Unmet Treatment Need and Challenges Associated with Comparative Evidence Generation in BCG-unresponsive...

The overall objective of this modified Delphi panel study was to develop a consensus of European expert clinical opinion on unmet need, clinical evidence generation, and appropriate trial endpoints in Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC).

A panel of European clinical experts participated (N = 12, n = 9 at consensus meeting). Consensus statements and topics were developed and tested in online surveys conducted in January-February and April-May 2023, before discussion in a consensus meeting in August 2023. Consensus was defined as agreement by ≥80% of the panelists.

Panelists agreed that there is a significant unmet need within the BCG-unresponsive NMIBC population, particularly among patients who are unfit to undergo radical cystectomy (RC). In many cases, RC may not be feasible due to medical complications, or the risk associated with comorbidities, and patients may also be unwilling to undergo surgery. This highlights the urgent need for effective nonsurgical alternatives. While randomized controlled trials (RCTs) were considered feasible, panelists acknowledged unresolved ethical and technical barriers to their implementation in this setting. Technical challenges identified include difficulties with recruiting an adequate number of patients overall, difficulties with recruiting a sufficiently homogeneous population to generate reliable results, and difficulties with objectively defining unfitness for surgery. In contrast, single-arm trials (SATs) were viewed as an appropriate and ethical approach under these constraints. Panelists agreed that the following endpoints should be measured within a randomized or single-arm clinical trial in this indication: complete response, duration of response, and safety.

While conducting RCTs in this area was considered feasible and acceptable, ethical and technical challenges still appeared to be unresolved, suggesting a need for evidence generated through other means. Data from SATs may be considered an acceptable alternative. These findings therefore suggest a way forward to address this unmet need.

European experts agree there is a substantial treatment gap for people with bladder cancer that no longer responds to Bacillus Calmette-Guérin, especially those too unwell for bladder removal surgery, or who do not wish to have this surgery-so effective, safer sparing therapies are urgently needed. Because large randomized trials are difficult to conduct fairly in this population, the experts support simpler study designs that assess whether the cancer responds, how long the response is maintained, and how safe the treatment is.