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 =
"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
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
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
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
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."