TY - JOUR
T1 - Clinical and Translational Results from PORTER, a Multicohort Phase I Platform Trial of Combination Immunotherapy in Metastatic Castration-Resistant Prostate Cancer
AU - Galsky, Matthew D.
AU - Autio, Karen A.
AU - Cabanski, Christopher R.
AU - Wentzel, Kristopher
AU - Graff, Julie N.
AU - Friedlander, Terence W.
AU - Howes, Timothy R.
AU - Shotts, Kristin M.
AU - Densmore, Julie
AU - Spasic, Marko
AU - Da Silva, Diane M.
AU - Chen, Richard O.
AU - Lata, Jennifer
AU - Skolnik, Jeffrey
AU - Keler, Tibor
AU - Yellin, Michael J.
AU - LaVallee, Theresa M.
AU - Fairchild, Justin
AU - Boffo, Silvia
AU - O’Donnell-Tormey, Jill
AU - Dugan, Ute
AU - Bhardwaj, Nina
AU - Subudhi, Sumit K.
AU - Fong, Lawrence
N1 - Publisher Copyright:
©2025 The Authors; Published by the American Association for Cancer Research.
PY - 2025/4/15
Y1 - 2025/4/15
N2 - Purpose: Current immune checkpoint therapies offer limited benefits for metastatic castration-resistant prostate cancer. Novel combinations may enhance immunotherapy efficacy. Patients and Methods: We conducted an open-label, non-comparative platform trial (NCT03835533) in metastatic castration-resistant prostate cancer to assess nivolumab-based combinations. The cohorts were as follows: (A) bempegaldesleukin 0.006 mg/kg and nivolumab 360 mg i.v. every 3 weeks; (B) stereotactic body radiotherapy 30 to 50 Gy, CDX-301 75 μg/kg s.c. for 5 days, poly-ICLC 1 mg intramuscularly weekly twice for 3 weeks, and nivolumab 480 mg every 4 weeks; 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 to 3, and then every 12 weeks, and nivolumab 480 mg every 4 weeks. 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: A total of 43 patients were enrolled (n = 14, 15, and 14 in cohorts A, B, and C, respectively). Grade 3 to 4 treatment-related adverse events occurred in 10 (71%), 2 (13%), and 2 (14%) patients, respectively, with one grade 5 treatment-related adverse event 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 preexisting memory/regulatory T cells, TNFα, and other inflammatory pathways. Conclusions: Cohort B, which combined radiotherapy with CDX-301, poly-ICLC, and nivolumab, demonstrated encouraging clinical activity. Preexisting rather than treatment-induced immune activation was associated with clinical benefit across cohorts, highlighting the importance of baseline immune fitness.
AB - Purpose: Current immune checkpoint therapies offer limited benefits for metastatic castration-resistant prostate cancer. Novel combinations may enhance immunotherapy efficacy. Patients and Methods: We conducted an open-label, non-comparative platform trial (NCT03835533) in metastatic castration-resistant prostate cancer to assess nivolumab-based combinations. The cohorts were as follows: (A) bempegaldesleukin 0.006 mg/kg and nivolumab 360 mg i.v. every 3 weeks; (B) stereotactic body radiotherapy 30 to 50 Gy, CDX-301 75 μg/kg s.c. for 5 days, poly-ICLC 1 mg intramuscularly weekly twice for 3 weeks, and nivolumab 480 mg every 4 weeks; 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 to 3, and then every 12 weeks, and nivolumab 480 mg every 4 weeks. 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: A total of 43 patients were enrolled (n = 14, 15, and 14 in cohorts A, B, and C, respectively). Grade 3 to 4 treatment-related adverse events occurred in 10 (71%), 2 (13%), and 2 (14%) patients, respectively, with one grade 5 treatment-related adverse event 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 preexisting memory/regulatory T cells, TNFα, and other inflammatory pathways. Conclusions: Cohort B, which combined radiotherapy with CDX-301, poly-ICLC, and nivolumab, demonstrated encouraging clinical activity. Preexisting rather than treatment-induced immune activation was associated with clinical benefit across cohorts, highlighting the importance of baseline immune fitness.
UR - https://www.scopus.com/pages/publications/105003538705
U2 - 10.1158/1078-0432.CCR-24-3693
DO - 10.1158/1078-0432.CCR-24-3693
M3 - Article
C2 - 39964352
AN - SCOPUS:105003538705
SN - 1078-0432
VL - 31
SP - 1463
EP - 1475
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 8
ER -