PROVENGE

Sipuleucel-T Immunotherapy for Castration-Resistant Prostate Cancer

N Engl J Med 2010; 363:411-422

Background

Prostate cancer is the most common noncutaneous cancer among men in the United States and is the second leading cause of death from cancer in men. Localized prostate cancer may be cured with surgery or radiation therapy, but the disease recurs in approximately 20 to 30% of patients. Androgen-deprivation therapy, the most common treatment after recurrence, is effective, but the disease eventually progresses in most patients who receive such treatment. For men with metastatic castration-resistant prostate cancer, the median survival in recent phase 3 studies has ranged from 12.2 to 21.7 months. A chemotherapeutic agent, docetaxel, is the only approved therapy that has been shown to prolong survival among men with this condition, conferring a median survival benefit of 2 to 3 months, as compared with mitoxantrone and prednisone.Combination therapy with mitoxantrone plus a glucocorticoid has been reported to provide palliation but no survival benefit, as compared with a glucocorticoid alone.

Sipuleucel-T is an active cellular immunotherapy, a type of therapeutic cancer vaccine, consisting of autologous peripheral-blood mononuclear cells (PBMCs), including antigen-presenting cells (APCs), that have been activated ex vivo with a recombinant fusion protein (PA2024). PA2024 consists of a prostate antigen, prostatic acid phosphatase, that is fused to granulocyte–macrophage colony-stimulating factor, an immune-cell activator.

Sipuleucel-T, an autologous active cellular immunotherapy, has shown evidence of efficacy in reducing the risk of death among men with metastatic castration-resistant prostate cancer.In this double-blind, placebo-controlled, multicenter phase 3 trial, we randomly assigned 512 patients in a 2:1 ratio to receive either sipuleucel-T (341 patients) or placebo (171 patients) administered intravenously every 2 weeks, for a total of three infusions. The primary end point was overall survival, analyzed by means of a stratified Cox regression model adjusted for baseline levels of serum prostate-specific antigen (PSA) and lactate dehydrogenase.

Results

In the sipuleucel-T group, there was a relative reduction of 22% in the risk of death as compared with the placebo group. This reduction represented a 4.1-month improvement in median survival (25.8 months in the sipuleucel-T group vs. 21.7 months in the placebo group). The 36-month survival probability was 31.7% in the sipuleucel-T group versus 23.0% in the placebo group. The time to objective disease progression was similar in the two study groups. Immune responses to the immunizing antigen were observed in patients who received sipuleucel-T. Adverse events that were more frequently reported in the sipuleucel-T group than in the placebo group included chills, fever, and headache. The use of sipuleucel-T prolonged overall survival among men with metastatic castration-resistant prostate cancer. No effect on the time to disease progression was observed.

 

New Therapies for Castration-Resistant Prostate Cancer

N Engl J Med 2010; 363:479-481

On April 29, 2010, the Food and Drug Administration (FDA) approved a new immunotherapy, sipuleucel-T, for the treatment of patients with asymptomatic or minimally symptomatic castration-resistant prostate cancer.

Other immunization strategies are being tested in patients with prostate cancer. A vaccine called GVAX that is composed of two allogeneic prostate-cancer cell lines infected with adenoviruses that allow the cells to secrete GM-CSF was unsuccessful in phase 3 testing.7 However, another product, called PROSTVAC-VF, composed of two recombinant vaccinia-based viral vectors containing PSA and three immune costimulatory molecules, prolonged median survival by 8.5 months in a randomized phase 2 study.Like sipuleucel-T, PROSTVAC-VF improved survival without improving progression-free survival. It is now being tested in phase 3 studies.

Other prospects for vaccine development include peptide vaccines, DNA-based vaccines, and novel strategies such as targeting antigens to major histocompatibility complex class I pathways with chemokine–antigen chimeric molecules.

Another concern with sipuleucel-T treatment is the cost. The current cost of care for men with prostate cancer has been estimated to be about $1,800 per month.The manufacturer has set the cost of a 1-month course of sipuleucel-T at $93,000, or $23,000 per month of survival advantage. The high cost may affect use. It is also uncertain what role sipuleucel-T will ultimately play in the treatment of prostate cancer, given the other promising treatments in development.

Castration-resistant prostate cancer was formerly known as hormone-refractory prostate cancer. However, even after tumors progress through combined androgen blockade, they retain dependence on the androgen receptor. Many novel agents are in development, some of which have shown dramatic antitumor effects in the earliest phases of clinical testing. Abiraterone blocks the synthesis of androgens; 51% of men who were treated with 1 g of the drug per day had a reduction in PSA levels of at least 50%, and 27% of patients had a partial tumor response. Experimental drug MDV3100 blocks nuclear translocation of the androgen receptor. In a phase 1 and 2 study, antitumor effects were noted at every dose of the agent, including a reduction in PSA levels of at least 50% in 56% of patients, responses in soft-tissue lesions in 22% and in stabilized bone lesions in 56%, and a reduction in circulating tumor-cell counts in 49%.

The prospects for improved therapy for prostate cancer have never been so encouraging. The poor prognosis for men with prostate cancer will probably be substantially improved by the findings that emerge from ongoing clinical research.