Phase 3 TROPiCS-04 Trial: Sacituzumab Govitecan Fails to Meet Survival Endpoints in Advanced Urothelial Cancer

The antibody-drug conjugate sacituzumab govitecan (Trodelvy) failed to demonstrate significant survival benefits compared to physician's choice of chemotherapy in patients with pretreated advanced urothelial carcinoma, according to final analysis results from the phase 3 TROPiCS-04 trial presented at the 2024 ESMO Asia Congress.

Patients receiving sacituzumab govitecan achieved a median overall survival (OS) of 10.3 months compared to 9.0 months with standard chemotherapy (HR, 0.86; 95% CI, 0.73-1.02; P = .087), falling short of the trial's primary endpoint. Twelve-month OS rates were 44% and 37% for the sacituzumab govitecan and chemotherapy arms, respectively.

Efficacy Outcomes

The trial showed modest improvements in secondary endpoints. Progression-free survival reached 4.2 months with sacituzumab govitecan versus 3.6 months with chemotherapy (HR, 0.86; 95% CI, 0.72-1.03). The objective response rate was higher in the sacituzumab govitecan arm at 23% compared to 14% with chemotherapy, including complete response rates of 5% and 3%, respectively.

Safety Profile and Complications

Treatment-related adverse events were more frequent with sacituzumab govitecan, with 77% of patients experiencing grade 3 or higher events compared to 51% in the chemotherapy arm. Of particular concern were neutropenic complications, with 16 infection events occurring in the setting of neutropenia, 14 of which developed within the first month of treatment.

"Several reasons may have contributed to the results beyond efficacy," explained Dr. Petros Grivas from the University of Washington, citing "early deaths due to toxicity with sacituzumab govitecan, a higher number of patients randomized but not treated with physician's choice of treatment, and subsequent therapies, including enfortumab vedotin."

Study Design and Patient Population

The global, open-label trial enrolled 711 patients with metastatic or locally advanced urothelial carcinoma who had progressed following platinum-based therapy and PD-(L)1 treatment. Patients were randomized 1:1 to receive either sacituzumab govitecan or physician's choice of chemotherapy (paclitaxel, docetaxel, or vinflunine).

Regulatory Impact

Based on these results, Gilead announced in October 2024 the voluntary withdrawal of sacituzumab govitecan's US indication for pretreated locally advanced or metastatic urothelial cancer. This indication had received accelerated approval in April 2021 based on earlier phase 2 TROPHY-U-01 study data.

Clinical Implications

The trial results highlight the ongoing challenges in developing effective treatments for advanced urothelial cancer. While sacituzumab govitecan showed some activity in this patient population, the lack of significant survival benefit and increased toxicity concerns, particularly regarding neutropenic complications, underscore the need for continued research into more effective therapeutic approaches.