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Early evidence of anti-PD-1 activity in enzalutamide-resistant prostate cancer.
- Source :
-
Oncotarget [Oncotarget] 2016 Aug 16; Vol. 7 (33), pp. 52810-52817. - Publication Year :
- 2016
-
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.<br />Competing Interests: 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.
- Subjects :
- 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
Benzamides
Drug Administration Schedule
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 metabolism
Prostate-Specific Antigen immunology
Prostate-Specific Antigen metabolism
Prostatic Neoplasms, Castration-Resistant immunology
Prostatic Neoplasms, Castration-Resistant metabolism
Remission Induction
Antineoplastic Combined Chemotherapy Protocols therapeutic use
Drug Resistance, Neoplasm drug effects
Programmed Cell Death 1 Receptor antagonists & inhibitors
Prostatic Neoplasms, Castration-Resistant prevention & control
Subjects
Details
- Language :
- English
- ISSN :
- 1949-2553
- Volume :
- 7
- Issue :
- 33
- Database :
- MEDLINE
- Journal :
- Oncotarget
- Publication Type :
- Academic Journal
- Accession number :
- 27429197
- Full Text :
- https://doi.org/10.18632/oncotarget.10547