Provenge Shows Survival Benefit in Prostate Cancer
Elsevier Global Medical News. 2009 Apr 30, S Birk
CHICAGO (EGMN) - Autologous active cellular immunotherapy with sipuleucel-T, the controversial investigative agent with the brand name Provenge, extended survival by a median of 4.1 months in men with metastatic androgen-independent prostate cancer, according to the most recent data from the IMPACT study.
The much-anticipated results of the phase III, multicenter, randomized, double-blind, placebo-controlled trial were presented in a late-breaking science forum at the annual meeting of the American Urological Association.
"The data show that sipuleucel-T is the first active immunotherapy to demonstrate an improvement in overall survival for advanced prostate cancer," said coinvestigator Dr. David F. Penson of the University of Southern California in Los Angeles.
"Provenge appears to have a highly favorable benefit-to-risk profile [and] a short duration of therapy, and perhaps most importantly, will not only change the way we manage prostate cancer, but also has the potential to create an entirely novel therapeutic paradigm across the field of oncology," he said.
Median survival reached 25.8 months with treatment and 21.7 months with placebo. The 3-year survival rate was 31.7% with treatment and 23% with placebo, a relative increase of 38% (P = .032). The hazard ratio was 0.775, indicating a 22.5% reduction in the risk of death in the sipuleucel-T treatment arm.
The experimental vaccine from Dendreon Corp. still had not met the primary end point when interim results from the IMPACT (Immunotherapy for Prostate Adenocarcinoma Treatment) trial were made public in fall 2008. An earlier Food and Drug Administration decision not to approve Provenge, pending more data, had triggered demonstrations by patient advocates of the therapy.
Subjects in the IMPACT trial were 512 patients with minimally symptomatic or asymptomatic advanced androgen-independent prostatic adenocarcinoma with metastasis to lymph nodes or bone, who had a life expectancy of at least 6 months and a serum prostate-specific antigen (PSA) level greater than 5 ng/mL. They were randomized at a 2:1 ratio to receive the experimental vaccine or a placebo.
The active cellular immunotherapy is designed to stimulate and optimize production of the patient's T cells and to enlist these cells in the destruction of specific tumor cell types.
Patients underwent an apheresis to collect antigen-presenting cells. The cells were shipped to a central laboratory, where they were exposed to recombinant fusion protein-containing prostate antigen fused with an immune cell activator. The activated cells were returned to patients and reinfused on an outpatient basis. The process was repeated three times at 2-week intervals, with treatment completed in approximately 1 month. In all, 90% of patients completed treatment.
At the time of disease progression, patients in both arms of the study were able to receive treatment at the physician's discretion. Patients who were randomized to placebo had the option of receiving immunotherapy in which they received a version of sipuleucel-T prepared from their own cryopreserved cells, which had been harvested at the time of placebo generation. Patients randomized to sipuleucel-T had the option of receiving an additional dose of docetaxel (Taxotere).
The investigational therapy produced only minor - in most cases, transitory - side effects, according to Dr. Penson. The most common complications included chills (54.1% vs. 12.5% with placebo), pyrexia (29.3% vs. 13.7%), headache (16.1% vs. 5%) and influenza (9.8% vs. 4.3%). The majority of these complications occurred within 1 day of infusion, resolved within 1-2 days, and was mild to moderate in severity. Side effects were successfully treated with acetaminophen or Demerol.
This favorable safety profile makes the immunotherapy particularly promising as a treatment for patients with terminal prostate cancer because it preserves quality of life while prolonging life, said Dr. Penson. "I've given this agent to a number of subjects, and I'm always very impressed by how well this drug is tolerated," he commented during a later press conference.
He said that the survival benefit found with sipuleucel-T in this study has major significance for patients with advanced prostate cancer. "When you consider that these patients have less than a 2-year survival advantage on average, and you're going to give them 4 more months of life, that's a 20% advantage."
Although most patients in the same position probably would say no to another dose of docetaxel because of the drug's toxicity, he said, "if I offer these same patients additional survival, and I say, 'By the way, this drug has minimal or no side effects, and you'll be done with it in 1 month as opposed to 3 or 4 months,' I think that's very significant.
"With the results of the IMPACT study, we are entering a new era in the treatment of prostate cancer, where we can offer our patients a completely novel therapeutic modality that improves clinical outcome with minimal toxicity," he said.
To rule out the possibility of the survival benefit being driven by a particular group of patients, the treatment effect was assessed in multiple population subsets. All subpopulations demonstrated a positive treatment effect, Dr. Penson reported. "The story is exactly the same in every single subgroup analysis, and that is very reassuring to me," he said.
The results of an additional sensitivity analysis also were consistent with the primary statistical model. Adjusted for the use of docetaxel and the time of use of docetaxel, the hazard ratio was 0.763 and the P value was .036, indicating no evidence that chemotherapy after disease progression altered survival results from sipuleucel-T.
The survival benefit of sipuleucel-T shown in this study is consistent with two earlier multicenter, randomized, double-blind, placebo-controlled trials of the agent, Dr. Penson said. These studies found a survival benefit of 4.5 months and 3.3 months, respectively. The percentage of patients alive at 36 months in the two previous studies (34% and 32%, respectively) is also consistent with the newest data.
An integrated analysis of the three studies, which includes a total of 737 patients, reveals a hazard ratio of 0.735, which represents a 26.5% reduction in the risk of death, with a P value of less than .001, he said.
Dr. Penson disclosed that he has no financial conflicts of interest related to this study.
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