Olaparib (Lynparza®) is a poly(ADP-ribose) polymerase (PARP) inhibitor that prevents the repair of single-strand DNA breaks. Durvalumab (Imfinzi®) is a programmed cell death ligand 1 (anti-PD-L1) inhibitor, which functions by promoting antitumour immune responses. Inhibition of vascular endothelial growth factor (VEGF) has been reported to enhance PARP inhibitor activity. Combinations of immune checkpoint inhibitors and bevacizumab have shown promising results in other tumour types. Here, the efficacy and safety of bevacizumab (anti-VEGF-A antibody) is investigated in combination with olaparib + durvalumab in platinum-sensitive relapsed (PSR) non-gBRCAm ovarian cancer (OC) pts (NCT02734004).
Initially, 148 pts were enrolled across several tumour types (small-cell lung cancer, gastric cancer, germline BRCA-mutated [gBRCAm] breast cancer, or PSR gBRCAm OC). Pts received olaparib 300 mg po bid for a 4-wk run-in, followed by olaparib 300 mg po bid and durvalumab 1.5 g IV q4w. Primary endpoints were disease control rate (DCR) at 12 wks, safety and tolerability. Secondary endpoints: pharmacokinetics (PK), DCR at 28 wks, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Tumours were assessed at baseline, 4 wks and every 8 wks thereafter. Enrolment was completed for these initial cohorts, and new PSR OC cohorts (Table) have been added, based on the preliminary results. These cohorts have no olaparib run-in, tumour assessments are performed at baseline and every 8 wks thereafter, bevacizumab 10 mg/kg is given q 2 weeks, and pts with 1–2 prior chemotherapy lines are allowed.Table: 448TiP
New MEDIOLA cohorts
|OC cohort name||Drugs||Population||Primary endpoint|
|Expansion (N = 80)||Olaparib+Durvalumab||gBRCAm||ORR|
|Doublet (N = 30)||Olaparib+Durvalumab||non-gBRCAm||DCR 24 wks|
|Triplet (N = 30)||Olaparib+Durvalumab+ Bevacizumab||non-gBRCAm||DCR 24 wks|
Other endpoints: Safety and tolerability, PK, DCR at 56 wks, ORR, PFS, and OS. Biomarker endpoints: Analysis of tumour-infiltrating lymphocytes and PD-L1 expression.
Clinical trial identification
Legal entity responsible for the study
R.T. Penson: Scientific advisory boards: Amgen Inc., Genentech, Inc., AstraZeneca, Endocyte Inc., Eisai Inc., Vascular Biogenics Ltd, Baxalta Oncology, AbbVie, Clovis Oncology, Tesaro; Research funding: Genentech Inc., ImClone Systems Inc., Endocyte Inc., AstraZeneca, Eisai Inc., Amgen Inc., Vascular Biogenics Ltd; Royalties: BMJ, Blackwell; Publishing Medicine at a Glance, UpToDate Commercial: Advance Medical: Second Medical Opinion. B. Kaufman: Advisory board: AstraZeneca. C. Gresty, H.K. Angell, K. Meyer, M. Lanasa, P. Herbolsheimer: Employee and stockholder: AstraZeneca. S. Domchek: Honoraria: AstraZeneca, Clovis, and Bristol-Myers Squibb. All other authors have declared no conflicts of interest.