A Pilot Study of the Combination of 5-Azacitidine and All-trans Retinoic Acid in Biochemically Recurrent Prostate Cancer.

Purpose: Biochemical recurrence (BCR) after definitive local therapy remains a major clinical challenge in prostate cancer (PCa), with heterogeneous disease trajectories and few established strategies to delay further progression without prolonged androgen deprivation. This pilot study evaluated the combination of 5-azacitidine (AZA) and all-trans retinoic acid (ATRA) to induce tumor dormancy and delay clinical progression in patients with BCR.

Experimental Design: In a prospective, open-label, randomized, single-institution pilot trial, patients with BCR of PCa and no recent hormonal or definitive therapy received low-dose AZA and sequential ATRA.

HER2 and urothelial carcinoma: current understanding and future directions.

Human epidermal growth factor receptor 2 (HER2) has emerged as a crucial biomarker across various cancers, shaping therapeutic strategies and prognostic evaluations. In urothelial carcinoma, HER2 positivity rates can reach up to 68% when HER2-low tumours (immunohistochemistry 1+) are included in the analysis. HER2 overexpression and ERBB2 genomic alterations have been linked to advanced disease stages and poor outcomes in urothelial carcinoma.

Adjuvant nivolumab in muscle-invasive urothelial carcinoma: exploratory biomarker analysis of the randomized phase 3 CheckMate 274 trial.

Nivolumab monotherapy has been approved for the adjuvant treatment of adult patients with urothelial carcinoma who are at high risk of recurrence after undergoing radical resection of urothelial carcinoma based on results of the phase 3 CheckMate 274 trial, in which adjuvant nivolumab versus placebo demonstrated improvement in the primary endpoint of disease-free survival (DFS) in high-risk muscle-invasive urothelial carcinoma (MIUC). Identification of biomarkers associated with treatment outcomes can help refine patient selection, and inform on the immunobiology of disease. To assess the relevance of key biomarkers in the adjuvant MIUC setting, extensive exploratory analyses of tumor biomarkers, including associations with DFS, were performed.

Pathogenic Genomic Alterations in Circulating Tumor DNA Predict Overall Survival in Men with Metastatic Castrate-resistant Prostate Cancer.

Background And Objective: Although validated prognostic models exist for men with metastatic castration-resistant prostate cancer (mCRPC), current tools do not incorporate genomic biomarkers such as circulating tumor DNA (ctDNA) aneuploidy or pathogenic genetic alterations (PGAs). This study aimed to estimate the prevalence of PGAs in ctDNA, assess their correlation with ctDNA aneuploidy fraction, and evaluate their association with overall survival (OS). Additionally, we developed and validated a clinical-genetic (CG) model to predict OS.

Muscle-Invasive Bladder Cancer: A Watershed Moment.

The treatment of muscle-invasive bladder cancer (MIBC) has evolved substantially over the past several decades. Muscle-invasive bladder cancer is a disease of older individuals who often have comorbidities and age-associated changes in physiologic function. This has historically created a disconnect between the efficacy of treatment for MIBC as defined in the setting of clinical trials and the effectiveness of treatments when applied to the broader population of patients.

SGNDV-001: disitamab vedotin with pembrolizumab in HER2-expressing locally advanced or metastatic urothelial carcinoma.

Introduction: Platinum-based chemotherapy for the treatment of locally advanced or metastatic urothelial carcinoma (la/mUC), has been the first-line standard of care for many decades. Enfortumab vedotin, an antibody-drug conjugate, combined with pembrolizumab, a programmed death 1 (PD-1) inhibitor, recently demonstrated improved efficacy versus chemotherapy in la/mUC. Since 60%-80% of patients with UC have tumors expressing human epidermal growth factor receptor 2 (HER2), HER2-directed vedotin-based antibody-drug conjugates may also be beneficial in la/mUC.

The Evolving Treatment Paradigm for Upper Tract Urothelial Carcinoma.

Treatment decisions for patients with upper tract urothelial carcinoma (UTUC) require individualized assessments that weigh tumor characteristics, patient factors, and the evidence available. Adjuvant immune checkpoint blockade represents a significant advance in UTUC management, particularly for patients who are ineligible for cisplatin and those with residual disease after neoadjuvant therapy.

Sasanlimab plus BCG in BCG-naive, high-risk non-muscle invasive bladder cancer: the randomized phase 3 CREST trial.

Bacillus Calmette-Guérin (BCG) induction and maintenance (I+M) after transurethral resection of bladder tumor is standard of care (SOC) in high-risk non-muscle invasive bladder cancer (NMIBC). However, disease recurrence/progression occurs in approximately 40% of patients at 2 years, with unfavorable prognosis. Limited bladder-sparing therapeutic options exist, and no improvements to response durability have been observed in decades.

Enfortumab vedotin plus pembrolizumab versus chemotherapy in patients with previously untreated locally advanced or metastatic urothelial cancer (EV-302): patient-reported outcomes from an open-label, randomised, controlled, phase 3 study.

Background: In the ongoing EV-302 trial, first-line enfortumab vedotin plus pembrolizumab improved progression-free survival and overall survival versus platinum-based chemotherapy in patients with locally advanced or metastatic urothelial cancer. Patient-reported outcomes (PROs) from EV-302 are reported here.

Methods: EV-302 was a phase 3, open-label, two-group, randomised global study to evaluate the combination of enfortumab vedotin plus pembrolizumab versus standard-of-care platinum-based chemotherapy (gemcitabine with cisplatin or carboplatin) in patients with previously untreated locally advanced or metastatic urothelial cancer.

Characterization of Patients with Lymph Node Only Metastatic Urothelial Carcinoma Treated with Nivolumab Plus Gemcitabine-Cisplatin Versus Gemcitabine-Cisplatin Alone from the CheckMate 901 Trial.

Nivolumab (NIVO) plus gemcitabine-cisplatin (GC) demonstrated deep, durable responses in patients with untreated unresectable or metastatic urothelial carcinoma (mUC) with superior overall (OS) and progression-free (PFS) survival versus GC alone. We report post hoc exploratory analyses with 33.6 mo of median follow-up in patients with lymph node (LN) only disease from CheckMate 901.

Atezolizumab plus personalized neoantigen vaccination in urothelial cancer: a phase 1 trial.

Features of constrained adaptive immunity and high neoantigen burden have been correlated with response to immune checkpoint inhibitors (ICIs). In an attempt to stimulate antitumor immunity, we evaluated atezolizumab (anti-programmed cell death protein 1 ligand 1) in combination with PGV001, a personalized neoantigen vaccine, in participants with urothelial cancer. The primary endpoints were feasibility (as defined by neoantigen identification, peptide synthesis, vaccine production time and vaccine administration) and safety.

Circulating tumour DNA and circulating tumour cells in bladder cancer - from discovery to clinical implementation.

Liquid biopsies, indicating the sampling of body fluids rather than solid-tissue biopsies, have the potential to revolutionize cancer care through personalized, noninvasive disease detection and monitoring. Circulating tumour DNA (ctDNA) and circulating tumour cells (CTCs) are promising blood-based biomarkers in bladder cancer. Results from several studies have shown the clinical potential of ctDNA and CTCs in bladder cancer for prognostication, treatment-response monitoring, and early detection of minimal residual disease and disease recurrence.

PGV001, a Multi-Peptide Personalized Neoantigen Vaccine Platform: Phase I Study in Patients with Solid and Hematologic Malignancies in the Adjuvant Setting.

The PGV001 platform is feasible, safe, and immunogenic. The OpenVax pipeline predicted immunogenic neoantigens in tumors with wide-ranging mutational burdens. Data from this study prompted three additional PGV001 trials, one in newly diagnosed glioblastoma, one in urothelial cancer in combination with an ICI, and another in prostate cancer.

An evaluation of nivolumab plus gemcitabine and cisplatin in the treatment of advanced urothelial carcinoma.

Introduction: For decades, first-line treatment for advanced/metastatic urothelial cancer has been platinum-based chemotherapy. However, many patients do not respond to platinum-based chemotherapy alone, and the vast majority do not have durable responses. While immune checkpoint blockade has demonstrated benefit in this setting, initial trials of concurrent chemotherapy and immune checkpoint blockade did not demonstrate improvements in overall survival.

Clinical and Translational Results from PORTER, a Multicohort Phase I Platform Trial of Combination Immunotherapy in Metastatic Castration-Resistant Prostate Cancer.

Purpose: Current immune checkpoint therapies offer limited benefits for metastatic castration-resistant prostate cancer. Novel combinations may enhance immunotherapy efficacy.

Patients And Methods: We conducted an open-label, noncomparative platform trial (NCT03835533) in metastatic castration-resistant prostate cancer to assess nivolumab-based combinations.

Different PD-L1 Assays Reveal Distinct Immunobiology and Clinical Outcomes in Urothelial Cancer.

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.

Development of TAR-200: A novel targeted releasing system designed to provide sustained delivery of gemcitabine for patients with bladder cancer.

Treatment options for recurrent high-risk non-muscle-invasive bladder cancer (HR NMIBC) and muscle-invasive bladder cancer (MIBC) are limited, highlighting a need for clinically effective, accessible, and better-tolerated alternatives. In this review we examine the clinical development program of TAR-200, a novel targeted releasing system designed to provide sustained intravesical delivery of gemcitabine to address the needs of patients with NMIBC and of those with MIBC. We describe the concept and design of TAR-200 and the clinical development of this gemcitabine intravesical system in the SunRISe portfolio of studies.

Prediction of checkpoint inhibitor immunotherapy efficacy for cancer using routine blood tests and clinical data.

Predicting whether a patient with cancer will benefit from immune checkpoint inhibitors (ICIs) without resorting to advanced genomic or immunologic assays is an important clinical need. To address this, we developed and evaluated SCORPIO, a machine learning system that utilizes routine blood tests (complete blood count and comprehensive metabolic profile) alongside clinical characteristics from 9,745 ICI-treated patients across 21 cancer types. SCORPIO was trained on data from 1,628 patients across 17 cancer types from Memorial Sloan Kettering Cancer Center.

Financial Toxicity Among Patients With Advanced Solid Tumors Participating in Early-Phase Clinical Trials.

Purpose: Financial toxicity (FT) adversely influences patient quality of life and is a barrier to clinical trial enrollment. Early-phase clinical trials (EPCTs) recruit patients who may have high baseline FT and require additional visits and procedures, potentially increasing FT.

Methods: In this prospective survey study, we sought to assess FT at baseline and after 2 months among patients with advanced solid malignancies participating in EPCTs.

Molecular heterogeneity in urothelial carcinoma and determinants of clinical benefit to PD-L1 blockade.

Checkpoint inhibitors targeting programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) have revolutionized cancer therapy across many indications including urothelial carcinoma (UC). Because many patients do not benefit, a better understanding of the molecular mechanisms underlying response and resistance is needed to improve outcomes. We profiled tumors from 2,803 UC patients from four late-stage randomized clinical trials evaluating the PD-L1 inhibitor atezolizumab by RNA sequencing (RNA-seq), a targeted DNA panel, immunohistochemistry, and digital pathology.