Survival Benefit Propels Prostate Cancer Vaccine to Phase III Trial

James L. Gulley, MD, PhD

An investigational prostate cancer vaccine has shown potential to improve survival in patients with metastatic castration-resistant prostate cancer (CRPC), according to the results of early clinical evaluations.

In one randomized trial, patients treated with PROSTVAC-VF lived almost 9 months longer than did patients in a control group, and almost twice as many vaccine-treated patients were alive at 3 years.

In all, the investigational immunotherapy has been well tolerated in phase I-II studies involving about 300 patients, setting the stage for a global phase III trial involving 1200 men with asymptomatic or minimally symptomatic metastatic CRPC.

“The primary endpoint is overall survival,” James L. Gulley, MD, PhD, of the Center for Cancer Research at the National Cancer Institute, and colleagues reported in a poster presentation during the 2013 Annual Meeting of the American Urological Association. “The secondary endpoint is the proportion of patients who remain event-free at 6 months.”

Exploratory analyses in the trial will include immune response to immunizing antigens, non-vaccine-contained prostate antigens, and tumor-associated antigens; changes in biomarkers and circulating tumor cells; and characterization of T-cell subpopulations.

During the conference, Gulley discussed the development of PROSTVAC- VF and reviewed results of two phase II randomized trials.

Several factors have pointed to prostate cancer as a candidate disease for treatment strategies involving stimulation of the immune system, he said. The cancer progresses slowly, providing time for immunesystem priming and activation. Patients with asymptomatic CRPC tend to be immunocompetent because chemotherapy is reserved for advanced disease in most cases. In addition, prostate-specific antigen (PSA) is an organ-specific biomarker that can be measured readily.

In contrast to sipuleucel-T, PROSTVAC-VF is an “off-the-shelf” immunotherapeutic comprising two recombinant poxvirus vectors: vaccinia (PROSTVAC-V), which primes the immune system; and fowlpox (PROSTVAC-F), an immune system booster.

As described by Gulley, each vector contains four human genes: PSA and three costimulatory molecules (TRICOM) that enhance T-cell activation; leukocyte function-associated antigen-3; intercellular adhesion molecule-1; and B7-1.

In a phase II, randomized, double-blind, placebo-controlled trial, 125 patients with minimally symptomatic metastatic CRPC were randomized 2:1 to PROSTVAC-VF or to control empty vectors (J Clin Oncol. 2010;28:1099-1105). Patients randomized to the immunotherapy received a priming dose of PROSTVAC-V, followed by six booster doses of PROSTVAC-F given with low-dose granulocyte- macrophage colony-stimulating factor (GM-CSF).

The trial had a primary endpoint of 6-month progression-free survival (PFS), which did not differ between treatment arms (23% for PROSTVAC-VF, 25% for control). However, the immunotherapytreated group had a median overall survival of 25.1 months versus 16.6 months in the control group, which translated into a hazard ratio of 0.56 in the prespecified stratified analysis (P=.0061). An analysis that included all randomized patients produced a hazard ratio of 0.58 in favor of the vaccine (P=.0095).

Gulley and colleagues previously reported results of a smaller phase II trial designed to investigate the effect of GM-CSF with the vaccine and the influence of immunologic and prognostic factors on overall survival (Cancer Immunol Immunother. 2010;59:663-674). All 32 patients received the vaccine as a priming dose of PROSTVAC-V followed by monthly booster doses of PROSTVAC-F until progression, but the use of GM-CSF in these patients was not universal.

How pox viral vaccines activate tumor-associated antigen specific T- cells.

Laboratory and pathology results showed that 12 of 32 patients had decreases in PSA levels, accompanied by modest tumor regression in two of the 12 cases. Median overall survival was 26.6 months, as compared with a survival predicted at 17.4 months by the Halabi nomogram.

Patients with greater PSA-specific T-cell responses exhibited a trend toward improved survival (P=.055). GM-CSF had no effect on T-cell response. Patients with Halabi-predicted overall survival <18 months had a median overall survival of 14.6 months (versus a predicted median of 12.3 months), and those with a Halabi-predicted survival ≥18 months (predicted median of 20.9) had a median survival that exceeded 3 years. Of 15 patients with predicted survival ≥18 months, 12 (75%) exceeded expectations (P=.035).

Regulatory T-cell function declined after vaccine administration among patients who outlived predictions and increased in those whose survival was less than predicted.

Gulley and colleagues interpreted results of the smaller trial as suggesting that patients with more indolent-type prostate cancer (Halabi-predicted survival ≥18 months) might derive the most benefit from the vaccine.

Enrollment in the phase III trial of PROSTVAC-VF is ongoing. Patients are being randomized to three treatment groups: PROSTVAC- VF, vaccine plus GM-CSF, or vector placebo control. The trial has a primary endpoint of overall survival and is statistically powered to detect an 18% difference in the hazard ratio for all between-group comparisons. An informational website has been established for the trial (www.continueyourfight.com).

Gulley J, Gabrail N, Vogelzang N, et al. PROSPECT: A randomized, double-blind, phase 3 efficacy trial of PROSTVAC-VF in metastatic castration-resistant prostate cancer. Presented at: the Annual Meeting of the American Urological Association; May 4-8, 2013: San Diego, CA. Abstract 970.