With POTOMAC we set out to improve the outcome of high-risk non-muscle invasive bladder cancer. For many decades, more than four decades, non-muscle invasive bladder cancer was treated with BCG instillation therapy and there has been no progress. So our idea was to add systemic immunotherapy with durvalumab to BCG induction and maintenance therapy and maintenance therapy for two years in our study, the usual standard is something between one and three years of BCG maintenance. The reason for BCG not working might be the up-regulation of PD-L1 in the bladder so we thought that the introduction of one year of immune checkpoint inhibition with durvalumab might improve the outcome which is disease free survival in our trial.
What was the study design?
The study was a global, randomised phase III open-label study. We included 1,018 patients into the trial. The patients were adults and the median age was 68. Good ECOG performance status, they all had to be BCG naïve with a diagnosis of high-risk non-muscle invasive bladder cancer which was defined by the EAU guidelines 2017 at the time when we designed the trial.
What were the results?
We randomised patients into three arms: one year of durvalumab plus BCG induction and maintenance, one year of durvalumab plus BCG induction only and BCG induction and maintenance as the control arm. The first endpoint was disease free survival and POTOMAC was a positive trial. Disease free survival was improved by 32% in the total population, so the ITT population. This was highly statistically significant, the hazard ratio was 0.68 and the p-value 0.0154.
The curves, by the way, separated very early and stayed apart throughout. The median follow-up was long with 60.7 months and this is the longest we have seen in this area of research.
What was the safety profile?
Safety showed that the combination of durvalumab plus BCG induction and maintenance is tolerable and manageable. Of course with the addition of one year of durvalumab we see additional immune-mediated side effects from the systemic therapy. We saw 8% of grade 3 and 4 immune-mediated adverse events, otherwise we did not see an increase in BCG-mediated side effects, so the local treatment was not worse with the addition of durvalumab.
What could be the impact of these results?
The POTOMAC study supports one year of durvalumab in addition to BCG induction and maintenance therapy as a new treatment option in high-risk non-muscle invasive bladder cancer.
