There is no standard first-line chemotherapy for advanced urothelial carcinoma (aUC) in cisplatin-ineligible (cisplatin-unfit) patients. The study assessed the efficacy and tolerability profile of two vinflunine-based cytotoxic regimens in this setting. Patients with aUC a creatinine clearance (CrCl) of <60 but ≥30 ml/min, performance status 0 or 1 and no prior chemotherapy for advanced disease were randomized (1 : 1). They received vinflunine 250 or 280 mg/m² (based on baseline CrCl) on day 1, plus either gemcitabine [750 mg/m² escalated to 1000 mg/m² in cycle 2 if no toxicity grade (G) ≥2 on days 1 and 8 (VG) or plus carboplatin area under the curve 4.5 day 1 (VC) every 21 days]. To detect a 22% improvement in each arm compared with H0 (41%) in the primary end point, disease control rate (DCR = complete response + partial response + stable disease), 31 assessable patients per arm were required (α = 5%, β = 20%). Sixty-nine patients were enrolled (34 VG, 35 VC). Less G3/4 haematological adverse events (AEs) were reported with VG: neutropaenia was seen in 38% (versus 68% with VC) and febrile neutropaenia in 3% (versus 14% with VC) of patients. No major differences were observed for non-haematological AEs. DCR was 77% in both groups; overall response rate (ORR) was 44.1% versus 28.6%, with a median progression-free survival of 5.9 versus 6.1 months and median OS of 14.0 versus 12.8 months with VG and VC, respectively. Both vinflunine-based doublets offer a similar DCR, ORR and OS. The better haematological tolerance favours the VG combination, which warrants further study. NCT 01599013.

The De Ritis ratio (=aspartate transaminase/alanine transaminase) has shown prognostic value in different cancer types. This is the first such analysis in prostate cancer patients undergoing radioligand therapy (RLT) with [¹⁷⁷Lu]Lu-PSMA-617. This retrospective monocentric analysis included 91 patients with a median of 3 RLT cycles (range 1–6) and median cumulative activity of 17.3 GBq. Univariable Cox regression regarding overall survival (OS) included age, different types of previous treatment, metastatic patterns and different laboratory parameters before RLT. Based on multivariable Cox regression, a prognostic score was derived. Seventy-two patients (79%) died (median follow-up in survivors: 19.8 months). A higher number of previous chemotherapy lines, the presence of liver metastases, brain metastases, a higher tumor load on PSMA-PET, a higher prostate-specific antigen (PSA) level, lower red blood cell count, lower hemoglobin, higher neutrophil-lymphocyte ratio and higher De Ritis ratio were associated with shorter OS (each p < 0.05). In multivariable Cox, a higher number of chemotherapy lines (range, 0–2; p = 0.036), brain metastases (p < 0.001), higher PSA (p = 0.004) and higher De Ritis ratio before RLT (hazard ratio, 1.27 per unit increase; p = 0.023) remained significant. This prognostic score separated five groups with a significantly different median OS ranging from 4.9 to 28.1 months (log-rank test, p < 0.001). If validated independently, the De Ritis ratio could enhance multifactorial models for OS after RLT.

Testing for PD-L1 expression by IHC is used to predict immune checkpoint blockade (ICB) benefits but has performed inconsistently in urothelial cancer clinical trials. Different approaches are used for PD-L1 IHC. We analyzed paired PD-L1 IHC data on urothelial cancer samples using the SP142 and 22C3 assays from the phase III IMvigor130 trial and found discordant findings summarized by four phenotypes: PD-L1 positive by both assays, PD-L1 positive by the SP142 assay only, PD-L1 positive by the 22C3 assay only, and PD-L1 negative by both assays double negative. PD-L1 positive by both assays and PD-L1 positive by the SP142 assay only urothelial cancers were associated with more favorable ICB outcomes and increased dendritic cell (DC) infiltration. SP142 PD-L1 staining co-localized with DC-LAMP, a DC marker, whereas 22C3 staining was more diffuse. PD-L1 positive by the 22C3 assay only urothelial cancers, associated with worse outcomes, were enriched in tumor cell (TC)–dominant PD-L1 expression. Multiplex IHC in an independent ICB-treated cohort confirmed that TC-dominant PD-L1 expression was associated with shorter survival. Using different PD-L1 assays, we uncovered that SP142 may preferentially stain PD-L1–expressing DCs, key to orchestrating antitumor immunity, whereas TC-dominant PD-L1 expression, which underlies a subset of “PD-L1–positive” specimens, is associated with poor ICB outcomes. See related Spotlight by Karunamurthy and Davar, p. 454 .

Purpose To assess the epidemiology, treatment patterns, and Bacillus Calmette–Guérin (BCG) instillations in Non-Muscle-Invasive Bladder Cancer (NMIBC) patients to evaluate guidelines compliance and effectiveness of adherence on real-world outcomes. Methods NMIBC patients with BCG-treatment were identified in a retrospective cohort study using German health claims data. The first BCG prescription was defined as index date. Crude and standardized annual incidence were calculated. Subsequent treatment regimens were described based on prescriptions to assess adherence. BCG-maintenance adherents were compared with non-adherents using a landmark time approach and Cox proportional hazard model. Results The annual standardized incidence per 100,000 for intermediate- and high-risk NMIBC patients ranged from 7.6 to 10.4 in males and 1.2 to 1.9 in females from 2017 to 2021. The main cohort consisted of 817 patients (mean age: 72.5; male: 78%). Most patients (98%) received transurethral resection of bladder tumor (TURBT) as initial treatment followed by BCG, with a median number of 13 BCG instillations per patient (IQR: 8–21). 28% continued BCG in the maintenance phase at 24 months post-induction and 62% received at least one Re-TURBT post-index. BCG maintenance-adherent patients showed lower risk compared with non-adherent patients: adjusted hazard ratio (aHR): 0.92 [0.73–1.18] for all-cause death; aHR: 0.49 [0.36–0.67] for advanced treatment; aHR: 0.65 [0.53–0.80] for disease progression. Conclusion Real-world compliance with clinical guidelines may require improvement based on BCG maintenance duration and adherence to treatment schedules. The benefits of BCG adherence in improving oncology-relevant outcomes support guidelines recommendations for sufficient BCG maintenance.