Phase 2 trial of pTVG-HP ± pTVG-AR DNA vaccines and pembrolizumab in patients with metastatic, castration-resistant prostate cancer (mCRPC).

backgroundWe previously reported a trial using pembrolizumab with a DNA vaccine encoding prostatic acid phosphatase (pTVG-HP) in patients with metastatic castration-resistant prostate cancer (mCRPC). Favorable clinical outcomes were associated with T-cell activation, suggesting immune response to vaccination was critical. In the current trial, we evaluated whether immunization with two vaccines, to broaden the T-cell response to other cancer-associated antigens, would elicit greater anti-tumor efficacy. MATERIALS AND

methods60 patients with mCRPC were treated with vaccine on days 1 and 8 of a 3 week cycle, with pembrolizumab given on day 1 of each cycle. Patients in Arm A (n=30) received pTVG-HP as the vaccine, and patients in Arm B (n=30) received pTVG-AR (encoding the ligand-binding domain of the androgen receptor) alternating with pTVG-HP every two cycles. After eight cycles (6 months), patients continued to receive pembrolizumab alone, with the option to receive further booster immunizations at prostate-specific antigen (PSA) progression. The primary objective was 6-month progression-free survival (PFS). Secondary objectives included safety, objective response rate, PSA response rate, overall survival (OS), and immunological evaluations.

resultsOverall median time to progression was 24 weeks (24 weeks Arm A, 24 weeks Arm B, p=0.80). The month 6 PFS rate was 51% in Arm A and 45% in Arm B. Median OS was 2.8 years (2.5 years Arm A, 3.7 years Arm B, p=0.16). 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 partial response. Eight patients received booster immunizations after 6 months, 3 of whom subsequently experienced a PSA decline. Three patients in Arm B experienced creatine kinase elevation with or without increased transaminases, which were not observed in Arm A. T cell immune responses to both antigens were detected in patients treated in Arm B.

conclusionsTreatment with DNA vaccines and pembrolizumab demonstrated 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 AR. TRIAL REGISTRATION NUMBER: NCT04090528.