Pancreatic resection with perioperative drug repurposing of propranolol and etodolac - the phase II randomized controlled PROSPER trial.

Abstract

Purpose: The perioperative period is characterized by psychological stress and inflammatory reactions that can contribute to disease recurrence or metastatic spread. These reactions are mediated particularly by catecholamines and prostaglandins. The PROSPER trial aimed to evaluate whether a perioperative drug repurposing with a non-selective betablocker (propranolol) and a COX-2 inhibitor (etodolac) is feasible and safe in the setting of pancreatic cancer surgery.

Methods: Patients undergoing partial pancreatoduodenectomy for pancreatic cancer were randomized to perioperative treatment with propranolol and etodolac or placebo. Main safety endpoint was the rate of serious adverse events (SAE) and the main feasibility endpoint was adherence. Overall and disease-free survival (DFS) as well as recurrences were assessed as efficacy parameters and the trial was accompanied by a translational study.

Results: The trial was prematurely closed due to slow recruitment. 26 patients were randomized, but 6 never started trial medication. Finally, 9 patients received the trial medication and 11 patients placebo. There were 6 SAE in the treatment vs. 14 in the placebo group. Adherence was lower in the treatment group, but without statistically significance. Median DFS was 16.36 months (95%-CI 1.18 - not reached) in verum vs. 11.25 (95%-CI 2.2 - 17.25) in placebo group. The rate of distant recurrences was 11.1% in verum vs. 54.5% in placebo group.

Conclusion: There were no safety concerns, but the trial intervention was not feasible given slow recruitment and limited adherence. However, the translational study and preliminary efficacy data revealed some promising findings, warranting further investigation.

Registration: DRKS00014054.