Provenge.
Provenge (formerly APC-8015) is a dendritic cell-based vaccine in Phase III development by Dendreon. The company prepares the vaccine by isolating dendritic cells (an important element of the immune system) from a patient’s blood and then incubating them with a fusion protein comprising prostatic acid phosphatase (PAP) and a dendritic cell-targeting element, which is structurally similar to GM-CSF. The vaccine is prepared over 48 hours. When readministered to the patient, these cells “teach” the immune system to search out and destroy PAP-producing cells. Investigations have confirmed that the key target for Provenge therapy—PAP—is expressed by 95% of CaP tumors (Small EJ, 2003). On the basis of Phase II trials demonstrating that Provenge is safe and well tolerated and induces antigen immunity, Dendreon initiated three Phase III trials: two trials (DD-901 and DD-902B) involve patients with hormone-refractory metastatic CaP; the third trial (P-l 1) involves patients with rising PSA but without signs of metastases. The ongoing DD-902B trial is designed to confirm DD-901 ‘s findings that Provenge improves survival and time to onset of pain in patients with a Gleason score of 7 or less (less aggressive cancers). A National Cancer Institute (NCI)-sponsored Phase II trial (P-16) is investigating Provenge in combination with the angiogenesis inhibitor bevacizumab (Genentech / Roche’s Avastin) among patients with hormone-responsive CaP.
Dendreon’s first Phase III trial, DD-901, involved 127 men with metastatic, hormone-resistant CaP. Patients were randomized in a 2:1 ratio to receive three vaccinations of Provenge or placebo every two weeks for three cycles. The primary end point was the time to objective disease progression. Median patient age was 73, median Gleason score 7, and median PSA 46. The vaccine was prepared over 48 hours. A trend toward improved time to progression was observed in the Provenge arm (p = 0.061), but researchers observed a statistically significant clinical benefit only after a subset analysis. Among patients with a Gleason score of seven or less (approximately 75% of hormone-resistant patients), the placebo group had a median time to progression of 9.0 weeks compared with 16.0 weeks in the Provenge-treated group (p = 0.001). Seventy-eight percent of these men responded to treatment. Patients with a Gleason score of 7 or less also had a significantly increased time to onset of pain (p = 0.016). Median time to onset of disease-related pain was 18.7 weeks for the placebo arm, while the median time was not yet reached for Provenge-treated patients. The vaccine’s effect on PSA levels was minor: only 2% of vaccine-treated patients had a 25-50% reduction in PSA levels and only 5% had a greater than 50% reduction. No placebo-treated patients experienced a PSA reduction. T-cell stimulation was seven times higher in patients with a low Gleason score versus those with a Gleason score of 8 or more. Additionally, according to a preliminary analysis of the same trial reported by Dendreon in August 2002, the subset of Provenge patients who had not progressed six months after randomization achieved a greater than eight-fold advantage in progression-free survival compared with those patients who received placebo (34.7% versus 4%).
The vaccine’s common side effects were grade 1 and 2. They included rigors (60% of vaccine-treated patients versus 7% of placebo patients), pyrexia (29% versus 2%), dyspnea (17% versus 4%), and fever, which were most often infusion-related and short-lived.
According to Dendreon, data from the final three-year follow-up of this Phase III trial showed a statistically significant survival benefit in patients who were treated with Provenge, regardless of Gleason score (Dendreon, press release, October 28, 2004). Although Dendreon did not provide details describing the magnitude of the survival benefit, the company claims this benefit is greater than that observed with any type of treatment in any published Phase III study in late-stage prostate cancer. At the 36-month final follow up, the percentage of patients alive in the Provenge-treated group was substantially greater than the percentage of patients alive in the placebo-treated group.
Preliminary survival results described in a previous press release show a benefit for vaccine-treated patients. Patients with Gleason scores of seven or less receiving Provenge had, on average, an 89% overall increase in their survival time as compared with placebo-treated patients (log rank: p = 0.047, hazard ratio = 1.89). Median survival time for patients receiving Provenge increased by 8.4 months (30.7 months versus 22.3 months). Thirty months from randomization, the survival rate for Provenge-treated patients was 3.7 times higher than for patients receiving placebo (53% versus 14%, p = 0.001). On a crossover salvage protocol, patients on the placebo arm whose disease progressed received the vaccine for three cycles. Among patients in the placebo arm who received the vaccine as salvage therapy, mean survival time was 23.9 months versus 4.6 months for those who did not receive the salvage therapy.
In a Phase II trial presented at ASCO 2003, 11 patients with nonmetastatic, hormone-responsive CaP and rising PSA (0.4-6.0 ng / mL) after radical prostatectomy or radiation therapy received Provenge and bevacizumab. Provenge was given intravenously on weeks 0, 2, and 4. Bevacizumab (10 mg / kg) was given intravenously on weeks 0, 2, and 4 and every two weeks thereafter until toxicity or progressive disease. The median patient age was 61, the Gleason score ranged from 5 to 8, and median baseline PSA was 1.88 ng / mL. Investigators measured T-cell proliferation and cytokine production in response to PAP and dendritic-cell costimulatory / activation marker expression. Of nine evalu-able patients, only three experienced a reduction in PSA doubling time and one experienced a PSA decline approaching 50%. No patient had objective disease progression.
Thirty-one patients with hormone-refractory CaP were treated with Provenge in a Phase I / II trial. In the Phase I portion, all patients had metastases, the median patient age was 69, the performance status was 0-1, and the median PSA was 41.3 ng / mL. Sixty-six percent of patients had received chemotherapy. In the Phase II portion, the patients did not have metastases. Twelve patients in the Phase I part of the trial received increasing doses of Provenge, and six of them received the maximum dose. Nineteen more patients subsequently received treatment at the maximum dose in the Phase II portion. No treatment-related hematologic, hepatic, or renal toxicity occurred. Fifteen percent of infusions were associated with febrile reactions—two of which were grade 3; the others were grade 1 or 2. Mild myalgias occurred in two patients and mild fatigue in one. Five patients experienced mild urinary complaints. All patients developed immune responses to the recombinant fusion protein used to prepare Provenge and 38% developed immune responses to PAP. Three patients experienced a greater than 50% reduction in PSA and three experienced PSA reductions of 25-49%. Time to disease progression correlated with the development of an immune response to PAP (34 weeks median time to progression for immune responders versus 13 weeks for nonresponders) and with the dose of dendritic cells received (median 31.7 weeks for patients receiving more than 100 x 106 cells versus 12.1 weeks for patients receiving fewer cells). Seven Phase II patients had not progressed by the end of one year of follow-up. Investigators noted that the correlation of immune response to PAP with time to progression should be treated with caution: disease burden or aggressiveness of disease may have been confounding factors.
Provenge’s limitations include the need for intravenous administration, a requirement that is likely to restrict its administration to oncologists, and the fact that the vaccine must be prepared for each individual over a 48-hour period, a requirement that will make its manufacture expensive.