RAD-IO: Durvalumab plus chemoradiotherapy is feasible in MIBC

Feasibility, safety, and early efficacy results from the RAD-IO multi-stage trial showed that the addition of durvalumab (Imfinzi) to standard chemoradiotherapy (CRT) with 5-fluorouracil (5-FU) and mitomycin C (MMC) was feasible and tolerable in patients with muscle-invasive bladder cancer (MIBC), with a 12-month disease-free survival (DFS) rate of 80%—well above the prespecified threshold for further investigation—and a 100% bladder preservation rate at 12 months.

Nicholas D. James, MD, PhD, a professor of prostate and bladder cancer research at the Institute of Cancer Research and The Royal Marsden NHS Foundation Trust in London, United Kingdom, presented the data at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting.¹

Background

Bladder preservation with radical radiotherapy and synchronous radiosensitizing chemotherapy is an established standard of care for MIBC, recognized across major international guidelines as an alternative to radical cystectomy.² The BC2001 trial, which James led, established robust phase 3 evidence for CRT with 5-FU and MMC in this setting, demonstrating improved locoregional control over radiotherapy alone.^3,4 Long-term BC2001 data show a 12-month DFS rate of approximately 60%, which served as the benchmark for RAD-IO.⁴ Checkpoint inhibition has demonstrated benefits across multiple disease settings in bladder cancer, providing the rationale for combining immunotherapy with CRT in MIBC.

RAD-IO trial design

RAD-IO is a multi-stage UK trial with an initial randomized feasibility and safety stage (Stage 1) followed by a single-arm phase 2 efficacy stage (Stage 2). Stage 1 enrolled patients with T2-T4aN0M0 urothelial MIBC and randomly assigned them 2:1 to CRT plus durvalumab vs CRT alone, stratified by neoadjuvant chemotherapy use. Stage 1 subsequently expanded to include node-positive patients (up to N2). The control regimen—used as the benchmark—consisted of a single dose of MMC administered prior to the first radiotherapy fraction, infusional 5-FU (500 mg/m² per 24 hours) during weeks 1 and 4, and 55 Gy in 20 fractions to the bladder. For node-positive patients, 46 Gy in 20 fractions was delivered to the nodal volume with an option to boost involved nodes to 51 Gy. James noted that, unlike trimodality therapy paradigms, no maximal transurethral resection or complete debulking was required in this protocol.

In the experimental arm, durvalumab was added as a priming neoadjuvant dose 1 week before CRT, a second dose during CRT, and then 11 adjuvant fixed-dose cycles thereafter—a perioperative schema mirroring the NIAGARA trial (NCT03732677) design. Stage 2 was originally intended to be fully randomized, but recruitment was substantially disrupted by the COVID-19 pandemic, which halted UK trial enrollment and created sustained reluctance among patients to attend for adjuvant infusions; the design was therefore pragmatically converted to a single-arm phase 2 using 12-month DFS rate as the primary end point. Stage 1 patients receiving CRT plus durvalumab were included in Stage 2 analyses. The independent data monitoring committee released 1-year data only for the present analysis; the control arm comparison data, 2-year outcomes, and patient-reported outcome data are pending.

The prespecified go/no-go decision framework for 12-month DFS was: less than 60% = no-go; 60%-75% = contextual; 75% or greater = go for further evaluation.

Patient characteristics

Fifty-five patients were enrolled in the CRT plus durvalumab arm. One patient withdrew before receiving any treatment; data are reported for the 54 patients who initiated treatment. Mean age was 69 years (interquartile range, 62-76). Eighteen percent were female and 82% were male. The majority (75%) had received prior neoadjuvant chemotherapy, reflecting standard of care in the United Kingdom. Clinical tumor stage was T2 in 80% and T3 in 20%, with 13% of patients having node-positive disease (N1 in 4 patients, N2 in 3).

Treatment delivery

All 54 patients who started treatment completed the full 55 Gy in 20 fractions; no patient stopped radiotherapy early. Treatment extensions or delays occurred in 7 patients (13%), with most lasting just 2 to 3 days; only 2 (4%) were attributable to toxicity, with the remainder due to patient choice or logistical factors. All 54 patients received MMC (7% at a reduced dose) and completed week 1 5-FU infusion (17% at reduced dose, largely driven by dihydropyrimidine dehydrogenase [DPD] status). Week 4 5-FU was administered in 78% of patients; 19% of those required dose reduction, delay, or interruption, and 22% discontinued chemotherapy early—a rate broadly consistent with BC2001. Durvalumab completion was 61% (33/54), with 39% discontinuing early. Of those who discontinued, 47.6% did so due to toxicity, 23.8% due to relapse, 9.5% due to patient withdrawal, and the remainder due to other or combined reasons.

Primary efficacy end point

The primary end point—12-month DFS rate—was 80% (40/50 evaluable patients; 95% CI, 0.67-0.89), with 2 patients pending assessment and 3 not evaluable. The lower confidence limit comfortably exceeded both the 60% no-go threshold and the 75% go threshold. Disease-free survival was defined as the absence of distant metastases, locoregional nodal disease, new muscle-invasive or non–muscle-invasive bladder tumor, upper tract urothelial cancer, or death from bladder cancer.

Of the 55 evaluable patients for the progression-free survival (PFS) analysis at 12 months, 83.6% had no event. Disease events included distant metastasis in 5 patients (9.1%) and local disease in 4 patients (7.3%), with the latter category including non–muscle-invasive relapses. The 12-month PFS results placed the trial in the go zone, consistent with the primary DFS end point.

"We saw 80% [DFS]—and you'll see the lower limit is well above the 60% margin," James said. "The lower limit actually excludes 75%. So this is clearly in the go zone."

Overall survival and bladder preservation

Overall survival at 12 months was 96.4% (53/55 patients without death). Two deaths occurred: 1 from bladder cancer (1.8%) and 1 from non-cancer causes (1.8%). By comparison, the 12-month overall survival rate in BC2001 was approximately 80%. The 12-month cystectomy rate was 0% (0/52 evaluable patients; 1 pending, 2 not evaluable), representing complete bladder preservation in all assessable patients.

"One hundred percent bladder preservation at a year—this looks to be a very good way of preserving people's bladders," James said.

Safety

Serious adverse events and suspected unexpected serious adverse reactions were generally infrequent and distributed across individual patients, with no single event occurring at notably high frequency. Adverse events of special interest were predominantly grade 1 or 2; 1 grade 4 myocarditis was observed, consistent with rates seen in other checkpoint inhibitor trials and managed within the trial. James emphasized that no evidence of bowel radiosensitization—an a priori safety concern with the addition of immunotherapy to pelvic CRT—was observed, in contrast to experiences in some other institutional trials using extreme hypofractionation. The overall safety profile was deemed consistent with the known component toxicities of CRT and durvalumab.

"We didn't see any evidence of sensitization of bowel by adding the synchronous durvalumab," James said. "The adverse events were in line with the component parts of the therapy—the chemoradiation and the durvalumab."

Conclusions

James concluded that the addition of neoadjuvant, synchronous, and adjuvant durvalumab to CRT in MIBC is feasible and well tolerated, with efficacy data meeting prespecified criteria for further evaluation when benchmarked against BC2001. The trial's 80% 12-month DFS rate and 0% cystectomy rate at 12 months were characterized as a strong benchmark for future studies examining the role of radical cystectomy vs bladder-preserving CRT-based approaches in this population. Partially randomized comparison data, 2-year outcomes, and patient-reported outcome results are forthcoming.

REFERENCES

1. James ND, van de Wiel J, De Santis M, et al. Feasibility and safety results from RAD-IO: A multi-stage trial of durvalumab with chemoradiotherapy with 5-fluorouracil and mitomycin C in patients with muscle-invasive bladder cancer. J Clin Oncol. 2026;44(suppl 16; abstr 4504). doi:10.1200/JCO.2026.44.16_suppl.4504

2. van der Heijden AG, Bruins HM, Carrion A, et al. European Association of Urology Guidelines on Muscle-Invasive and Metastatic Bladder Cancer: Summary of the 2025 Guidelines. Eur Urol. 2025;87(5):582-600. doi:10.1016/j.eururo.2025.02.0193.

3. James ND, Hussain SA, Hall E, et al. Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med. 2012;366(16):1477-1488.

4. James ND, Hussain SA, Hall E, et al.; BC2001 Investigators. Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer: long-term results of the BC2001 randomised controlled trial. J Clin Oncol. 2016;34(15):1573-1582. doi:10.1056/NEJMoa1106106