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

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

Julie N Graff  1   2 , Joshi J Alumkal  1 , Charles G Drake  3 , George V Thomas  4 , William L Redmond  5 , Mohammad Farhad  5   6 , Jeremy P Cetnar  1 , Frederick S Ey  1 , Raymond C Bergan  1 , Rachel Slottke  1 , Tomasz M Beer  1
Affiliations
Clinical Trial

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

Julie N Graff et al. Oncotarget. .

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.

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

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Conflict of interest statement

JNG has received honoraria from Astellas/Medivation. She has received research funding from Astellas/Medivation and Merck. CGD has received research funding from Bristol Myers Squibb (BMS). He has received consulting fees from BMS, Merck, Astra Zeneca (AZ) and Medimmune. He has patents licensed to AZ, BMS and Medimmune. WLR has received research grants, consulting fees, and/or royalties from Bristol-Myers Squibb, Merck, Galectin Therapeutics, and Nektar Therapeutics. TMB Research funding from Astellas and Medivation; consulting fees from Astellas. JJA, GVT, MF, JPC, FSE, RCB and RS have no conflicts. This research was funded by Merck Sharp & Dohme Corporation. Funds from the Bloomberg Kimmel Institute (BKI) supported a portion of the laboratory work. Additional laboratory funding was funded by Merck.

Figures

Figure 1
Figure 1. Radiographic Responses in Patients With Measurable Disease
Figure 2
Figure 2. Multi-spectral imaging reveals leukocyte infiltration in biopsies from men with metastatic castrate-resistant prostate cancer (mCRPC)
A-C) Lymph node (LN) and D-F) liver biopsies were obtained from men with mCRPC. A) H+E and B) single-color images (plus nuclear stain; DAPI) of CD3, CD8, CD163, PD-L1, cytokeratin (CK), DAPI and C) merged image from a LN biopsy of patient A. D) H+E, E) single-color, and F) merged from a liver biopsy of patient B. Note: images depicted in (B-C and E-F) were selected from representative “hot spots” of leukocyte infiltrates in each biopsy. A, D) H+E images 20X; B, C, E, F) multi-spectral images 200X.
See this image and copyright information in PMC

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