Trial design drives outcomes: harmonising efficacy across BCG-unresponsive bladder carcinoma in situ trials.

OBJECTIVES: To evaluate how heterogeneity in response assessment protocols, including biopsy timing, complete response (CR) assessment, retreatment policies, and the handling of withdrawals, influences reported efficacy outcomes across single-arm registrational trials of patients with bacillus Calmette Guérin unresponsive (BCG-U) carcinoma in situ (CIS). PATIENTS AND METHODS: We reconstructed survival data from six registrational BCG-U CIS trials and conducted simulation analyses to test how trial design affects efficacy estimates. Specifically, we: (i) reclassified patients who underwent re-induction as non-responders; (ii) adjusted for false-negative rates of cystoscopy/cytology vs biopsy (as uniquely reported in the nadofaragene firadenovec trial, hence chosen as the analytical reference); (iii) harmonised CR assessment timing across trials. The exact binomial test was utilised for comparisons. RESULTS: Re-induction reclassification reduced the 12-month CR rate for nogapendekin alfa inbakicept (NAI) + BCG from 44% to 33% and for cretostimogene grenadenorepvec from 45% to 38%. After adjusting for an 11% false-negative rate in trials lacking mandatory biopsies, the pembrolizumab 12-month CR rate declined to 17% (P = 0.07), and NAI, accounting for re-induction reclassification, achieved a CR rate of 29% (P = 0.4). TAR-200 outperformed the analytical reference, with a 12-month CR rate of 45% under mandatory biopsy protocols (P < 0.01). CONCLUSIONS: Trial design artefacts significantly impact reported efficacy in BCG-U CIS studies. Published CR rates are not directly comparable across agents. Future trials should standardise biopsy timing and clearly define retreatment policies to ensure meaningful cross-study comparisons.