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Molecular testing has the potential to personalize treatments for muscle-invasive bladder cancer in the perioperative setting. In a in the 2024 ASCO Educational Book, Hemenway et al. provides current updates in management of muscle-invasive bladder cancer with a focus on biomarkers of minimal residual disease (MRD), bladder preservation approaches, and evolution of the treatment paradigm for frontline treatment of advanced urothelial carcinoma.

Circulating tumor DNA (ctDNA) and urinary tumor DNA are non-invasive means of evaluating MRD for both predictive and prognostic purposes. Hemenway and colleagues eloquently summarize the clinical trials to date that have tested their utility in the perioperative setting and future ongoing efforts.

While the phase III did not reveal survival improvement with adjuvant atezolizumab in the intention-to-treat analysis of patients with muscle-invasive urothelial carcinoma, an demonstrated a significant association of detectable ctDNA to the risk of disease recurrence. A greater reduction in ctDNA levels with atezolizumab was associated with longer overall survival.

The is a prospective trial that will evaluate the role of adjuvant atezolizumab in patients with detectable ctDNA. Another study, the , is an integrated phase II/III and phase III study of MRD-based optimization of adjuvant treatment with nivolumab ± relatlimab, a LAG-3 inhibitor. Taken together, these phase III studies will provide key insights to guide patient selection for adjuvant immunotherapy.

For patients treated with bladder-preserving approaches, patient selection remains key. At present, commonly used chemotherapy regimens in the radiosensitizing setting include weekly cisplatin, fluorouracil/mitomycin, and biweekly gemcitabine. Neoadjuvant chemotherapy does not have an established role at present prior to definitive chemoradiation. The authors summarize ongoing trials of immunotherapy being evaluated in organ-sparing studies, as well as novel approaches exploring genomic predictors of response to treatment in this setting.

Systemic treatment of advanced urothelial carcinoma witnessed several exciting updates in 2023. The was a phase III frontline study comparing the combination of enfortumab vedotin (EV)/pembrolizumab (pembro) with gemcitabine and platinum-based therapy. The significant improvement in objective response rate (68% vs 44%), complete response rate (29% vs 13%), and overall survival (31.5 months vs 16.1 months) with EV/pembrolizumab fortified its role as a new standard of care.

In contrast, the compared gemcitabine/cisplatin/nivolumab for up to six cycles followed by maintenance nivolumab for 2 years with standard gemcitabine/cisplatin alone. The primary end point of this study was also met, with improvement in overall survival in the intervention-to-treat arm (hazard ratio 0.78).

While both studies met their clinical end points, the improvement in overall survival and objective response rates demonstrated with EV/pembro are unprecedented. In this trial, EV/pembro was continued until disease progression or toxicity.

Ultimately, treatment selection requires careful consideration of patient comorbidities, disease biology, cost, and access. Clinicians will need to remain vigilant with management of long-term toxicities of EV/pembro, especially neuropathy and skin toxicities that can sometimes be fatal.

Hemenway and co-authors discuss strategies for alternative dosing and de-escalation strategies for EV/pembro that are currently being explored. Overall, this chapter provides a comprehensive review summarizing clinical data and nuances in current management of urothelial carcinoma.

is a GU medical oncologist at the University of Massachusetts Chan Medical School in Worcester.

Read the review here and a Q&A about it here.