Metastatic urothelial cancer, associated with a poor prognosis, is still major cause of cancer-related death, with scarce options of effective treatment after progression to platinum-based chemotherapy and immunotherapy. The human epithelial growth factor receptor 2 (Her-2) has been identified as a new therapeutic target in medical oncology. However, despite the encouraging results in breast and gastric cancers, clinical trials with anti-Her-2 monoclonal antibodies and tyrosine-kinase inhibitors have shown limited efficacy of this strategy in urothelial tumors. Notably, more favorable data have been recently shown that antibody-drug conjugates are currently emerging as a novel promising approach for Her-2 targeted therapy in advanced urothelial cancer.

There is substantial heterogeneity between different subtypes of sarcoma regarding their biological behavior and microenvironment, which impacts their responsiveness to immunotherapy. Alveolar soft-part sarcoma, synovial sarcoma and undifferentiated pleomorphic sarcoma show higher immunogenicity and better responses to checkpoint inhibitors. Combination strategies adding immunotherapy to chemotherapy and/or tyrosine–kinase inhibitors globally seem superior to single-agent schemes. Therapeutic vaccines and different forms of adoptive cell therapy, mainly engineered TCRs, CAR-T cells and TIL therapy, are emerging as new forms of immunotherapy for advanced solid tumors. Tumor lymphocytic infiltration and other prognostic and predictive biomarkers are under research.

Immune checkpoint inhibitors (ICI) have changed the therapeutic landscape of many solid tumors. Modulation of the intestinal microbiota by antibiotics (Abx) has been suggested to impact on ICI outcomes. Retrospective analysis of 475 patients with advanced solid tumors treated with ICI from 2015 to 2022. For each patient, the use of Abx was recorded from 1 month before ICI initiation until disease progression or death. The impact of Abx on objective response rates (ORR), disease control rates (DCR), progression-free survival (PFS), and overall survival (OS) was analyzed. Kaplan-Meier and log-rank tests were used to compare survival outcomes. In total 475 patients with advanced solid tumors were evaluated. Median age was 67.5 years and performance status (PS) was 0-1 in 84.6%. 66.5% of patients received Abx during treatment with ICI, mainly beta-lactams (53.8%) and quinolones (35.9%). The early exposure to Abx (from 60 days before to 42 days after the first cycle of ICI) was associated with a lower ORR (27.4% vs 39.4%; P < .01), a lower DCR (37.3% vs 57.4%; P < .001), lower PFS (16.8 m vs 27.8 m; HR 0.66; P < .001]) and lower OS (2.5 m vs 6.6 m; HR 0.68; P = .001]). The negative impact of Abx on OS and PFS was confirmed by a multivariable analysis. This effect was not observed among patients receiving Abx after 6 weeks from ICI initiation. Our results validate the hypothesis of a detrimental effect of an early exposure to Abxon the efficacy of ICI in a multi-tumor cohort of patients.

Metastatic urothelial carcinoma (mUC) is a common tumor associated with high mortality. To date, the standard chemotherapy-based treatment has yielded suboptimal outcomes, characterized by limited survival and a substantial impact on patients’ quality of life. The introduction of new therapies has significantly improved overall survival (OS) and progression-free survival (PFS) rates. However, bringing novel treatments into clinical practice comes with an unfamiliar toxicity profile that may influence the choice of systemic therapy. The aim of this review is to analyze the toxicity of these new therapies and reflect on the role of appropriate management in treatment selection and planning of therapeutic sequencing in patients with mUC.

Urothelial carcinoma ranks among the most common solid tumors and exhibits aggressive behavior, with limited survival in the metastatic setting despite recent therapeutic advances. Currently, 3 first-line systemic treatment options are supported by level IA evidence, yet no validated predictive biomarkers exist to guide selection among them. Alterations in DNA damage response (DDR) pathways occur in a substantial proportion of urothelial tumors and have emerged as potential predictive biomarkers of treatment sensitivity. This review examines the biological basis of DDR pathways and their implications in carcinogenesis, summarizes the frequency and spectrum of DDR gene alterations in urothelial carcinoma, and critically appraises the available evidence linking these alterations to responses to platinum-based chemotherapy, immune checkpoint inhibitors, and PARP inhibitors in both muscle-invasive and metastatic settings. Although retrospective data suggest associations between DDR alterations and improved outcomes with certain therapies, results across studies are heterogeneous, likely reflecting inconsistent definitions of DDR alterations, the variable functional impact of individual mutations, and differences in patient populations. We discuss these limitations and highlight the need for standardized criteria and prospective validation to determine whether DDR pathway alterations can be reliably integrated into clinical decision-making for patients with urothelial carcinoma.