Early evidence of anti-PD-1 activity in enzalutamide-resistant prostate cancer

Oncotarget. 2016 Aug 16;7(33):52810-52817. doi: 10.18632/oncotarget.10547.


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.

Keywords: Immune response; Immunity; Immunology and Microbiology Section; PD-1; enzalutamide; immunotherapy; prostate cancer.

Publication types

  • Clinical Trial, Phase II

MeSH terms

  • Aged
  • Aged, 80 and over
  • Antibodies, Monoclonal, Humanized / administration & dosage
  • Antibodies, Monoclonal, Humanized / adverse effects
  • Antibodies, Monoclonal, Humanized / immunology
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / immunology
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Benzamides
  • Drug Administration Schedule
  • Drug Resistance, Neoplasm / drug effects*
  • Humans
  • Hypothyroidism / chemically induced
  • Hypothyroidism / immunology
  • Male
  • Middle Aged
  • Myositis / chemically induced
  • Myositis / immunology
  • Neoplasm Metastasis
  • Nitriles
  • Phenylthiohydantoin / administration & dosage
  • Phenylthiohydantoin / adverse effects
  • Phenylthiohydantoin / analogs & derivatives
  • Phenylthiohydantoin / immunology
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors*
  • Programmed Cell Death 1 Receptor / metabolism
  • Prostate-Specific Antigen / immunology
  • Prostate-Specific Antigen / metabolism
  • Prostatic Neoplasms, Castration-Resistant / immunology
  • Prostatic Neoplasms, Castration-Resistant / metabolism
  • Prostatic Neoplasms, Castration-Resistant / prevention & control*
  • Remission Induction


  • Antibodies, Monoclonal, Humanized
  • Benzamides
  • Nitriles
  • Programmed Cell Death 1 Receptor
  • Phenylthiohydantoin
  • enzalutamide
  • pembrolizumab
  • Prostate-Specific Antigen