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, noncomparative 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.

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©2025 The Authors; Published by the American Association for Cancer Research
2025
American Association for Cancer Research
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Supplementary data

Table S1

Table S1 shows the representativeness of participants enrolled in this study.

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Table S2

Table S2 shows the antibody panel used for CyTOF experiments.

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Table S3

Table S3 summarizes exposure to the study drugs in Cohort A.

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Table S4

Table S4 summarizes exposure to the study drugs in Cohort B.

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Table S5

Table S5 summarizes exposure to the study drugs in Cohort C.

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Table S6

Table S6 lists demographics, baseline disease characteristics, and outcomes for patients who achieved disease control.

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Table S7

Table S7 summarizes demographic and baseline disease characteristics by 6-month disease control status.

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Table S8

Table S8 shows the biopsy location and specimen type for tumor biopsy samples used for RNA-seq analysis.

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Table S9

Table S9 shows pathways that are differentially expressed pre-treatment between patients who achieved disease control and those who did not from gene set enrichment analysis of RNA-Seq data.

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Figure S1

Figure S1 shows the gating strategy for mass cytometry (CyTOF).

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Figure S2

Figure S2 shows the percentage change in PSA from baseline for Cohorts A, B, and C. Values are capped at 200% for visualization purposes. The dashed horizontal line represents a 50% decrease in PSA. For Cohort C, the vertical gray line at Day 28 indicates the end of the immune-priming lead-in phase and the beginning of nivolumab administration at Cycle 1 Day 1.

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