Overall survival analysis of a phase II randomized controlled trial of a Poxviral-based PSA-targeted immunotherapy in metastatic castration-resistant prostate cancer

Abstract

Purpose: Therapeutic prostate-specific antigen (PSA) -targeted poxviral vaccines for prostate cancer have been well tolerated. PROSTVAC-VF treatment was evaluated for safety and for prolongation of progression-free survival (PFS) and overall survival (OS) in a randomized, controlled, and blinded phase II study.

Patients and methods: In total, 125 patients were randomly assigned in a multicenter trial of vaccination series. Eligible patients had minimally symptomatic castration-resistant metastatic prostate cancer (mCRPC). PROSTVAC-VF comprises two recombinant viral vectors, each encoding transgenes for PSA, and three immune costimulatory molecules (B7.1, ICAM-1, and LFA-3). Vaccinia-based vector was used for priming followed by six planned fowlpox-based vector boosts. Patients were allocated (2:1) to PROSTVAC-VF plus granulocyte-macrophage colony-stimulating factor or to control empty vectors plus saline injections.

Results: Eighty-two patients received PROSTVAC-VF and 40 received control vectors. Patient characteristics were similar in both groups. The primary end point was PFS, which was similar in the two groups (P = .6). However, at 3 years post study, PROSTVAC-VF patients had a better OS with 25 (30%) of 82 alive versus 7 (17%) of 40 controls, longer median survival by 8.5 months (25.1 v 16.6 months for controls), an estimated hazard ratio of 0.56 (95% CI, 0.37 to 0.85), and stratified log-rank P = .0061.

Conclusion: PROSTVAC-VF immunotherapy was well tolerated and associated with a 44% reduction in the death rate and an 8.5-month improvement in median OS in men with mCRPC. These provocative data provide preliminary evidence of clinically meaningful benefit but need to be confirmed in a larger phase III study.

Fig 1.

Disposition of patients: CONSORT diagram.

Fig 2.

Primary end point is progression-free survival. Kaplan-Meier estimator for PROSTVAC (a vaccine containing two recombinant viral vectors [vaccinia and fowlpox] and three immune costimulatory molecules [B7.1, ICAM-1, and LFA3]) arm is shown as a solid gold line and the estimator for the control arm is a dashed blue line. The small vertical tic marks show the censoring times. The estimated median progression-free survival is 3.8 months in the PROSTVAC arm and 3.7 months in the control arm.

Fig 3.

Serum tumor marker response. Semi-log graphs of (A) prostate-specific antigen levels from 40 to 5 ng/mL and of (B) prostatic acid phosphatase levels from 10 to 1 ng/mL over time in a specific PROSTVAC-treated patient (PROSTVAC is a vaccine containing two recombinant viral vectors [vaccinia and fowlpox] and three immune costimulatory molecules [B7.1, ICAM-1, and LFA3]). Gold circles represent time points for the samples. The responses occurred over 3 to 6 months (end of study). The patient survived 929 days.

Fig 4.

Overall survival. Kaplan-Meier estimator for PROSTVAC (a vaccine containing two recombinant viral vectors [vaccinia and fowlpox] and three immune co-stimulatory molecules [B7.1, ICAM-1, and LFA3]) arm is shown as a solid gold line and estimator for the control arm is a dashed blue line. The small vertical tic marks show the censoring times. The estimated median overall survival is 25.1 months for the PROSTVAC arm and 16.6 months for the control arm.

Fig 5.

Effect modifier analysis. Forest plot for putatively prognostic factors. Continuous factors are analyzed by dichotomization at the common median. PROSTVAC, a vaccine containing two recombinant viral vectors (vaccinia and fowlpox) and three immune costimulatory molecules (B7.1, ICAM-1, and LFA3); HLA-A2, human leukocyte antigen A2; PSA, prostate-specific antigen; Alk phos, alkaline phosphatase; LDH, lactate dehydrogenase; HGB, hemoglobin; ECOG PS, Eastern Cooperative Oncology Group performance status.