Current immune checkpoint therapies offer limited benefits for metastatic castration-resistant prostate cancer (mCRPC). Novel combinations may enhance immunotherapy efficacy.
We conducted an open-label, non-comparative platform trial (NCT03835533) in mCRPC to assess nivolumab-based combinations. The cohorts were: A) bempegaldesleukin 0.006 mg/kg and nivolumab 360 mg intravenously Q3W, B) stereotactic body radiation therapy 30-50 Gray, CDX-301 75 μg/kg subcutaneously for 5 days, poly-ICLC 1 mg intramuscularly twice weekly for 3 weeks, and nivolumab 480 mg Q4W, and C) CDX-301 75 μg/kg for 10 days, INO-5151 3 mg intramuscularly on Lead-in Day 8, Day 1 of Cycles 1-3, then Q12W, and nivolumab 480 mg Q4W. The primary endpoint was safety; secondary endpoints included composite response rate (radiographic, PSA, or circulating tumor cell responses), 6-month disease control rate, progression-free survival, and overall survival. Serial blood and tissue samples were analyzed for pharmacodynamics and association with disease control.
43 patients enrolled (N = 14, 15, 14 in Cohorts A, B, C). Grade 3-4 treatment-related adverse events (TRAEs) occurred in 10 (71%), 2 (13%), and 2 (14%) patients, respectively, with one Grade 5 TRAE in Cohort A. Composite response rates were 7% (1/14), 33% (5/15), and 7% (1/14). Across cohorts, 6-month disease control was associated with pre-existing memory/regulatory T cells, TNFα, and other inflammatory pathways.
Cohort B, which combined radiation therapy with CDX-301, poly-ICLC, and nivolumab, demonstrated encouraging clinical activity. Pre-existing rather than treatment-induced immune activation was associated with clinical benefit across cohorts, highlighting the importance of baseline immune fitness.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2025 Feb 18 [Epub ahead of print]
Matthew D Galsky, Karen A Autio, Christopher R Cabanski, Kristopher Wentzel, Julie N Graff, Terence W Friedlander, Timothy R Howes, Kristin M Shotts, Julie Densmore, Marko Spasic, Diane M Da Silva, Richard O Chen, Jennifer Lata, Jeffrey Skolnik, Tibor Keler, Michael J Yellin, Theresa M LaVallee, Justin Fairchild, Silvia Boffo, Jill O'Donnell-Tormey, Ute Dugan, Nina Bhardwaj, Sumit K Subudhi, Lawrence Fong
Icahn School of Medicine at Mount Sinai, New York, NY, United States., Memorial Sloan Kettering Cancer Center, New York, NY, United States., Parker Institute for Cancer Immunotherapy, San Francisco, CA, United States., Angeles Clinic and Research Institute, Los Angeles, CA, United States., Oregon Health & Science University, Portland, OR, United States., University of California, San Francisco, San Francisco, CA, United States., Parker Institute for Cancer Immunotherapy, San Francisco, Ca, United States., Personalis (United States), Fremont, CA, United States., Inovio Pharmaceuticals (United States), Plymouth Meeting, PA, United States., Celldex Therapeutics, Inc., Hampton, NJ, United States., Celldex Therapeutics (United States), United States., Coherus BioSciences (United States), Redwood City, United States., Parker Institute for Cancer Immunotherapy, United States., Bristol-Myers Squibb (United States), Lawrenceville, NJ, United States., Cancer Research Institute, New York, NY, United States., The University of Texas MD Anderson Cancer Center, Houston, United States., University of California, San Francisco, Seattle, WA, United States.