Clinical activity and safety of cediranib and olaparib combination in patients with metastatic pancreatic ductal adenocarcinoma without BRCA mutation.

Lessons learned Cediranib and olaparib combination did not result in clinically meaningful activity in patients with metastatic pancreatic ductal adenocarcinoma without known BRCA mutation. Background Cediranib, a vascular endothelial growth factor receptor inhibitor, suppresses expression of BRCA1/2 and RAD51 inducing homologous recombination DNA repair deficiency (HRD) in several cancer cell lines and xenograft models [1]. Olaparib provides a clinical benefit in patients with metastatic pancreatic adenocarcinoma (mPDAC) with germline BRCA mutation (gBRCAmt) [2]. We hypothesized that cediranib induces HRD in the absence of gBRCAmt and synergizes with olaparib resulting in an objective response in mPDAC patients. Methods Patients with mPDAC with at least one prior systemic chemotherapy were enrolled. Patients with known gBRCAmt were excluded. Patients took cediranib 30mg daily and olaparib 200mg twice daily, orally. The primary endpoint was objective response (OR) rate. Results Nineteen patients received the study drugs. Seven patients came off treatment before the first restaging scan: six due to clinical progression and one due to an adverse event. No OR was observed. Six patients had stable disease (SD) as a best overall response. The median duration of SD was 3.1 months. The median overall survival was 3.4 months. Common treatment-related adverse events were fatigue, hypertension, and diarrhea. Conclusion Cediranib and olaparib combination did not result in clinically meaningful activity in patients with mPDAC without gBRCAmt.