First evidence of significant clinical activity of PD-1 inhibitors in metastatic, castration resistant prostate cancer (mCRPC)

Abstract

Background: PD-1 inhibition has demonstrated improved survival for patients with various solid tumors, but its role in prostate cancer has yet to be defined. Based on observations that PD-L1 expression is increased upon resistance to enzalutamide and androgen inhibition modulates the immune response to prostate cancer, we hypothesized that the addition of the PD-1 inhibitor pembrolizumab to enzalutamide at resistance could result in clinically important anti-tumor activity. Methods:We treated men with mCRPC progressing on the androgen receptor antagonist enzalutamide on a phase II study of pembrolizumab 200 mg IV every 3 weeks for 4 doses with continued enzalutamide. Prior chemotherapy for mCRPC was prohibited. The primary endpoint is the proportion of men with a prostate specific antigen (PSA) response ≥ 50%. The secondary endpoints are objective disease response, PSA progression free survival, and overall survival. The sample size sufficient to detect a 25% response rate served as the basis for the statistical design. Tissue biopsy is performed if feasible. Results: As of 22 July 2016, 20 patients have completed pembrolizumab treatment with a median follow up of 18 weeks. 4 of 20 subjects treated to date (20%) have achieved a confirmed PSA reduction ≥ 50%, reached a serum PSA < 0.1 ng/ml, and remain progression free after 16-61 weeks. 7 have stable disease of 9-50 weeks. 8 patients had progressive disease. 2 of the 4 PSA responders had measurable disease (liver, lymph nodes) and are evaluable for objective response. Both achieved a partial response and remain in response status after 61 and 22 weeks of follow-up. Two of the responders were able to discontinue opioid analgesic after reporting resolution of cancer-related pain. 5 patients had significant immune-related adverse events (grade 2 myositis, grade 3 hypothyroidism, grade 2 hypothyroidism, 2 with grade 3 colitis). Immunohistochemistry from baseline biopsies of two responders showed the presence of CD3 + , CD8 + , and CD163+ leukocyte infiltrates and PD-L1 expression. 2 of the 4 responders had a tumor biopsy and 1 had microsatellite instability in the tumor. Conclusions: Early results demonstrate reproducible, profound, and - to date - durable responses to PD-1 inhibition with enzalutamide in men with mCRPC.