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

Julie Graff, Joshi Alumkal, Charles G. Drake, George Thomas, William L. Redmond, Mohammad Farhad, Jeremy Cetnar, Frederick (Fred) Ey, Raymond Bergan, Rachel Slottke, Tomasz (Tom) Beer

Research output: Contribution to journalArticle

158 Citations (Scopus)

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 immunerelated 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.

Original languageEnglish (US)
Pages (from-to)52810-52817
Number of pages8
JournalOncotarget
Volume7
Issue number33
DOIs
StatePublished - Aug 1 2016

Fingerprint

Prostatic Neoplasms
Cell Death
Castration
Hypothyroidism
Biopsy
Neoplasms
Microsatellite Instability
Myositis
Prostate-Specific Antigen
MDV 3100
Leukocytes
Immunohistochemistry
Antibodies
pembrolizumab

Keywords

  • Enzalutamide
  • Immune response
  • Immunity
  • Immunology and Microbiology Section
  • Immunotherapy
  • PD-1
  • Prostate cancer

ASJC Scopus subject areas

  • Oncology

Cite this

Early evidence of anti-PD-1 activity in enzalutamide-resistant prostate cancer. / Graff, Julie; Alumkal, Joshi; Drake, Charles G.; Thomas, George; Redmond, William L.; Farhad, Mohammad; Cetnar, Jeremy; Ey, Frederick (Fred); Bergan, Raymond; Slottke, Rachel; Beer, Tomasz (Tom).

In: Oncotarget, Vol. 7, No. 33, 01.08.2016, p. 52810-52817.

Research output: Contribution to journalArticle

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