ASCO GU 2025: Targeting Bladder Cancer with Antibody Drug Conjugates

(UroToday.com) The 2025 GU ASCO annual meeting featured a session on the ABCs of antibody drug conjugates and a presentation by Dr. Di Maria Jiang discussing the targeting of bladder cancer with antibody drug conjugates. Dr. Jiang started her presentation by noting that the treatment of metastatic urothelial cancer prior to antibody drug conjugates was associated with a median overall survival for patients with metastatic urothelial carcinoma of 15 months.

Treatment options were limited to (i) platinum-based chemotherapy (OS benefit), (ii) maintenance avelumab or second line pembrolizumab (OS benefit), (iii) erdafitinib for a small subset of patients with FGFR alterations (OS benefit), and (iv) taxane or vinflunine chemotherapy. In this context, antibody drug conjugates have emerged as a new treatment modality. The mechanism of action for antibody drug conjugates is highlighted as follows:

The key antibody drug conjugates in metastatic urothelial cancer include enfortumab vedotin, sacituzumab govitecan, trastuzumab deruxtecan, and disitamab vedotin:
Antibody drug conjugate monotherapy post platinum chemotherapy and immune checkpoint inhibitors includes FDA approved enfortumab vedotin based on the phase III EV-301 trial.¹ Among 608 patients randomized to enfortumab vedotin versus taxane/vinflunine, the objective response rate was 41.3%, median progression free survival was 5.55 months, and median overall survival was 12.9 months. Sacituzumab govitecan is also in this disease space and was evaluated the TROPiCS-04 Cohort 3 trial randomizing patients to sacituzumab govitecan versus taxane/vinflunine, with an objective response rate of 23%, median progression free survival of 4.2 months, and median overall survival of 10.3 months. However, FDA approval was withdrawn for this indication of sacituzumab govitecan. HER2 antibody drug conjugates are also showing promising activity in early phase studies, notably, the phase II DESTINY-Pan Tumor02 (Bladder) assessing trastuzumab deruxtecan and phase II RC48-C005, RC48-C009 assessing disitamab vedotin:
Dr. Jiang notes that not all antibody drug conjugates are created equal. The following figure highlights the impact of mechanism of action, specifically assessing the target, linker, and payload:

 Dr. Jiang notes that there is rationale for combining antibody drug conjugates with immune checkpoint inhibitors given that preclinical evidence suggests that antibody drug conjugates have immunomodulatory activity. This occurs by inducing immunogenic cell death, recruitment of T cells to the tumor microenvironment, and activating dendritic cells. This provides a strong rationale for testing antibody drug conjugate combination strategies with immune checkpoint inhibitors. In the EV-302/KEYNOTE-A39 trial² patients were randomized 1:1 to either enfortumab vedotin + pembrolizumab (n = 442) or gemcitabine + cisplatin/carboplatin (n = 444) for a maximum of 6 cycles. The dual primary endpoints were progression-free survival, assessed via blinded independent central review and overall survival. The study design is as follows:
Compared to platinum-based chemotherapy, enfortumab vedotin + pembrolizumab prolonged progression-free survival from a median of 6.3 months to 12.5 months (HR: 0.45, 95% CI: 0.38 – 0.45, p<0.001). Overall survival was nearly doubled in the enfortumab vedotin + pembrolizumab arm, with median survivals of 31.5 and 16.1 months, respectively (HR: 0.47, 95% CI: 0.38 – 0.58, p<0.00001). Additionally, the overall response rate for enfortumab vedotin + pembrolizumab was 67.7%, including a complete response rate of 29.1%:
Other antibody drug conjugate combinations with immune checkpoint inhibitors include sacituzumab govitecan + pembrolizumab in the phase II TROPHY-U01 Cohort 3 trial, trastuzumab deruxtecan + nivolumab in the phase Ib DS8201-A-U105 trial, disitamab vedotin + toripalimab in the phase Ib/II RC48-C014 trial, and disitamab vedotin + pembrolizumab in the phase II RC48-G001 cohort C trial:

Several trials are also looking at antibody drug conjugates in the curative muscle invasive bladder cancer setting, including EV-103 cohort H, SURE-01, RC48-C017:
Like any therapy, it is important to overcome resistance, which is highlighted as follows based on each mechanism of resistance:
There are several novel antibody drug conjugates in development, specific to different targets:

• Nectin-4: BT8009 and 9MW2281
• HER-2: MRG002
• Trop2: Datopotamab deruxtecan
• EGFR/HER3: BL-B01D1 bispecific

Dr. Jiang finished her presentation listing ongoing trials assessing antibody drug conjugates in each urothelial carcinoma disease space. In the metastatic setting, there is the (i) phase III SGNDV-001 trial, (ii) phase III NCT05302284 trial, (iii) phase II/III DURAVELO-2 trial, and (iv) phase II BLAD RAD01/GETUG-AFU V07 trial:
In the muscle invasive bladder cancer space, ongoing trials include the (i) phase III KEYNOTE-B15/EV34 trial, (ii) phase III KEYNOTE 905/EV303, and (iii) phase III VOLGA trial:
In the non-muscle invasive bladder cancer space, ongoing trials include the (i) phase I EV104 trial, (ii) the phase I/II TroFuse-027 trial, (iii) phase II NCT06187506 trial, and (iv) phase II NCT06630871 trial:

An important question for these non-muscle invasive bladder cancer trials is what is the optimal treatment duration and management of relapse?

Dr. Jiang concluded her presentation discussing the targeting of bladder cancer with antibody drug conjugates with the following take-home points:

• Antibody drug conjugates aim to expand the therapeutic index by delivering potent cytotoxins directly to tumor cells, although off-target toxicities remain a challenge
• Not all antibody drug conjugates (and combinations) are created equal—differences in mechanism of action impact outcomes
• EV-302 has transformed the treatment paradigm for metastatic urothelial cancer, setting a new benchmark and driving more trials testing combination strategies
• Antibody drug conjugates may have a broader impact in earlier stage disease, enabling more bladder-sparing approaches and improving cure rates
• Ongoing efforts are needed to improve global access, optimize patient selection, treatment delivery, and sequencing

Presented by: Di Maria Jiang, MD, MSc, FRCPC, Princess Margaret Hospital, University Health Network, Toronto, Canada

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2025 Genitourinary (GU) American Society of Clinical Oncology (ASCO) Annual Meeting, San Francisco, CA, Thurs, Feb 13 – Sat, Feb 15, 2025. 

References:

1. Powles T, Rosenberg JE, Sonpavde GP, et al. Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma. N Engl J Med 2021 Mar 25;384(12):1125-1135.
2. Powles T, Valderrama BP, Gupta S, et al. Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer. N Engl J Med. 2024 Mar 7;390(10)875-888.