Randomized Phase II Study Evaluating the Addition of Pembrolizumab to Radium-223 in Metastatic Castration-resistant Prostate Cancer

Abstract

The checkpoint immunotherapeutic pembrolizumab induces responses in a small minority of patients with metastatic castration-resistant prostate cancer (mCRPC). Radium-223 (R223) may increase immunogenicity of bone metastases and increase pembrolizumab (P) activity. In a randomized phase II study, we assessed the effect of R223+P compared with R223 on tumor immune infiltration, safety, and clinical outcomes in patients with mCRPC. The primary endpoint was differences in CD4+ and CD8+ T-cell infiltrate in 8-week versus baseline bone metastasis biopsies; secondary endpoints were safety, radiographic progression-free survival (rPFS), and overall survival (OS). Of the 42 treated patients (29 R223+P, 13 R223), 18 R223+P and 8 R223 patients had evaluable paired tumor biopsies. Median fold-change of CD4+ T cells was −0.7 (range: −9.3 to 4.7) with R223+P and 0.1 (−11.1 to 3.7) with R223 (P = 0.66); for CD8+ T cells, median fold-change was −0.6 (−7.4 to 5.3) with R223+P and −1.3 (−3.1 to 4.8) with R223 (P = 0.66). Median rPFS and OS was 6.1 (95% confidence interval: 2.7–11.0) and 16.9 months [12.7–not reached (NR)], respectively, with R223+P and 5.7 (2.6–NR) and 16.0 (9.0–NR), respectively, with R223. Although R223+P was well tolerated with no unexpected toxicity, the combination did not improve efficacy. High-dimensional flow cytometry demonstrated minimal immune modulation with R223, whereas R223+P induced CTLA-4 expression on circulating CD4+ T cells. Clinical responders possessed lower circulating frequencies of Ki67+ T and myeloid cells at baseline and higher circulating frequencies of TIM-3+ T and myeloid cells by week 9. Although R223+P did not induce T-cell infiltration into the tumor microenvironment, exhaustion of induced peripheral T-cell immune responses may dampen the combination's clinical activity.

DirectHRD enables sensitive scar-based classification of homologous recombination deficiency (HRD)

“…All patients had metastatic castration-resistant prostate cancer (mCRPC), primarily to bone, so tumor biopsies were not routinely performed. Instead, ULP-WGS of cfDNA was carried out and targeted sequencing of cfDNA was performed using an institutional prostate cancer-specific panel of 319 genes with duplex sequencing 28 . Germline and somatic variants were called using DeepVariant 29 and Mutect2 23 , and these variants were annotated with Funcotator 30 .…”