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.

4504 Background: Immune checkpoint inhibitors have a defined role peri-operatively and in the adjuvant setting when cystectomy is used as radical definitive treatment (Powles, T., et al. 2024, Galsky, M. D., et al. 2024). Their role when chemoradiation therapy (CRT) is used as definitive treatment remains to be established. RADIO is a multi-stage partially randomised trial comparing CRT (RT/5FU/mitomycin C) with durvalumab (CRT-D) given prior to, concurrently and 12 months following CRT in localized muscle-invasive bladder cancer. The trial is funded by AstraZeneca. Methods: Eligible patients had T2–T4aN0–N2M0 urothelial carcinoma of the bladder. Neoadjuvant chemotherapy was delivered as standard of care, where fit, prior to trial therapy. After randomised feasibility and safety criteria were met, the trial transitioned to a single-arm CRT-D design. Here we report the primary endpoint of 1-year disease-free survival rate (1yDFS) for all evaluable CRT-D participants, plus progression free survival (PFS), disease free survival (DFS), and overall survival (OS). DFS patients with disease present at 3-month imaging are categorised as having never been disease free. The design aimed to detect 1yDFS improvement, based on our previous trials, from 60% (CRT) to 75% (CRT-D) with 80% power and one-sided α=0.10. Results: All data are preliminary. Between Oct 2020–Mar 2024, 55 participants (45 male; 10 female) with median age 70 (IQR 62-76) years of whom 40 (73%) had T2N0, 8 (14%) had T3N0 and 7 (13%) had TxN1-2 were enrolled to receive CRT-D. 41 (74.5%) received neoadjuvant CT. Of the 54 participants who started treatment, all completed planned RT (55Gy/20Fr); 47 (87%) within the expected timeframe, 7 (13%) required an extension (2-6 days) (toxicity 3, patient choice 3, other 1). Toxicities extending RT: urinary tract infection, chest pain, and low platelets. At abstract submission, 48/55 were evaluable: 1yDFS 79% (38/18; 95% CI 66%, 88%). 12-month Kaplan-Meier estimates were: PFS 83% (95% CI 73%, 94%), DFS 72% (95% CI 61%, 85%), OS 96% (95% CI 91%, 100%). Safety: 35 SAEs; 17 unrelated SAEs, 12 SARs, 6 SUSARs. 10 SAEs were related to durvalumab, 3 were related to CT, and 5 were related to both durvalumab and CT. 3 SAEs led to discontinuation (5FU 2, durvalumab 1). 168 AESIs have been reported (most common: diarrhoea (19%), rash (12%), creatinine increased (8%)), and an additional 41 grade ≥3 AEs. Conclusions: Durvalumab combined with CRT demonstrated promising 1-year DFS and survival outcomes compared to our previously reported CRT outcomes (Hall, E., et al , 2022) with manageable safety profile. CRT-D is a safe treatment with a side effect profile in keeping with known side effects of CRT and durvalumab. Further investigation is warranted. Clinical trial information: 43698103.