Surrogate endpoints such as disease-free survival (DFS) and distant metastasis-free survival (DMFS) could expedite the approval of novel agents and enable earlier access to these agents, but their validity in this setting has not been well established. Recent immunotherapy trials in the adjuvant setting have observed improved DFS as a primary endpoint.4,5 This study sought to evaluate whether DFS and DMFS are reliable surrogates for OS in patients with MIBC treated with adjuvant cisplatin-based chemotherapy after radical cystectomy.6
Individual patient data (n = 1082) were pooled from 9 randomized controlled trials (RCTs) that compared adjuvant cisplatin-based chemotherapy plus radical cystectomy versus local therapy alone in patients with locally advanced bladder cancer without prior neoadjuvant chemotherapy. The main objective of the study was to assess DFS as a surrogate for OS, primarily for the intent-to-treat (ITT) population of each RCT. Secondary objectives were to assess DMFS as a surrogate for OS and to conduct subgroup analyses for both endpoints at individual and trial levels based on lymph node status (node-negative vs node-positive). Patient-level association was measured between DFS/DMFS and OS using Spearman’s correlation coefficient (ρ). Trial-level surrogacy was assessed by squared correlation of hazard ratios (R²).
At the time of analysis, the median follow-up for OS across the 9 RCTs ranged from 3.5 to 14.8 years, with a median of 6.4 years across all trials. Data for the analysis of DFS were available for 1075 patients, with 615 DFS events and 553 OS events across the 9 RCTs. Patient-level correlation in the ITT population showed that DFS was strongly associated with OS (ρ = 0.89; 95% confidence interval [CI], 0.87–0.90). At the trial level, DFS demonstrated a moderate association with OS overall (R² = 0.69; 95% CI, 0.34–1.00) that was weaker in node-positive patients. For DMFS, data were available for 884 patients from 6 RCTs, which included 474 DMFS events and 438 death events. DMFS demonstrated a particularly strong association with OS (ρ = 0.91; 95% CI, 0.89–0.92) at the patient level. A strong association was seen with DMFS and OS (R² = 0.90; 95% CI, 0.74–1.00) that was consistent across both node-negative and node-positive subgroups at the trial level.
DFS showed a weak association with OS in lymph node–positive patients, but associations were strong for lymph node–negative patients and for DMFS. The weaker trial-level correlation of DFS with OS in node-positive patients highlights important subgroup differences—in this higher-risk population, local recurrences captured by DFS appear less reliable in predicting long-term survival. Notably, findings from the EORTC 30994 trial demonstrated that 4 cycles of adjuvant chemotherapy improved OS in node-negative patients but not in node-positive patients, suggesting that the lack of benefit in higher-risk patients may contribute to the weaker surrogacy of DFS for OS observed in node-positive patients.7
Both DFS and DMFS were strongly associated with OS at the patient level. At the trial level, however, DMFS emerges as a more robust surrogate for OS in the adjuvant setting. DFS may be acceptable in certain populations, but is less reliable in node-positive disease. These findings suggest that DMFS may provide a more consistent early measure of treatment benefit than DFS, particularly for node-positive disease.
Limitations of the current analysis include its non-uniform definitions of DFS and DMFS across trials. Additionally, since these trials predated widespread use of neoadjuvant chemotherapy and modern immunotherapy, applicability to current regimens requires validation. Finally, some trial-level estimates had wide CIs, particularly in smaller subgroups.
This pooled analysis provides the strongest evidence to date that DMFS is a valid surrogate endpoint for OS in the adjuvant treatment of MIBC with cisplatin-based chemotherapy. Given the weaker trial-level surrogacy of DFS in node-positive patients in our analysis and the larger benefit seen in node-negative patients than in node-positive patients with 4 cycles of therapy in the EORTC 30994 trial,7 future trials might consider alternative surrogates, stronger therapeutic regimens, or longer treatment and follow-up periods when designing adjuvant therapy for node-positive patients with MIBC. Use of DMFS in future adjuvant trials may shorten the time to clinically meaningful results, drastically aiding drug development and patient access to effective therapies.
Written by:
- Cora N. Sternberg, MD, Professor of Medicine, Clinical Director of the Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY
- Marc Buyse, ScD, Founder, Chief Scientific Officer, International Drug Development Institute (IDDI), Louvain-la-Neuve, Belgium
- Kaufmann E, Black P, Catto J, et al. Oncological surveillance after radical cystectomy: a narrative review of the Enhanced Recovery After Surgery Cystectomy Committee. JU Open Plus. 2023;1(10):e00051. doi: 10.1097/JU9.0000000000000046
- Advanced Bladder Cancer (ABC) Meta-analysis Collaborators Group. Adjuvant chemotherapy for muscle-invasive bladder cancer: a systematic review and meta-analysis of individual participant data from randomised controlled trials. Eur Urol. 2022;81(1):50-61. doi:10.1016/j.eururo.2021.09.028
- Yin M, Joshi M, Meijer RP, et al. Neoadjuvant chemotherapy for muscle-invasive bladder cancer: a systematic review and two-step meta-analysis. Oncologist. 2016;21(6):708-715. doi:10.1634/theoncologist.2015-0440
- Bajorin DF, Witjes JA, Gschwend JE, et al. Adjuvant nivolumab versus placebo in muscle-invasive urothelial carcinoma. N Engl J Med. 2021;384(22):2102-2114. doi:10.1056/NEJMoa2034442
- 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
- Sternberg CN, Squifflet P, Saad ED, et al. Evaluating surrogates for overall survival in the adjuvant treatment of bladder cancer with chemotherapy. Urol Oncol. Published online August 21, 2025. doi:10.1016/j.urolonc.2025.07.013
- Sternberg CN, Skoneczna I, Kerst JM, et al. Immediate versus deferred chemotherapy after radical cystectomy in patients with pT3-pT4 or N+ M0 urothelial carcinoma of the bladder (EORTC 30994): an intergroup, open-label, randomised phase 3 trial. Lancet Oncol. 2015;16(1):76-86. doi:10.1016/S1470-2045(14)71160-X