Inhibition of the adenosine 2A receptor (A2AR) diminishes the immunosuppressive effects of adenosine and may complement immune-targeting drugs. This phase 2 study evaluated the A2AR antagonist AZD4635 in combination with durvalumab or oleclumab in patients with metastatic castration-resistant prostate cancer.
Patients with histologically/cytologically confirmed disease progressing within 6 months on ≥ 2 therapy lines were randomly assigned to either Module 1 (AZD4635 + durvalumab) or Module 2 (AZD4635 + oleclumab). Primary endpoints were objective response rate per RECIST v1.1 and prostate-specific antigen (PSA) response rate. Secondary endpoints included radiological progression-free survival (rPFS), overall survival, safety, and pharmacokinetics.
Fifty-nine patients were treated (Module 1, n = 29; Module 2, n = 30). Median number of prior therapies was 4. One confirmed complete response by RECIST (Module 1) and 2 confirmed PSA responses (1 per module) were observed. The most frequent adverse events (AEs) possibly related to AZD4635 were nausea (37.9%), fatigue (20.7%), and decreased appetite (17.2%) in Module 1; nausea (50%), fatigue (30%), and vomiting (23.3%) in Module 2. No dose-limiting toxicities or treatment-related serious AEs were observed. In Module 1, AZD4635 geometric mean trough concentration was 124.9 ng/mL (geometric CV% 69.84; n = 22); exposures were similar in Module 2. In Modules 1 and 2, median (95% CI) rPFS was 2.3 (1.6 -3.8) and 1.5 (1.3- 4.0) months, respectively. Median PFS was 1.7 versus 2.3 months for patients with high versus low blood-based adenosine signature.
In this heavily pretreated population, AZD4635 with durvalumab or oleclumab demonstrated minimal antitumor activity with a manageable safety profile.
gov identifier: NCT04089553.
Cancer immunology, immunotherapy : CII. 2024 Mar 02*** epublish ***
Gerald S Falchook, James Reeves, Sunil Gandhi, David R Spigel, Edward Arrowsmith, Daniel J George, Janet Karlix, Gayle Pouliot, Maureen M Hattersley, Eric T Gangl, Gareth D James, Jeff Thompson, Deanna L Russell, Bhavickumar Patel, Rakesh Kumar, Emerson Lim
Drug Development Unit, Sarah Cannon Research Institute at HealthONE, Denver, CO, USA. ., Florida Cancer Specialists South, Sarah Cannon Research Institute, Fort Meyers, FL, USA., Florida Cancer Specialists South, Sarah Cannon Research Institute, St. Petersberg, FL, USA., Tennessee Oncology, Sarah Cannon Research Institute, Nashville, TN, USA., Duke Cancer Institute, Durham, NC, USA., Sarah Cannon Research Institute, Gainesville, FL, USA., Oncology R&D, AstraZeneca, Waltham, MA, USA., BioPharma R&D, AstraZeneca, Boston, MA, USA., Medical Statistics Consultancy Ltd, London, UK., Oncology R&D, AstraZeneca, Cambridge, UK., Oncology R&D, AstraZeneca, Gaithersburg, MD, USA., Medical Oncology & Hematology-LHCP, Corewell Health Medical Group, Grand Rapids, MI, USA.