Testimony to FDA About Dendreon's Provenge, March 29, 2007
Christopher Logothetis M. D.
Chair, Genitourinary Medical Oncology
MD Anderson Cancer Center
DR. LOGOTHETIS: My name is
Christopher Logothetis. I am a medical
oncologist at the MD Anderson Cancer Center
with a 30-year interest in GU tumors and
particularly prostate cancer. I'm going to
try to provide context to you on the results
that were presented. So what I will discuss
is challenges to clinical trial design in
prostate cancer patients and the current
clinical practice in prostate cancer as it's
rolled out in our clinics.
There are several limitationsthat are specific to prostate cancer in the
conduct of clinical trials. These include
in the areas of response, progression, and
the use of survival. Responses are
difficult to assess because a bone scan is a
non-specific, sensitive and indirect measure
of the disease. PSA remains controversial
in patients with advanced disease because
it's not tightly correlated with prognosis
or survival. As a consequence, progression
is difficult to measure. Results are
inconsistent, the bone scan issues again
remain as a vexing problem and they fail to
correlate closely with survival, an
important feature that has been confounding
the conduct of trials. This appreciation is
relatively new and as a consequence,
survival has become the most meaningful
measure of efficacy of drugs that are
reliably presented.
Now there are also specific trial
design challenges to the use of a therapy such as sipuleucel-T which has a delayed
effect. Because of the recently appreciated in the two clinical trials presented early observed progression of patients with
prostate cancer, an agent which has a
delayed effect will be greatly influenced by
this. Thus, distant endpoints such as
survival are more reliable measures for this
therapy rather than progression which is a
very imprecise clinical measure.
Now the challenge of prostate cancer as it confronts us in North America today. There are a total of 132,600
patients with androgen-independent prostate
cancer today, 96,000 of these approximately
have metastatic disease and they're almost
evenly split with those patients who have
asymptomatic metastatic androgen-independent
prostate cancer as opposed to those with
metastatic symptomatic androgen-independent
prostate cancer. The treatment options in relationship to the disease state are outlined here, and as I'll note there's a tremendous amount of empiricism that is
applied into their application in the clinic
today. For patients with localized disease whose survival can be expected to be greater than 15 years the option of surveillance for patients who have low-risk disease is one that is often offered, and among those patients in whom[sic] cross the threshold to virulence in their disease, either surgery or radiation therapy is recommended. For those patients who, despite an initial attempt at control of their disease have a later rise in PSA concentration, termed here as serological recurrence, there's even a subset that observation is recommended because of the delayed rise or the rate of rise being so slow which would not indicate an immediate threat. For the patients who
have immediate progression of their disease and that rise is considered to be threatening, hormonal therapy at present
remains the standard. The options for patients with truly advanced disease with lethal potential are limited. For patients
with serological relapse whose survival is estimated to be less than five years surveillance is recommended for some
subsets, motivated different here by the
fact that futility for our therapy is often
an issue and the use of these agents delayed
in order to avoid side effects, and second
line hormonal therapies are often given with
empirical use and often change the course of PSA concentrations, but have no established long-term efficacy.
For patients with visible metastatic disease, the survival will range in the asymptomatic patients from 14 to 22
months depending on the study, and in here again because of feeling that the agents may not have possessed sufficient toxicity -- sufficient efficacy and the toxicity profile 1 doesn't favor routine use, observation is
used and second-line hormonal therapy. And in a subset of patients in whom symptoms are considered to be imminent, chemotherapy will
be used. For patients with metastatic disease, the choices are often between cytotoxic chemotherapy, the only agent that
has an impact on survival, or palliative care in order to manage the anticipated symptoms.
The improved agents are
enumerated here. Only one, docetaxel,
impacts the survival of patients with
metastatic disease. The remaining agents
possess significant but modest effect
directed principally at altering the course
of the symptoms that patients possess. The
impact on survival of docetaxel in the trial
comparing docetaxel to mitoxantrone is
unquestioned, but unfortunately relatively
modest. Seen here you can see in the two categories of patients in question, those both with asymptomatic and symptomatic disease, there is a modest difference in the palliative effect and the prolongation of
survival observed with these agents, leading
to the common practice in the clinic of
delaying the initiation of cytotoxic therapy
till symptoms are either imminent or present
in patients with prostate cancer. This
perhaps accounts for this surprising finding, and that is that in androgen
independent patients with prostate cancer nationally there's relatively little
penetrance of the widespread use of cytotoxic therapy. Only 8 percent of patients at any point in time receive
cytotoxic therapy, and for the patients who
have metastatic symptomatic disease it's
almost 20 percent, for the asymptomatic
patients it's 4 percent.
So what role would sipuleucel-T
be considered for in patients with metastatic prostate cancer? And I believe 1 it fits into the subset of patients in whom there are minimal symptoms, minimal to no
symptoms and in whom hopefully a prolongation of good survival will result in an improved both quality-of-life and length
of survival. The limited efficacy of agents in these places, the absence of therapeutic alternatives for patients that are
imminently threatened is one that would be a great advance for the patients with prostate cancer. Thank you. And our next speaker.
DR. MULÉ: Thank you, Dr. Logothetis.
More like this:
Testimony from Prostate Cancer
Patients and Partners,
FDA, March 29 2007.
Complete Record of FDA Meeting, .pdf
News reports and releases and about Provenge
and other vaccines
