Immune biomarkers of response and resistance to ipilimumab and nivolumab in metastatic castration-resistant prostate cancer
Immune checkpoint therapies have shown limited efficacy in metastatic castration-resistant prostate cancer (mCRPC). The AMADEUS prostate expansion cohort (NCT03651271) evaluated the efficacy, safety, and biomarkers of escalating ipilimumab doses combined with nivolumab. Patients received ipilimumab 1 milligram per kilogram (mg/kg) + nivolumab 360 mg (I1+N360), ipilimumab 3 mg/kg + nivolumab 1 mg/kg (I3+N1), or ipilimumab 5 mg/kg + nivolumab 1 mg/kg (I5+N1). Coprimary endpoints were 6-month disease control rate (DCR) and changes in tumoral CD8 percentage. Thirty-two patients were enrolled. DCRs were 33% (4 of 12) for I1+N360, 20% (1 of 5) for I3+N1, and 20% (3 of 15) for I5+N1. Across cohorts, tumoral CD8 percentage increased by a median of 5.0%. Although higher ipilimumab doses were tolerable, I1+N360 achieved similar disease control and immune activation with a more favorable safety profile. Early disease progression was associated with increased expression of a TREM2-associated myeloid gene signature, which was also significantly enriched in two independent prostate cancer datasets.
Authors
- Bilal Ahmed Siddiqui (ORCID: https://orcid.org/0000-0002-6806-1294)
- Wai Chin Foo (ORCID: https://orcid.org/0000-0002-0471-4911)
- Danny N. Khalil (ORCID: https://orcid.org/0000-0003-4688-0958)
- Sumit Kumar Subudhi (ORCID: https://orcid.org/0000-0001-5208-7732)
- Ute Dugan (ORCID: https://orcid.org/0009-0008-9408-2671)
- Apostolia Maria Tsimberidou (ORCID: https://orcid.org/0000-0003-2713-233X)
- Christopher R. Cabanski (ORCID: https://orcid.org/0009-0007-9938-1331)
- Alexandra Drakaki (ORCID: https://orcid.org/0000-0001-8865-3548)
- Jamie Arnott (ORCID: https://orcid.org/0009-0009-6073-6259)
- Silvia Boffo (ORCID: https://orcid.org/0000-0002-6352-160X)
- Farah A. Alayli (ORCID: https://orcid.org/0009-0003-1155-1756)
- Shikha Gautam (ORCID: https://orcid.org/0000-0003-4885-7823)
- Justin P. Fairchild (ORCID: https://orcid.org/0000-0002-4478-7146)
- Padmanee Sharma (ORCID: https://orcid.org/0000-0003-4658-055X)
- Sreyashi Basu (ORCID: https://orcid.org/0000-0002-5028-3833)
- Kwame Okrah (ORCID: https://orcid.org/0009-0003-7210-5741)
- Diane M. Da Silva (ORCID: https://orcid.org/0000-0001-7317-4886)
- Mike Schachter
Institutions
- Memorial Sloan Kettering Cancer Center (US)
- The University of Texas MD Anderson Cancer Center (US)
- University of California, Los Angeles (US)
- Bristol-Myers Squibb (United States) (US)
- Parker Institute for Cancer Immunotherapy (US)
- UCLA Jonsson Comprehensive Cancer Center
Publication Details
- Journal
- Science Advances
- Published
- 2026-10-14
- DOI
- https://doi.org/10.1126/sciadv.aee8730
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Cancer Research Institute
- Prostate Cancer Foundation
- Bristol-Myers Squibb
- American Society of Clinical Oncology
- Parker Institute for Cancer Immunotherapy