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

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 activityseen 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.

Graff JN1,2, Alumkal JJ1, Drake CG3, Thomas GV4, Redmond WL5, Farhad M5,6, Cetnar JP1, Ey FS1, Bergan RC1, Slottke R1, Beer TM1 

1Division of Hematology/Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
2VA Portland Health Care System, Portland, OR, USA.
3Sidney Kimmel Comprehensive Cancer Center and the Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
4Pathology and Laboratory Medicine, Oregon Health and Science University, Portland, OR, USA.
5Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, OR, USA.
6Cell, Developmental, and Cancer Biology Department, Oregon Health and Science University, Portland, OR, USA.

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

PubMed https://www.ncbi.nlm.nih.gov/pubmed/?term=Early+evidence+of+anti-PD-1+activity+in+enzalutamide-resistant+prostate+cancer