The SUNRISE 2 trial's chemoradiation arm showed unexpectedly strong results. This is likely due to a protocol requiring a repeat resection (RIT-URBT) before randomization, which weeded out aggressive tumors and selected a patient population with a better prognosis, making the control arm unusually difficult to beat.
After failing to outperform chemoradiation in muscle-invasive disease, TAR-200 may be repositioned. Instead of a primary treatment, it could be used sequentially after an effective systemic therapy to control the high-grade, non-muscle invasive relapses that often occur in patients who achieve a major response and wish to preserve their bladder.
In the SUNRISE 2 trial, 44% of patients had no detectable tumor after pre-treatment resection. This high baseline inflates the final clinical complete response (CR) rates (e.g., 59% in the control arm), making CR a misleading indicator of the actual therapeutic benefit, which was a much smaller improvement over baseline.
The event-free survival curve for the TAR-200 arm in SUNRISE 2 exhibits a sharp decline around the first assessment at 4 months. This pattern indicates that the localized, intravesical drug delivery is failing to control more deeply invasive or micrometastatic disease, leading to rapid, early treatment failures compared to chemoradiation.
The control arm relapse rate in the SUNRISE 2 trial was only ~20%, while in the EV-303/KEYNOTE-905 trial it was ~60%. This huge discrepancy highlights that current clinical staging and selection criteria are poor at identifying patient risk, signaling an urgent need for better stratification tools like ctDNA for more effective clinical trials.
The chemoradiation control arm in SUNRISE 2 performed so well (e.g., 95% 1-year overall survival) that it challenges the long-held belief that surgery is unequivocally superior. This result, alongside other recent studies, suggests chemoradiation should be considered a potent standard-of-care contender for bladder preservation in appropriately selected patients.