June 29, 2016
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Provenge

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Reviewed by Arefa Cassoobhoy, MD, MPH

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Provenge




CLINICAL PHARMACOLOGY

Mechanism Of Action

PROVENGE is classified as an autologous cellular immunotherapy. While the precise mechanism of action is unknown, PROVENGE is designed to induce an immune response targeted against PAP, an antigen expressed in most prostate cancers. During ex vivo culture with PAP-GM-CSF, APCs take up and process the recombinant target antigen into small peptides that are then displayed on the APC surface.

In Study 1, 237 out of the 512 patients randomized were evaluated for the development of humoral and T cell immune responses (proliferative and gamma-interferon (γIFN) ELISPOT) to the target antigens at Baseline, and at Weeks 6, 14, and 26. Antibody (IgM and IgG) responses against PAP-GM-CSF and PAP antigen alone were observed through the follow-up period in the PROVENGE group. Neutralizing antibody responses to GM-CSF were transient. T cell proliferative and γIFN ELISPOT responses to PAP-GM-CSF fusion protein were observed in cells collected from peripheral blood of patients through the follow-up period in the PROVENGE treatment group but not in controls. In some patients a response to PAP antigen alone was observed. No conclusions could be made regarding the clinical significance of the observed immune responses.

Clinical Studies

The effect of PROVENGE on patients with metastatic castrate-resistant (hormone-refractory) prostate cancer was studied in three similar randomized, double-blind, placebo-controlled, multicenter trials. Following randomization, patients from both treatment groups underwent a series of 3 leukapheresis procedures (at approximately Weeks 0, 2, and 4). Each leukapheresis was followed approximately 3 days later by infusion of PROVENGE or control. The control was autologous peripheral blood mononuclear cells that had not been activated [see DESCRIPTION]. Following disease progression, patients were treated at the physician's discretion with other anti-cancer interventions.

Study 1

Study 1 was a randomized, double-blind, placebo-controlled, multicenter trial in patients with asymptomatic or minimally symptomatic metastatic castrate-resistant (hormone-refractory) prostate cancer. Eligible patients had metastatic disease in the soft tissue and/or bone with current or historical evidence of disease progression concomitant with surgical or medical castration, as evidenced by progression of serum Prostate Specific Antigen (PSA) and/or bone or soft tissue disease. Exclusion criteria included visceral (liver, lung, or brain) metastases, moderate to severe prostate cancer-related pain, and use of narcotics for cancer-related pain.

A total of 512 patients were randomized in a 2:1 ratio to receive PROVENGE (n=341) or control (n=171). The median age was 71, and 90% of the patients were Caucasian. Thirty-five percent of patients had undergone radical prostatectomy, 54% had received local radiotherapy, and 82% had received combined androgen blockade. All patients had baseline testosterone levels < 50 ng/mL. Forty-eight percent of patients were receiving bisphosphonates, and 18% had received prior chemotherapy, including docetaxel. Eighty-two percent of patients had an ECOG performance status of 0; 58% had primary Gleason scores of four or more; 44% had bone and soft tissue disease; 48% had bone-only disease; 7% had soft tissue-only disease; and 43% had greater than ten bony metastases.

Supportive Studies

Study 2 was a randomized, double-blind, placebo-controlled, multicenter trial in patients with metastatic castrate-resistant prostate cancer and no cancer-related pain. The primary endpoint was time to disease progression; analysis of the primary endpoint did not reach statistical significance. All patients were to be followed for survival; however, the survival analysis was not pre-specified.

Summary Of Study Results

Figure 1 and Table 2 present overall survival results observed in two randomized, Phase 3 studies of PROVENGE in men with metastatic castrate-resistant prostate cancer. The survival findings were consistent across multiple subgroups. Analyses of time to disease progression did not meet statistical significance in any Phase 3 study of PROVENGE. Page 14 of 19

Figure 1 : Kaplan-Meier Overall Survival Curve for Study 1

Kaplan-Meier Overall Survival Curve - Illustration

Table 2 : Summary of Overall Survival (All Patients as Randomized)

  Study 1 Study 2
PROVENGE
(N=341)
Control
(N=171)
PROVENGE
(N=82)
Control
(N=45)
Overall Survival
  Median, months (95% CI) 25.8 (22.8, 27.7) 21.7 (17.7, 23.8) 25.9 (20.0, 32.4) 21.4 (12.3, 25.8)
  Hazard Ratio (95% CI) 0.775a (0.614,0.979) 0.586b (0.388, 0.884)
  p-value 0.032a 0.010c
a Hazard ratio and p-value based on the Cox Model adjusted for PSA (ln) and LDH (ln) and stratified by bisphosphonate use, number of bone metastases, and primary Gleason grade.
b Hazard ratio based on the unadjusted Cox Model (not pre-specified).
c p-value based on a log-rank test (not pre-specified).
Abbreviations: CI = confidence interval.

Last reviewed on RxList: 3/7/2016
This monograph has been modified to include the generic and brand name in many instances.

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