Dr Friedlander on Emerging Agents of Interest in Urothelial Cancer

Terence W. Friedlander, MD, genitourinary oncologist, associate clinical professor, Division of Hematology/Oncology, Robert and Virginia O’Reilly Family Endowed Professor of Medicine, University of California San Francisco (UCSF), UCSF Health; chief, Hematology-Oncology, Zuckerberg San Francisco General; associate director, Cancer Research, Helen Diller Family Comprehensive Cancer Center, discusses emerging agents of interest in urothelial carcinoma.

Several promising therapies are emerging in the treatment of bladder cancer, particularly thse targeting HER2, FGFR, and TROP2, Friedlander begins. HER2-targeted therapies are among the most advanced, with antibody-drug conjugates (ADCs) like fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) and disitamab vedotin (Aidixi) showing significant potential. Disitamab vedotin, which carries the same MMAE payload as enfortumab vedotin-ejfv (Padcev), demonstrated encouraging efficacy in early studies with an objective response rate (ORR) of 50% to 60% in HER2 3+ patients, he adds. The phase 3 DV-001 trial (NCT05911295) is currently evaluating disitamab vedotin in combination with pembrolizumab (Keytruda) in the frontline setting, and the synergy of these 2 agents is highly anticipated, Friedlander states. Other studies are examining the use of HER2-targeting agents, including T-DXd, in earlier treatment lines.

FGFR-targeting agents are another area of active investigation, Friedlander continues. Erdafitinib (Balversa) is already approved, but newer, more selective FGFR inhibitors like LOXO-435, futibatinib (Lytgobi), and TYRA-300 are being evaluated in clinical trials. These agents aim to improve on-target efficacy while reducing off-target adverse effects.

In the realm of TROP-2–targeting agents, sacituzumab govitecan-hziy (Trodelvy) initially showed promise in early trials for patients with unselected metastatic bladder cancer, Friedlander reports. However, phase 3 trial results with the agent were disappointing, likely due to the toxicity of its payload rather than its TROP-2 targeting. Despite this, other TROP-2–targeted agents are currently in development, he says.

Additionally, TGF-β is emerging as a potential target for overcoming immunoresistance, Friedlander notes. Early-phase studies are exploring agents that target the TGF-β signaling pathway. These therapies could potentially reinvigorate the immune system in patients who have already received anti–PD-1 immunotherapy, offering new hope for improved outcomes in bladder cancer