Clinical and Translational Results from PORTER, a Multi-cohort Phase 1 Platform Trial of Combination Immunotherapy in Metastatic Castration-Resistant Prostate Cancer
Clinical Cancer Research, 2025
Galsky M., Autio K., Cabanski C., Wentzel K., Graff J., Friedlander T., Howes T., Shotts K., Densmore J., Spasic M., Da Silva D., Chen R., Lata J., Skolnik J., Keler T., Yellin M., LaVallee T., Fairchild J., Boffo S., O'Donnell-Tormey J., Dugan U., Bhardwaj N., Subudhi S., Fong L.
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
Oncology Immunotherapy | Pathophysiology Patient Stratification | Serum | O Olink Target 96 |
Abstract
Purpose: Current immune checkpoint therapies offer limited benefits for metastatic castration-resistant prostate cancer (mCRPC). Novel combinations may enhance immunotherapy efficacy. Patients and Methods: 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. Results: 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. Conclusions: 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.