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Update: "Provenge", Dendreon's
Prostate Cancer Vaccine
(November 2007)
Patients and physicians are interested to know the
current status of FDA licensing approval of Provenge for use in
metastatic HRPC. The short answer: approval has been deferred pending
analysis of mature survival data from three Phase III trials, and a
decision may be delayed possibly until as long as 2010, although an
interim analysis scheduled for 2008 might be the basis of an earlier
approval. Two completed Phase III trials and a third, the 500 man Phase
III IMPACT study (Immunotherapy for Prostate AdenoCarcinoma
Treatment), recently closed to registration, will be the basis
for the evaluation of efficacy.
Dr. Eric Small, a principle investigator in these
studies, presented a complete review of the development of Provenge
(generic name: sipuleucel-T) and a summary of the trial findings in
Expert Opin Biol Ther (2007)7(8).
In brief, the preparation of Provenge
begins with an ex-vivo incubation of a patient's mononuclear cells with
a fusion molecule combining the prostate membrane antigen PAP (prostatic
acid phosphatase) with GM-CSF (granulocyte-macrophage colony stimulating
factor). GM-CSF targets this fusion product to developing dendritic
cells, which mature from mononuclear precursors during the 40 hours of
incubation. This preparation of sensitized dendritic cells (Provenge)
is administered intravenously to the patient where they home
to lymph nodes, take up residence, and proceed to educate the patient's
T lymphocytes to recognize and destroy the prostate cells bearing the
PAP target.
Initially seven small ( ~20 or so patients each ) Phase I
and II studies were carried out in prostate cancer patients, three
involving men with hormone-sensitive PC showing serologic progression,
and four in men with metastatic hormone refractory disease. These trials
established that Provenge was capable of eliciting the desired
T-Cell immunologic response in 100% of the subjects in three trials.
Important declines in PSA values were seen in a substantial number of
patients. The safety of Provenge was established; and side effect
were well-tolerated - essentially infusion reactions such as rigors,
pyrexis, tremors and feeling cold.
Encouraged by these early findings, Dendreon sponsored
and completed two Phase III randomized, placebo controlled, trials (D
9901 and D 9902), comprised of men with hormone-insensitive,
asymptomatic metastatic disease - a total of 147 treated with
Provenge compared to 78 placebo controls. The primary end-point for
these trials was TTP (Time To disease Progression,
defined as objective progression or the development of pain). In one of
the studies there was a nonsignificant improvement in TTP for treated
men, 11.7 weeks vs. 10 weeks for controls. Survival was not a designated
study end-point. However, at 3 years the survival for the treatment
group was 34% vs. 11% for the control cohort; and the median overall
survival comparison was 25.9 months vs. 21.4 months, respectively. These
median survival data were among the materials presented to the FDA for
the combination of the two studies: 23.2 months for Provenge
treated patients vs 18.9 months for controls; and the median survival at
36 months was 33% vs. 15%, respectively.
The lack of sufficient mature data establishing a
statistically supported survival benefit for Provenge was the
basis for the FDA withholding its approval. When the FDA conducts its
future review it will have more mature survival data from the first two
studies, and additionally, data from the now-closed IMPACT trial.
A study of perhaps greater relevance to treatment options
in the management of prostate cancer is the now closed P-11 study, in
which 175 men with minimal serologic progression after primary therapy
were randomized to Provenge vs control in a 2.1 ratio. Since
there is a general consensus that an effective prostate cancer vaccine
would most likely be optimally applied in a setting of low tumor burden,
P-11, if positive, would hold great promise. It could nicely be
introduced into a niche in the early progression of prostate cancer
where hormone intervention can be judiciously withheld.
If the FDA approves
Provenge for clinical use, a unique and important non-toxic
treatment will have been added to our armamentarium.
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