A phase II, open-label, randomized trial of durvalumab with olaparib or cediranib in patients with mismatch repair–proficient colorectal or pancreatic cancer

Background The use of immunotherapy in mismatch repair proficient colorectal cancer (pMMR-CRC) or pancreatic adenocarcinoma (PDAC) is associated with limited efficacy. DAPPER (NCT03851614) is a phase 2, basket study randomizing patients with pMMR CRC or PDAC to durvalumab with olaparib (durvalumab+olaparib) or durvalumab with cediranib (durvalumab+cediranib). Methods PDAC or pMMR-CRC patients were randomized to either durvalumab+olaparib (arm A), or durvalumab+cediranib (arm B). Co-primary endpoints included pharmacodynamic immune changes in the tumor microenvironment (TME) and safety. Objective response rate, progression-free survival (PFS) and overall survival (OS) were determined. Paired tumor samples were analyzed by multiplexed immunohistochemistry and RNA-sequencing. Results A total of 31 metastatic pMMR-CRC patients were randomized to arm A (n=16) or B (n=15). In 28 evaluable patients, 3 patients had stable disease (SD) (2 patients treated with durvalumab+olaparib and 1 patient treated with durvalumab+cediranib) while 25 had progressive disease (PD). Among patients with PDAC (n=19), 9 patients were randomized to arm A and 10 patients were randomized to arm B. In 18 evaluable patients, 1 patient had a partial response (unconfirmed) with durvalumab+cediranib, 1 patient had SD with durvalumab+olaparib while 16 had PD. Safety profile was manageable and no grade 4-5 treatment-related adverse events were observed in either arm A or B. No significant changes were observed for CD3+/CD8+ immune infiltration in on-treatment biopsies as compared to baseline for pMMR-CRC and PDAC independent of treatment arms. Increased tumor-infiltrating lymphocytes at baseline, low baseline CD68+ cells and different immune gene expression signatures at baseline were associated with outcomes. Conclusions In patients with pMMR-CRC or PDAC, durvalumab+olaparib and durvalumab+cediranib showed limited anti-tumor activity. Different immune components of the TME were associated with treatment outcomes. Micro Abstract Immunotherapy (IO) as single agent and combinations have failed to elicit tumor responses in non-immunogenic histologies such as mismatch repair proficient colorectal cancer (pMMR-CRC) or pancreatic adenocarcinoma (PDAC). Paucity of data exists on the study of the tumor microenvironment (TME) and its changes after IO exposure in patients with pMMR-CRC and PDAC. The DAPPER phase 2 trial (NCT03851614) studies the dynamics of the TME in pMMR-CRC and PDAC exposed to IO combinations. Our study adds insights to the understanding of the intrinsic mechanisms of IO resistance in these histologies and provides unique observations on the intersection of key elements of the TME. Despite the limited activity observed with durvalumab plus olaparib and durvalumab plus cediranib in pMMR-CRC and PDAC, the findings presented here will inform the development of new rational IO combinations and strategies to induce inflammation in the TME.