Clinical Summary: 

• Andrea Necchi, MD, discusses final results from the phase 3 ENERGIZE trial comparing neoadjuvant nivolumab plus gemcitabine and cisplatin followed by surgery and adjuvant nivolumab versus neoadjuvant chemotherapy followed by surgery in patients with resectable muscle-invasive bladder cancer.
• The addition of nivolumab did not significantly improve event-free survival (HR, 0.94; P = .67) or pathologic complete response (39.1% vs 29.6%) compared with chemotherapy alone, while overall survival data remained immature and safety findings were consistent with known treatment profiles.
• These findings highlight the limitations of adding perioperative nivolumab to cisplatin-based chemotherapy and support further investigation of biomarker-guided strategies, including ctDNA assessment, to optimize treatment selection in muscle-invasive bladder cancer.

Andrea Necchi, MD, San Raffaele Hospital and Vita-Salute San Raffaele University, Milan, Italy, discusses final results from the phase 3 ENERGIZE  trial evaluating perioperative nivolumab plus gemcitabine and cisplatin versus neoadjuvant chemotherapy alone in patients with resectable muscle-invasive bladder cancer. 

Dr Necchi reviews the lack of statistically significant improvements in event-free survival or pathologic complete response with the addition of nivolumab, despite a numerical increase in pathologic response rates. He also discusses exploratory ctDNA findings and how these results may inform future perioperative treatment strategies and biomarker-guided clinical trials in muscle-invasive bladder cancer.

Transcript: 

Hello, I'm Andrea Necchi. I'm a medical oncologist, the director of GU medical oncology at San Raffaele Hospital, a professor of oncology at San Raffaele University in Milan, Italy. It's a pleasure to be here today at the ESMO meeting presenting the final results of the ENERGIZE trial.

The ENERGIZE trial was a phase 3 trial randomizing patients with muscle-invasive bladder cancer to receive neoadjuvant nivolumab, gemcitabine, and cisplatin, followed by cystectomy and followed by adjuvant nivolumab, or the standard of care that was at that time cisplatin-based chemotherapy, cisplatin and gemcitabine, followed by cystectomy and just observation alone.

The trial included patients from over 27 countries, and the coprimary end points of the trial were pathologic complete response (pCR) and event-free survival (EFS). 

The final analysis is related to EFS, and the study was stopped because of the fact that the trial did not meet the coprimary end points for both pCR and event-free survival.

There was an interesting 9.5% difference in the gain in pCR rate with nivolumab, gemcitabine, and cisplatin. This absolute difference did not meet the prespecified threshold for significance.

Event-free survival was not improved. The hazard ratio was 0.94, and the same for overall survival, which is just presented descriptively.

There were initially very interesting data related to ctDNA that we have presented with Signatera tests that measured baseline and post-neoadjuvant therapy, showing that patients who were negative at baseline or who got a clearance of the ctDNA if they were positive at baseline benefited with an improvement in EFS as compared to those who were positive and remained positive post-neoadjuvant therapy.

Overall, the study is practice-informing and comes to put data into the ground of neoadjuvant therapies, a developing world of neoadjuvant therapies, and may be informative in particular with regards to the use of chemotherapy, standard chemotherapy as a backbone therapy for neoadjuvant therapies that will be unlikely an option for further trials, and it will be hard to pursue in the real-world as an option, as a chemoimmunotherapy combination in tomorrow's patient that we have to treat with bladder cancer.

Source: 

Necchi A, Gupta S, Van de Heijden MS, et al. Results from a phase 3 trial of neoadjuvant (neoadj) chemotherapy alone vs in combination with nivolumab followed by postsurgical adjuvant nivolumab in patients (pts) with muscle-invasive bladder cancer (MIBC). Presented at ESMO Congress. October 23-27, 2026; Madrid, Spain. Abstract 4736O.