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TPS5090 Background: Responses to checkpoint inhibitor (CPI) monotherapy in patients with metastatic castration resistant prostate cancer (mCRPC) have been limited. This is in part attributed to low tumour mutational burden (TMB) and low tumour infiltrating lymphocytes (TILs). Previously ~20% patients with prostate cancer have demonstrated high TILs or TMB1. We hypothesize that patients with higher TMB due to mismatch repair deficiency (dMMR) or defective DNA damage response (dDDR) and patients with high TILs are more likely to respond to combination CPI with anti PD-1 and anti CTLA-4 therapy. Methods: NEPTUNES is a single arm phase II trial designed to assess the efficacy of nivolumab and ipilimumab in biomarker selected patients with mCRPC that have progressed following ≥1 line of therapy. The immunogenic signature (ImS) biomarker is defined by ≥1 of the following: 1) dMMR by immunohistochemistry (IHC); 2) dDDR detected by the UW-OncoPlex sequencing assay and; 3) high TILs on multiplexed IHC. The UW-OncoPlex assay detects mutations in >260 genes and provides an estimation of TMB. Assuming an ImS+ rate of 20%, we aim to pre-screen 175 patients in order to enrol 35 patients into the main study. The primary endpoint is composite response rate (CRR), achieved if ≥1 of the following criteria are satisfied: 1) radiological response by RECIST 1.1; 2) PSA response ≥50%; 3) conversion of circulating tumour cells (CTC) count from ≥5 cells at baseline to <5 cells at week 9. The treatment will be deemed ineffective if the CRR is <20%. Nivolumab (1 mg/kg) and ipilimumab (3 mg/kg) is dosed every three weeks for up to 4 times, followed by a 480mg flat dose of nivolumab every 4 weeks for up to one year. Baseline biopsies are mandated and paired biopsy at week 12 is encouraged. The secondary endpoints include safety, overall survival, and radiological and PSA progression free survival. Exploratory biological markers including TMB, mutational profiles, change in TILs and liquid biomarkers will be correlated with the primary clinical endpoint. Since opening in February 2018, 126 patients have been pre-screened with 25 ImS+. To date, 9/25 ImS+ patients have been enrolled into the main study. The trial is ongoing, with patient accrual expected to complete by late 2019. References: 1Linch, M., Goh, G., Hiley, C., Shanmugabavan, Y., McGranahan, N., Rowan, A., . . . Swanton, C. (2017). Intratumoural evolutionary landscape of high-risk prostate cancer: the PROGENY study of genomic and immune parameters. Ann Oncol, 28(10), 2472-2480. doi:10.1093/annonc/mdx355. Clinical trial information: NCT03061539.

Background: Responses to checkpoint inhibitor (CPI) monotherapy in patients with metastatic castration resistant prostate cancer (mCRPC) have been limited. This is likely due to a “cold” tumour immune microenvironment. We hypothesised that patients with mCRPC will be more likely to respond if they have a positive immunogenic signature (ImS+). We report the response/safety for NIVO + IPI in pts with ImS+ mCRPC from cohort 1 of the NEPTUNES study. Methods: Pts with mCRPC who progressed following ≥1 line of therapy and ImS+ were eligible. ImS+ was defined by ≥1 of the following: 1) mismatch repair deficient (MMRD) by immunohistochemistry (IHC); 2) DNA damage repair deficient (DDRD) excluding MMRD, detected by the UW-OncoPlex targeted exome sequencing assay and; 3) high tumour infiltrating lymphocytes (TILs) on multiplexed immunohistochemistry (CD4, CD8 or FoxP3+ &gt;20% nucleated cells). Treatment was NIVO 1 mg/kg + IPI 3 mg/kg Q3W for 4 doses, then NIVO 480 mg every 4 weeks. Primary endpoint was composite response rate (CRR) defined by ≥1 of the following: 1) radiological response by RECIST 1.1; 2) PSA response ≥50%; 3) conversion of circulating tumour cells (CTC) at week 9. Treatment would be deemed ineffective if the CRR was &lt;20%. Results: 50/211 pts were ImS+, and 35 patients were treated with NIVO/IPI with a median follow up of 7.2 months (range 2.1-20.5). The overall CRR was 9/35 (26%, 95%CI 12-43%). The ImS+ determinants in responding/all treated patients included MMRD (n=4/5), BRCA1/2 (n=3/4), exclusively high TILs (n=2/9) and CDK12 (n=1/7). In responders, median duration of response was 4.9 months (range 1.8-19.7). Grade 3-4 treatment-related adverse events occurred in 17/35 (49%). Conclusions: NIVO + IPI demonstrated significant activity in biomarker selected, pre-treated pts with mCRPC. The safety profile is consistent with this dosing schedule. Accrual to expansion cohort 2 started in September 2020. Determinants of immunogenic signature in responding patientsPatientInflammatory Infiltrate (%)MMRD (Y/N)DDRD (Y/N)TMB Mut/MBNEP-03340NN1NEP-03610NY Biallelic BRCA24NEP-0964NY Biallelic BRCA28NEP-1093Y MSH2/MSH6N14NEP-12625Y MSH2/MSH6N21NEP-13110Y PMS2/MLH1N13NEP-15920Y MSH2/MSH6Y BRCA127NEP-16525NY Biallelic CDK125NEP-06930NN1 Citation Format: Mark D. Linch, Yien Ning Sophia Wong, Robert Jones, Peter Sankey, Debra H. Josephs, Simon J. Crabb, John Staffurth, Anjali Zarkar, Laura White, Marian Duggan, Giulia Pellizzari, Graham Wheeler, Sandy Beare, Hayley Cartwright, Josep Linares, Ayse Akarca, Sergio A. Quezada, Leah Ensell, John Hartley, Gerhardt Attard, Joanna Burr, Anuradha Jayaram, Bihani Kularatne, Mahaz Kayani, Moon Chung, Colin C. Pritchard, Alex Freeman, Aiman Haider, Teresa Marafioti. Nivolumab (NIVO) and ipilimumab (IPI) treatment in prostate cancer with an immunogenic signature: cohort 1 of the NEPTUNES multi-centre, two-stage biomarker-selected Phase II trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB004.