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A major shift in the front-line treatment paradigm for muscle-invasive urothelial cancer (MIUC) means patients are now living longer, but complex clinical challenges remain, according to experts writing in a review in the .

In untreated locally advanced or metastatic urothelial carcinoma (mUC), for instance, the phase III demonstrated significant survival improvements with enfortumab vedotin (EV; Padcev) plus pembrolizumab (P; Keytruda) compared with standard-of-care chemotherapy. This finding "challenged the platinum paradigm" for initial upfront treatment, said Pooja Ghatalia, MD, of Fox Chase Cancer Center in Philadelphia, and colleagues.

Now, as platinum agents move into the second-line setting, the sequencing of multiple lines of therapy to optimize efficacy and minimize toxicity represents "the next uncharted territory" in contemporary urothelial cancer management, the authors said. "The decision regarding which first-line regimen to choose has become uniquely more complex as we continue to lack biomarkers to reliably predict response to each therapy, data on when to discontinue treatment, and how best to sequence these novel agents with traditional chemotherapy."

Ghatalia and co-authors did not respond to requests for comment, and the following Q&A is based on the text from the review.

How prevalent is MIUC among urothelial cancers overall, and what is the survival rate associated with diagnosis?

MIUC accounts for approximately 25% of new urothelial cancer diagnoses. About 50% of patients progress to within 2 years.

How effective is platinum-based chemotherapy in the first-line treatment of MIUC?

The integration of cisplatin-based neoadjuvant chemotherapy with local therapy of MIUC -- namely, -- has conferred an 8% absolute increase in in patients with MIUC. However, is associated with significant toxicity, and many patients do not benefit.

How are recent advances changing this?

The landscape of MIUC is changing rapidly, both from a molecular standpoint and from a therapeutic one. The former is driven by advances in ctDNA [circulating tumor DNA] and utDNA [urine tumor DNA] technologies to detect relapse or minimal residual disease, predict responses, and prognosticate distinct molecular subtypes.

Also, in patients with disease progression or inoperable disease, our first-line treatment arsenal now encompasses multiple types of therapeutics with vastly improved overall survival compared with traditional platinum-based chemotherapy.

What did the EV-302 trial data show?

The data indicated that in patients with mUC treated with EV-P in the initial front-line setting, the risk of death was reduced by 53% compared with standard of care. Over a follow-up period of 17.2 months, overall survival was 31.5 months with EV-P compared with 16.1 months with chemotherapy.

What's your main take-home message for physicians?

EV-P will become the new standard of care for mUC in the initial front-line setting. Determining the optimal dosing framework and sequencing of subsequent lines of treatment will create truly personalized medicine.

What looks promising for increasing rates of bladder preservation?

Our ability to identify clinically relevant molecular aberrations and to predict responses to different classes of agents, including [Trodelvy] and FGFR3 [fibroblast growth factor receptor 3]-directed therapies such as [Balversa] has become increasingly important.

The addition of perioperative biomarker testing, using ctDNA and/or utDNA, is an important step forward toward understanding which patients with MIUC are at increased risk for relapse and would benefit from additional therapy because of minimal residual disease positivity.

Ultimately, the identification of tumor characteristics that suggest a lower likelihood of recurrence may better predict who would benefit from bladder preservation versus those tumors with an aggressive phenotype requiring bladder removal.

What role does chemoradiotherapy play in helping patients with localized disease avoid cystectomy?

represents a unique approach to definitively treat localized disease with the potential for bladder preservation in select individuals. Our report reviews the role of definitive radiation in combination with chemotherapy for MIUC using the most up-to-date evidence, and gives consideration to the challenges associated with comparing this approach with neoadjuvant chemotherapy followed by cystectomy. It also looks at the importance of patient selection in determining candidacy for bladder preservation.

Read the review here and expert commentary about it here.