The perioperative treatment landscape for muscle-invasive bladder cancer (MIBC) has evolved with the integration of immune checkpoint inhibitors into cisplatin-based chemotherapy. Although phase III trials have demonstrated improvements in outcomes with certain perioperative immunotherapy-based regimens, the efficacy of individual strategies continues to be evaluated.
The phase III CA017-078 (ENERGIZE) trial investigated whether adding nivolumab to neoadjuvant gemcitabine–cisplatin (GC), followed by adjuvant nivolumab after radical cystectomy, could improve pathological complete response (pCR) and event-free survival (EFS) in patients with previously untreated, resectable MIBC.
The final results of the phase III ENERGIZE trial were published in Annals of Oncology on October 23, 2026, under the title “Neoadjuvant nivolumab plus gemcitabine–cisplatin followed by postsurgical adjuvant nivolumab versus neoadjuvant gemcitabine–cisplatin in patients with muscle-invasive bladder cancer: final results from the phase III CA017-078 trial.”
The study was authored by G. Sonpavde, M.S. van der Heijden, S. Gupta, M.D. Galsky, G. Steinberg, J.E. Gschwend, J.P. Sade, D. Bimbatti, U. De Giorgi, G. Schepisi, S. Vázquez Estévez, S. Panay, G. Schinzari, A. Kotsakis, H. Miyake, J.J. Oh, J. Zhang, C. Jeyamohan, J. Neely, M. Jacques, Q. Duong, S. Sarkar, and A. Necchi.
The trial was conducted across 172 sites in 27 countries and included an exploratory analysis of circulating tumor DNA (ctDNA) to investigate its association with pathological response and long-term survival outcomes.
Study Design and Treatment
ENERGIZE was an international, randomized phase III trial enrolling adults with previously untreated, resectable cT2–T4aN0M0 MIBC who were eligible for cisplatin-based chemotherapy and radical cystectomy (RC).
The primary comparison included 653 patients, randomized to two treatment groups. Patients assigned to the experimental arm (n=325) were scheduled to receive four cycles of neoadjuvant nivolumab 360 mg every three weeks combined with GC, followed by RC and up to nine cycles of adjuvant nivolumab 480 mg every four weeks.
Patients assigned to the control arm (n=328) were scheduled to receive four cycles of neoadjuvant GC followed by RC, without protocol-specified adjuvant study treatment. The trial originally included a third arm investigating nivolumab, GC, and linrodostat, but this arm was discontinued. The final efficacy analysis focused on the nivolumab plus GC and GC-alone groups.
The coprimary endpoints were pCR, defined as ypT0N0 by blinded central pathological review, and EFS. Overall survival (OS) and safety were secondary endpoints. A post hoc exploratory analysis assessed pretreatment ctDNA detection and changes in ctDNA status during neoadjuvant therapy using the tumor-informed Signatera assay.
At the February 16, 2026 data cut-off, median follow-up was 54.5 months. Baseline characteristics were generally balanced between groups, and approximately 77% of patients had cT2 disease.
Efficacy Results: Numerical Increase in pCR Without EFS Benefit
The addition of perioperative nivolumab did not meet either coprimary endpoint. Pathological complete response was achieved in 127 of 325 patients (39.1%) assigned to nivolumab plus GC, compared with 97 of 328 patients (29.6%) assigned to GC alone. The adjusted difference was 9.5 percentage points (99.91% CI −2.6 to 21.6), with an adjusted odds ratio of 1.54 (99.91% CI 0.88–2.69).
Although the experimental arm demonstrated a numerical increase in pCR, the difference did not meet the prespecified multiplicity-adjusted significance threshold. The combined rate of pCR or pathological partial response (≤ypT1N0) was also numerically higher with nivolumab plus GC, at 51.7% versus 41.8%.
However, the numerical increase in pathological response was not accompanied by a significant improvement in EFS. At final analysis, 104 EFS events had occurred in each treatment arm. Median EFS was not reached with nivolumab plus GC and was 67.6 months with GC alone. The EFS hazard ratio was 0.94 (95.74% CI 0.71–1.25; P=0.6697). Estimated 36-month EFS rates were nearly identical between groups, at 68.1% with nivolumab plus GC and 68.5% with GC alone.
Overall survival also showed no clear difference between treatment groups. Median OS was not reached in either arm, with an HR of 0.88 (95% CI 0.64–1.21). At 36 months, estimated OS rates were 79.8% and 80.5%, respectively.
Because the EFS endpoint did not meet the prespecified significance criterion, OS was evaluated descriptively without formal hypothesis testing. Subgroup analyses did not identify a consistent survival benefit associated with nivolumab according to tumor PD-L1 expression or clinical T stage.
Exploratory ctDNA Analysis: Association With Long-Term Outcomes
An important component of ENERGIZE was its exploratory investigation of ctDNA as a prognostic biomarker during neoadjuvant treatment. Pretreatment ctDNA status was assessable in 416 patients, of whom 229 (55%) had detectable ctDNA. Among patients with assessable pretreatment ctDNA, positivity was observed in 108 of 211 patients (51%) in the GC-alone arm and 121 of 205 patients (59%) in the nivolumab plus GC arm.
Across the pooled population and within individual treatment arms, detectable ctDNA before treatment was associated with shorter EFS and OS compared with undetectable ctDNA.
The investigators also evaluated changes in ctDNA status between cycle 1 day 1 (C1D1) and cycle 4 day 1 (C4D1). Among 199 patients with detectable ctDNA at baseline and evaluable paired samples, 153 (76.9%) achieved ctDNA clearance by C4D1. Clearance was observed in 81.3% (87/107) of patients receiving nivolumab plus GC and 71.7% (66/92) receiving GC alone. Although numerically higher with nivolumab, the difference was not statistically significant (P=0.130).
Patients with ctDNA undetectable at both assessed time points had the most favorable survival outcomes, followed by those who achieved clearance during neoadjuvant therapy.
In contrast, detectable ctDNA at C4D1 was associated with shorter EFS and OS. In the pooled trajectory analysis, patients with detectable ctDNA at C4D1 had a median EFS of 8.5 months (95% CI 6.7–11.2) and a median OS of 28.1 months (95% CI 16.4–not reached). Median EFS and OS were not reached in the other ctDNA trajectory groups.
The relationship between molecular and pathological response provided additional information. Patients who achieved both ctDNA clearance and pCR (n=60) generally had the most favorable EFS and OS, whereas those who achieved neither response (n=43) had the poorest outcomes.
Patients who cleared ctDNA without achieving pCR (n=93) had intermediate survival outcomes. These findings support the prognostic relevance of ctDNA dynamics alongside pathological response, although the exploratory analyses did not establish their independent prognostic contributions. Only 346 patients had paired C1D1–C4D1 ctDNA results, and the analyses were not powered to establish whether ctDNA status predicted differential benefit from nivolumab.
Therefore, although ctDNA detection and clearance were associated with survival outcomes, the study did not establish ctDNA as a predictive biomarker for selecting perioperative nivolumab.
Safety and Treatment Exposure
The overall safety profile was consistent with the known toxicities of nivolumab and cisplatin-based chemotherapy, without new safety signals. Across the overall treatment period, grade 3–4 treatment-related adverse events occurred in 50.0% of patients receiving nivolumab plus GC and 49.5% receiving GC alone.
Treatment-related serious adverse events were more frequent in the nivolumab group, occurring in 15.7% versus 9.8% of patients. Treatment-related adverse events leading to discontinuation were also more frequent with the perioperative nivolumab regimen (22.3% vs 14.2%). The most commonly reported treatment-related adverse events included nausea, anemia, neutropenia, fatigue, and decreased neutrophil count.
One treatment-related death due to pneumonitis occurred in the nivolumab plus GC arm. Treatment exposure is also relevant when interpreting the results. Among 318 treated patients in the nivolumab plus GC group, 183 (57.5%) completed both the neoadjuvant and adjuvant treatment phases.
Furthermore, the nivolumab arm included postoperative treatment, whereas the GC-alone arm had no protocol-specified adjuvant therapy, resulting in different treatment and safety observation periods.
Clinical Implications
The final ENERGIZE results contribute to the growing evidence on perioperative immunotherapy in resectable MIBC. Unlike the phase III NIAGARA trial, which demonstrated EFS and OS benefits with perioperative durvalumab plus GC, ENERGIZE did not demonstrate improved long-term outcomes with perioperative nivolumab.
Differences in patient populations, clinical stage distribution, endpoint definitions, treatment schedules, and subsequent therapies limit direct comparisons between these trials.
Notably, approximately 77% of patients in ENERGIZE had cT2 disease, compared with a lower proportion in NIAGARA. ENERGIZE also enrolled only patients with clinically node-negative disease. The numerical increase in pCR without a corresponding EFS improvement illustrates an important limitation of using pathological response alone to assess treatment benefit in MIBC.
At the same time, the exploratory ctDNA findings add to evidence supporting the prognostic relevance of molecular response during neoadjuvant treatment. Detectable ctDNA before treatment or failure to clear ctDNA during neoadjuvant therapy was associated with shorter EFS and OS, whereas ctDNA clearance was associated with more favorable outcomes. Nevertheless, these results do not establish a role for ctDNA-guided treatment modification within the ENERGIZE regimen.
Conclusion
The final results of the phase III ENERGIZE trial demonstrated that adding perioperative nivolumab to neoadjuvant gemcitabine–cisplatin did not significantly improve pathological complete response or event-free survival in patients with resectable MIBC. Although pCR was numerically higher with nivolumab, no corresponding EFS benefit was observed, and the descriptive OS analysis showed no clear survival difference between treatment groups.
The exploratory ctDNA findings were clinically relevant, demonstrating associations between pretreatment ctDNA detection, molecular clearance during neoadjuvant therapy, and long-term survival. Overall, ENERGIZE provides mature randomized evidence on the limitations of this perioperative nivolumab strategy while supporting further investigation of ctDNA as a prognostic biomarker and a potential tool for refining risk assessment in MIBC.
The full article is available in Annals of Oncology.
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