Background: Intensification of upfront treatment with the addition of docetaxel chemotherapy and/or a novel androgen signaling inhibitor to androgen deprivation therapy (ADT) have improved clinical outcomes for patients with de novo metastatic hormone sensitive prostate cancer (mHSPC). However, most patients develop castration resistance, the lethal form of disease. ADT early in the hormone-sensitive setting and docetaxel may have immunostimulatory effects which sensitize tumors to immune checkpoint blockade. Immunotherapy may be most effective in patients with pre-existing antitumor immunity or DNA damage repair defects (DDRD). Methods: We are conducting a multicenter, multicohort, phase 2 clinical trial of ADT, docetaxel, plus nivolumab in patients with de novo mHSPC. Cohort allocation is assigned based on tumor PD-L1 and CD8 staining by a multiplexed immunofluorescence platform (ImmunoProfile), and DDRD status on a targeted cancer next-generation sequencing panel (OncoPanel). Planned enrollment goal is 60 patients (20 patients per cohort; Table). Eligible patients must have newly diagnosed metastatic prostate cancer on conventional imaging, ECOG performance status 0-2 (ECOG 2 allowed if attributed to metastatic disease), PSA >4.0 ng/mL before ADT initiation, adequate organ function, and be candidates for docetaxel chemotherapy. Patients are allowed to receive up to 140 days of ADT prior to C1D1 study treatment. All patients receive continuous ADT, docetaxel 75 mg/m² plus nivolumab 360mg IV Q3W for 6 cycles, followed by nivolumab 480mg IV Q4W for up to 2 years. After January 2022, the addition of standard of care abiraterone/prednisone was allowed after 7 months of study treatment at investigator discretion. The primary endpoint is PSA ≤ 0.2 ng/mL at 7 months from initiation of chemoimmunotherapy. Key secondary endpoints include PSA ≤ 0.2 ng/mL during chemoimmunotherapy, time to castration resistance, time to clinical progression, time to PSA progression, objective response rate, overall survival, and safety. Planned exploratory analysis include profiling circulating tumor cell (CTC) enumeration and analysis of PD-L1 and HLA I expression on CTCs. The first patient was enrolled on 5/4/2020, and 45/60 patients have been enrolled to date (N=7 in Cohort 1, N=18 in Cohort 2, and N=20 in Cohort 3). Study enrollment is ongoing. Clinical trial information: NCT04126070.

PD-L1 Combined Positive Score (CPS) ≥ 1 and/or CD T cell density ≥ 200. Homozygous deletions and/or deleterious mutations in a DDR gene, including and not limited to BRCA2, ATM, CHECK2, BRCA1, PALB2, RAD51D, ATR, NBN, PMS2, GEN1, MLH1, MSH2, MSH6, RAD51C, MRE11A, BRIP1, FAM175A, and CDK12.