The 2026 ASCO Genitourinary Cancers Symposium (ASCO GU) has once again opened as one of the most authoritative and influential global meetings in genitourinary oncology. As always, it sets the direction for advances in urothelial carcinoma, prostate cancer, and renal cell carcinoma. This year, precision-targeted therapy in urothelial carcinoma stands firmly at the center of attention.With the rapid development and clinical implementation of antibody–drug conjugates (ADCs), human epidermal growth factor receptor 2 (HER2)—a classical oncologic target—is redefining the global treatment paradigm for urothelial carcinoma.
Oncology Frontier – Urology Stream invited Prof. Thomas Powles from Barts Cancer Institute, Queen Mary University of London, to discuss the clinical value of HER2 as a biomarker, testing considerations, and the growing global impact of Chinese innovative agents such as disitamab vedotin.
01
Oncology Frontier: What is your view on the diagnostic and therapeutic value of HER2 in patients with urothelial carcinoma?
Prof. Powles:
The clinical relevance of HER2 as a biomarker in urothelial carcinoma is becoming increasingly evident, largely driven by the successful development of HER2-targeted antibody–drug conjugates, particularly disitamab vedotin and trastuzumab deruxtecan (T-DXd).
Clinical data suggest that approximately 80% of patients with urothelial carcinoma exhibit some degree of HER2 expression. This includes patients with strong overexpression (IHC 3+), as well as those with intermediate (IHC 2+) or low-level expression (IHC 1+).
Disitamab vedotin has demonstrated substantial anti-tumor activity in HER2-expressing urothelial carcinoma. Data from the Chinese C005 and C009 studies showed an objective response rate (ORR) of 50.5% with single-agent RC48. Even more notably, the phase 3 randomized RC48-C016 trial evaluated disitamab vedotin combined with toripalimab in HER2-expressing advanced urothelial carcinoma. This was the first randomized phase 3 trial of a HER2-targeted ADC in this disease setting worldwide.
The results demonstrated a significant synergistic anti-tumor effect compared with platinum-based chemotherapy, with superior efficacy in a biomarker-driven population. The concurrent publication of these findings in The New England Journal of Medicine represents a landmark moment in urothelial carcinoma research.
02
Oncology Frontier: Some studies differentiate between HER2 overexpression and low expression. How should HER2 expression be assessed in clinical practice to guide treatment decisions?
Prof. Powles:
There is still ongoing debate regarding the optimal approach to HER2 testing and interpretation. Historically, HER2 positivity was defined as IHC 3+ or positive in situ hybridization (ISH). However, this definition applies to only around 20% of bladder cancer patients and was originally established for conventional targeted therapies—not ADCs.
With ADCs now widely used, the clinical relevance of low HER2 expression (IHC 1+ or IHC 2+/ISH–) has changed substantially. Disitamab vedotin has shown activity across all levels of HER2 expression (IHC 1+, 2+, and 3+), covering the majority of patients with urothelial carcinoma.
Importantly, clinical data indicate no significant difference in efficacy between traditionally defined HER2-positive patients and those with low HER2 expression. There is no clear enrichment of benefit confined to the IHC 3+ subgroup.
Therefore, the key clinical question is not how to further refine HER2 positivity, but rather whether HER2 expression is present at all. Patients with completely negative HER2 expression have lower response rates to disitamab vedotin. However, once HER2 expression is detected—even at low levels—treatment benefit appears broadly comparable, and further stratification is generally unnecessary.
03
Oncology Frontier: Based on available evidence, how do you view the impact of Chinese innovative drugs on the global treatment landscape of urothelial carcinoma?
Prof. Powles:
Chinese innovative agents—led by disitamab vedotin—have already had a transformative impact. The pivotal clinical data supporting disitamab vedotin, both as monotherapy and in combination with toripalimab, were generated in China. The phase 3 trial led by Professor Jun Guo’s team and published in The New England Journal of Medicine has significantly reshaped routine clinical practice within China.
Globally, enfortumab vedotin (EV) plus pembrolizumab remains the most widely adopted regimen, supported by multinational trials such as EV-302, EV-303, and EV-304. Notably, EV-303 demonstrated improved pathological response rates and disease-free survival in cisplatin-ineligible muscle-invasive bladder cancer.
A key distinction is that the EV-based regimen is not biomarker-driven, whereas disitamab vedotin is guided by HER2 expression. Despite this difference, the two regimens demonstrate broadly similar clinical activity, with more similarities than differences in efficacy.
The ongoing global randomized trial evaluating disitamab vedotin plus pembrolizumab may further expand treatment options worldwide. In the future, treatment selection may increasingly reflect physician preference and biomarker availability rather than substantial efficacy differences.
In China, HER2-overexpressing urothelial carcinoma is now commonly treated with disitamab vedotin plus toripalimab, while EV plus pembrolizumab remains the dominant global standard outside China.
Beyond disitamab vedotin, Chinese pharmaceutical companies are rapidly advancing a broad pipeline of next-generation ADCs—including HER3- and HER1-targeted ADCs with topoisomerase I payloads, as well as sacituzumab govitecan derivatives. These agents are entering global development programs at an accelerated pace.
China has evolved from conducting primarily domestic clinical trials to actively participating in—and increasingly leading—global multicenter studies. Today, China is deeply integrated into the global oncology drug development ecosystem and plays an influential role in shaping future therapeutic strategies.
Closing Remarks
HER2-targeted ADC therapy has ushered in a new era for urothelial carcinoma, redefining biomarker interpretation and treatment selection. At the same time, Chinese innovation—particularly in ADC development—is exerting a profound and growing influence on the global oncology landscape.
As HER2-driven strategies continue to mature, the integration of biomarker-guided precision therapy and next-generation ADC platforms is poised to further transform clinical practice worldwide.
Prof. Thomas Powles
