Aim: The aim of this multicenter study was to assess patient characteristics and short-term survival outcomes of first-line (1L) enfortumab vedotin plus pembrolizumab (EVP) as compared with conventional chemotherapy in locally advanced or metastatic urothelial carcinoma (la/mUC). Methods: The database included 642 patients with la/mUC diagnosed between January 2008 and December 2025 at 12 collaborating hospitals. Baseline characteristics and follow-up data, including overall and organ-specific objective tumor response according to the RECIST v1.1, progression-free survival, and duration of response, were compared among the 1L regimens. Treatment-related adverse events (TRAEs) were graded according to the CTCAE v5.0 in patients treated with 1L EVP. Results: The objective response and disease control rate were higher with 1L EVP than with chemotherapy (66% vs. 42% and 83% vs. 68%, respectively). The organ-specific response rate for liver metastatic lesions was 85%. Median progression-free survival (95% confidence interval) for 1L EVP, gemcitabine plus cisplatin, and gemcitabine plus carboplatin was 14.5 months (10.5–not determined), 10.5 months (8.4–13.3), and 9.2 months (6.7–14.2), respectively. In the safety analysis set including 40 patients, all-grade TRAEs occurred in 36 (90%) patients, including grade 1–2 events in 30 (75%) and grade 3–4 toxicities in 6 (15%). Grade 3–4 TRAEs included skin toxicity (7.5%), anorexia (5.0%), anemia (5.0%), gastrointestinal disorders (2.5%), renal dysfunction (2.5%), and interstitial lung disease (2.5%). The median number of administered EV cycles was 4 (range, 1–13), 5 (2–13), and 10 (4–13) in the overall, responder, and complete-response populations, respectively. EV dose modifications and interruptions were frequent in the initial 2 months but rare thereafter. Conclusions: This multicenter study provides real-world evidence on short-term outcomes and safety with 1L EVP, highlighting its impact on the evolving treatment landscape for la/mUC.

Endocrine resistance in estrogen receptor-positive (ER+) breast cancer has undergone a fundamental reconceptualization over the past decade. The discovery that activating mutations in the ESR1 gene encoding ERα emerge under aromatase inhibitor (AI) selection pressure and drive ligand-independent receptor activation established a shift from empirical treatment sequencing to molecularly guided intervention. This review provides a synopsis of the structural biology underlying constitutive ER activation, the evolutionary dynamics of ESR1-mutant clones detectable through circulating tumor DNA (ctDNA), and the clinical evidence demonstrating that early molecular detection can trigger therapeutic switches that alter disease trajectory. The regulatory approval of elacestrant for ESR1-mutant disease and randomized trial data showing progression-free survival (PFS) benefit from ctDNA-guided endocrine switching (PADA-1, SERENA-6) position ESR1 genotyping as a dynamic biomarker with direct therapeutic implications. We examine the integration of oral selective ER degraders (SERDs) into treatment algorithms, the role of co-occurring alterations in the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway, and emerging directions, including machine learning approaches to ctDNA kinetics and adaptive trial designs that treat clonal evolution as an actionable target. The convergence of structural mechanisms, liquid biopsy technology, and biomarker-driven drug development provides a framework for precision oncology in endocrine-resistant breast cancer. While these advances are substantial, important challenges remain, including the lack of mature overall survival (OS) data from interception trials, cost and accessibility barriers to serial ctDNA monitoring in diverse global healthcare settings, the unresolved question of optimal therapeutic sequencing in patients with concurrent ESR1 and PI3K pathway alterations, and the need to distinguish clinically actionable low-variant allele frequency (VAF) ESR1 calls from background noise in liquid biopsies.

This commentary discusses the FDA’s drug approvals in 2025, with a particular focus on cancer therapies and the role of companion diagnostics (CDx). Cancer has emerged as the leading therapeutic area, accounting for 35% of all new drug approvals, largely driven by targeted therapies, with kinase inhibitors representing nearly half of these drugs. Many of the drugs have received orphan drug designations and/or have utilized the Accelerated Approval Program. A key finding was the widespread adoption of the drug-diagnostic co-development model, in which a CDx assay is developed along with the drug and used for patient selection in clinical trials. However, a significant challenge is the frequent lack of concurrent drug and CDx assay approvals. The absence of an analytically and clinically validated CDx assay may pose a challenge for healthcare providers in accurately identifying eligible patients, potentially delaying access to appropriate therapy. The FDA’s cancer drug approvals for 2025 highlight an ongoing commitment to precision medicine, with several new targeted treatments, such as antibody-drug conjugates and kinase inhibitors, where CDx assays play an important role in identifying the appropriate patient population.