GAITHERSBURG, Maryland—An FDA advisory panel has supported the requested approval of the cancer vaccine Provenge (sipuleucel-T, Dendreon) for the treatment of asymptomatic, metastatic, hormone-refractory prostate cancer. [As ONI went to press, Dendreon received an "approvable" letter from FDA requesting additional clinical data in support of efficacy.] Although members of the Cellular, Tissue, and Gene Therapies Advisory Committee did not formally vote to recommend approval, its members did tell FDA that the data submitted to them showed that Provenge is reasonably safe and has substantial evidence of efficacy.

The decision came after the panel heard presentations by Dendreon and an FDA review team on two similarly designed phase III trials submitted by Dendreon. Neither study met its primary endpoint of improved time to progression. However, post hoc analyses found that the larger of the studies showed a significant advantage for Provenge in overall survival after 3 years. Overall survival in the second trial did not reach significance.

Studies 1 and 2 were randomized, double-blind, placebo-controlled, multicenter trials. Eligibility criteria included metastatic prostate cancer without vis-ceral metastases, tumor progression despite androgen deprivation, no cancer-related pain, no systemic steroids or prior immunotherapy, and an ECOG status of 0 or 1. The primary endpoint for both studies was time to progression.

The two trials used 2:1 randomization, with patients to receive Provenge or placebo three times, with 2 weeks between each treatment. Study 1 randomized 82 men (median age 73; 89% white) to Provenge and 45 (median age 71; 93.3% white) to placebo. The treatment group had a nonsignificant median time to progression of 11.0 weeks, compared with 9.1 weeks in the placebo arm (P = .085).

After study 1 failed to meet its primary endpoint, researchers halted enrollment in study 2 following accrual of 98 of 120 planned patients with similar age and racial characteristics as those in study 1. The difference in time to progression in the second study also was nonsignificant, 10.9 weeks for Provenge vs 9.9 weeks for placebo (P = .719). The two trials found no significant regression in tumor size among the treated patients.

Although neither study specified overall survival as an endpoint, a post hoc analysis of the study 1 data showed an overall median survival benefit for the Provenge arm, compared with placebo, of 25.9 months vs 21.4 months (P = .01). "Overall survival is the least biased, least variable, and most clinically meaningful assessment of an oncology product," said Mark Frohlich, MD, Dendreon's vice president of clinical affairs.

An analysis of study 2 found a median overall survival of 19 months for the treatment arm vs 15.7 months for the placebo group, a difference that failed to reach statistical significance (P = .331). "It should be noted that the survival time in this study was shorter than the counterpart in study 1, which suggests that significant populations in these two studies may not be exactly the same," remarked FDA clinical reviewer Ke Liu, MD, PhD. Dendreon also presented combined overall survival data from the two trials, showing a significant advantage for Provenge, 23.2 weeks vs 18.9 weeks for placebo (P = .011)

Safety Analysis