Immune checkpoint blockade is minimally active in unselected castration-resistant prostate cancer (CRPC) and does not reproducibly yield durable decreases in prostate-specific antigen (PSA) levels.
The Quick Efficacy Seeking Trial was designed to employ a combination of agents to initiate an immune response (with BN-Brachyury vaccine), potentiate that response (with nogapendekin-alfa inbakicept (NAI), an interleukin (IL)-15 receptor superagonist), and reduce or eliminate immunosuppressive entities in the tumor microenvironment (with bintrafusp alfa, a dual inhibitor of programmed death-ligand 1 and transforming growth factor beta). Epacadostat (an indoleamine 2,3-dioxygenase (IDO) inhibitor) was also employed in one cohort to reduce immune suppression induced by IDO's conversion of tryptophan to kynurenine.
Patients with CRPC enrolled sequentially to receive vaccine + bintrafusp alfa (Arm 2.1), vaccine + bintrafusp alfa + NAI (Arm 2.2), and vaccine + bintrafusp alfa + NAI + epacadostat (Arm 2.3), with the primary objective to determine response rate. Adverse events in Arms 2.1 and 2.2 were manageable and consistent with the safety profiles of each agent individually, and notable for five individuals developing isolated adrenocorticotropic hormone deficiency. Arm 2.3 was closed early due to skin toxicity. Sustained declines in PSA were seen in 1/13 (8%) patients in Arm 2.1, 7/24 (29%) patients in Arm 2.2, including six with proficient mismatch repair/microsatellite stable tumors, and 0/6 (0%) patients in Arm 2.3.
Analyses of peripheral immune profiles provided evidence of a multifaceted antitumor immune response, including IL-15 receptor superagonist NAI-dependent expansion and activation of natural killer cells and CD8+ T cells, increased effector-to-suppressor immune cell ratios, and induction of cytotoxic immune gene programs.
NCT03493945.
Journal for immunotherapy of cancer. 2026 Jul 24*** epublish ***
Jason Mark Redman, Ravi A Madan, Renee N Donahue, Nicole J Toney, Fatima Karzai, Julius Strauss, Claudia Palena, Lucas A Horn, Jaydira Del Rivero, Jennifer L Marté, Lisa Cordes, Megan T Lynch, Thomas J Meyer, Margaret Cam, Patrick Soon-Shiong, Jeffrey Schlom, James L Gulley
Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA., Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA., Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA., CCR Collaborative Bioinformatics Resource, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA., ImmunityBio Inc, San Diego, California, USA., Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA .