Magnitude and timing of clinical benefit associated with pathologic complete response in perioperative muscle-invasive bladder cancer: A reconstructed IPD analysis of NIAGARA trial.

4607 Background: Pathologic complete response (pCR) is widely used as an early efficacy endpoint in neoadjuvant or perioperarive bladder cancer trials. However, formal surrogacy analyses linking pCR to long-term clinical outcomes are lacking. In particular, the magnitude and timing of clinically meaningful benefit associated with pCR remain poorly defined. We aimed to quantify the absolute benefit and temporal emergence of event-free survival (EFS) and overall survival (OS) associated with pCR in NIAGARA trial. Methods: Individual patient data (IPD) were reconstructed from the most recent publicly available Kaplan-Meier curves of the NIAGARA trial, including stratification by pCR and non-pCR status for each treatment arm. The primary analysis compared outcomes between pCR and non-pCR patients within each treatment arm. Restricted mean survival time differences (ΔRMST) were estimated at 24 months for EFS and 36 months (mo) for OS. Time to benefit (TTB) was defined as the earliest time point at which ΔRMST reached ≥1 mo for EFS and ≥2 mo for OS. Exploratory analyses compared outcomes within pCR patients and within non-pCR patients between treatment arms, to explore whether the clinical benefit associated with pCR is purely prognostic or reflects treatment-related modulation within pathological response strata. Results: At 24 months, pCR was associated with a large and early EFS benefit across treatment arms. Among patients receiving durvalumab + cisplatin-gemcitabine (CG), pCR was associated with a ΔRMST of +5.87 mo (95% CI 4.78-6.96; p<0.0001) compared with non-pCR, with a TTB of 9 mo. Similar results were observed in the CG arm (ΔRMST of +5.63 mo, 95% CI 4.49-6.77; p<0.0001), with a TTB of 9 mo. At 36 months, pCR was also associated with a substantial OS benefit. In the durvalumab + CG arm, pCR was associated with a ΔRMST of +5.32 mo (95% CI 3.89-6.74; p<0.0001) versus non-pCR, with a TTB of 22 mo. Comparable findings were observed in the CG arm (ΔRMST +5.89 mo, 95% CI 4.30-7.47; p<0.0001), and a TTB of 20 mo. In exploratory analyses, no significant EFS or OS differences were observed between treatment arms among pCR patients (ΔRMST <1 month), with a TTB of 38 mo for EFS and not reached within 60 mo for OS. Among non-pCR patients, treatment-related differences were similarly modest (ΔRMST ~1 month), with delayed TTB (19 mo for EFS and 50 mo for OS). Conclusions: Using reconstructed IPD from NIAGARA, pCR identifies a large, early EFS benefit and a later OS benefit, informing, in the absence of formal surrogacy validation, a quantitative and temporal clinical interpretation of pCR. In contrast, no additional treatment-related survival benefit was observed within pCR or non-pCR subgroups, raising the hypothesis that survival differences may be largely attributable to pCR rather than to treatment-related modulation within response strata.