{"doi":"10.1002/pros.24110","title":"Nivolumab plus ipilimumab, with or without enzalutamide, in AR‐V7‐expressing metastatic castration‐resistant prostate cancer: A phase‐2 nonrandomized clinical trial","abstract":"BACKGROUND: AR-V7-positive metastatic prostate cancer is a lethal phenotype with few treatment options and poor survival. METHODS: The two-cohort nonrandomized Phase 2 study of combined immune checkpoint blockade for AR-V7-expressing metastatic castration-resistant prostate cancer (STARVE-PC) evaluated nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg), without (Cohort 1) or with (Cohort 2) the anti-androgen enzalutamide. Co-primary endpoints were safety and prostate-specific antigen (PSA) response rate. Secondary endpoints included time-to-PSA-progression-free survival (PSA-PFS), time-to-clinical/radiographic-PFS, objective response rate (ORR), PFS lasting greater than 24 weeks, and overall survival (OS). RESULTS: Thirty patients were treated with ipilimumab plus nivolumab (N = 15, Cohort 1, previously reported), or ipilimumab plus nivolumab and enzalutamide (N = 15, Cohort 2) in patients previously progressing on enzalutamide monotherapy. PSA response rate was 2/15 (13%) in cohort 1 and 0/15 in cohort 2, ORR was 2/8 (25%) in Cohort 1 and 0/9 in Cohort 2 in those with measureable disease, median PSA-PFS was 3.0 (95% confidence interval [CI]: 2.1-NR) in cohort 1 and 2.7 (95% CI: 2.1-5.9) months in cohort 2, and median PFS was 3.7 (95% CI: 2.8-7.5) in cohort 1 and 2.9 (95% CI: 1.3-5.8) months in cohort 2. Three of 15 patients in cohort 1 (20%, 95% CI: 7.1%-45.2%) and 4/15 patients (26.7%, 95% CI: 10.5%-52.4%) in cohort 2 achieved a durable PFS lasting greater than 24 weeks. Median OS was 8.2 (95% CI: 5.5-10.4) in cohort 1 and 14.2 (95% CI: 8.5-NA) months in cohort 2. Efficacy results were not statistically different between cohorts. Grade-3/4 adverse events occurred in 7/15 cohort 1 patients (46%) and 8/15 cohort 2 patients (53%). Combined cohort (N = 30) baseline alkaline phosphatase and cytokine analysis suggested improved OS for patients with lower alkaline phosphatase (hazards ratio [HR], 0.30; 95% CI: 0.11-0.82), lower circulating interleukin-7 (IL-7) (HR, 0.24; 95% Cl: 0.06-0.93) and IL-6 (HR, 0.13; 95% Cl: 0.03-0.52) levels, and higher circulating IL-17 (HR, 4.53; 95% CI: 1.47-13.93) levels. There was a trend towards improved outcomes in men with low sPD-L1 serum levels. CONCLUSION: Nivolumab plus ipilimumab demonstrated only modest activity in patients with AR-V7-expressing prostate cancer, and was not sufficient to justify further exploration in unselected patients. Stratification by baseline alkaline phosphatase and cytokines (IL-6, -7, and -17) may be prognostic for outcomes to immunotherapy.","journal":"The Prostate","year":2021,"id":153011,"datarank":1.7334507621331483,"base_score":4.276666119016055,"endowment":4.276666119016055,"self_citation_contribution":0.6414999178524083,"citation_network_contribution":1.09195084428074,"self_endowment_contribution":0.6414999178524083,"citer_contribution":1.09195084428074,"corpus_percentile":null,"corpus_rank":null,"citation_count":71,"citer_count":62,"citers_with_citation_signal":44,"citers_with_endowment":44,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9522,"is_data_producer":true,"deposit_databanks":{"ClinicalTrials.gov":["NCT02601014"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":650523,"name":"Karim Boudadi","orcid":null,"position":1,"is_corresponding":false},{"id":257980,"name":"Wei Fu","orcid":"0000-0002-0996-1137","position":2,"is_corresponding":false},{"id":277001,"name":"Hao Wang","orcid":"0000-0001-6489-6940","position":3,"is_corresponding":false},{"id":650524,"name":"Rana Sullivan","orcid":null,"position":4,"is_corresponding":false},{"id":650525,"name":"Alice Jordan","orcid":null,"position":5,"is_corresponding":false},{"id":650526,"name":"Donna Dowling","orcid":null,"position":6,"is_corresponding":false},{"id":650527,"name":"Rana Harb","orcid":null,"position":7,"is_corresponding":false},{"id":333405,"name":"Joseph D. Schonhoft","orcid":"0000-0002-5860-5040","position":8,"is_corresponding":false},{"id":335376,"name":"Adam Jendrisak","orcid":null,"position":9,"is_corresponding":false},{"id":232512,"name":"Michael A. Carducci","orcid":"0000-0002-7908-1215","position":10,"is_corresponding":false},{"id":334086,"name":"Mario A. Eisenberger","orcid":"0000-0002-8787-3271","position":11,"is_corresponding":false},{"id":62913,"name":"James R. Eshleman","orcid":"0000-0002-9274-8459","position":12,"is_corresponding":false},{"id":278998,"name":"Jun Luo","orcid":"0000-0002-1414-473X","position":13,"is_corresponding":false},{"id":59423,"name":"Charles G. Drake","orcid":"0000-0001-9610-3677","position":14,"is_corresponding":false},{"id":59439,"name":"Drew M. Pardoll","orcid":"0000-0001-6215-1013","position":15,"is_corresponding":false},{"id":272258,"name":"Emmanuel S. 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