Personalised Peptide Vaccination for Castration-Resistant Prostate Cancer Progressing after Docetaxel Chemotherapy: A Randomised, Double-Blind, Placebo-Controlled, Phase 3 Trial

Background: To develop a new treatment modality, we conducted a phase 3 randomised trial of personalized peptide vaccination (PPV) for human leukocyte antigen (HLA) -A24-positive patients with castration-resistant prostate cancer (CRPC) for whom docetaxel chemotherapy failed. Methods: This randomized, double-blind, placebo-controlled, phase 3 trial was done at 68 medical centers in Japan. Eligible patents were aged 20 years or older with HLA-A24-positive, CRPC progressing after docetaxel chemotherapy, positive immunoglobulin G (IgG) responses to at least 2 of 12 warehouse peptides, an Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of at least 12 weeks, serum testosterone level of ≤ 50 ng/dl, and satisfactory bone marrow function, hepatic function, and renal function. Patients were randomly assigned in a 2:1 ratio to receive PPV or placebo. Four of 12 warehouse peptides selected based on pre-existing peptide-specific IgG levels or the corresponding placebo were subcutaneously injected in 6 doses weekly and then bi-weekly following the maximum of 30 doses until disease progression. The primary end point was overall survival (OS), and secondary end points were progression-free survival (PFS) and immune responses. Efficacy analyses were by the full analysis set. Findings: Between August 2013 and April 2016, 310 patients were randomly assigned (207 to PPV and 103 to placebo), and 306 patients were analyzed by the full analysis set (204 to PPV and 102 to placebo). Baseline characteristics were balanced between groups. The estimated median OS was 16.1 months (95% confidence interval [CI], 13–18·2) with PPV and 16·9 months (95% CI, 13·1–20·4) with placebo (hazard ratio [HR], 1·04; 95% CI, 0·80–1·37; p=0·77). The median PFS was not significantly different between groups. Grade < 3 adverse events were observed in 41% in both groups. The most common AEs were < grade 3 injection site reactions in both groups. The analysis of treatment arm effects among subgroups revealed lower HRs for OS in favor of the PPV arm in patients with < 64% neutrophils (HR, 0·55; 95% CI, 0·33–0·93, p=0·03) or ≥ 26% lymphocytes (HR, 0·70; 95% CI, 0·52–0·92, p=0·02) at base line by the significant interaction test (p=0·003 or p=0·007). Interpretation: PPV did not prolong OS or PFS in HLA-A24-positive patients with CRPC progressing after docetaxel chemotherapy. Subgroup analysis suggested that the patients with a lower proportion of neutrophils or a higher proportion of lymphocytes at base line can receive survival benefits from PPV treatment. Trial Regstration: This study is registered with UMIN Clinical Trials Registry (UMI11308), and patient enrollment is complete. Funding Statement: This study was supported by grants from the Japan Agency for Medical Research and Development (No. 18im0110802h0008) and Fujifilm Company. Declaration of Interests: MN has served as an advisory board consultant for BrightPath biotherapeutics Co. Ltd. KI received research funding from Taiho Pharmaceutical Company. SN has served as a consultant to BrightPath biotherapeutics Co. Ltd and received an honorarium from Sanofi. All other authors declare no competing interests. Ethics Approval Statement: The trial was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. The protocol was approved by institutional review boards or ethical committees at all of the institutions. All patients were Japanese and provided written informed consent before participating in this study.