ORLANDOA novel therapeutic vaccine therapy (see illustration) increased survival in patients with advanced prostate cancer during a phase III clinical trial, lead investigator Eric J. Small, MD, reported in an oral presentation and a media briefing at the 2005 Multidisciplinary Prostate Cancer Symposium (abstract 264). "This immunotherapy has the potential to provide a new treatment option for a group of patients with precious few options," said Dr. Small, professor of medicine and urology, University of California, San Francisco, School of Medicine. "On a broader scale, this is the first study ever to show a survival advantage for the immune approach in prostate cancer."
Dr. Small and his colleagues randomized 127 men with asymptomatic metastatic androgen-independent prostate cancer 2:1 to two groups: 82 patients received APC8015 (Provenge, developed by Dendreon Corp., Seattle, which sponsored the trial), and 45 controls were given a placebo.
Provenge utilizes a recombinant form of prostatic acid phosphatase (PAP) and Dendreon’s Antigen Delivery Cassette technology. The researchers collected antigen-presenting cells from patients in the treatment arm. The cells were enriched to increase the number of antigen-presenting cells and activated by culturing with a fusion protein composed of PAP and the targeting molecule GM-CSF. Each man received his individualized vaccine intravenously at weeks 0, 2, and 4.
"We basically saw no significant side effects," Dr. Small said at the media briefing. "Some people have flu-like symptomsfever, chills, and muscle aches that go away with Tylenol and last a day or two. Not one patient stopped therapy because of side effects."
The primary endpoint of the study was time to objective disease progression, either the development of new pain or a new lesion found during CT or bone scanning. In both cohorts, a large number of men progressed within the first 3 months. After progression, patients on placebo were offered the vaccine. The trial showed trends toward later median time to progression in men in the treatment arm, but it was not statistically significant (P = .06).
"The immune responses take 2 to 3 months to kick in," Dr. Small said. "We learned that time to progression might not be the best endpoint to use in therapies like APC8015, because the biologic effect takes a little longer."
Dr. Small also measured T-cell immune response against PAP in a subset of patients at week 8 and compared it to baseline. The median stimulation index ratio in the treatment arm was 16.9, compared with 1.99 in the control arm, approximately eightfold higher. "These data show us we have a biologic effect, in addition to a survival benefit," Dr. Small said. "What we can’t tell is if there is a direct correlation between those two. That analysis is under way now."
The researchers continued to follow the study participants for 36 months to assess for survival in the intent-to-treat population: 34% of men receiving the vaccine were alive at the end of the study vs 11% in the control arm (P = .0046). Median survival in the treatment arm was 25.9 months, compared with 21.4 months in the placebo group, a 4.5-month benefit (hazard ratio 1.7; P = .01). "For these patients, it’s an important increment," Dr. Small said. "There is a threefold increase in survival at 36 months."
Dr. Small indicated that additional studies are under way to confirm the results and to expand the indications for the vaccine to patients with earlier-stage disease, possibly as an adjuvant therapy.
"This is potentially a very important study, if in fact it is true, because it is the first demonstration in any solid tumor that a vaccine can alter survival," said Philip Kantoff, MD, director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute. "It’s the culmination of a principle that has been around for decades: that you can alter the immune system in a way that has a salutary effect in regards to cancer."
Small Sample Size
Dr. Kantoff called the effect quite dramatic, and thought that further research administering the vaccine to men with less-advanced disease and lower tumor volume might result in a greater benefit. However, he cautioned that the small sample size of the current study could have resulted in an aberration of statistics. Dr. Small acknowledged the limitation of the study size but said the two groups were carefully matched for known prognostic factors.
A second, similar phase III trial is under way at various cancer centers around the country and is expected to report results by the end of the year. Once these findings are in, Dendreon expects to submit the data to the US Food and Drug Administration.
"For the field as a whole, I think this is really exciting, because it suggests there is something to this kind of approach," Dr. Small said. "These are stunning data. They are robust in terms of long-term follow up, and the statistical significance is solid."