Phase II proof-of-concept study of durvalumab and cediranib with and without olaparib in recurrent ovarian cancer
We report the efficacy and translational research findings of durvalumab, olaparib, and cediranib (D+O+C) and durvalumab plus cediranib (D+C) from the recurrent epithelial ovarian cancer (EOC) cohort within a single center, multi-arm, non-randomized, multi-cohort phase I/II trial (NCT02484404). Sixty-eight patients were enrolled (39 in D+O+C, 29 in D+C). The objective response rate (ORR) was 19.4% (95% CI, 9.5-43.5) for D+O+C and 29.6% (95% CI, 13.8-46.9) for D+C. Median progression-free survival (PFS) was 4.5 months in both arms, with each arm including four exceptional responders (PFS = 12 months). Pre- and on-treatment biopsies and blood samples were collected for pre-specified transcriptomic and immunophenotypic profiling; signature analyses and preclinical studies were exploratory. We identified distinct transcriptional signatures associated with clinical outcomes. Baseline tumors from exceptional responders and patients with clinical benefit (partial response or stable disease [SD] with PFS = 4 months) demonstrated strong enrichment of immune activation and metabolic pathways. Conversely, tumors with no clinical benefit (NCB; progressive disease or SD with PFS < 4 months) exhibited upregulation of vascular adaptation and cytoskeletal remodeling pathways. The correlation between immune, metabolic, and NCB signatures and clinical outcomes within each arm was independent of prior platinum response. These findings support proof-of-concept clinical activity of D+O+C and D+C and identify molecular signatures with potential predictive value in subsets of recurrent EOC. Overall design: Pre-treatment biopsies for RNAseq were available for 31 patients in the D+O+C arm (21 CB including 4 exceptional responders, and 10 NCB) and 24 in the D+C arm (14 CB including 3 exceptional responders, and 10 NCB). Paired pre- and on-treatment biopsies were available for 11 and 9 patients in the D+O+C and D+C arms, respectively. RNAseq was performed on tumor biopsies to characterize gene expression profiles. RNA samples were pooled and sequenced on NovaSeq Xplus 1.5B using Illumina® Stranded Total RNA Prep, Ligation with Ribo-Zero Plus and paired-end sequencing.