Abstract CT138: Evaluating nivolumab (nivo) plus ipilimumab (ipi) in patients with metastatic castration-resistant prostate cancer (mCRPC): Clinical and translational results from the AMADEUS prostate expansion cohort

Abstract Background: Immune checkpoint inhibitors (ICIs) have transformed cancer treatment, offering durable responses for some patients. However, response to ICIs remains limited for many solid tumors, including metastatic castration-resistant prostate cancer (mCRPC). The AMADEUS primary cohort (NCT03651271) and CheckMate 650 (NCT02985957) trials demonstrated promising durable antitumor responses in a subset of mCRPC patients treated with nivo in combination with ipi at 1 mg/kg or 3 mg/kg, respectively. The AMADEUS prostate expansion cohort was initiated to evaluate the safety and efficacy of a higher ipi dose (5 mg/kg) in combination with nivo. Methods: This open-label, multicenter cohort enrolled mCRPC patients with no restriction on the number of prior treatments. The first 10 patients with 15% tumoral CD8 T cells were randomized 1: 1 to receive either ipi at 3 mg/kg (ipi3) or 5 mg/kg (ipi5) IV Q6W for up to 2 doses. In addition, all patients received nivo 1 mg/kg IV Q3W for 4 doses, followed by nivo 480 mg IV Q4W until PD or intolerable toxicity. After a safety pause, 10 additional patients were enrolled to the ipi5 arm. Co-primary endpoints were DCR (CR, PR, or SD ≥ 6 months) and conversion of tumor %CD8 T cells from low (15%) to high (≥ 15%). Baseline and on-treatment tumor and blood samples were analyzed for multi-omic biomarkers. This cohort was not powered for formal statistical analysis. Results: DCR was 20% in both ipi3 (N=1/5) and ipi5 (N=3/15) arms. In patients with an on-treatment biopsy, CD8 conversion from low to high occurred in 33% (1/3) of patients in ipi3 and 13% (1/8) in ipi5. However, 50% (4/8) of patients in ipi5 had on-treatment CD8 ≥ 14. 8%. Baseline CD8 T cell frequencies and CD8 conversion were not associated with disease control or PSA reduction. The frequency and severity of AEs was consistent with the known safety profile of ipi/nivo, although more patient in ipi5 discontinued treatment owing to an AE (33% vs 0% in ipi3). Both arms showed increased activated (ICOS+, CD38+) and proliferating (Ki67+) CD4 T cells, CD8 T cells, Tregs, inflammatory cytokines (IFNg), chemokines (CXCL9, CXCL10), and soluble PD-1 in circulation. Conclusions: Across both arms, ipi/nivo induced clinical responses and increased %CD8 in a subset of “cold” mCRPC tumors with low CD8 cells. Additionally, the safety profile of ipi 5 mg/kg combined with nivo was consistent with previous trials that tested lower doses of ipi. Further translational analyses may inform which mCRPC patients could benefit from immunotherapy treatment. Trial registration: ClinicalTrials. gov (NCT03651271) Citation Format: Apostolia M. Tsimberidou, Alexandra Drakaki, Danny N. Khalil, Kwame Okrah, Mike Schachter, Shikha Gautam, Diane M. Da Silva, Farah A. Alayli, Christine N. Spencer, Wai Chin Foo, Matthew Adamow, Phillip Wong, Justin Fairchild, Jamie Arnott, Ute Dugan, Silvia Boffo, Lisa Salvador, Christopher R. Cabanski, Sumit K. Subudhi, Padmanee Sharma. Evaluating nivolumab (nivo) plus ipilimumab (ipi) in patients with metastatic castration-resistant prostate cancer (mCRPC): Clinical and translational results from the AMADEUS prostate expansion cohort abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (7Suppl): Abstract nr CT138.