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

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.

The Changing Therapeutic Landscape in Metastatic Prostate Cancer

“…20 In a recent phase II trial, patients who had progressed on enzalutamide were treated with the anti-PD-1 antibody pembrolizumab. 21 Three of the first 10 patients treated had rapid and significant decreases in PSA from pre-treatment levels of 46, 71, and 2,503 to <0.1. Two of the three patients with measurable disease (one with liver metastases) had a partial response and two were able to discontinue opiate analgesics.…”

“…None of the responders had an immune-related AE. 21 A phase III trial in men with locally advanced or mCRPC, comparing the anti-PD-L1 antibody, atezolizumab plus enzalutamide with enzalutamide alone, is currently in progress (NCT03016312).…”

Heterogeneity of advanced prostate cancer: clinical implications of genomics

“…16 Graff et al showed that in 20 mCRPC patients who had previously progressed on enzalutamide, there were four responders when pembrolizumab was added to the enzalutamide, with at least one patient, who was shown to be MMR-deficient, having a rapid and deep biochemical response. 17,18 Several commercial and investigatorinitiated studies are currently being set up to test which patients may benefit from immune checkpoint blockade including MMR as a biomarker (eg the PERSEUS and NEPTUNE trials).…”

Prostate cancer immunotherapy, particularly in combination with androgen deprivation or radiation treatment. Customized pharmacogenomic approaches to overcome immunotherapy cancer resistance

“…However, a recent intriguing trial has allowed, instead, to find out unexpected antitumor effects, including PSA significant decrease, in enzalutamide-resistant mCRPC patients undergone immune-based treatment with pembrolizumab -as another anti-PD-1 mAb agenttherefore the enzalutamide enhancing such check point blockade-mediated antitumor immune response (9,21,22).…”

“…The ADT, indeed, by lowering the human cancer cells expression of antiapoptotic genes, may enhance cancer sensitivity to immune-mediated lysis, so that making clear the effectiveness of ADT/immunotherapy combination (22,62).…”