In a randomized, double-blind, placebo-controlled trial of men with early recurrent androgen-dependent prostate cancer, active cellular immunotherapy with sipuleucel-T (Provenge) failed to meet its primary endpoint for delaying time to biochemical failure.
In May, FDA made the controversial announcement that it required additional data before making a ruling on approval of sipuleucel-T, which remains investigational. The agency said it would accept either a positive interim or final analysis of survival from the ongoing IMPACT study to amend the biologics license application for the drug. Dendreon Corp., sipuleucel-T's manufacturer, said it expected to complete enrollment in IMPACT this year and anticipated interim survival results in 2008.
The ASCO study enrolled men with a rise in serum PSA as the only sign of disease recurrence after prostatectomy for localized disease. A total of 176 patients were randomized 2:1 to sipuleucel-T or placebo. The assigned treatment was administered every other week for a total of three doses beginning after a 3-month course of hormone ablation therapy.
Secondary endpoints for the study comprise time to confirmed biochemical failure (defined by a second confirmatory PSA ≥3.0 ng/mL measured 2 to 4 weeks after the first PSA ≥3.0 ng/mL), PSADT, time to metastasis, survival, toxicity, and measures of immune response. There was a trend favoring sipuleucel-T (HR=0.80) in the analysis of time to confirmed biochemical failure, and PSADT analyses showed statistically significant increases in the men treated with sipuleucel-T compared with controls.
Only 16% of men in the study (sipuleucel-T, 14.5%; placebo, 18.6%) have developed distant metastasis. Analysis of those results showed a trend in favor of sipuleucel-T for delaying distant failure (HR=0.73).
"While we are reporting the final analysis for time to biochemical failure, in this patient population, that endpoint is considered exploratory, rather than a direct measure of treatment benefit," said first author Tomasz M. Beer, MD, associate professor of medicine, division of hematology and medical oncology, Oregon Health & Science University Cancer Institute, Portland. "Time to distant failure is perhaps the most clinically relevant outcome measure for men with early recurrent prostate cancer, and the trend favoring sipuleucel-T is encouraging.
"However, because there were very few metastatic events so far, the benefit was not statistically significant. Follow-up is continuing, and additional analyses will be forthcoming for time to distant failure and survival."
Analyses of PSADT showed significant differences favoring sipuleucel-T, whether PSADT was calculated from 30, 60, or 90 days following randomization to the time of biochemical failure. For all of those methods, PSADT was increased by about 35% in men treated with sipuleucel-T compared with placebo (~125 days vs. ~92 days). There was a 48% increase in PSADT comparing the immunotherapy group and controls in an analysis where PSADT was calculated after testosterone recovery (155 days vs. 105 days).
The men enrolled in the sipuleucel-T and placebo groups had similar demographic characteristics. Median age was 65 years, and most men (90%) were Caucasian and had a Gleason sum score of 7 (81%). Median PSA measured during the run-in period prior to hormone treatment was 2.2 ng/mL for the total population, and it decreased to 0.09 ng/mL after hormone ablation at the time of randomization to sipuleucel-T or placebo.