title: Early evidence of anti-PD-1 activity in enzalutamide-resistant prostate cancer.
abstract: While programmed cell death 1 (PD-1) inhibitors have shown clear anti-tumor efficacy in several solid tumors, prior results in men with metastatic castration resistant prostate cancer (mCRPC) showed no evidence of activity. Here we report unexpected antitumor activity seen in mCRPC patients treated with the anti-PD-1 antibody pembrolizumab. Patients with evidence of progression on enzalutamide were treated with pembrolizumab 200 mg IV every 3 weeks for 4 doses; pembrolizumab was added to standard dose enzalutamide. Three of the first ten patients enrolled in this ongoing phase II trial experienced rapid prostate specific antigen (PSA) reductions to ≤ 0.2 ng/ml. Two of these three patients had measurable disease upon study entry; both achieved a partial response. There were three patients with significant immune-related adverse events. One had grade 2 myositis, one had grade 3 hypothyroidism, and one had grade 2 hypothyroidism. None of these patients had a response. Two of the three responders had a baseline tumor biopsy. Immunohistochemistry from those biopsies showed the presence of CD3+, CD8+, and CD163+ leukocyte infiltrates and PD-L1 expression. Genetic analysis of the two responders revealed markers of microsatellite instability in one. The surprising and robust responses seen in this study should lead to re-examination of PD-1 inhibition in prostate cancer.
authors.affiliation: Division of Hematology/Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.|VA Portland Health Care System, Portland, OR, USA.
authors.forename: Julie N
authors.initials: JN
authors.lastname: Graff
authors.affiliation: Division of Hematology/Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
authors.forename: Joshi J
authors.initials: JJ
authors.lastname: Alumkal
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center and the Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Charles G
authors.initials: CG
authors.lastname: Drake
authors.affiliation: Pathology and Laboratory Medicine, Oregon Health and Science University, Portland, OR, USA.
authors.forename: George V
authors.initials: GV
authors.lastname: Thomas
authors.affiliation: Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, OR, USA.
authors.forename: William L
authors.initials: WL
authors.lastname: Redmond
authors.affiliation: Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, OR, USA.|Cell, Developmental, and Cancer Biology Department, Oregon Health and Science University, Portland, OR, USA.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Farhad
authors.affiliation: Division of Hematology/Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
authors.forename: Jeremy P
authors.initials: JP
authors.lastname: Cetnar
authors.affiliation: Division of Hematology/Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
authors.forename: Frederick S
authors.initials: FS
authors.lastname: Ey
authors.affiliation: Division of Hematology/Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Bergan
authors.affiliation: Division of Hematology/Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Slottke
authors.affiliation: Division of Hematology/Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
authors.forename: Tomasz M
authors.initials: TM
authors.lastname: Beer
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D001549:Benzamides; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D007037:Hypothyroidism / Q000139:chemically induced / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009220:Myositis / Q000139:chemically induced / Q000276:immunology; D009362:Neoplasm Metastasis; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000276:immunology; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017430:Prostate-Specific Antigen / Q000276:immunology / Q000378:metabolism; D064129:Prostatic Neoplasms, Castration-Resistant / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D012074:Remission Induction
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D001549:Benzamides; D009570:Nitriles; D061026:Programmed Cell Death 1 Receptor; D010669:Phenylthiohydantoin; C540278:enzalutamide; C582435:pembrolizumab; D017430:Prostate-Specific Antigen
keywords: Immune response; Immunity; Immunology and Microbiology Section; PD-1; enzalutamide; immunotherapy; prostate cancer