Adjuvant pembrolizumab affects fatigue but not HRQOL in muscle-invasive UC

Adjuvant pembrolizumab (Keytruda) after radical surgery for high-risk muscle-invasive urothelial carcinoma (MIUC) was associated with modest increases in patient-reported fatigue and dyspnea that affected physical functioning and role functioning but had no impact on overall health-related quality of life (HRQOL) compared with observation, according to patient-reported outcome data from the phase 3 AMBASSADOR trial (Alliance A031501, NCT03244381) presented at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting.¹

Ronald C. Chen, MD, MPH, FASCO, FASTRO, professor and chair of radiation oncology at the University of Kansas Medical Center in Kansas City, presented the findings on behalf of the Alliance for Clinical Trials in Oncology. He noted that the data are intended to inform patient decision-making regarding adjuvant therapy and identify a possible need for supportive services after treatment.

Background

High-risk disease was defined as pT3 or higher, pN-positive, or positive surgical margins in patients without prior neoadjuvant cisplatin-based chemotherapy, or ypT2 or higher, ypN-positive, or positive margins following neoadjuvant cisplatin-based chemotherapy. Pembrolizumab was evaluated as adjuvant therapy in this setting to address this unmet need.

The primary efficacy results of the AMBASSADOR trial were previously reported by Apolo et al,² demonstrating that adjuvant pembrolizumab significantly increased median disease-free survival (DFS) from 14.2 months in the observation arm to 29.6 months in the pembrolizumab arm (HR, 0.73). Overall survival results are currently pending. The analysis presented at the 2026 ASCO Annual Meeting reports the trial's patient-reported HRQOL outcomes.

Study design and HRQOL assessment

The AMBASSADOR trial enrolled 702 patients with muscle-invasive urothelial carcinoma of the bladder, urethra, renal pelvis, or ureter who had undergone radical surgery 4 to 16 weeks prior to enrollment and met high-risk criteria as described above. Patients were randomly assigned 1:1 to pembrolizumab 200 mg intravenously every 3 weeks for 1 year or observation. Dual primary end points were DFS and overall survival (OS).

HRQOL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and the bladder cancer–specific supplement (BLM30) at baseline and at 6, 12, and 24 months. The QLQ-C30 evaluated specific symptoms, including fatigue, dyspnea, and nausea/vomiting; physical functioning (activities of daily living, walking, and strenuous activities); role functioning (limitations in work, hobbies, and other activities); and global health/overall HRQOL. The BLM30 assessed urinary symptoms and sexual function. The EQ-5D-5L instrument was also collected to assess overall HRQOL and health status for future calculations of quality-adjusted survival when OS data become available. The minimally important difference (MID) for QLQ-C30 symptom and functioning scales was 5 to 10 points; differences at or above this threshold were considered clinically meaningful.

Patient characteristics

Baseline characteristics were well-balanced between arms. Median age was 67 to 68 years; approximately 73% to 77% of patients were male. ECOG performance status was 0 to 1 in 95% to 97% of patients. Lower tract (bladder/urethra) disease was present in 77% to 79% of patients, and upper tract disease in 21% to 23%. Approximately 63% to 65% of patients had received prior neoadjuvant chemotherapy.

Symptom outcomes

For fatigue (QLQ-C30; higher scores indicate worse outcomes), mean change from baseline in the observation arm was −2.19, +0.19, and −0.77 points at 6, 12, and 24 months, respectively, reflecting general stability. In the pembrolizumab arm, fatigue scores increased progressively, reaching changes of +2.01, +2.91, and +4.57 points at 6, 12, and 24 months. At 24 months, the between-arm difference of 5.34 points crossed the MID threshold, though the difference was not statistically significant, likely due to smaller sample sizes at that time point.

For dyspnea, the mean change from baseline in the observation arm was −1.53, +0.83, and +0.48 points at 6, 12, and 24 months, respectively. In the pembrolizumab arm, changes were +1.33, +2.77, and +7.57 points at the same time points. The between-arm difference at 24 months was 7.09 points, which exceeded the MID threshold and was also statistically significant (P < .05). No statistically significant differences between arms were observed for nausea/vomiting at any time point, and the differences did not exceed the MID.

Functioning outcomes

For physical functioning (QLQ-C30; higher scores indicate better outcomes), mean change from baseline in the observation arm was +0.14, −0.09, and −0.81 points at 6, 12, and 24 months, respectively. In the pembrolizumab arm, changes were −0.57, −0.07, and −5.97 points. The 24-month between-arm difference of 5.16 points was above the MID threshold but was not statistically significant.

For role functioning, reflecting patient-reported limitations in work and hobbies, the mean change from baseline in the observation arm was +3.32, +3.22, and +3.17 points at 6, 12, and 24 months, respectively. In the pembrolizumab arm, changes were −1.32, −1.23, and −5.95 points. The 24-month between-arm difference of 9.12 points exceeded the MID threshold and was statistically significant (P < .05).

Disease-specific and overall HRQOL outcomes

For BLM30 urinary symptoms, mean changes from baseline followed a similar trajectory in both arms, with no statistically significant between-arm difference at any time point and no difference above the MID threshold at any time point. Sexual function scores likewise showed no statistically significant difference between arms and no MID-level difference at any time point.

For the QLQ-C30 global health/HRQOL scale, mean change from baseline was modest and similar in both arms across all time points (observation: +0.09, +0.07, +1.30; pembrolizumab: +1.42, +1.45, +3.49 at 6, 12, and 24 months, respectively). There was no statistically significant difference between arms at any time point, and no between-arm difference exceeded the MID.

On the EQ-5D-5L index (MID, 0.03–0.07), mean changes from baseline were similarly small in both arms (observation: −0.03, −0.03, −0.04; pembrolizumab: −0.001, −0.01, −0.06 at 6, 12, and 24 months, respectively). No statistically significant between-arm difference was observed at any time point, and no MID-level difference was identified.

Limitations

Chen noted that sample sizes at later time points—particularly 24 months—were smaller, which reduced statistical power to detect between-arm differences. The attrition in the HRQOL population may be attributable in part to disease progression leading to patient dropout from quality-of-life assessments.

Conclusions

Chen concluded that adjuvant pembrolizumab for high-risk MIUC after radical surgery extends median DFS from 14.2 to 29.6 months and is associated with pembrolizumab's known adverse effects, including fatigue and dyspnea, which modestly affect physical functioning and role functioning. However, the treatment did not adversely affect patient-reported global health or overall HRQOL. He noted that the HRQOL data help inform patient decision-making regarding adjuvant therapy and identify a potential need for supportive services to address the physical and role functioning effects observed during treatment.

"These data help inform patient decision-making regarding adjuvant therapy and also point to a possible need for supportive services to help survivors after treatment," Chen said.

DISCLOSURES: Chen reported disclosures related to AbbVie, Astellas Pharma, Bayer, Blue Earth Diagnostics, Genentech, Janssen, Medivation/Astellas, Myovant Sciences, Pfizer, VIR Biotechnology, Accuray, Reflexion Medical, and Telix Pharmaceuticals.

REFERENCES

1. Chen R, Dueck AC, Fruth B, et al. Health-related quality of life (HRQOL) with pembrolizumab or observation for high-risk muscle-invasive urothelial carcinoma after surgery: results from the AMBASSADOR randomized trial (Alliance A031501). J Clin Oncol. 2026;44(suppl 16):4513. doi:10.1200/JCO.2026.44.16_suppl.4513

2. Apolo AB, Ballman KV, Sonpavde G, et al. Adjuvant pembrolizumab versus observation in muscle-invasive urothelial carcinoma. N Engl J Med. 2025;392(1):45-55. doi:10.1056/NEJMoa2401726