{
  "abstract": "Background A previous study with a DNA vaccine encoding prostatic acid phosphatase (PAP, pTVG-HP) in combination with pembrolizumab in patients with metastatic, castration-resistant prostate cancer (mCRPC) showed a median progression-free survival (PFS) of 5.6 months. The current trial evaluated whether inclusion of an additional vaccine encoding the androgen-receptor ligand-binding domain (AR, pTVG-AR) would improve the 6-month PFS rate.Methods 60 patients with mCRPC received 3-week cycle treatments with a DNA vaccine (days 1 and 8) and pembrolizumab (day 1). Patients were randomized to receive either pTVG-HP alone (Arm A), or pTVG-HP and pTVG-AR in alternating cycles (Arm B). After 6 months, patients continued to receive pembrolizumab and had the option to receive additional vaccine booster cycles at time of progression. Primary endpoint was 6-month PFS. Secondary endpoints included safety, overall objective response rate and PSA response rate.Results 30 patients were randomized to each treatment arm. Overall median time to progression was 24.4 weeks (24.4 weeks Arm A, 24.0 weeks Arm B, p=0.69). 30% of patients in Arm A and 27% of patients in Arm B remained on treatment beyond 6 months without progression. Median overall survival (mOS) was 2.7 years (2.7 years Arm A, 3.7 years Arm B, p=0.28). Of 47 patients previously treated with an ARPI mOS was 2.5 years. Of 14 patients previously treated with both a taxane and ARPI, the mOS was 2.1 years. 20% of patients in each arm experienced a PSA decline of ≥ 50%. 20 patients (n=8 Arm A, n=12 Arm B) had measurable disease, and 6/20 (30%) experienced a PR (3 in each arm). 8 patients went on to receive booster immunizations after 6 months, 3 of whom subsequently experienced modest PSA declines. irAE > grade 1 were detected in 9 patients in Arm A and 17 patients in Arm B. Notably, 5 patients in Arm B experienced CK elevation with or without increased transaminases, which were not observed in Arm A.Conclusions Treatment with a DNA vaccine and pembrolizumab demonstrated evidence of anti-tumor activity in terms of PSA declines and objective responses. The addition of pTVG-AR did not significantly increase measures of clinical efficacy, however it was associated with a slight increase in toxicity to tissues that also express the AR. These findings suggest that future studies exploring this combination treatment should use pTVG-HP alone. Further correlative studies evaluating tumor tissues and systemic measures of immunity are underway.Acknowledgements Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA provided drug and financial support for the study. Vaccines were provided by Madison Vaccines, Inc. Additional funding support was provided by the Prostate Cancer Foundation.Trial Registration Trial Registration: NCT04090528Ethics Approval This study was approved by the University of Wisconsin Health Sciences IRB, approval number 2018-0938.",
  "authors": [
    {
      "affiliations": [
        "University of Wisconsin-Madison, Madison, WI, USA"
      ],
      "name": "Christos Kyriakopoulos"
    },
    {
      "affiliations": [
        "Washington University School of Medicine, St. Louis, MO, USA"
      ],
      "name": "Russell K Pachynski"
    },
    {
      "affiliations": [
        "University of Wisconsin-Madison, Madison, WI, USA"
      ],
      "name": "Jens C Eickhoff"
    },
    {
      "affiliations": [
        "University of Wisconsin-Madison, Madison, WI, USA"
      ],
      "name": "Tommaso P Tonelli"
    },
    {
      "affiliations": [
        "University of Wisconsin-Madison, Madison, WI, USA"
      ],
      "name": "Donghwan Jeon"
    },
    {
      "affiliations": [
        "University of Wisconsin-Madison, Madison, WI, USA"
      ],
      "name": "Ichwaku Rastogi"
    },
    {
      "affiliations": [
        "University of Wisconsin-Madison, Madison, WI, USA"
      ],
      "name": "Douglas G McNeel"
    }
  ],
  "title": "499 Phase 2 trial of pTVG-HP DNA vaccine, with or without pTVG-AR DNA vaccine, and pembrolizumab in patients with castration-resistant, metastatic prostate cancer",
  "uid": "90b13979-2c2f-5e5f-8db2-1964fb70fea3"
}