BACKGROUND:Androgen receptor pathway inhibitors (ARPIs) and docetaxel are established standards of care for chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC). We aimed to assess the efficacy and safety of adding nivolumab to docetaxel versus docetaxel alone in ARPI-pretreated, chemotherapy-naive mCRPC. METHODS:CheckMate 7DX was a double-blind, randomised, phase 3 trial that enrolled adult patients (aged ≥18 years) with histologically confirmed, ARPI-pretreated, and chemotherapy-naive mCRPC at 291 hospitals and cancer centres across 27 countries. Patients had documented progression within 6 months of screening and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1) to nivolumab (360 mg), or equivalent placebo, and docetaxel (75 mg/m2) intravenously every 3 weeks for up to ten doses, followed by nivolumab (480 mg) or equivalent placebo every 4 weeks. Randomisation, stratified by previous ARPI therapy and visceral disease, was done using interactive response technology in permuted blocks with a block size of six. Patients, investigators, and the trial sponsor were masked to individual patient treatment assignment. The primary endpoints were radiographic progression-free survival by blinded independent central review and overall survival, assessed in all randomly assigned patients. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT04100018, and is completed. FINDINGS:Between March 11, 2020, and Aug 2, 2022, 1414 patients were screened for eligibility, 1030 of whom were randomly assigned to nivolumab plus docetaxel (n=514) or placebo plus docetaxel (n=516). All participants were male, median age was 70 years (range 34-91), 662 (64%) were White, 240 (23%) were Asian, and 35 (3%) were Black or African American. With a median follow-up of 17·2 months (IQR 13·2-22·0), median radiographic progression-free survival was 9·4 months (95% CI 8·5-10·3) in the nivolumab plus docetaxel group versus 8·7 months (95% CI 8·4-10·0) in the placebo plus docetaxel group (hazard ratio [HR] 0·96 [99% CI 0·77-1·19]; p=0·59) and median overall survival was 18·7 months (95% CI 17·0-21·0) versus 18·9 months (95% CI 17·3-22·0, HR 1·09 [99·41% CI 0·84-1·43]; p=0·36). Grade 3-4 treatment-related adverse events occurred in 223 (44%) of 510 patients in the nivolumab plus docetaxel group and 187 (37%) of 510 in the placebo plus docetaxel group. The most common grade 3-4 events in both treatment groups were neutropenia (37 [7%] in the nivolumab plus docetaxel group and 50 [10%] in the placebo plus docetaxel group) and decreased neutrophil count (41 [8%] and 39 [8%]). Any-grade treatment-related serious adverse events occurred in 107 (21%) patients in the nivolumab plus docetaxel group and 77 (15%) in the placebo plus docetaxel group. 12 deaths were attributed to nivolumab plus docetaxel (three due to sepsis; one each due to Guillain-Barré syndrome, diverticulitis, myocarditis, liver injury, peritonitis, pneumonitis, pneumonia, and diarrhoea; and one due to unknown causes) and one was attributed to placebo plus docetaxel (due to pneumocystis). INTERPRETATION:Nivolumab plus docetaxel did not improve progression-free survival or overall survival versus placebo plus docetaxel in patients with ARPI-pretreated, chemotherapy-naive mCRPC. These findings do not support the use of combinations of anti-PD-1 immune checkpoint inhibitors and docetaxel in the treatment of unselected populations of patients with ARPI-pretreated, chemotherapy-naive mCRPC. FUNDING:Bristol Myers Squibb.

BACKGROUND:Papillary renal cell cancer (pRCC) represents the largest subgroup within non-clear cell (ncc) RCC. Compared with clear cell RCC (ccRCC), pRCC is considered less sensitive to currently available systemic therapies. Here, we report exploratory results from the pRCC subgroup of the SUNNIFORECAST trial comparing ipilimumab/nivolumab with standard of care (SOC) based on central pathological review. METHODS AND PATIENTS:SUNNIFORECAST was a prospective, investigator-initiated, phase II trial evaluating ipilimumab/nivolumab versus SOC in patients with untreated, advanced nccRCC. The primary endpoint was the 12-month overall survival (OS) rate. Secondary endpoints included OS, progression-free survival (PFS), and overall response rate (ORR). PD-L1 expression was assessed exploratory. RESULTS:Of 309 randomized patients, 127 had confirmed papillary histology, in 56/173 cases the local diagnosis of pRCC required revision. Among the 127 patients with pRCC, 64 received ipilimumab/nivolumab and 63 SOC, predominantly TKI monotherapy. In the pRCC subgroup, the 12-month OS rate was 74.77% in the ipilimumab/nivolumab arm and 63.44% in the SOC arm (p = 0.085). Median OS was 24.89 months with ipilimumab/nivolumab versus 18.88 months with SOC. PD-L1 expression was evaluable in 116 of 127 patients. A CPS > 1 was more frequently observed with increasing IMDC risk category. Among patients with CPS < 1, the 12-month OS rate was 75.00% with ipilimumab/nivolumab and 68.36% with SOC (p = 0.963). In patients with CPS > 1, the 12-month OS rate was 82.38% in the ipilimumab/nivolumab arm and 63.33% in the SOC arm. DISCUSSION:This exploratory analysis has several limitations; however, it suggests that patients with pRCC treated with ipilimumab/nivolumab may derive a benefit in terms of 12-month OS rate, median OS, and ORR compared with SOC, particularly among those with CPS > 1. (Funded by Bristol Myers Squibb grant CA209-499; ClinicalTrials.gov, EUDRACT Number: 2016-000706-12; NCT03075423.).

700 Background: Urothelial cancer (UC) is the fifth most common cancer in Spain. Advanced UC (aUC) is an aggressive disease with a high mortality rate. Enfortumab vedotin (EV) has been recently approved in Spain for the treatment of adult patients (pts) with aUC, although real-world data remain limited. We aim to describe clinical characteristics, treatment, outcomes and safety of EV treatment in routine practice. Methods: This retrospective observational study included pts with aUC who received EV across 17 hospitals in Spain. Demographic, clinical, treatment-related (efficacy and safety) and healthcare resource utilization data were collected. Progression-free survival (PFS), overall survival (OS) and time to treatment failure (TTF) were measured from EV initiation. Survival was estimated using the Kaplan–Meier method. Investigator-assessed observed response rate (ORR) was assessed for evaluable pts with scans after ≥1 cycle EV. Adverse events (AEs) were recorded and graded by CTCAE 5.0. Hospital admissions during EV treatment were collected. Results: A total of 195 pts were included. Median age was 71 years, 76.9% were male. 49.7% had localized disease at diagnosis with a median time to metastasic progression of 17.9 months. The primary tumor site was bladder in 82.1%, and upper urinary tract in 15.9%. 76.3% had pure urothelial, 22.2% variant differentiation and 3 (1.5%) non-urothelial carcinoma. ECOG PS was 0,1 and ≥2 in 25.1%, 63.6% and 11.3% pts, respectively. Patients received a median of 2 prior lines of systemic treatment. The most common immediate prior treatments were PD-1/L1 inhibitor monotherapy (41.0%) and chemotherapy (13.9%), while 27.7% received these in combination or as maintenance. Median follow-up was 34.4 months. Median PFS, OS and TTF were 7.4 [5.87-8.89], 12.8 [11.2-14.3] and 6.2 [5.54-7.97] months, respectively. ORR was 52.1%. EV related AEs occurred in 68.7% of pts, with ≥ grade 3 in 20.9%. Peripheral sensory neuropathy and rash were the most frequent AEs. 29.7% pts required hospitalization during EV treatment, with a median stay of 7 days. Baseline characteristics are summarized in Table 1. Conclusions: In this multicenter cohort, EV demonstrated efficacy and safety consistent with clinical trials, supporting its role as a standard option for previously treated patients with aUC. Despite the overall clinical burden, EV achieved meaningful disease control with favorable ORR and TTF outcomes in routine practice. Baseline characteristics. Characteristics (n) Results [n(%)] Current/former Smokers (195) 32(16.4%) Bellmunt risk (195) = 0 = 1 = 2 = 3 32 (20.3%)82 (51.9%)38 (24.1%)6 (3.8%) Liver metastasis (%) (195) 43 (22.0%) Exclusive lymph node involvement (192) 38 (19.8%) FGFR2/3 mutation (64) 12(18.8%) Pts with prior response to platinum chemotherapy (194) 100 (51.5%) Pts with prior response to immunotherapy (193) 7 (3.6%)

Bladder cancer is a fast-moving and recurrent malignancy where survival hinges on early detection and precise risk stratification. The search for robust biomarkers is urgent, and CD44v6 has emerged as a compelling candidate. In this study, we explored the clinical and functional associations of CD44v6 expression in bladder cancer. Integrated analyses of patient samples and cell lines showed that high CD44v6 expression is strongly associated with poor patient outcomes, enhanced migratory and invasive behavior, and increased resistance to cisplatin. These results suggest that CD44v6 may serve as a prognostic biomarker and a potential therapeutic target in bladder cancer. Overall, our findings highlight the translational relevance of CD44v6 and provide a foundation for future studies aimed at elucidating the mechanistic pathways underlying its role in tumor aggressiveness and chemoresistance.

PURPOSE:Angiogenesis plays an essential role in neuroendocrine tumors (NETs). This study evaluates efficacy and safety of axitinib in extrapancreatic (ep)-NETs. PATIENTS AND METHODS:AXINET was an international, randomized, double-blind, placebo-controlled, phase II/III trial including patients age 18 years and older, with unresectable/metastatic G1-2 epNETs and up to two previous treatment lines. Patients were randomly assigned (1:1) to axitinib 5 mg or placebo, both orally twice a day, in combination with intramuscular octreotide long-acting release 30 mg once every 28 days until disease progression or unacceptable toxicity. Randomization was stratified by primary tumor site, Ki-67 index (≤5% or >5%), and time from diagnosis (> or ≤12 months). The primary end point was investigator-assessed progression-free survival (PFS). Efficacy was also assessed by a blinded independent central review (BICR). RESULTS:From October 2011 to May 2019, 256 patients were assigned to axitinib (n = 126) or placebo (n = 130). Investigator-assessed median PFS was 17.2 months (95% CI, 13.6 to 24.7) versus 13.1 months (95% CI, 10.9 to 18.6) in the axitinib and placebo groups, respectively (hazard ratio [HR], 0.86 [95% CI, 0.65 to 1.15]). The median BICR PFS was 16.6 months (95% CI, 13.5 to 24.2) versus 9.9 months (95% CI, 8.2 to 13.9) in the axitinib and placebo groups, respectively (HR, 0.71 [95% CI, 0.54 to 0.94], P = .017). Objective response rate (ORR) was significantly greater for axitinib per investigator assessment (17.5% v 4.6%; P = .001) and BICR (12.8% v 3.2%; P = .005). Most common grade ≥3 toxicities were hypertension (24.0% v 9.2%) and diarrhea (13.6% v 1.5%). CONCLUSION:Axitinib significantly increased PFS per BICR assessment and ORR both per investigator and BICR assessment compared with placebo, although the primary study end point was not met. Toxicity profile was manageable with no new safety concerns.

143 Background: In ARASENS, darolutamide (DARO) + ADT + docetaxel (DOC) significantly reduced the risk of death by 32.5% (HR 0.68; 95% CI 0.57–0.80; P <0.0001) vs placebo (PBO) + ADT + DOC with similar incidence of treatment-emergent adverse events (TEAEs) between groups in patients (pts) with mHSPC. DARO + ADT + DOC has become one of the standards of care in mHSPC. We report post-hoc efficacy and safety in pts by age subgroups (<75 y, ≥75 y) in ARASENS. Methods: Pts were randomized to receive DARO 600 mg orally twice daily or PBO, with ADT + DOC. Age subgroups were analyzed for baseline characteristics including ongoing comorbidities, treatment duration, completion of DOC therapy, use of first subsequent therapy, key efficacy outcomes, and safety. Results: Of 1305 pts analyzed in ARASENS, ages ranged from 41–89 y, with 1086 pts <75 y (83%; DARO n=546; PBO, n=540) and 219 pts ≥75 y (17%; DARO n=105; PBO n=114). Baseline characteristics were generally similar in the DARO and PBO groups by age subgroup. The most common comorbidities by system organ class in pts <75 y and ≥75 y were vascular (55%, 67%), musculoskeletal/connective tissue (42%, 42%), and metabolism/nutrition (35%, 43%) disorders. Treatment duration was consistently longer with DARO vs PBO (<75 y: 41.2 vs 16.8 mo; ≥75 y: 38.5 vs 15.0 mo). Most patients completed 6 cycles of DOC (<75 y: 89%, 88%; ≥75 y: 80%, 76%). Among pts who entered follow-up, fewer DARO vs PBO pts initiated subsequent therapy independent of age (<75 y: 57% vs 76%; ≥75 y: 54% vs 73%). The overall survival (OS) benefit of DARO vs PBO was consistent across age subgroups (<75 y: HR 0.70, 95% CI 0.58–0.84; ≥75 y: HR 0.61, 95% CI 0.41–0.91). Time to metastatic castration-resistant prostate cancer (mCRPC) was longer with DARO vs PBO across age subgroups (<75 y: HR 0.35, 95% CI 0.30–0.43; ≥75 y: HR 0.42, 95% CI 0.28–0.64) as was time to initiation of subsequent therapy (<75 y: HR 0.40, 95% CI 0.34–0.48; ≥75 y: HR 0.35, 95% CI 0.22–0.54). TEAEs were generally similar between DARO and PBO, with slightly higher incidence rates in older pts. Few patients discontinued DARO or PBO due to TEAEs in both age subgroups (<75 y: 13.2%, 9.1%; ≥75 y: 15.1%, 17.7%). The most common grade 3/4 TEAEs were generally similar between DARO and PBO across age subgroups and occurred most frequently during overlapping DOC treatment. TEAEs commonly associated with androgen receptor pathway inhibitors occurred at similar incidences between treatment groups in both age subgroups. Conclusions: Pts with mHSPC benefited from DARO + ADT + DOC irrespective of age (<75 y and ≥75 y), with consistent improvements in OS, time to mCRPC, and time to initiation of subsequent therapy. DARO was well tolerated in both age subgroups, with similar incidences of TEAEs vs PBO. Clinical trial information: NCT02799602 .

BACKGROUND:A contemporary standard of care for patients with metastatic androgen pathway modulator-naive/sensitive (APMN/S) prostate cancer (also known as metastatic hormone-sensitive prostate cancer) is androgen deprivation therapy (ADT) plus an androgen receptor pathway inhibitor (ARPI) until progression. PSMAddition aimed to evaluate the efficacy and safety of [177Lu]Lu-PSMA-617 (177Lu-PSMA-617) combined with ADT plus ARPI in prostate-specific membrane antigen (PSMA)-positive metastatic APMN/S prostate cancer. METHODS:PSMAddition is an ongoing, randomised, controlled, phase 3 superiority trial conducted at 169 sites across 20 countries, including hospitals, medical centres, and specialist cancer centres. Eligible male patients had treatment-naive or minimally treated metastatic APMN/S prostate cancer diagnosed by CT, MRI, or bone scan and one or more PSMA-positive metastatic lesion on centrally read baseline [68Ga]Ga-PSMA-11 PET. Patients were randomly assigned 1:1 to open-label, intravenous 177Lu-PSMA-617 (7·4 GBq [200 mCi] ±10% every 6 weeks for up to six cycles) with ADT plus ARPI (177Lu-PSMA-617 arm) or ADT plus ARPI (control arm). ADT and ARPI were investigator-chosen according to local authorisation and administered per local product labelling. Control arm patients with centrally confirmed radiographic progression could cross over to 177Lu-PSMA-617. The primary endpoint was radiographic progression-free survival (centrally assessed per Prostate Cancer Clinical Trials Working Group 3-modified RECIST 1.1 or death); secondary endpoints included safety and tolerability. We report the second interim analysis of radiographic progression-free survival in the intention-to-treat population (all randomly assigned participants; data cutoff Jan 13, 2025). Safety was assessed in all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT04720157, and is ongoing. FINDINGS:From June 15, 2021, to July 25, 2023, 1529 patients were screened and 1144 were randomly assigned (n=572 per arm; 1144 [100%] male, 572 [50%] with de novo metastatic APMN/S prostate cancer, 779 [68%] with high-volume disease; median age 68·0 years [IQR 62·0-73·0]). Baseline characteristics were balanced between arms. At second interim analysis for radiographic progression-free survival (median time from randomisation to data cutoff 23·6 months [IQR 20·3-29·2]; median radiographic progression-free survival follow-up time 19·6 months [IQR 14·0-24·1]), 139 (24%) of 572 participants in the 177Lu-PSMA-617 arm and 172 (30%) of 572 participants in the control arm had radiographic disease progression or death. Radiographic progression-free survival was significantly improved in the 177Lu-PSMA-617 arm versus the control arm, with a 28% reduction in the relative risk of radiographic progression or death (HR 0·72 [95% CI 0·58-0·90]; p=0·0021; median radiographic progression-free survival not reached in either arm). The primary endpoint was thus met. Grade 3 or worse adverse events occurred in 286 (51%) of 564 patients in the 177Lu-PSMA-617 arm and 243 (43%) of 565 patients in the control arm. Serious adverse events occurred in 180 (32%) of 564 patients in the 177Lu-PSMA-617 arm and 162 (29%) of 565 in the control arm; of which 17 (3%) in the 177Lu-PSMA-617 arm were 177Lu-PSMA-617-related. The most common adverse event was dry mouth, in 258 (46%) patients in the 177Lu-PSMA-617 arm and 21 (4%) patients in the control arm; all were grade 1 or 2 and none were serious. Other common adverse events with higher incidence in the 177Lu-PSMA-617 arm included cytopenias and gastrointestinal disturbances. INTERPRETATION:Combining 177Lu-PSMA-617 with ADT plus ARPI prolonged radiographic progression-free survival in patients with PSMA-positive metastatic APMN/S prostate cancer. Although adverse events were more frequent, there were no unexpected safety findings associated with the drug combination. Therefore, combining 177Lu-PSMA-617 with ADT plus ARPI might be a new treatment option in metastatic APMN/S prostate cancer. FUNDING:Novartis.

INTRODUCTION:Deferred cytoreductive nephrectomy (dCN) is a selective strategy for managing metastatic renal cell carcinoma (mRCC), in the era of immune checkpoint inhibitors (ICI) and tyrosine kinase inhibitors (TKI), particularly for patients who achieve favorable responses to initial systemic therapy. This study aims to describe the clinical outcomes of dCN following first-line systemic treatment within a sequential management approach. METHODS:This multi-institutional retrospective study included 50 patients with clear cell mRCC who underwent dCN after first-line therapy. Patients were categorized according to treatment regimen (TKI monotherapy or ICI-based combinations). Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Prognostic factors were evaluated with Cox proportional hazards regression. A P-value < 0.05 was considered statistically significant. RESULTS:Median follow-up was 19 months (range 1-174 months). First-line therapy included ICI + ICI in 24%, ICI + TKI in 46%, and TKI alone in 30% of patients. The overall response rate was 64%, and the disease control rate was 84%. Median time from systemic therapy initiation to cytoreductive nephrectomy was 5.6 months. Median PFS was 36 months, 12-, 36-, and 60-month PFS rates of 77%, 49%, and 40%, respectively. Longer PFS occurred in patients with a Karnofsky performance status (KPS) >80% (51 vs. 14 months; P = 0.037) and complete response (P = 0.0021). Median OS reached 91 months. Limitations included a retrospective design and a modest sample size. CONCLUSIONS:dCN may offer durable benefit in well-selected patients achieving disease control and good performance status after systemic therapy. The optimal timing remains uncertain and warrants validation in larger prospective trials.

5129 Background: Metastatic progression is the leading cause of mortality in prostate cancer, yet clinicopathological stratification incompletely identifies primary tumors with latent metastatic potential. Emerging evidence supports metastatic competence as a gradual transcriptional reprogramming, motivating molecular tools that capture continuous risk states. Methods: Transcriptomes from primary and metastatic prostate tumors (n = 766; PRIMARY = 507, MET = 259) spanning 16,234 gene features were integrated to train an interpretable XGBoost model. SHapley Additive exPlanations were used to derive a minimal 30-gene signature and define a continuous metastasis-likeness transcriptomic score (MET-score). MET-score was applied to primary tumors to quantify metastasis-likeness and characterize associated biology. External validation was performed in an independent primary prostate cohort profiled with exon microarrays (GSE21034) without model retraining. Results: The minimal 30-gene signature captured metastasis-associated signal with high discriminative performance (ROC AUC ≈ 0.98). In primary tumors (n = 507), MET-score exhibited a right-skewed continuous distribution (mean 0.0079, SD 0.0640; range 0.0023–0.9953), consistent with heterogeneous degrees of metastasis-like transcriptional activity within primary disease. Using a prespecified high-risk threshold at the 0.85 quantile (cutoff 0.002603), 81/507 (16.0%) primary tumors were classified as HIGH MET-score and 426/507 as LOW, identifying a subset with transcriptomic profiles most closely resembling metastatic disease. MET-score generalized robustly to GSE21034 while preserving its continuous structure and enabling molecular stratification despite platform differences and partial gene loss: 26/30 signature genes were present in the microarray cohort (missing C15orf40, ADIRF, CTC1, NTPCR). However, prognostic validation against clinical endpoints could not be performed because the publicly available metadata did not include clearly annotated time-to-event and event-status variables. Conclusions: An explainable 30-gene MET-score was developed to quantify metastasis-likeness as a continuous transcriptomic trait in primary prostate cancer. The score identifies a high-risk primary subset and transfers to an independent external cohort (GSE21034) without model retraining, supporting cross-platform robustness and prioritizing MET-score for clinical outcome validation in RNA-seq–annotated cohorts.

Predictive biomarkers for immune checkpoint inhibitors (ICIs) are largely identified retrospectively, but their prospective clinical utility remains unproven. Here, we report DUTRENEO, a prospective randomized phase 2 trial testing whether a retrospectively validated 18-gene bulk tumor inflammation signature (TIS) can guide neoadjuvant ICI therapy in muscle-invasive bladder cancer. The trial does not meet its primary endpoint, and this demonstrates that bulk gene-expression stratification does not sufficiently enrich for responders. To define the biology underlying this failure, we generate single-cell spatial transcriptomic profiles of 377 genes in ∼5.4 million cells across large tissue areas. Response is governed by spatial architectures invisible to bulk assays, including CD8+ T cell proximity to cancer cells, localized checkpoint co-expression within epithelial cancer-rich neighborhoods, and fibroblast-rich immune-excluded communities in non-responders. We provide a quantitative framework showing that ≥77 genes and ≥3-mm tissue diameter regions preserve predictive spatial signal at scalable throughput. The registration details of the trial are EudraCT 2017-002246-68.

BACKGROUND:Fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) is a rare, molecularly defined subgroup of non-clear cell RCC (nccRCC) lacking an approved standard treatment. We report the exploratory analysis of this entity within the SUNNIFORECAST trial. METHODS:SUNNIFORECAST evaluated ipilimumab/nivolumab versus standard of care (SOC) in previously untreated, advanced nccRCC. The primary endpoint was the 12-months overall survival (OS) rate. Secondary endpoints included median OS, progression free survival (PFS) and overall response rate (ORR). PD-L1 expression was assessed exploratorily. RESULTS:Of 309 randomized patients, 30 had centrally confirmed FH-deficient RCC (ipilimumab/nivolumab, n=14; SOC, n= 16). The 12-months OS rate was 85.7% (95% confidence interval [CI] 53.9-96.2%) versus 73.3% (95% CI 43.6-89.1%), median OS was 35.7 months (95% CI 16.8 months-NE) versus 24.7 months (95% CI 10.6-37.7 months, hazard ratio [HR] 0.46 [0.17-1.20]), and ORR 42.9% versus 33.3%, favoring ipilimumab/nivolumab. Twenty-four patients were evaluable for PD-L1 expression; 21 had a combined positive score (CPS) ≥1. In this subgroup, the 12-months OS rate was 80.0% (95% CI 40.9-94.6%) versus 72.7% (95% CI 37.1-90.3%), median OS 38.3 months (95% CI 8.8 months-NE) versus 24.7 months (95% CI 8.8 months-NE, HR 0.43 [0.14-1.34]) and ORR 40.0% versus 36.4% for ipilimumab/nivolumab versus SOC, respectively. INTERPRETATION / DISCUSSION:Exploratory analyses suggest trends toward improved 12-months OS-rate, median OS and ORR with ipilimumab/nivolumab versus SOC in FH-deficient RCC. The majority of tumors demonstrated PD-L1-expression (e.g. CPS ≥ 1), warranting further investigation in prospective studies.

BACKGROUND:BladderGATE evaluated the safety, tolerability, and efficacy of intravenous (IV) atezolizumab combined with intravesical Bacillus Calmette-Guérin (BCG) in patients with BCG-naïve high-risk non-muscle invasive bladder cancer (NMIBC). MATERIALS AND METHODS:This was a phase Ib/II open-label, nonrandomized, dose de-escalation clinical trial of atezolizumab (1200 mg IV infusion on day 1 of each 21-day cycle) plus BCG (1 instillation/week) with an induction treatment period of 6 weeks, followed by a maintenance treatment period of 52 weeks maximum. During induction, dose-limiting toxicity (DLT) and maximum tolerated dose of atezolizumab were determined. The primary study outcome was recurrence-free survival (RFS). RESULTS:A total of 36 patients with high-risk NMIBC with a median age of 70 years were enrolled in this study. Twenty participants completed the whole treatment schedule. No DLTs were recorded during the study period. The median RFS was not reached; RFS rates were 83% (95% CI 70.6%-95.4%) and 73% (95% CI 57.4%-88.2%) at the end of the first and second year, respectively. The incidence of serious drug-related adverse events was low. Additionally, no impairment in Health-related quality of life status throughout the study was observed. CONCLUSIONS:IV atezolizumab plus intravesical BCG in high-risk BCG-naïve NMIBC patients resulted in a high RFS rate and a manageable safety profile. These results appear consistent with those of the ALBAN study, which did not demonstrate a significant benefit of this combination over BCG alone.

4583 Background: The DISCUS trial compared 3 versus 6 cycles (3C versus 6C) of chemotherapy followed by avelumab in 267 patients receiving first-line treatment for metastatic urothelial cancer. It showed 3 cycles of chemotherapy followed by maintenance avelumab was associated with better QoL than six cycles (NCT06892860). Efficacy outcomes of the two arms appeared similar. Here we compare the cisplatin (cis) or carboplatin (carbo) chemotherapy subsets in the 3C and 6C arms. Methods: Patients were randomized to receive either 3 or 6 cycles of chemotherapy. Cisplatin or carboplatin was allocated by physician choice. Progression free survival (PFS), Overall survival (OS), response rates, patient-reported outcomes (PROs) and treatment related adverse events were collected (TRAEs) were collected. The analysis was exploratory and p values nominal. Results: 267 were included of whom 55 received 3C/cis, 55 6C/cis, 78 3C/carbo and 79 6C/carbo. Patients receiving carboplatin had poor performance status (ECOG >=1 in 17% cis vs 35% carbo). Table 1 showed similar efficacy outcomes with potentially marginally superior OS with cisplatin. The comparison of efficacy and QOL endpoints for 3 vs 6 cycles of carboplatin showed many similarities. Six cycles of cisplatin-based chemotherapy was associated with a major drop in QOL compared to 3 cycles without showing any clear benefits in efficacy endpoints. Conclusions: The QoL benefits of shorter chemotherapy appear to be more marked in patients receiving cisplatin than carboplatin. The efficacy results for 3 cycles of cisplatin were impressive. This study was not powered for non-inferiority. Clinical trial information: NCT06892860 . Outcomes by treatment arm. 3C/cis (n=56) 3C/carbo (n=77) 6C/cis (n=54) 6C/carbo(n=80) CR (%) 16% 10% 14% 12% PFS (months), median(95% CI) 8.8(6.5-12.8) 8.0(5.8-12.0) 8.7(6.4-18.9) 9.0(6.6-13.1) OS (months), median(95% CI) Not reached(12.8-.) 18.5(12.6-.) 21.9(10.5-.) 15.0(9.8-.) G3 and above TRAE (n) 32 40 49 79 PRO (change from baseline to C7D1) 2.96 -2.51 -13.44 -4.86

We report on the randomized portion of the phase 2, open-label CheckMate 650 trial (NCT02985957), in which docetaxel-experienced, biologically male patients with chemotherapy-refractory metastatic castration-resistant prostate cancer were randomized 2:2:1:2 to nivolumab 3 mg /kg plus ipilimumab 1 mg /kg (n = 73), nivolumab 1 mg /kg plus ipilimumab 3 mg /kg (n = 74), ipilimumab 3 mg /kg (n = 38), or cabazitaxel (n = 74). Primary endpoints were objective response rate and radiographic progression-free survival; key secondary endpoints included overall survival, prostate-specific antigen response rate, and safety. This portion of CheckMate 650 was not designed to statistically compare between cohorts. Respectively, objective response rates (95% CI) were 9.3% (2.6-22.1), 19.5% (8.8-34.9), 4.5% (0.1-22.8), and 12.2% (4.1-26.2), and median radiographic progression-free survival (95% CI) was 3.9 (2.2-7.6), 4.2 (3.3-5.6), 3.5 (2.1-5.8), and 7.9 (5.6-9.3) months. Respective incidence of grade ≥3 treatment-related adverse events was 28.8%, 30.1%, 18.4%, and 34.7%. Preliminary post hoc biomarker analyses in patients who received treatment with any immunotherapy regimen (i.e., treated with either of the nivolumab plus ipilimumab regimens or with ipilimumab alone, n = 12) identified a transcriptional signature, derived from the most highly expressed genes across cell types within select perivascular immune niches (comprising CD31+ endothelial, CD14+HLA-DR+ myeloid, and CD4+ and CD8+ T cells), which was associated with prolonged overall survival. These results provide further evidence of antitumor activity with nivolumab plus ipilimumab in select patients with metastatic castration-resistant prostate cancer and nominate a candidate prognostic biomarker that warrants confirmation in future prospective clinical trials.

LBA138 Background: Mevrometostat (M) is a potent and selective inhibitor of EZH2. Dose exploration of M + enzalutamide (E) + androgen deprivation therapy (ADT) showed a manageable safety profile with evidence of EZH2 pharmacodynamic inhibition, objective response (OR), and decline in prostate-specific antigen of ≥50% from baseline (PSA 50 ) in patients (pts) with mCRPC (NCT03460977). We report outcomes from the open-label, randomized, dose expansion part of this study. Methods: Pts with mCRPC who received prior abiraterone, ≤1 prior chemotherapy in any setting, with evidence of progression per modified Prostate Cancer Working Group 3 criteria were included. Pts receiving ADT were randomized 1:1 to M (orally, 1250 mg BID on empty stomach) + E (160 mg QD) or E, stratified by prior chemotherapy. Primary endpoints were radiographic progression-free survival (rPFS) per investigator assessment and safety. Secondary endpoints included OR by RECIST 1.1 (for pts with measurable disease at baseline), PSA 50 , and pharmacokinetics. Results: As of Sept 2, 2024,81 pts were included (M+E, n=41; E, n=40). Median (IQR) follow-up was 9.6 (3.1-14.5) mo. Median (range) age (yrs) was 70 (48-86) for M+E and 71.5 (50-86) for E. Overall, 43.9% of pts in the M+E group and 45.0% in the E group received prior taxane therapy. Median (95% CI) rPFS was 14.3 (7.5, not estimable) mo for M+E and 6.2 (4.1, 13.9) mo for E (hazard ratio 0.51; 90% CI 0.28, 0.95). In pts with measurable disease at baseline (M+E, n=15; E, n=14), OR rate (95% CI) was 26.7% (7.8, 55.1) for M+E (4 partial responses [PRs]) and 14.3% (1.8, 42.8) for E (2 PRs). Confirmed PSA 50 (95% CI) was observed in 34.1% (20.1, 50.6) of pts for M+E and 15.4% (6.0, 31.3) for E. Most common treatment-emergent adverse events (TEAEs) were diarrhea (78.0%), decreased appetite (58.5%), and dysgeusia (58.5%) for M+E, and asthenic conditions (42.5%), nausea (25.0%), and anemia (22.5%) for E. Grade ≥3 TEAEs were observed in 53.7% of pts in M+E (most common diarrhea, neutropenia and sepsis) and 42.5% in E. There were no treatment-related deaths. Geometric mean plasma exposures of M after multiple doses in combination with E were comparable for M 1250 mg on empty stomach and M 875 mg with food (AUC tau [h*ng/mL]: 1250 mg, 8733; 875 mg, 9631; C max [ng/mL]: 1250 mg, 2371; 875 mg, 1868). In M+E combination, M 875 mg with food had an improved safety profile compared with M 1250 mg on empty stomach. Conclusions: M+E shows improved outcomes vs E in pts with mCRPC, with a manageable AE profile. In M+E combination, M 875 mg with food has similar plasma exposure as M 1250 mg on empty stomach. Further investigation of M+E in pts with mCRPC is warranted. Disclosure: Pfizer's generative AI tool, MAIA, was used to draft this abstract (accessed: 2024-10-24); authors reviewed, edited, and take full responsibility for the content. Clinical trial information: NCT03460977 .

BACKGROUND AND OBJECTIVE:Prostate cancer is typically a disease of older men. As patients age, they develop comorbidities and require more medications, which may adversely affect or be affected by prostate cancer treatments. We investigated whether the survival benefits and favorable safety profile of darolutamide in the phase 3 ARASENS trial could be seen regardless of age. METHODS:Patients received darolutamide 600 mg or placebo orally twice daily plus androgen-deprivation therapy and docetaxel. Outcomes were assessed in subgroups of patients aged <75 yr (n = 1086) and ≥75 yr (n = 219). KEY FINDINGS AND LIMITATIONS:Most patients in both age groups had comorbidities (<75 yr: 94%; ≥75 yr: 97%) and concomitant medications (median 8-9). In both age subgroups, compared with placebo, darolutamide increased overall survival (<75 yr: hazard ratio 0.70 [95% confidence interval 0.58-0.84]; ≥75 yr: 0.61 [0.41-0.91]), delayed time to metastatic castration-resistant prostate cancer (<75 yr: 0.35 [0.30-0.43]; ≥75 yr: 0.42 [0.28-0.64]), and delayed time to initiation of subsequent therapy (<75 yr: 0.40 [0.34-0.48]; ≥75 yr: 0.35 [0.22-0.54]). Treatment-emergent adverse events were similar in the darolutamide/placebo groups, with slightly higher incidences in older patients. This analysis is limited by its post hoc nature. CONCLUSIONS AND CLINICAL IMPLICATIONS:In the 219 patients aged ≥75 yr in ARASENS, darolutamide demonstrated improved efficacy versus placebo and favorable safety, consistent with the findings in patients aged <75 yr. Thus, darolutamide and androgen-deprivation therapy with docetaxel can be considered a standard of care triplet therapy for metastatic hormone-sensitive prostate cancer regardless of patients' age.