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Updated: Mar 17, 2026
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
Early evidence of anti-PD-1 activity in enzalutamide-resistant prostate cancer
Julie N Graff1,2, Joshi J Alumkal1, Charles G Drake3
1Division of Hematology/Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
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.
Insights
Unexpected antitumor activity was observed in metastatic castration-resistant prostate cancer (mCRPC) patients treated with the anti-programmed cell death 1 (PD-1) antibody pembrolizumab. This suggests a potential new avenue for treating advanced prostate cancer.
Area of Science:
- Oncology
- Immunology
- Medical Research
Background:
- Programmed cell death 1 (PD-1) inhibitors demonstrate anti-tumor efficacy in various solid tumors.
- Previous studies showed no activity of PD-1 inhibitors in metastatic castration-resistant prostate cancer (mCRPC).
Purpose of the Study:
- To investigate the potential antitumor activity of the anti-PD-1 antibody pembrolizumab in mCRPC patients.
- To evaluate the efficacy and safety of pembrolizumab in combination with enzalutamide for mCRPC.
Main Methods:
- An ongoing phase II trial treated mCRPC patients progressing on enzalutamide with pembrolizumab (200 mg IV every 3 weeks for 4 doses) plus standard-dose enzalutamide.
- Tumor biopsies and genetic analysis were performed on responders.
- Immune-related adverse events were monitored.
Main Results:
- Three of the first ten patients achieved rapid prostate-specific antigen (PSA) reductions to ≤ 0.2 ng/ml.
- Two patients with measurable disease achieved partial responses.
- Tumor biopsies from responders showed CD3+, CD8+, CD163+ leukocyte infiltrates and PD-L1 expression; one responder had microsatellite instability.
Conclusions:
- Pembrolizumab demonstrated unexpected antitumor activity in mCRPC patients.
- The findings warrant re-examination of PD-1 inhibition strategies for prostate cancer treatment.
- Further research is needed to understand the mechanisms driving response and identify predictive biomarkers.
