Neoadjuvant treatment patterns and biomarker selection in muscle-invasive bladder cancer

Abstract

As the feasibility of risk-adaptive bladder-sparing treatment is increasingly validated, the prospects for neoadjuvant therapy in muscle-invasive bladder cancer (MIBC) are rapidly evolving. For patients seeking effective and tolerable treatment options, platinum-based chemotherapy, particularly dose-dense MVAC (ddMVAC), remains the preferred standard. However, the emergence of novel interventions such as immune checkpoint inhibitors (ICIs), FGFR inhibitors, and antibody-drug conjugates (ADCs) offers promising alternatives, especially for those ineligible for cisplatin-based regimens. Ongoing clinical trials, including KEYNOTE-B15, RC48-C017, and NIAGARA, are actively investigating the efficacy of combining these agents with existing neoadjuvant therapies, aiming to establish new first-line treatment options. Although predictive models based on histological features, DNA damage repair (DDR) genes, molecular subtyping, liquid biopsies, and in vitro organoids have demonstrated potential in guiding treatment selection, the clinical translation process remains slow. There is a pressing need to accelerate the exploration of genetic heterogeneity in MIBC and to validate the clinical utility of emerging biomarkers to optimize patient selection for neoadjuvant therapy. This review will comprehensively examine the evolution of neoadjuvant treatment paradigms, focusing on high-quality evidence from evidence-based medicine and translational clinical research, with the aim of enhancing and updating readers' knowledge of neoadjuvant therapy for MIBC and providing insights for future practice and research directions.

Keywords: Clinical trials; Liquid biopsy; Muscle-invasive bladder cancer; Neoadjuvant therapy.

Fig. 1

Timeline of the development of neoadjuvant therapy for MIBC. In the 1980s, MVAC became the first chemotherapy regimen used for neoadjuvant therapy in MIBC. Over the following two decades, the results of several large Phase III randomized trials established NAC as the standard treatment for localized MIBC. Recently, ICI, targeted therapies, and ADCs have been approved for mUC treatment, leading to updates in the neoadjuvant treatment landscape for MIBC. BCa Bladder Cancer; MVAC Methotrexate, Vinblastine, Doxorubicin, and Cisplatin; mUC Metastatic Urothelial Carcinoma; CA Cisplatin and Doxorubicin; RT Radiotherapy; GC Gemcitabine and Cisplatin; ddMVAC Dose-Dense MVAC; SCUC Small Cell Urothelial Carcinoma; CMV Cisplatin, Methotrexate, Vinblastine; ddGC Dose-Dense GC; ICI Immune Checkpoint Inhibitor; ADC Antibody–Drug Conjugate; NAC Neoadjuvant Chemotherapy; RCT Randomized Controlled Trial; MIBC Muscle-Invasive Bladder Cancer (Created with BioRender.com)

Fig. 2

The mechanisms of neoadjuvant therapy drugs for mIBC and potential combination strategies. The cisplatin-based neoadjuvant chemotherapy (NAC) impedes DNA transcription and replication by targeting DNA to form Pt–DNA cross-links, leading to cytotoxic events. Radiotherapy (RT) employs high-energy ionizing radiation, which damages DNA directly or generates charged species within cells, inducing impairment and apoptosis in cancer cells. Furthermore, RT is thought to possess immunomodulatory effects and exhibits a synergistic relationship with immune checkpoint inhibitors (ICI). ICIs activate or restore T-cell antitumor activity by blocking the interaction of checkpoint molecules such as cytotoxic T lymphocyte-associated protein 4 (CTLA-4) or programmed cell death receptor 1 (PD-1)/programmed cell death ligand 1 (PD-L1) with their respective receptors. Bladder cancer (BCa) cells are known to highly express surface proteins such as Nectin-4, HER2, and Trop-2. Antibody–drug conjugates (ADC) combine specificity and potency by chemically linking monoclonal antibodies targeting these markers with cytotoxic drugs, enabling selective delivery of therapeutically effective payloads to tumor sites. Target agents (TA) selectively inhibit pathway alterations associated with specific gene mutations in BCa cells, effectively blocking tumor progression. The aforementioned combinations of neoadjuvant therapeutic options are currently being evaluated in clinical trials. MVAC Methotrexate, Vinblastine, Doxorubicin, and Cisplatin; GC Gemcitabine and Cisplatin; ddMVAC Dose-Dense MVAC; CMV Cisplatin, Methotrexate, Vinblastine (Created with BioRender.com)

Fig. 3

Evolving paradigms of neoadjuvant therapy for MIBC. In current practice, platinum-based neoadjuvant chemotherapy (NAC) is the standard treatment for patients with muscle-invasive bladder cancer (MIBC). Neoadjuvant immunotherapy remains limited to the clinical trial setting. Patients who receive neoadjuvant treatment and achieve clinical/pathological remission have a better prognosis and a higher chance of bladder preservation. The criteria for neoadjuvant treatment eligibility are being optimized, and with the advent of the era of immunotherapy, combination regimens involving immune checkpoint inhibitors (ICI) are expected to replace single-agent neoadjuvant chemotherapy as the new standard of care. Precision medicine will further guide individualized clinical decision-making, utilizing information from multi-omics phenotypes and organoid drug sensitivity predictions to help patients achieve the greatest benefit. ADC, antibody–drug conjugates; RC, radical cystectomy (Created with BioRender.com)