Pursuit of ADCs in Bladder Cancer Comes With Questions About Toxicity, Cost

There’s no question that antibody drug conjugates (ADCs) have revolutionized treatment of patients with bladder cancer, and hope abounds with increased survival times and more drugs and combinations in the pipeline.

The promise of ADCs—delivering the cytotoxic payload directly to the tumor—remains a work in progress, as scientists are still working to limit off target effects. As with many therapies, ADCs were first given when other treatments had failed, but now it seems they are offering the best hope early on, by sparing healthy tissue for the long battle ahead.

Yet the enthusiasm for these cancer “smart bombs” is tempered with many challenges: how to manage toxicity, how to understand sequencing, and how to ensure access when the cost of some combinations is projected to exceed $400,000 a year.

Speakers addressed these issues at Friday session, “The ABCs of ADCs: Unleashing the Power of Antibody-Drug Conjugates in Advanced Bladder Cancer,” during the American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU), held in San Francisco, California.

Not all alike. Although ADCs have common elements—the antibody that binds to the tumor antigen, the linker, and cancer-killing payload—ADCs can vary greatly, said Di "Maria" Jiang, MD, MSc, FRCPC, of Princess Margaret Cancer Center at the University of Toronto. She offered examples of how well-known ADCs use different biomarkers—or none—different antibodies, and different linkers, and how varying mechanisms of action affect outcomes.

“Many ADCs exhibit bystander effects,” said Jiang, in which the payload kills tumor cells regardless of their target expression. “ADCs also engage with the immune system and promote immunogenic cell death via the antibody and also the payload activity.”

Targeting HER2. Funda Meric-Bernstam, MD, FASCO, of The University of Texas MD Anderson Cancer Center, explained how ADCs that target HER2 have opened a new frontier in treating bladder cancer. She explained that next-generation sequencing (NGS) is not a substitute for immunohistochemistry (IHC) testing to find patients who may have HER2 amplification that does not appear on NGS.

Funda Meric-Bernstam, MD, FASCO | Image: MD Anderson

She shared data for trastuzumab deruxtecan (Enhertu; AstraZeneca), well known for its efficacy in certain patients with breast cancer, and highlighted subsets of patients with colorectal cancer within the application for the tumor-agnostic approval granted this ADC for patients HER2 IHC 3+ tumors. Like Jiang, Meric-Bernstam suggested firstline treatment may be the opportunity to use ADCs.

Meric-Bernstam expects new drugs with different payloads and more activity with bispecifics, as there are other mutations in bladder cancer and small molecules opportunities as well. Combinations will continue to be important, she said.

“There's a lot of acceptance from [immuno-oncology] combinations, potentially for ADC combinations, potentially combining targeted therapies with other ADCs, as well as other novel combinations to enhance the activity,” Meric-Bernstam said. “Sequence of therapy is going to be a very interesting area to watch.”

Managing toxicity. Daniel Castellano, MD, of University Hospital Madrid, explained how the complex, 3-part mechanism of ADCs contributes to the toxicity challenges, which are generally divided into off target and on target effects. Despite their design to reduce the footprint of the cytotoxic payload, most end up with toxicity levels that are nearly the same, he said; notably 55% of patients can develop skin reactions.

Biomarker development will help, as this will allow clinicians to identify patients who will gain the most from treatment with an ADC. Dose de-escalation strategies, and pinpointing who will benefit, will also be important.

Combinations abound. Terry Friedlander, MD, of UCSF Helen Diller Family Comprehensive Cancer Center, reviewed what’s ahead in combinations with ADCs—starting with why they are needed. Data show only 48% of newly diagnosed patients get to firstline systemic therapy, only 17% get to second-line and only 6% get to third-line therapy.

Terry Friedlander, MD | Image credit: UCSF

“We should be giving our best therapies first,” Friedlander said. As others argued, ADCs offer the chance to give patients with bladder cancer a powerful, targeted attack against the tumor. Striving for synergistic combinations can promote the ADC bystander effect, limit overlapping toxicity, and help overcome ADC resistance.

The approach requires balance, however. There is the risk of increased AEs, as well as financial toxicity. Friedlander shared a sobering chart about the cost of ADC combinations: those he highlighted ranged from $120,494 to $438,660 per year.

Still, he offered some trials worth watching: of note are erdafitinib (Balversa; Janssen) plus enfortumab vedotin (EV) (Padcev;Astellas) in metastatic urothelial cancer with FGFR2/3 alterations, which has presented promising phase 1b data; and EV plus cabozantinib (Cabometyx; Exelixis) which is being investigated in phase 1/2 studies in several cancers including bladder cancer.

Phase 1 results.1The session concluded with the presentation of data from a phase 1 study of SHR-A2102, a novel ADC that targets nectin-4, a cleavable linker, and a payload with high membrane permeability. Preliminary findings in urothelial cancer to assess safety and tolerability confirmed an objective response rate of 38.4% in all patients and 32.3% in the 6 mg/kg group, with 50.0% in the 8 mg/kg group. The 6-month duration of response was 59.3% in all patients, with 66.7% and 54.0% in the 6 and 8 mg/kg doses, respectively. Grade 3 or higher treatment-related AEs were seen in 43.8% of patients, the most common being anemia, decreased white blood count, and decreased neutrophil count. Investigators concluded the study drug showed promising anti-tumor activity in aUC, even after prior ADC therapy.

Reference

1. Tang B, Sheng X, Guo J, et al. Nectin-4 targeted ADC, SHR-A2102, in patients with advanced or metastatic urothelial carcinoma: A phase 1 study. J Clin Oncol. 2025;43(suppl 5): Abstract 657.DOI: 10.1200/JCO.2025.43.5_suppl.657