Spotlighting Sequencing and Biomarkers in Bladder Cancer Management

The management of advanced urothelial carcinoma (UC) is undergoing rapid changes. With the integration of immunotherapy, antibody-drug conjugates (ADCs), and targeted agents, therapeutic sequencing and biomarker-driven decision-making have added high complexity and great promise. For community oncologists navigating this shifting terrain, understanding current standards and emerging data is critical.

Ahead of his presentation at the 4th Annual Miami Cancer Institute Precision Oncology Symposium, January 30 to 31, 2026, Targeted Oncology spoke with Petros Grivas, MD, PhD, FASCO, professor and medical director of the International Program and Local/Regional Outreach, Fred Hutch Cancer Center/University of Washington in Seattle, Washington. He provided a detailed roadmap for practice, emphasizing precision oncology, multi-/inter-disciplinary care, and the central role of clinical trials.

Frontline Standard and the Imperative of Early Biomarker Testing

The frontline paradigm for metastatic UC is now clearly defined, with enfortumab vedotin (EV; Padcev) plus pembrolizumab (Keytruda) established as the preferred regimen if available per European Society of Medical Oncology (ESMO) and many other guidelines.¹ However, Grivas emphasized that treatment planning for subsequent lines must begin at the time of advanced/metastatic disease diagnosis.

“I send comprehensive genomic profiling (CGP) using a multi-gene panel and immunohistochemistry (IHC) for HER2 using the gastric scoring system at the time of diagnosis of advanced/metastatic disease (not amenable to curative intent therapy),” Grivas, said. “This proactive testing is crucial, as the results, while typically not altering first-line therapy regimen, are essential for informing potential ‘salvage’ strategies.”

The key alterations sought are FGFR3 activating mutations or fusions/rearrangements (“susceptible” alterations), for potential use of the FGFR inhibitor erdafitinib (Balversa), and HER2 IHC expression (3+ by gastric scoring) for potential use of the anti-HER2 ADC trastuzumab deruxtecan (T-DXd; Enhertu).

“I want to have the results readily available if the patient has progression on frontline therapy,” he noted, highlighting that the optimal sequencing of subsequent “salvage therapies is not well defined.” Having such genomic and IHC data facilitates a more informed dialogue with patients if/when progression occurs.

In contrast, for patients with localized, muscle-invasive disease undergoing curative-intent therapy, Grivas does not routinely order CGP outside of a clinical trial context, as no FDA-approved therapies in that setting are currently selected based on such molecular profiling.

Post-EV/Pembrolizumab Crossroads

A primary challenge for oncologists arises after progression on frontline therapy, for example EV/pembrolizumab. Grivas outlined a nuanced decision tree without a single prospectively defined standard. “It’s a very important point to make: a well-informed discussion and shared decision making with the patient.”

For a patient experiencing progression post-EV/pembrolizumab, options include platinum-based chemotherapy (gemcitabine/cisplatin preferred or gemcitabine/carboplatin, based on fitness for cisplatin), especially for platinum-naïve patients, or targeted therapy if biomarkers are present. “Do you go to gemcitabine/cisplatin or carboplatin, or a targeted therapy approach with either erdafitinib or trastuzumab deruxtecan depending on biomarker presence?” he posited. This decision making is complex and integrates biomarker results, efficacy and toxicity profile of each regimen, route of administration, prior therapies, provider familiarity, medical comorbidities, functional/nutritional status, patient preference/wishes, etc.

He also addressed the status of sacituzumab govitecan-hziy (Trodelvy), an anti-TROP2 ADC with a topoisomerase I inhibitor payload, whose FDA approval in previously treated metastatic UC was withdrawn in late 2024 for its indication in metastatic UC.² Previously, the agency had granted accelerated approval to this ADC in 2021 based on phase 2 trial data.³

“The question is, is that an option?” Grivas asked. He stated that he may use it selectively in later lines of therapy, following life-prolonging therapies, and with primary prophylaxis using granulocyte colony-stimulating factor to mitigate neutropenia risk.

The Evolving Role of ctDNA: Prognostic, Predictive, and Context-Dependent

The role of circulating tumor DNA (ctDNA) is distinct from and complementary to tissue-based genomic profiling. He noted that quantitative (minimal residual disease [MRD] assessment), tumor-informed ctDNA assay is finding a practical niche in specific clinical scenarios, particularly in the adjuvant setting post-radical cystectomy. Moreover, ctDNA can be used in advanced/metastatic disease to complement tumor tissue genomic profiling, aiming to capture to some degree the tumor heterogeneity.

“I am seeing a useful role for quantitative ctDNA (MRD assessment) in clinical practice in the adjuvant, post-radical cystectomy setting, in checkpoint inhibitor-naïve patients,” Grivas said. When the decision between adjuvant nivolumab vs close active surveillance is uncertain, ctDNA status can inform the discussion and timing. This is supported by data from several adjuvant trials, such as IMvigor010 (NCT02450331), IMvigor011 (NCT04660344), CheckMate 274 (NCT02632409), and TOMBOLA (NCT04138628), which have shown a robustly prognostic and likely predictive role for ctDNA in this specific context.

However, he cautions that these data do not yet inform when to stop or ‘de-escalate’ checkpoint inhibitor that was initiated in the neoadjuvant period, as in the EV-303 (NCT03924895), EV-304 (NCT04700124), and NIAGARA trials (NCT03732677). “The role of ctDNA in the peri-operative EV/pembrolizumab trials needs further investigation in the context of those trials.”

Key Takeaways for Community Oncology

Dr Grivas’s closing advice for community oncologists synthesizes the conversation into actionable points:

• Embrace multidisciplinary care: “We have a multidisciplinary bladder cancer clinic… with urology, medical oncology, radiation oncology, pathology, radiology expertise.” He cites published data showing that such review may significantly change management plans based on clinical expertise, imaging, pathology review, histology subtypes and/or clinical staging nuances.
• Master the frontline regimen: Familiarity with available regimens, such as EV/pembrolizumab, its adverse events profile, optimal management of those, and detailed patient education on timely and accurately reporting of adverse events are fundamental.
• Implement early biomarker testing: At diagnosis of advanced/metastatic disease, order synchronous CGP (including FGFR3 “susceptible” alterations) and HER2 IHC (gastric scoring) to guide future potential ‘salvage’ therapy discussions.
• Understand the salvage landscape: Recognize the options post-EV/pembrolizumab, e.g. platinum/gemcitabine chemotherapy, erdafitinib (FGFR3-altered), trastuzumab deruxtecan (HER2 IHC 3+ based on gastric scoring), and clinical trials—and engage patients in well-informed and shared decision-making.
• Consider ctDNA selectively: Its most defined current utility as quantitative MRD assessment is for adjuvant checkpoint inhibitor decision in checkpoint inhibitor -naïve patients post-radical cystectomy (with or without neoadjuvant chemotherapy).
• Prioritize clinical trials: “Clinical trials are the vehicle through which we make major progress,” Grivas said. He strongly encourages referrals to clinical trial centers and efforts to open trials locally closer to patient’s home.
• Collaborate with experts: “Reach out to experts who do this very often to help the dialogue moving forward. “We all need and learn from each other,” Grivas said.

The landscape of advanced/metastatic UC therapy has several options but demands a structured, biomarker-informed approach. By integrating early molecular testing, multidisciplinary input, and a commitment to clinical research, community oncologists can effectively navigate this complex landscape and contribute to better patient outcomes. “There is such an amazing progress in the field of urothelial carcinoma, in both the localized and metastatic setting,” Grivas concluded.

DISCLOSURES: In the last 2 years, Dr Grivas has done consulting with MSD, Bristol Myers Squibb, AstraZeneca, EMD Serono, Pfizer, Janssen, Roche, Astellas Pharma, Gilead Sciences, Strata Oncology AbbVie, Bicycle Therapeutics, Replimune, Daiichi Sankyo, Foundation Medicine, Eli Lilly, Urogen, Tyra Biosciences, Natera; research funding from MSD, EMD Serono, Gilead Sciences, Acrivon Therapeutics, ALX Oncology, Genentech (paid to institution).

REFERENCES

1. Powles T, Bellmunt J, Comperat E, et al; ESMO Guidelines Committee. ESMO Clinical Practice Guideline interim update on first-line therapy in advanced urothelial carcinoma. Ann Oncol. 2024;35(6):485-490. doi:10.1016/j.annonc.2024.03.001

2. Gilead provides update on U.S. indication for Trodelvy in metastatic urothelial cancer. News release. October 18, 2024. Accessed January 29, 2026. https://tinyurl.com/5n8v95vn

3. FDA grants accelerated approval to sacituzumab govitecan for advanced urothelial cancer. FDA. April 13, 2021. Accessed January 29, 2026. https://tinyurl.com/dyvesj8h