Treatment options remain limited for patients with locally advanced or metastatic urothelial carcinoma whose disease progresses after platinum-based therapy. Combining immune checkpoint inhibition with an antibody–drug conjugate has been investigated as a potential strategy to increase antitumour activity in this setting.
Results from the MORPHEUS-Urothelial Carcinoma study showed that adding sacituzumab govitecan to atezolizumab did not improve objective response rate, progression-free survival, or overall survival compared with atezolizumab alone. The combination was also associated with greater toxicity and numerically more frequent adverse event-related treatment discontinuation.
The article, titled “A Phase Ib/II, Open-label, Multicenter, Randomized Umbrella Study Evaluating the Combination of Atezolizumab With Sacituzumab Govitecan in Patients With Locally Advanced or Metastatic Urothelial Carcinoma and Previously Treated With a Platinum-based Treatment Regimen (MORPHEUS-Urothelial Carcinoma),” appears as a short communication in the August 2026 issue of ESMO Open.
Authors: S.J. Shin, J.L. Lee, T. Powles, J. Martin-Liberal, R. Morales-Barrera, A. Drakaki, T. Friedlander, F. Joly, S.A. Shah, J. Vuky, I. Ianculescu, F. Michielin, X. Gan, and A. Bamias.
Study Design and Treatment
MORPHEUS-UC, also identified as NCT03869190, was a global, phase Ib/II, open-label, multicentre, randomised umbrella study in which patients were assigned to one of seven atezolizumab-based treatment combinations or atezolizumab monotherapy.
The analysis compared atezolizumab plus sacituzumab govitecan with atezolizumab monotherapy. Sacituzumab govitecan is a trophoblast cell surface antigen 2-directed antibody–drug conjugate, while atezolizumab is an anti–PD-L1 immune checkpoint inhibitor.
Eligible patients were checkpoint inhibitor-naïve and had experienced disease progression or recurrence during or after no more than one platinum-containing treatment regimen. Patients were required to have locally advanced disease, defined as stage T4b with any nodal status or any tumour stage with N2-N3 disease, or metastatic stage IV disease.
Atezolizumab was administered intravenously at 1200 mg on day 1 of each 21-day cycle in both groups. Patients assigned to the experimental group also received sacituzumab govitecan at 10 mg/kg intravenously on days 1 and 8 of each cycle.
The primary endpoints were investigator-assessed objective response rate according to RECIST version 1.1 and safety. Secondary efficacy endpoints included progression-free survival, duration of response, disease control rate, and overall survival.
The trial was designed to identify preliminary efficacy and safety signals rather than conduct a formally powered hypothesis test. No explicit statistical power or type I error assumptions were incorporated into the study design.
Read more about Sacituzumab Govitecan (Trodelvy) on OncoDaily.
Patient Population
Across 14 study sites in France, Greece, Spain, the Republic of Korea, the United Kingdom, and the United States, 45 patients were enrolled and randomly assigned.
Fifteen patients received atezolizumab plus sacituzumab govitecan, while 30 were assigned to atezolizumab alone. One patient in the atezolizumab group did not receive treatment after randomisation because an exclusion criterion related to infection was identified, leaving 29 patients in the efficacy- and safety-assessable control population.
At the clinical data cutoff of October 27, 2023, median survival follow-up was 13.2 months in the combination group and 17.8 months in the atezolizumab group.
No Improvement in Antitumour Activity
The confirmed objective response rate was 6.7% with atezolizumab plus sacituzumab govitecan, compared with 27.6% with atezolizumab alone. One patient in the combination group achieved a complete response, while no partial responses were reported. In the atezolizumab group, three patients achieved complete responses and five achieved partial responses.
Stable disease was observed in 46.7% of patients receiving the combination and 34.5% of those receiving atezolizumab alone. The disease control rate was 33.3% and 48.3%, respectively.
Median progression-free survival was:
- 3.5 months with atezolizumab plus sacituzumab govitecan
- 6.1 months with atezolizumab alone
Median overall survival was:
- 14.6 months with the combination
- 18.8 months with atezolizumab monotherapy
Overall, the addition of sacituzumab govitecan did not improve objective response rate, disease control rate, progression-free survival, or overall survival.
Read more about Bladder Cancer Treatment: The Game-Changing Role of Antibody-Drug Conjugates on OncoDaily.
Safety Outcomes
All patients in both groups experienced at least one adverse event of any grade. Grade 3 or 4 adverse events occurred in 73.3% of patients receiving atezolizumab plus sacituzumab govitecan and 31.0% of those receiving atezolizumab alone.
Treatment-related adverse events were reported in 86.7% and 65.5% of patients, respectively. Treatment-related serious adverse events occurred in 33.3% of patients in the combination group, compared with 3.4% in the atezolizumab group.
Adverse events led to withdrawal of study treatment in three patients, representing 20.0% of the combination group, but in no patients receiving atezolizumab alone. Treatment-related adverse events also resulted in more frequent dose modifications or interruptions with the combination: 53.3% versus 10.3%.
The most frequent treatment-related adverse events with atezolizumab plus sacituzumab govitecan included anaemia, neutropenia, pruritus, nausea, and alopecia. In the atezolizumab group, the most frequent events included pruritus, decreased appetite, rash, and fatigue.
Two patients receiving the combination experienced treatment-related serious febrile neutropenia during the first treatment cycle. Neither had received primary prophylaxis with granulocyte colony-stimulating factor.
One grade 5 adverse event caused by sepsis occurred in the combination group but was considered unrelated to the study treatments. No grade 5 treatment-related adverse events were reported.
Interpretation and Study Limitations
The safety profile of the combination was generally consistent with the known toxicities of the individual treatments, and no new or unexpected safety signals were identified. However, treatment-related adverse events, adverse event-related treatment discontinuations, and dose modifications or interruptions were numerically more frequent with atezolizumab plus sacituzumab govitecan.
The investigators noted that the greater toxicity and lower treatment exposure in the combination group may have contributed to the poorer efficacy outcomes observed.
Several limitations should be considered when interpreting the findings. The study included a very small number of patients, randomisation was not stratified, and there was no prespecified statistical analysis plan. Baseline sites of disease were also imbalanced between the treatment groups.
In addition, atezolizumab monotherapy, which served as the control treatment, is no longer considered the standard of care in this clinical setting. The investigators identified the signal-seeking design as a strength because it allowed potential new treatments to be examined rapidly.
Read about Antibody-Drug Conjugate Success Rate on OncoDaily.
Takeaway
In the MORPHEUS-UC study, adding sacituzumab govitecan to atezolizumab did not improve objective response rate, disease control rate, progression-free survival, or overall survival compared with atezolizumab alone in checkpoint inhibitor-naïve patients with platinum-experienced, locally advanced or metastatic urothelial carcinoma.
The combination was also associated with greater toxicity and numerically more frequent adverse event-related treatment discontinuation. Taken together, the efficacy and safety findings suggest limited rationale for further development of atezolizumab plus sacituzumab govitecan in this patient population.
The full article is available in ESMO Open.