001, respectively). Focusing on MIBC tumor microbiome, we showed that intracellular Gram negative bacteria and other commensals were more frequent in tumoral than in normal urothelium ( p= 0.04). Interestingly, basal CXCL13-secreting CD4+ T cells and IgG directed against urinary pathobionts such as Escherichia coli predicted prolonged PFS ( p= 0.01 and p= 0.001, respectively). Conclusions: Our results suggest that urothelial commensals could induce specific Tfh and B cell responses that were re-invigorated by PD-1 blockade and associated with clinical benefit to pembrolizumab. Further analyses are needed to validate the predictive value of commensal-specific Tfh in UC and other epithelial cancers that are directly or indirectly exposed to bacteria. Clinical trial information: NCT03212651.

430 Background: Primary urethral cancer (PUC) is a rare and heterogeneous malignancy. Due to its scarcity, little data are available on the optimal treatment sequence and survival, especially in metastatic patients. Methods: Data from patients diagnosed with a PUC between 01/01/2000 and 12/31/2018 were retrospectively collected from nine French referral centers. Survival rate were estimated with the Kaplan-Meier method and prognostic factors were analyzed using the Cox proportional hazards model and the log-rank test. In order to increase the statistical power of survival analysis in the metastatic stage, patients with synchronous and metachronous metastatic disease were pooled. Results: We identified 44 (62%) males and 27 (38%) females with a PUC. The most frequent histological types were urothelial carcinomas (40.0%), squamous cell carcinomas (34.3%) and adenocarcinomas (14.3%). Twenty-five (35.2%) patients were diagnosed at a localized stage (≤ T2, N0, M0); 35 (49.3%) at a locally advanced stage (≥ T3 or ≥ N1, M0) and 11 (15.5%) at a distant stage (M1). Twenty-seven patients had a metachronous metastatic cancer. Multimodality therapy was used in 24.0% and 57.1% of the patients with a localized and locally advanced disease, respectively. In the entire cohort, median overall survival (OS) was 52.5 months (IC95% 32.2 – 64.1) and stage at diagnosis was a predictor of OS (p < 0.0001). For the 60 patients with a non-metastatic disease, 39 (65%) had a recurrence or were dead and the median disease-free survival (DFS) was 21.2 months (IC95% 16.8 – 34.5). Nodal involvement was the only factor associated with DFS (HR: 2.03, p = 0.0390). Multimodal treatment compared with unimodal treatment was not significantly associated with DFS (HR: 1.22, p = 0.5419). Regarding survival of the 38 metastatic patients, the median OS was 15.2 months (IC95% 8.2 – 23.5) and the median progression-free survival was 6.4 months (IC95% 4.4 – 9.8). Conclusions: This retrospective study showed an important heterogeneity in terms of histology, stage at diagnosis, and treatment of PUC. In this cohort, the multimodal approach did not show any improvement in survival of non-metastatic patients. This study is one of the few to describe the survival in metastatic patients.