In patients with unresectable locally advanced or metastatic urothelial cancer, treatment with sacituzumab govitecan monotherapy after platinum-based chemotherapy and anti-PD-(L)1 therapy did not result in a statistically significant improvement in overall survival (OS) or progression-free survival (PFS) versus standard chemotherapy. Despite lack of significant survival benefit, a higher objective response rate (ORR) was observed with sacituzumab govitecan versus chemotherapy of physician’s choice.
Further validation of sacituzumab govitecan activity is needed in prospective randomised trials that utilise consistent primary prophylaxis with G-CSF starting at cycle 1 to mitigate the risk of complications arising from sacituzumab govitecan-related high-grade neutropenia according to Prof. Thomas Powles of the Barts Cancer Institute, Queen Mary University of London, Barts Health NHS Trust in London, UK and colleagues, who published the findings from a global open-label randomised phase III TROPiCS-04 study on 10 February 2025 in the Annals of Oncology.
Until recently, patients with advanced urothelial cancer whose cancer progresses on or after platinum-based chemotherapy and PD-(L)1 inhibitors have had relatively limited approved treatment options and poor prognosis. Historically, second-line single-agent chemotherapy with vinflunine, paclitaxel, or docetaxel has provided a median OS of 7-9 months, emphasising a need for new safe and effective treatment options. An OS of 10-13 months has been observed with immune checkpoint inhibitors, erdafitinib, and the antibody-drug conjugate enfortumab vedotin in the second-line and later settings.
There has also been a rapid evolution in the first-line treatment landscape. Despite the significant improvements in OS and PFS, there remains a major need for more therapies, especially in patients with progression on prior treatments.
Sacituzumab govitecan, an antibody directed to Trop-2, has shown notable antitumour activity in various solid tumours. It demonstrated efficacy and manageable toxicity in cohorts 1, 2 and 3 of the phase II TROPHY-U-01 study, conducted in patients with pretreated advanced urothelial cancer.
TROPiCS-04 study team hypothesised that sacituzumab govitecan would be superior to standard chemotherapy in patients with previously treated advanced urothelial cancer. In the latest article published in the Annals of Oncology, they reported efficacy and safety results from the final analysis of TROPiCS-04, a phase III study of treatment with sacituzumab govitecan in this patient population.
Patients with advanced urothelial cancer whose disease had progressed on prior platinum-based chemotherapy and checkpoint inhibitor therapy were randomised 1:1 to receive sacituzumab govitecan or treatment of physician’s choice (paclitaxel, docetaxel, or vinflunine). The primary endpoint was OS. Secondary endpoints included PFS and ORR by investigator and blinded independent committee review, as well as safety.
Overall, 711 patients were randomised. After a median follow-up of 9.2 months, the primary endpoint was not met with median OS for sacituzumab govitecan versus treatment of physician’s choice of 10.3 months versus 9.0 months (hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.73-1.02, p = 0.087). Median PFS with sacituzumab govitecan and treatment of physician’s choice was 4.2 months and 3.6 months (HR 0.86, 95% CI 0.72-1.03); ORR was 23% (95% CI 18% to 27%) and 14% (95% CI 10% to 18%).
The high levels of Trop-2 expression observed in tumour tissue samples in the biomarker analysis set were consistent with those reported in the TROPHY-U-01 study (cohorts 1-3) and in other large datasets from independent advanced bladder cancer cohorts. Subgroup analyses of OS and PFS showed a consistent benefit for sacituzumab govitecan versus treatment of physician’s choice; higher baseline Trop-2 expression was not associated with improved sacituzumab govitecan efficacy versus treatment of physician’s choice.
The most common grade ≥3 treatment-related adverse event (TRAE) with sacituzumab govitecan was neutropenia (35%, including 12% with febrile neutropenia). Incidence of grade ≥3 TRAEs (67% versus 35%) and grade 5 treatment-emergent adverse events (TEAEs; 7% versus 2%) was higher with sacituzumab govitecan versus treatment of physician’s choice. In the sacituzumab govitecan group, 16/25 grade 5 TEAEs were infections with neutropenia mostly occurring early in the treatment course of patients with multiple risk factors for febrile neutropenia. Primary prophylactic G-CSF usage with sacituzumab govitecan and treatment of physician’s choice was 21% and 22%, respectively.
The authors commented that median OS of 9.0 months in the treatment of physician’s choice group was similar to that reported previously in clinical trials of advanced urothelial cancer refractory to platinum-based chemotherapy. Despite lack of significant survival benefit, a higher ORR was observed with sacituzumab govitecan versus treatment of physician’s choice, and sacituzumab govitecan response rates were consistent with previous results from the phase II TROPHY-U-01 study, thus confirming that sacituzumab govitecan has activity in advanced urothelial cancer.
The efficacy and safety of sacituzumab govitecan as a first-line therapy either as monotherapy or in combination with other agents are being assessed in the TROPHY-U-01 cohorts 4, 6, and 7.
The study was supported by Gilead Sciences Inc, US.
Reference
Powles T, Tagawa S, Vulsteke C, et al. Sacituzumab govitecan in advanced urothelial carcinoma: TROPiCS-04, a phase III randomized trial. Annals of Oncology; Published online 10 February 2025. DOI: https://doi.org/10.1016/j.annonc.2025.01.011