UNITED STATES OF AMERICA

FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

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ONCOLOGIC DRUGS ADVISORY COMMITTEE

73^RD^ MEETING

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WEDNESDAY,

DECEMBER 18, 2002

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The above-entitled meeting was convened in the Versailles Room of the
Holiday Inn Bethesda, 8170 Wisconsin Avenue, Bethesda, Maryland, at 8:00
a.m., Donna Przepiorka, Chair, presiding.

[MEMBERS PRESENT]{.underline}:

DONNA PRZEPIORKA, M.D., Ph.D. Chair

DOUGLAS W. BLAYNEY, M.D.

OTIS W. BRAWLEY, M.D.

JOHN T. CARPENTER, JR., M.D.

BRUCE D. CHESON, M.D.

STEPHEN L. GEORGE, Ph.D.

DAVID P. KELSEN, M.D.

SILVANA MARTINO, D.O.

JODY L. PERLUSI, F.N.P., Ph.D. Consumer Representative

BRUCE G. REDMAN, D.O.

GREGORY H. REDMAN, M.D.

ALSO PRESENT

KAREN M. TEMPLETON-SOMERS, Ph.D. Executive Secretary

GEORGE BENSON, M.D. FDA

SCOTT MONROE, M.D. FDA

DANIEL SHAMES, M.D. FDA

DONNA J. GRIEBEL, M.D. FDA

MARK P. SCHOENBERG, M.D. Consultant

PHILLIP M. HANNO, M.D. Consultant

PETER C. ALBERTSEN, M.D. Consultant

GEORGE H. OHYE Industry

Representative

JAMES ANDERSON Patient

Representative

ALEXANDER KRIST, M.D. Consultant

A G E N D A

Opening Remarks:

Donna Przepiorka, M.D., Ph.D., Chair, ODAC 5

Introduction of Committee 5

Conflict of Interest Statement:

Karen M. Templeton-Somers, Ph.D., Executive

Secretary, ODAC 7

Open Public Hearing 9

Mr. Robert Samuels, Chairman

Florida Prostate Cancer Network 9

Mr. Anthony Caputi

American Foundation for Urologic Disease 12

Mr. Jan Marfyak

Pennsylvania Prostate Cancer Coalition 17

Merel Grey Nissenberg, Esq.

California Prostate Cancer Coalition 20

Sponsor Presentation

Introduction and Regulatory History

Gerard T. Kennealey, M.D. 25

Need for Casodex in Early Prostate Cancer

Howard I. Scher, M.D.

Memorial Sloan-Kettering Cancer Center 34

EPC Trial Program: Efficacy and Safety

William A. See, M.D.

Medical College of Wisconsin 42

Relevance to Clinical Practice

Mark S. Soloway, M.D.

University of Miami School of Medicine 66

Summary and Conclusions

Gerard T. Kennealey, M.D. 80

Questions from the Committee 90

FDA Presentation

Background and Review Issues

Daniel Shames, M.D.

Director, Division of Reproductive and Urologic

Drug Products, FDA 144

Medical Review Findings

Scott Monroe, M.D.

Medical Reviewer, FDA 154

Summary and Introduction of Questions

Daniel Shames, M.D. 178

Questions 182

Open Public Hearing 219

Committee Discussion and Vote 233

Adjournment 273

P R O C E E D I N G S

(8:06 a.m.)

CHAIRPERSON PRZEPIORKA:  My name is Donna Przepiorka, and I wanted to
welcome you to the second day of the Oncology Drugs Advisory Committee
Meeting for a discussion of Casodex. For those of you who are new to
this process, I just wanted to remind everyone that ODAC is not a
policy-making or a decision-making body. We sit as consultants to the
FDA, and the agenda for today will be an introduction from each of the
committee members, a reading of the Conflict of Interest Statement, an
initial open public hearing, presentations by the sponsor, presentations
by the FDA, a second open public hearing, and then a discussion of
questions by this committee regarding specific questions from the FDA
before we adjourn later this afternoon.

And what I want to do is actually then start with the introduction of
the Committee Members, and what we?ll do is just go around. If everyone
will introduce themselves, Mr. Ohye.

MR. OHYE:  George Ohye, Industry Representative.

DR. MARTINO:  Silvana Martino, Medical Oncology.

DR. PELUSI:  Jody Pelusi, Oncology Nurse Practitioner and Consumer Rep.

DR. HANNO:  Phil Hanno, Urologist.

DR. BRAWLEY:  Otis Brawley, Medical Oncologist.

MR. ANDERSON:  Jim Anderson, Patient Rep.

DR. KRIST:  Alex Krist, Family Physician.

CHAIRPERSON PRZEPIORKA:  Donna Przepiorka, Chief Malignant Hematology
and Transplantation, University of Tennessee.

DR. TEMPLETON-SOMERS:  Karen Templeton-Somers, Executive Secretary to
the Committee, FDA.

DR. KELSEN:  David Kelsen, Medical Oncology.

DR. REAMAN:  Gregory Reaman, Pediatric Oncology.

DR. CARPENTER:  John Carpenter, Medical Oncology.

DR. CHESON:  Bruce Cheson, Hematology Oncology.

DR. BLAYNEY:  Doug Blayney, Medical Oncologist.

DR. REDMAN:  Bruce Redman, Medical Oncology, University of Michigan.

DR. BENSON:  George Benson, Medical Officer, FDA.

DR. MONROE:  Scott Monroe, Medical Officer, FDA.

DR. SHAMES:  Dan Shames, Director Reproductive Urologic Drug Products,
FDA.

DR. GRIEBEL:  Donna Griebel, Deputy Director, FDA.

CHAIRPERSON PRZEPIORKA:  Thank you. Next Dr. Templeton-Somers will be
reading the conflict of interest statement.

DR. TEMPLETON-SOMERS:  The following announcement addresses the issue of
conflict of interest with regard to this meeting, and is made a part of
the record to preclude even the appearance of such at the meeting. Based
on the submitted agenda for the meeting and all financial interests
reported by the Committee Participants, it has been determined that all
interests and firms regulated by the Center for Drug Evaluation and
Research which have been reported by the participants present no
potential for an appearance of a conflict of interest at this meeting
with the following exception.

Dr. Sara Taylor is excluded from participating in today?s discussion and
vote concerning Casodex. We would also like to note for the record that
George Ohye is participating in this meeting as an Industry
Representative acting on behalf of regulated industry.

In the event that the discussions involve any other products or firms
not already on the agenda for which an FDA participant has a financial
interest, the participants are aware of the need to exclude themselves
from such involvement, and their exclusion will be noted for the record.
With respect to all other participants, we ask in the interest of
fairness that they address any current or previous financial involvement
with any firm whose products they may wish to comment upon. Thank you.

CHAIRPERSON PRZEPIORKA:  Thank you. It is usually at this point that we
have an open public hearing. Some participants have expressed the
interest to actually hear the information presented by the Sponsor and
FDA before making their comments. We have six individuals who have
registered for the open public hearing, and four would like to speak at
this time rather than wait until after the presentation, so I would call
to the podium Mr. Bob Samuels from the Florida Prostate Cancer Network,
Incorporated. And I would ask that each of the speakers for the open
public hearing also please state your financial conflict of interest, if
any.

MR. SAMUELS:  Thank you very much and good morning. My name is Bob
Samuels, and I would like to thank you for the opportunity to speak to
you today as Chairman of the Florida Prostate Cancer Network, and
actually on behalf of Casodex 150. We are a prostate cancer survival
organization whose mission is to advocate the prevention of prostate
cancer deaths in Florida. I appreciate the opportunity to speak about
one of the most serious health problems facing American men today,
prostate cancer.

As you know, this year more than 180,000 men are expected to be
diagnosed with prostate cancer, and over 30,000 men are expected to die
this year from prostate cancer. Sad to say, prostate cancer has become
almost epidemic among American men. In fact, last year prostate cancer
was the most commonly diagnosed non-skin cancer in this nation.

Unfortunately, there is a segment of our population that pays a
disproportionate price for this disease, and that is in the African
American community. As many of you probably know, African American males
have a 50 percent higher incidence rate, and die at twice the rate of
white males in this nation.

I am an eight-year prostate cancer survivor, and a three-year throat
cancer survivor. And in addition to being Chairman of the Florida
Prostate Cancer Network, I am also Co-Chairman of the Florida Prostate
Cancer Task Force, and I was the Founding Chairman of the National
Prostate Cancer Coalition. I am on the Board of Directors of the Moffitt
Cancer Center, and I served on the NCI?s Prostate Cancer Progress Review
Group. However, in 1992, I retired as Vice President of what is today
J.P. Morgan Chase and moved to Tampa, Florida. And in 1994, I got
diagnosed with prostate cancer. That set me off on a whole new direction
in life, because I will admit that I had very little understanding of
the disease prior to that.

Some of you may recall that earlier this year I testified on behalf of
Casodex 150. Little did I know at that time that I would wind up within
three months of that testimony actually being on Casodex 150. My PSA
began to rise earlier this year, and it got to 9. Needless to say, when
I consulted with my physician about what the next line of defense in my
battle with this disease would be, he prescribed Casodex 150.

Had you seen me at 7:00 this morning, I was putting three little tablets
in my mouth, and I do that every day in order to maintain a quality of
life, and hopefully to stay alive until we can find that silver bullet
that I hope is on the horizon, and thousands of us who battle this
disease every day.

You hear about the statistics, but my friends, I live with the faces and
the voices every day of those men who are looking for some hope. They
need all the weapons that we can come up with to give them hope, and
hopefully keep them alive until we can find that silver bullet, so I
would just urge you in your deliberation today to keep in mind the faces
and the voices that the 30,000 men this year represent, and those who
have already been diagnosed, and those of us who have been fighting.

Eight years I have been living with this disease. There are not a lot of
options left currently in the arsenal of things that are available to
me. This represents another weapon in that arsenal, and I can just once
again please urge you, pass Casodex 150. Thank you.

CHAIRPERSON PRZEPIORKA:  Thank you, Mr. Samuels. Next, Anthony Caputi
from the American Foundation for Urologic Disease.

MR. CAPUTI:  Good morning everyone. My name is Anthony Caputi, and I am
the Manager of Government Relations and Patient Advocacy for the
American Foundation of Urologic Disease. I?m also a prostate cancer
survivor, so I?m wearing two hats here. A couple of things first.

My organization does have a relationship with AstraZeneca, in that
AstraZeneca does provide us with unrestricted educational grants for our
educational programs. They also have paid some of my travel expenses
that were incurred in order to review this data on two separate
occasions. And also, I have signed a confidentiality agreement.

I?d like to read a statement that I prepared on behalf of my
organization for Casodex 150. I?m writing to offer the American
Foundation for Urologic Diseases\', AFUD\'s, support of AstraZeneca?s
application for Casodex 150 to be used as an adjuvant therapy of
curative intent for patients with locally advanced, non-metastatic
prostate cancer.

I am the Manager of Government Relations and Patient Advocacy for AFUD,
and have been in this position for 16 months. This change in career
direction began for me shortly after I was treated for prostate cancer
in March of 2000. I was diagnosed at the age of 43 with a PSA of 1.1.
This unexpected mid-life crisis motivated me to utilize my experience as
a very young man diagnosed with prostate cancer in an active way to
eliminate the complexities of the disease, and work towards improved
treatment, and an eventual cure. I, needless to say, have a keen
interest in prostate cancer from both a professional and a personal
standpoint.

I have carefully reviewed the data regarding Casodex 150, and am
satisfied that this therapy has merit as an effective treatment choice
for locally advanced, non-metastatic prostate cancer within the context
of the clinical realities that prostate cancer patients deal with on a
daily basis. Those of us that have been diagnosed with this disease are
very familiar with our PSA readings. This FDA-approved blood test for
the monitoring of progression of prostate cancer is not without
controversy, but the truth is that many men are alerted to their disease
due to an elevated PSA reading. And those of us that have been treated,
continue to monitor our PSA levels for the rest of our lives. This is
the reality that we live with.

In the patient?s world, changes in PSA levels are the clinical
indicators that guide a physician?s treatment and recommendations. As
patients, any treatment that inhibits the progression of PSA,
particularly for those of us who are at high risk for disease
recurrence, is welcome with due consideration of potential side effects.

For the patient, prostate cancer is a complicated and confusing disease.
Some men do very well with treatment, moving on with their lives and
experiencing only transient side effects. A significant number of
patients are not so fortunate, and find that their PSA levels are
increasing at an alarming rate.

At this point during the prostate cancer journey, treatment options are
limited, and side effects from the treatments for advancing disease can
be very distressing to a man?s quality of life. The current standard of
care for advanced non-metastatic disease is administration of an LHRH
analog. The side effects of this drug therapy include hot flashes, loss
of libido and bone loss. For many, this disruption in quality of life is
very distressing.

If Casodex 150 milligrams were approved by the FDA, this would provide
an additional tool for the treatment of high-risk disease. To me, the
data collected during the Casodex 150 trial phase is sufficient to
warrant its approval. For the high risk patient, Casodex 150 appears to
be effective in inhibiting the progression of prostate cancer as defined
by the standard of care in today?s clinical practice; and that is, PSA
monitoring.

The side effect profile offers certain quality of life improvements over
today?s standard therapy, such as reduction of hot flashes, retention of
sexual interest and function, and the preservation of bone mineral
density.

In summation, the AFUD believes that the approval of Casodex 150
milligram for the indications under consideration is a good thing for
patients as an effective agent for inhibiting the progression of PSA.
This drug therapy offers an additional tool for the doctor and patient
to consider when faced with high-risk disease. In addition, the limited
hot flashes, preservation of sexual desire and function, and the
retention of bone mass are desirable for many men who find the side
effects from currently approved treatments very difficult to bear.

I would like to thank the Committee for allowing me the opportunity to
offer comments today, and on behalf of all prostate cancer patients, we
appreciate your thoughtful consideration of this important matter. Thank
you very much.

CHAIRPERSON PRZEPIORKA:  Thank you for your words, Mr. Caputi. Next, Jan
Marfyak from the Pennsylvania Prostate Cancer Coalition.

MR. MARFYAK:  Good morning. This is an awesome group. I didn?t expect to
see so many of you here. As a former state employee of the State of
Wisconsin, running a budget shop and subsequent to that, 23 years with
the Department of Energy, I?ve conducted a number of hearings such as
these over the years. I would point out that normally we allowed our
people a good deal more time to speak than five minutes.

I?m a prostate cancer survivor, and I?m currently Co-Chairman of the
Pennsylvania State Coalition. In addition to that, I am working with the
NPCC, National Prostate Cancer Coalition, in setting up state coalitions
all over the United States. Furthermore, I also sit as an evaluator,
consumer evaluator for the Congressionally mandated program at Fort
Detrick that allocates roughly \$85 million a year to the study of
prostate cancer.

I am here as a supporter of this request by Casodex. They have paid my
way from Gettysburg to come here. I?m going to be very short and to the
point. You?ll have heard all these arguments later on, so I?ll be
succinct in what I have to say. I?m neither a statistician, nor a
pharmacist, and so I?m not equipped to address the numbers or the
science involved in AstraZeneca?s study. But I can address the
proposal?s efficacy from a consumer?s point of view. After all, they are
the beneficiary of whatever you decide.

My feeling has been, in examining the study that has been done here,
that you?re talking basically about promise versus risk. As Tony and as
my friend Bob from Florida have already stated, the consequences of
prostate cancer are enormous, and until you?ve watched people die from
this disease, watched the suffering that goes on, you really don?t have
a full understanding of what?s involved. And anything that alleviates
that, anything that creates a possibility is a welcome piece of
ammunition in our arsenal to fight this disease.

On the other hand, there is a risk, always a risk. And as Tony has
pointed out, there are a lot of liabilities on this. But if the patient
has informed understanding of what?s involved, then this is something
between the doctor and the patient to decide.

In the end, we weigh promise and risk, and if modality does no harm and
there is a modicum of promise with the attendant risks, we view such a
system or an outcome as a useful candidate for treatment. Our question
is simply this, does this promise outrun the risk? We think it does.
Thank you very much for your time and attention.

CHAIRPERSON PRZEPIORKA:  Thank you very much, Mr. Marfyak. I think our
last speaker is Merel Grey Nissenberg from the California Prostate
Cancer Coalition.

MS. NISSENBERG:  Good morning. I?m Merel Grey Nissenberg. I?m an
attorney in medical litigation issues in California, and I?m here today
because my pro bono work is heavily concentrated in cancer and related
issues. I also represent a very large constituency. I am in my fourth
term as President of the California Prostate Cancer Coalition, which is
a network of individuals, healthcare providers, and every support group
for prostate cancer in the state. I am also the Co-Chair for the State
Coalition Advisory Board for the National Prostate Cancer Coalition. I?m
a CARRA member for NCI, and I?m the legal advisor to the Cancer Task
Force in San Diego, so I come here to represent a great deal, a great
number of voices in asking you to recommend approval of Casodex 150 in
the proposed indications.

You should know that AstraZeneca has helped to defray some of my travel
expenses, but I have been privy to the data from AstraZeneca for nearly
two and a half years, and I would not be here today if I did not believe
that this would confer a significant benefit to prostate cancer
patients.

Simply put, prostate cancer patients need every available option for
treatment, plain and simple. Any new treatment or any new indication for
an existing therapy that can be possibly beneficial for these patients
should be encouraged. Since there is no 100 percent effective cure or
treatment for any and all prostate cancers, why not add to the existing
armamentarium of treatment modalities and give these patients a fighting
chance.

While for many men the diagnosis of prostate cancer is clinically
insignificant, for others it portends a future of untold suffering. Even
with early prostate cancer, many men will go on to relapse, develop
significant disease progression, and endure severe symptoms. So the
question is, can Casodex 150 in the proposed indications confer
significant clinical benefit to certain sets of patients? We believe the
answer is yes, we, the patients for whom I speak.

First, one must identify the specific subset of patients who would
benefit. The trials showed that for high-risk patients who have ever
undergone therapy with curative intent, or for those patients who are
also high risk but for medical or personal reasons have chosen watchful
waiting, Casodex 150 daily treatment resulted in an overall 42 percent
reduction in the risk of objective disease progression. A time to
progression benefit was shown, regardless of prior therapy at baseline,
stage of disease, tumor grade or nodal status, and when pre-therapy PSA
was greater than 4 nanograms.

Additionally, all three trials, all three trials showed a significant
reduction in the risk of PSA progression, important because this is a
clinical guidepost to the clinician. In everyday practice, this is
considered a sign of biochemical recurrence, and therapy for recurrence
is initiated at this point.

Second, one must ensure that adequate informed consent is obtained. The
fact that there have been side effects observed should not lead this
Committee to recommend that the new indications not be approved. As long
as a patient is aware of the risks of any side effects and still
proceeds or wants to proceed, that should be a decision that, for him,
the risk outweigh \-- excuse me \-- the benefits outweigh the risks of
the Casodex.

Third, can a benefit for these identified subsets of patients be
demonstrated? Trials 24 and 25 definitely showed benefit, both for
therapy patients who had undergone therapy of curative intent, and as
mono-therapy for those patients in the watchful waiting group. While
Trial 23\'s results were not overwhelming, there are good reasons for
that.

First, in the U.S. there was no watchful waiting group. There is no
reason to think that the watchful waiting patients here would be any
different than those in the rest of the world. Here is the main reason
why we believe the results would be different, and why Trial 23 should
not lead this Committee to vote against Casodex 150.

We believe that the results were immature. Three years was not enough
time for these patients to have benefits that would show up, because the
majority of patients had an overwhelming number of good prognosis
factors at time of diagnosis.

Additionally, the disparity in Gleason Grade should not be considered
paramount, because number one, the Gleason Grade is only one of several
prognostic factors that were shown in this regard. And the Gleason
Grading in the U.S. was done on surgical specimens, not on biopsy
specimens, which leads to an overall higher score.

Second, since most clinicians in the U.S. use PSA progression as a sign
of biochemical recurrence, a lot of patients dropped out of the trial,
or were taken out of the trial to initiate treatment for recurrence.

In conclusion, let me be the magnified voice of the prostate cancer
patients, even those as yet undiagnosed, in urging this Committee to
recommend the approval for the proposed indications for Casodex 150. The
benefits in the trials bestow hope that the ravaging symptoms of
advanced prostate cancer can be forestalled, and perhaps never
experienced. Thank you for your time.

CHAIRPERSON PRZEPIORKA:  Thank you, Ms. Nissenberg, for sharing your
assessment. Is there anyone else here who would like to speak at this
time? In that case, I just want to say from myself and from the
Committee that we are grateful to all these speakers that we heard this
morning for coming and sharing with us your wisdom. Thank you.

I want to move on now to the presentation by the Sponsor on Casodex,
AstraZeneca Pharmaceuticals. Introduction will be given by Dr.
Kennealey.

DR. KENNEALEY:  Good morning, Madam Chair, Members of the FDA Oncologic
Drugs Advisory Committee.

We are here today to present the Casodex Clinical Program in men with
early prostate cancer. This morning we will show the data that will
demonstrate the efficacy of Casodex in three large and distinct
subgroups of men with early prostate cancer and earn your endorsement of
Casodex for these indications.

My name is Gerry Kennealey, and I am Vice President of Oncology Research
at AstraZeneca. I am a medical oncologist, and I have been associated
with the Clinical Development Program for Casodex since 1987, when the
Phase I clinical trials were first initiated in men with advanced
prostate cancer.

We?re here today because AstraZeneca has conducted the largest ever
randomized clinical program in men with prostate cancer. As our data
demonstrates, Casodex 150 milligrams significantly reduced the risk of
objective progression in these men. However, the FDA issued a not
approvable letter in June, because of lingering questions about the
relevance of these data to U.S. patients, so today?s presentation will
answer the questions posed by the FDA in their Briefing Document.

With regard to these questions, we will show you that Casodex offers
important long-term benefits to men with early prostate cancer. We will
show that the men who derive benefit from Casodex can be identified
without resorting to global standardization of Gleason scores. We have
identified the men initially treated for curative intent with either
surgery or radiation therapy who will benefit the most from Casodex
therapy, and we will show that the data from non-U.S. patients managed
with watchful waiting can clearly be applied to U.S. men with prostate
cancer. These data will demonstrate that Casodex 150 milligrams deserves
to be approved.

Over the next hour or so we will present these data. Dr. Howard Scher is
Chief of Genitourinary Oncology at Memorial Sloan-Kettering Cancer
Center. Howard will discuss the need for new therapies, such as Casodex,
in the treatment of early prostate cancer.

Dr. William See is Professor and Chairman of Urology at the Medical
College of Wisconsin. He will concentrate his presentation of efficacy
on the three subgroups of men for whom we are seeking your endorsement.
Dr. See is a principal investigator in Trial 23, the North American
Trial.

Dr. Mark Soloway is Professor and Chairman of Urology at the University
of Miami, and Mark will then review the safety data and the relevance of
Casodex to clinical practice in the United States.

And finally, I will return to the podium together with my colleague, Dr.
George Blackledge and draw some conclusions from these data and resolve
the questions posed by the FDA in their Briefing Document.

We have several external investigators with us today who will be able to
help answer your questions. They are Dr. John Anderson, an investigator
in Trial 24; Dr. Peter Iverson, who is the Principal Investigator in
Trial 25; and Dr. David Paulson, who is Professor and Chairman of
Urology at Duke University. In addition, there are a number of senior
clinicians and scientists from AstraZeneca who will be able to address
these questions as well.

Now I will begin with a brief clinical and regulatory overview of
Casodex 150 milligrams in the treatment of early prostate cancer.
Casodex was first approved in 1995 at the 50 milligram dose for the
treatment of metastatic prostate cancer in combination with an LHRH
analogue. In the seven years since Casodex has been on the market in the
United States, and in 80 other countries, we have accumulated one
million patient-years of experience, which means a very comprehensive
safety profile.

Casodex is orally bioavailable and has a half-life of approximately one
week, and this permits convenient, once-daily oral dosing. Casodex does
not lower testosterone. Therefore, when used as monotherapy, Casodex may
avoid some of the side effects associated with castration, such as hot
flashes, loss of bone mineral density, decrease in sexual interest and
sexual function, and the debilitating weariness referred to as asthenia.
This slide shows the rationale and design for the Casodex program.

Casodex demonstrated both single agent activity and activity in
combination therapy in men with advanced prostate cancer. Investigators
therefore followed the breast cancer paradigm with Nolvadex, which was
shown to reduce the risk of disease progression by 36 percent, when
compared to placebo in the B-14 Trial. They decided to look at the
potential impact of Casodex in men with earlier prostate cancer.

As the endpoint of time to objective progression has been accepted as
valid by the FDA for approval in trials in hormonally sensitive cancers,
the Casodex program was powered and prospectively designed to show a
benefit at this endpoint.

This slide from your Briefing Document shows the extensive interactions
that have taken place with the FDA over the last seven years, beginning
with the agreement on the endpoint of Time to Progression in 1995.

The FDA in their Briefing Document refers to this as the sponsor?s
endpoint. It?s not. It is a standard endpoint. It?s commonly used in
clinical trials. It was agreed with the Agency in 1995, and it was the
endpoint upon which we decided to embark upon this very large clinical
trial program. The FDA\'s retrospective endpoint of time to bone scan
progression was requested by the Agency in 1995, following the close of
recruitment to this 8,000 patient study.

The actual objective of the program, as agreed in 1995, was to determine
the benefit of adding Casodex 150 milligrams to standard care for
patients with early stage prostate cancer. Approval was to be based on
Time to Progression, which was acceptable to the FDA if seen in more
than one trial. Survival was also an endpoint of this trial, and the FDA
acknowledged that survival data would be immature at the time of
submission.

To satisfy FDA requirements, AstraZeneca undertook three complementary
trials, prospectively designed for a combined analysis and stratified
geographically, as quality data from throughout the world are acceptable
to the Agency as the basis for approval.

In establishing the Casodex 150 milligram Prostate Cancer Program,
AstraZeneca consulted with prostate cancer experts throughout the world.
The Casodex program is briefly outlined on this slide, and Drs. See and
Soloway will be reviewing the program in much greater detail. However,
it?s important to note the following points. A total of 8,113 men with
localized or locally advanced prostate cancer, were recruited in less
than three years \-- it?s a monumental achievement \-- from 353 centers,
in 23 countries. This represents the largest clinical trial program ever
conducted in this disease.

The next two slides cover some very important definitions for this trial
program. Localized disease means that the cancer is confined to the
prostate gland ? that is T1 or T2 disease, and locally advanced disease
is defined as disease that has penetrated the capsule, and is designated
T3 or T4 disease.

Other important factors as defined by the recent literature that would
define patients at high risk for progression include high PSA at
diagnosis, having a detectable PSA following primary therapy, or a
higher biological aggressiveness as measured by a Gleason sum of 7 to
10.

Adjuvant therapy refers to therapy administered after curative intent in
the absence of known, macroscopic, residual disease, and immediate
therapy refers to the use of a drug, such as Casodex, the only
therapeutic intervention for prostate cancer.

The actual indications that we are seeking are outlined on these two
slides. Casodex is indicated as adjuvant therapy to surgery or radiation
therapy in patients with locally advanced prostate cancer who are at
high risk for disease recurrence. And Casodex 150 milligrams is
indicated as immediate treatment of localized, non-metastatic prostate
cancer in patients for whom therapy of curative intent is not indicated.

To try and put it simply, this slide shows the patient subgroups we
evaluated in this trial program. As Dr. Bill See will discuss, we are
seeking an indication for adjuvant treatment following radiation
therapy, adjuvant treatment following radical prostatectomy, and
immediate treatment for men with localized disease. The original
indications for Casodex, which we submitted last year, included locally
advanced disease following watchful waiting.

As described in the briefing document, the FDA has concluded from the
results of Trials 306 and 307 in men with locally advanced and
metastatic disease, that an additional trial would be indicated for this
indication. For this reason, we are not seeking approval for this
indication at this time. These definitions, as they relate to the
subgroups for which we are seeking approval, are in the back of your
binder, and we will be referring to them often throughout this morning.

Throughout our presentation we will be referring to a lot of figures, a
lot of Tables, a lot of data, and Kaplan-Meyer curves. But as you heard
from the Patient Representatives earlier this morning, we cannot lose
sight of the fact that we are talking about men with prostate cancer,
many of whom will develop symptomatic, metastatic disease.

More importantly, a new treatment option now exists. Casodex has the
potential to delay the onset of serious and painful disease-related
complications in men with prostate cancer. And now I?ll turn the podium
over to Dr. Howard Scher, who will describe the unmet need for Casodex
therapy in this disease.

DR. SCHER:  Good morning. I?m Howard Scher, and I?m Chief of the
Genitourinary Oncology Service at Memorial Sloan-Kettering Cancer Center
in New York.

As a medical oncologist, I focus on advancing therapy for patients with
prostate cancer. I?m involved in medical decision making for patients
with localized disease, and the treatment of patients with more advanced
and recurrent disease.

This slide shows what I?m going to discuss this morning. I?m going to
demonstrate that patients with prostate cancer would benefit from
additional treatment options. I will show where, in the spectrum of the
disease, additional options are needed. The spectrum includes newly
diagnosed patients with localized cancers who are at risk for
recurrence, and patients considered for watchful waiting.

Prostate cancer constitutes a real and significant health care problem
in the United States today. One hundred and eighty-nine thousand men
will be diagnosed with the disease this year. Unfortunately, despite
advances in treatment of early disease, many patients will fail therapy
and die, Thirty-thousand men this year alone. These patients often
experience severe and debilitating symptoms from their cancers, which
results in a significant deterioration in the quality of their lives.

Furthermore, patients who fail surgery or radiation suffer significant
morbidity from the castration options that are currently available. This
includes hot flashes, loss of libido and fatigue. So what treatments are
available for men with early prostate cancer in the United States?

There are a number of options. A patient may elect to undergo therapy
with curative intent by radical prostatectomy or radiation therapy. The
choice is determined by considering characteristics of the patient?s
cancer, their age, concomitant morbidities and preference. A patient may
opt, or may be advised to defer treatment and undergo active
surveillance, or watchful waiting, or a patient may elect to undergo
castration-based therapies in the hopes of slowing the progression of
their disease.

This slide summarizes data from six prostate cancer registries. It shows
the frequency of use of the individual primary therapies for early
prostate cancer in the United States. Radical prostatectomy is the most
frequently chosen primary treatment option. Radiation therapy is second,
and hormonal therapy is third. But it is important to note that upwards
of 20 percent of patients choose or are offered the option to defer
therapy, otherwise known as watchful waiting, upon the initial
diagnosis. And an additional 10 percent are treated with hormonal
therapy alone. This group now accounts for approximately 31,000 patients
per year in the United States.

This slide shows the spectrum of prostate cancer from diagnosis to
death. It includes both newly diagnosed and treated patients in a
disease continuum. Patients with clinically localized or clinically
locally advanced disease are treated by surgery or radiation, but are at
risk for disease progression to the state of a rising PSA. The risk of
progression increases with the extent of the disease or T stage, the
level of PSA, and the grade of the tumor.

Once the patient has reached the state of a rising PSA, he is then at
risk for progression to a state of clinical metastasis. At this point,
there is a transition to the more lethal form of prostate cancer because
the morbidity of the disease increases significantly, as does the risk
of death from prostate cancer. The goal of therapy at any point in the
illness is to prevent or delay progression to a more advanced state.

What happens when primary therapy fails? Typically, this is first
manifested as a rising PSA. It is a sign that the cancer has not been
cured. At this point, many men are offered castration. PSA progression
is followed by objective progression on a bone scan or other imaging
study. It is at this point forward that a patient?s quality of life
deteriorates both from the disease and its treatment. It cannot be
cured. The disease itself can cause bone pain, anemia, fatigue and/or
spinal cord compromise. And the castration-based therapies that are
currently available for PSA or objective progression are associated with
unacceptable side effects for many patients. We clearly need better
options to delay disease progression, and an option which we can discuss
with our patients who are at high risk for failure. So who are these
patients?

The level of prostate specific antigen, or PSA in the blood,
approximates the volume of cancer present. The higher the level, the
more advanced the disease. For patients who are treated with radiation
therapy, there is a higher risk of recurrence depending on the baseline
PSA at the time the treatment is initiated.

As shown, patients with a baseline PSA level of 10 or more have a 60 to
70 percent risk of failure in just four years. The goal of treatment for
such a high-risk patient is to avoid or delay disease progression. The
same relationship holds for patients treated by radical surgery. The
risk of progression increases with the level of PSA at the time of
surgery. Unfortunately, many patients are not cured.

Patients who have a higher T stage pathologically assessed at surgery,
are also at higher risk for progression to the state of a rising PSA.
Pathologically localized T1, T2 tumors have a relatively low rate of
progression at 10 years. But as the disease becomes more extensive,
i.e., there is penetration through the capsule or into the seminal
vesicles, the risk of failure exceeds 30 percent at 10 years.

Now let?s focus on the 20 percent of patients who are treated with
watchful waiting. What is the effect of no active treatment, and do
these patients also need additional options? Watchful waiting is a
conscious decision, or a formal recommendation to undergo no immediate
therapy after the diagnosis of prostate cancer is established. These
patients are felt to have competing causes of morbidity or mortality
that exceed the risk of symptoms or death from prostate cancer, or wish
to avoid the complications and side effects of radiation therapy or
surgery.

These data are summarized from a series of databases of United States
patients. The data demonstrate that there is a very consistent profile
of patients who may elect to undergo watchful waiting. As shown, the age
is generally between 70 and 74 years. Baseline PSA is about 6, and
upwards of three-quarters will have PSA levels greater than 4. The
majority have moderate to low-grade disease, Gleason 6 or less. But
despite our best efforts to select patients for watchful waiting, a
significant percentage progress, and they do so within a relatively
short time frame. These patients then require treatment to control the
disease.

As is the case for patients who are treated with radiation therapy and
surgery, the probability of requiring treatment within a 2 year (in
orange), or a 5 year period (in blue), increases with the baseline level
of PSA. These patients might be better served if there was a
better-tolerated option to prevent or delay disease progression, thereby
reducing the need for secondary therapy.

To summarize, the patients in need for additional options are: patients
at high risk for progression after radiation therapy or surgery;
patients with localized disease who are initially offered or who select
watchful waiting. Both groups might be better served by immediate or
adjuvant treatment. So is there a need for additional treatment options?

Prostate cancer represents a significant healthcare challenge. Radiation
therapy and radical surgery is not curative for many men. These patients
are at risk of objective progression, at which point their risk of death
from prostate cancer increases significantly. Preventing or delaying
progression can allow men to avoid the debilitating effects of their
cancers. Castration, the only systemic option available at this time, is
not acceptable to many men because of the side effect profile.

Watchful waiting is appropriate for some patients. It is widely
practiced in the United States. These patients would also benefit from
better- tolerated alternatives to prevent disease progression. So the
answer is yes, there is a need for better options. Thank you.

I would now like to introduce my colleague, Dr. William See, who will
present the Early Prostate Cancer Development Program for Casodex 150
milligrams.

DR. SEE:  Thank you, Dr. Scher. Good morning. My name is William See. I
am Professor and Chief of the Department of Urology at the Medical
College of Wisconsin. I?m speaking to you this morning as one of the
Principal Investigators for Trial 23, the North American Trial.

Now I?ve been asked to address one minor housekeeping item. Dr.
Kennealey alluded to some definitions that are used in this clinical
trial, and we noted that you were searching your binders for those.
Those are located on the outside of the back cover of your binder.

Now I?ve been an investigator in this trial program since its inception.
Many of my personal patients are included in this trial, and I am
intimately familiar with the details of this program, as well as the
results.

What I will demonstrate to you this morning is a very robust effect of
Casodex in reducing the risk of progression in patients with prostate
cancer, an effect which is clearly demonstrated by the data, and these
data strongly support the clinical benefit and use of Casodex for
specific patients in this country with early prostate cancer.

I?ve organized my presentation as follows. First, I will review the
objectives, the design, and the relevance of the EPC program. I will
then demonstrate the efficacy results of the Casodex 150 milligram dose
program, and I will place special emphasis upon those patient
populations who see greatest benefit from Casodex in the EPC trial
program. Specifically, patients at high risk for disease progression
managed in either the adjuvant or the immediate therapy setting. And
finally, I will summarize the data analysis of other clinically relevant
endpoints.

The Casodex 150 milligram trial program was designed to answer a
straightforward question. The program was designed to determine the
clinical benefit of Casodex at the 150 milligram dose, administered as
therapy in addition to standard of care for patients with non-metastatic
prostate cancer.

Patients participating in this program constituted two principal groups.
Those patients treated with curative intent with either radiation or
surgery, or those patients being managed by watchful waiting, in which
the physician or the patient did not consider curative therapy to be a
preferred option.

Our primary hypothesis was that Casodex would delay progression and
improve survival relative to placebo in patients with non-metastatic
prostate cancer, irrespective of their primary treatment modality.

The program consisted of three clinical trials, which were all
randomized, prospective, double masked, and placebo controlled. The
statistical considerations for the trial program are shown on this
slide.

It was estimated that 7,500 patients would be required to detect a 15
percent reduction in the rate of progression at a minimum follow-up of
two years. And importantly, the plan for a combined stratified analysis
was prospectively defined in the protocols, and is justified on the
basis that the individual trial programs were similarly designed and
used identical primary, as well as secondary outcome endpoints.

As I?ve mentioned, the trial program consisted of three different
clinical trial protocols. And as you heard, these were conducted around
the world. By design, these trials were designed to capture patients
constituting the entire spectrum, if you will, of non-metastatic
prostate cancer. While the overall design of each trial program was
fundamentally similar, differences in eligibility criteria and prior
treatment across the three trial programs were intended to capture the
spectrum of early prostate cancer patients.

Trial 23 shown here was carried out in North America, predominantly in
the United States. Patients in this trial treated with either radiation
or radical prostatectomy were randomized to receive either two years of
adjuvant therapy with Casodex at the 150 milligram dose, or placebo.
Across the disease continuum, Trial 23 was designed to capture patients
with earlier stage disease at a relatively low probability for disease
progression.

Consequently, patients at high probability for disease progression were
specifically excluded from this trial. These included node-positive
patients, or patients with a pre-treatment PSA greater than 20, if their
nodal status was not previously pathologically defined. And in order to
allow this to be a truly adjuvant trial, patients undergoing watchful
waiting were not eligible for inclusion.

Now Trial 24 was carried out principally in Europe, and included
patients at higher probability for disease progression. Included in this
trial were node-positive patients, and those undergoing watchful waiting
as their primary treatment modality. Patients in this study in the
adjuvant setting received treatment for a duration of five years,
whereas those on watchful waiting continued until the time of disease
progression. And finally, Trial 24, carried out in Scandinavia
constituted the other end of the disease continuum, and constituted
those patients at highest probability for disease relapse.

To that end, patients at low probability in this trial were specifically
excluded. And so, if you had a prostatectomy and your PSA was
non-detectible, or your margins were negative, and consequently were at
low risk, you were not eligible for this trial program. Patients in
Trial 25 received therapy until the time of disease progression.

There were two primary efficacy endpoints for this trial program. These
were objective progression, which did not include biochemical relapse,
and survival. Objective progression in this program was designed as
disease progression confirmed by bone scan or other imaging technique,
biopsy-proven local progression or death from any cause. In a specific
effort to avoid any bias related to treatment effect from the active
agent, all patients were required to have bone scans at two year
intervals.

The second primary endpoint of this trial program was survival. I will
tell you that given we only have three years of follow-up in this trial
program, survival and prostate cancer in this trial is immature.
Consequently, I?m going to be focusing on the outcome data for the
primary endpoint of objective disease progression.

Now there were secondary endpoints shown here. Time to PSA progression,
as we?ve heard from some of the initial speakers, is a disease-relevant
endpoint in this country. In U.S. practice, PSA progression is widely
considered to imply primary treatment failure, and often serves as a
prompt for the initiation or institution of second-line therapies.
Additional endpoints included time to treatment failure, and finally,
tolerability and safety, which will be addressed by the next speaker,
Dr. Mark Soloway.

The baseline characteristics across the two arms of the overall trial
program were very similar. However, not surprisingly, given the
differences in the eligibility criteria between the three different
clinical trial programs, there were some important differences in
demography across the three trials.

Patients in the North American trial, Trial 23, were the youngest with a
mean age of 64. In addition, they had the highest percentage of a
minority group with 12 percent African American participation. They also
had the highest percentage of treatment with curative intent, with 80
percent having radical prostatectomy.

At the other end of the spectrum, in Trial 25, in the Scandinavian
trial, this was a very homogeneous population, the majority of which
were managed by watchful waiting.

In the overall trial program, approximately two-thirds of patients have
clinically localized disease, and few than 2 percent of patients had
node-positive disease. However, patients in Trial 23 had the highest
percentage of localized disease, 74 percent, and the lowest PSA was also
noted in Trial 23. Here median PSA was 7.1, compared to 17.1 in the
Scandinavian trial. These data suggest that patients at highest risk for
disease progression were, in fact, in the non-U.S. trials.

There are some additional differences between trials in terms of Gleason
scoring. Patients in Trial 23 appear to have a higher percentage of
moderate to poorly differentiated tumors. Now you might justifiably ask
why is this?

You will recall that the majority of patients in Trial 23 had pathologic
definition of their Gleason sum based upon the fact that the majority
had undergone radical prostatectomy, in contrast to Europe and
Scandinavia where the majority of Gleason scores were derived from
biopsy specimens.

There?s also an interesting trend in the United States to upgrade
Gleason sums. This slide is derived from the CaPSURE database of over
7,200 patients, and it illustrates what has happened over the last
decade for the use of Gleason scoring in this country.

Over the past decade, we see a clear trend by pathologists to decrease
the use of the Gleason range from 2 to 4, and to increase the use of
intermediate to high Gleason Scores from 5 to 7. This does not reflect a
change in the fundamental biology of prostate cancer, but rather
reflects a grading shift among American pathologists in Gleason scoring.
This shift, together with the fact that Gleason scores in Trial 23 were
primarily derived from radical prostatectomy specimens explains the
apparent disparity between Gleason score and other clinical indicators
of tumor biology in Trial 23.

I?ve told you the EPC Trial Program represents a broad continuum of the
disease process we refer to as prostate cancer. It includes patients
with relatively low-risk, early disease, such as the subset seen in
Trial 23, as well as patients with higher tumor burdens, such as those
seen in Scandinavia and Europe.

Now patients in Trial 23 represent a subset of the overall trial program
with the lowest tumor burden as evidenced by their clinical stage and
pre-treatment PSA. However, it?s important to recognize that Trial 23 is
not only a subset of this overall clinical trial program, but in fact,
represents a subset of patients with prostate cancer which we encounter
and manage in the United States.

Conversely, Trial 24 and 25 included higher-risk patients. But here
again, these patients are found not only in Europe and Scandinavia, but
represent a significant proportion of the men we manage in this country.
Based upon our knowledge of stage, PSA and primary therapy in those
patients, we can extrapolate the results of the non-U.S. trials to U.S.
clinical practice.

I would now like to share with you the efficacy results from the largest
clinical trial program ever conducted in early prostate cancer. This is
a very important slide. It illustrates the Kaplan-Meier plot for the
prospectively defined primary endpoint of time to progression by the
overall analysis. Remember that this trial was designed to detect a 15
percent reduction in the risk of objective disease progression relative
to the placebo-controlled group.

Patients in this slide are represented by the orange line. What we see
is a 42 percent reduction in the risk of objective disease progression
associated with the use of Casodex. This 42 percent reduction is a
highly statistically significant difference.

This slide illustrates the benefits of Casodex 150 milligrams for
treatment groups according to their primary standard of care. Casodex
reduced the risk for objective disease progression regardless of the
primary standard of care, and this robust clinical benefit was observed
for all groups. So irrespective of whether you were treated with radical
prostatectomy, radiotherapy, or watchful waiting, there was a
statistically significant benefit in favor of Casodex for the reduction
in the risk of objective disease progression.

Now there were some differences across the three trial programs for
these endpoints. The largest difference between the two treatment arms
was observed in Trials 24 and 25. In the North American Trial, Trial 23,
we do not see a difference in time to progression between the two
treatment groups at this point in time.

Remember though, these are the patients at lowest risk for disease
progression, as shown by the low event rate in the placebo arm, and as
evidenced by their pre-treatment PSA and clinical stage. This, however,
does not imply something different about patients with prostate cancer
in this country. In fact, some additional data I will now show you
provides insights into the results of Trial 23.

Let?s shift for a moment from the endpoint of objective disease
progression and look at the effect of Casodex on biochemical failure for
the overall clinical trial program. This Kaplan-Meier plot for PSA
progression, with Casodex shown by the orange line, demonstrates a 59
percent reduction in the risk of PSA progression associated with the use
of Casodex.

Interestingly, and in contrast to what we saw for the endpoint of
objective disease progression, the effect of PSA on PSA progression was
consistent and significant across the three trial programs. When we look
at PSA progression, not only do we see a benefit in Trials 24 and 25,
but now we see a statistically significant clinical benefit for patients
enrolled in the North American Trial, Trial 23. This is an important
observation.

In U.S. practice, PSA progression is regarded as treatment failure, and
frequently triggers the initiation of systemic therapies, specifically
hormonal deprivation. Consequently, as we?ve heard, a treatment that
delays PSA progression is clinically relevant.

Even so, these data beg another important question. Why do we see an
effect in Trial 23 on PSA progression, but not an effect on objective
progression?

I previously indicated to you that patients in North America often
receive hormonal therapy at the first evidence of PSA, that is,
biochemical disease progression. It appears that this was true in Trial
23. In Trial 23, five times as many patients in the placebo arm, as
compared to Trials 24 and 25, had medical castration therapy introduced
in the absence of objective clinical progression. This truly confounds
our ability to interpret the effect of adjuvant hormonal therapy for
objective disease progression in Trial 23. What, in essence, we?ve ended
up with is immediate adjuvant therapy, or very early androgen
deprivation therapy at the first evidence of biochemical progression.

Interestingly, one could argue on that basis that in Trial 23, the most
interpretable and relevant endpoint could be an analysis of time to
first progression, or the addition of second line therapy. This is the
analysis that is shown on this slide.

When we performed this analysis, now not only do we see a statistically
significant effect in Trials 24 and 25, but now we see a statistically
significant reduction in the event rate in Trial 23 in favor of Casodex.

Let?s return now to a discussion of the primary data from the EPC trial
program. You will recall that the FDA has also asked these data to be
presented according to an analysis of bone scan confirmed progression
over the first two years of the trial. These data are shown here.

A highly significant reduction in the risk of developing bony metastasis
was seen in the overall analysis, as well as in Trials 24 and 25. These
data are consistent with, and support the validity of the primary
protocol-defined endpoint of time to objective progression.

Therefore, what we have demonstrated from the data in the primary
prospectively defined analysis is a significant overall effect on the
clinically relevant endpoint of objective disease progression, a
reduction in the risk or progression irrespective of the primary
treatment modality, whether it was radical prostatectomy, radiotherapy,
or watchful waiting. And finally, a statistically significant benefit in
two of the individual trials. But what about Trial 23?

In addition to the fact that patients in this trial constituted the
lowest-risk subset for disease progression, the results of this trial
have been clouded by the early use of second line hormonal therapies at
a time when we do not see benefit for the primary protocol endpoint.

Consequently, although an overall treatment effect has been seen, we
have to ask the question, who benefits most? And in truth, the FDA has
asked the sponsor to specifically define the target patient population
for this treatment strategy.

First, let?s consider the potential patient treatment groups and
treatment settings. This slide demonstrates a matrix of potential
treatment groups based upon either adjuvant or immediate treatment, and
segregated by localized versus locally advanced disease. Let?s start by
looking at the adjuvant treatment setting.

This is the Kaplan-Meier plot for time to objective disease progression
in patients with localized disease receiving adjuvant treatment.
Although there is a trend towards a benefit in favor of Casodex, at this
point in time the number of events are low. And consequently, the
sponsor would not focus on this specific subset of patients. So while
the current data does not support a use of Casodex as adjuvant therapy
in patients with localized disease, I will now show you data strongly
supporting the use of this treatment strategy in patients with locally
advanced disease at high risk for disease recurrence following therapy
with curative intent with either radiation or radical prostatectomy.

Let?s first talk about patients treated primarily with radiation
therapy. Based upon the literature, patients at high risk for failure of
mono-modality radiation therapy include those patients with clinically
staged, locally advanced disease, and an elevated pre-treatment PSA.

Multivariate analysis of the data from the EPC Trial Program confirmed
the relevance of these factors in our trial, and subgroup analysis data
that I?m now going to show you confirm that there was a marked benefit
for Casodex in this specific subset of patients.

This is the Kaplan-Meier progression curve for high risk radiation
therapy patients, defined as having locally advanced disease and a
pre-treatment PSA greater than 4 milligrams. Patients in the Casodex arm
are illustrated in the orange line. Overall in this high-risk group of
patients, the use of Casodex reduced the risk of objective disease
progression by 61 percent. This was a highly statistically significant
benefit in favor of the active agent.

Let?s move on now to patients treated by radical prostatectomy. The
literature suggests that those patients at greatest risk for failure of
surgical mono-therapy are those with locally advanced disease, or a
detectable post-operative PSA, or an elevated pre-operative PSA, or a
Gleason sum greater than 7.

As was the case for the radiation therapy group, multi-variate analysis
of data from our specific trial on radical prostatectomy patients
confirmed the prognostic importance of these variables in our trial. I
will now show you data from this specific subset of patients that
confirms a benefit for Casodex in reducing the risk of objective
progression.

This slide illustrates the Kaplan-Meier time to progression curve in
pathologically staged locally advanced prostate cancer patients at high
risk for disease progression defined as a pre-treatment PSA greater than
10, or a detectable post-prostatectomy PSA, or a Gleason sum greater or
equal to 7. The Casodex patients are shown, once again, in the orange
line. Overall in this high-risk group of patients, Casodex reduced the
risk of objective progression, that clinically relevant endpoint in
patients with this disease, by 47 percent, a highly statistically
significant benefit.

In reviewing the patient populations who are candidates for this
treatment strategy, while again we don?t see an indication for localized
disease, we do see a clear treatment effect for high-risk patients who
are treated initially with curative intent with either radiation or
radical prostatectomy.

Let?s now transition to this other subset of patients. Let?s talk about
the use of Casodex as immediate therapy as an alternative strategy.
These are patients who are not considered candidates for therapy with
curative intent. These are the so-called watchful waiting patients.

Dr. Kennealey, in his presentation, has highlighted some of the
controversies regarding the use of Casodex as immediate therapy in
patients with locally advanced disease. Given these controversies, the
sponsor is not requesting an indication for this subset of patients.
However, what I will now show you are data that strongly support a
treatment benefit for Casodex given as immediate therapy in patients
with locally advanced disease as an alternative to watchful waiting.

This is the Kaplan-Meier curve for time to objective disease progression
for Casodex administered as immediate therapy, rather than watchful
waiting. Casodex patients are shown by the orange line. Overall, Casodex
reduced the risk of objective disease progression in this subset of
patients by 35 percent. This is a clear and highly statistically
significant benefit in a subset of patients for which no standard of
care exists today.

Now these data come from Trials 24 and 25, so the real question is
whether these data can be applied to patients managed by watchful
waiting in this country.

Dr. Scher has shown you some of this data. We believe on the basis of
similarities between patients managed in the EPC trial program and those
being managed by watchful waiting in this country, that there is an
absolute relevance of this strategy for the use of this agent.

The similarities between the EPC patients and patients with watchful
waiting taken from a spectrum of United States databases show that the
groups are comparable in terms of mean age, median PSA, the percentage
of patients with pre-treatment PSAs greater than 4, and the percentage
of patients whose Gleason sum is less than 6.

Based upon the similarities of these important biologic factors, we can
see that patients in the United States managed by watchful waiting have
a similar risk of disease progression compared to those managed in
Europe and Scandinavia, and therefore, they will benefit the same as
patients in those trials.

Prostate cancer is the same the world over. The last time I checked,
prostate cancer doesn?t need a passport. Therefore, as we review the
patient matrix, the EPC trial program provides data strongly supporting
the use of Casodex as immediate therapy in patients with localized
disease who are not candidates for therapy of curative intent. This is
in addition to the data I showed you that strongly demonstrated a
treatment effect in the adjuvant setting for patients with locally
advanced, that is, high-risk, disease following therapy of curative
intent with either radiation or radical prostatectomy.

As I mentioned to you earlier, the survival data are simply immature.
This is the Kaplan-Meier plot of survival for the EPC Trial Program.
Remember, this is a disease, the outcome of which we gauge in terms of
10-year survivals, and today, we are at only a median of 3 years of
follow-up. Interestingly, however, that 3 years of follow-up has been
sufficient to demonstrate a benefit for objective disease progression.

Now there is one thing that?s important to take away from this slide.
You will note that there was no difference between the treatment arms
for non-prostate cancer deaths. This observation supports the
well-established safety profile of this specific agent.

So in summary, the data from the EPC trial program at a median follow-up
of 3 years shows that for the overall trial program, there is a 42
percent reduction in the risk of objective, clinically relevant disease
progression. For specific subsets of patients at high risk and in need
of therapy, we see a 61 percent reduction in the risk of objective
disease progression for high-risk radiation therapy patients, a 47
percent reduction in the risk of objective disease progression in
high-risk patients following radical prostatectomy, and a 35 percent
reduction in the risk of progression in patients who would have
historically be managed by so-called watchful waiting.

I can tell you that with additional follow-up now out to 4.2 years, the
data confirms these same observations, so this trial program has shown a
significant treatment effect for a clinically relevant disease endpoint.
The treatment benefit was observed for subgroups of patients for which
no standard of care currently exists today.

As a clinician, I strongly believe that Casodex 150 milligrams fulfills
an unmet and clinically important need. Thank you very much for your
attention this morning.

I would now like to turn the podium over to my colleague, Dr. Mark
Soloway, who will be presenting data on the safety of Casodex at this
dose. Dr. Soloway will also address the relevance of the dataset we have
presented today to clinical practice in the United States.

DR. SOLOWAY:  Thank you, Bill. That was really an impressive amount of
data, and I know not easy to absorb all of it in a limited period of
time.

By way of introduction, my name as indicated, Mark Soloway. I?m
Professor and Chairman of the Department of Urology at the University of
Miami, in Miami, Florida. In addition to my hat as chair, and many of
you in this room have a lot of administrative responsibilities, I see
about 100 patients a week as a urologic oncologist. Half of them are
prostate cancer patients, and I?ve been involved with the Casodex
program for a number of years, and have been participating in the
Casodex 150 EPC Program, as well.

Today, I want to initially present to you the safety profile related to
Casodex 150. I will then emphasize some of the factors involved with
quality of life, concentrating on sexual function, on bone mineral
density issues that relate to various treatments, particularly forms of
androgen deprivation related to prostate cancer. And then I want to
address the clinical relevance of this dataset to individuals, such as
myself, medical oncologists, radiation oncologists in the United States,
particularly highlighting the favorable benefit-to-risk ratio of this
drug.

We have an extensive database related to Casodex 150 which is, as many
of your know, or some of you know, marketed already in over 50 countries
around the world, and most recently in Canada, as well. So there are, in
fact, over 29,000 patients years of use of Casodex at the 150 milligram
dose. And in essence, adverse events are generally quite mild and
predictable from the pharmacologic action of this compound.

Now in the EPC program which Dr. See went through with you in detail, I
think you?ll note that if we look at adverse events here as indicated on
this slide, clearly the most common are breast pain and gynecomastia.
But also of note, one will see that typical effects that one sees with
the current forms that we have available of surgical or medical
castration, if we look at asthenia, if we look at impotence, if we look
at hot flashes, they?re almost the same between the Casodex 150 and
placebo, so that?s a dramatic difference from what we currently have
available for our patients.

Now the next slide shows withdrawal from therapy on the EPC program. And
again here we?ll note that the most common reason for withdrawal, in
fact, is adverse events from the Casodex 150 group. And in the placebo
group, the most common reason is progression from treatment.

On this slide we see the most common adverse events leading to
withdrawal, and as I said, and expected from the way Casodex works, it
is due to gynecomastia and breast pain. A small number of patients
withdrew due to asthenia or abnormal liver function.

It is important to note that the incidence of severe hepatic toxicity
was very low indeed. And, in fact, abnormal liver function studies when
they recur related to Casodex are usually reversible despite continued
therapy. The few patients who did have severe hepatic toxicity or excuse
me, hepatic abnormalities, elevated LFTs, were in fact related to liver
metastasis from their prostate cancer.

The incidence of adverse events and adverse events leading to death for
patients on Casodex 150 are quite similar, as you see Casodex and
placebo. And the events were of the type to be expected from an older
population, strokes, heart attacks, COPD risk problems, et cetera. So I
think in conclusion, regarding the safety profile of Casodex 150, it is
a favorable profile. That?s how I would look at it.

While there are tolerability issues to be considered, there are no
serious safety issues with this compound, and they are consistent with
the known safety profile of Casodex from the many patients who have gone
on previous trials.

The side effects observed are, in fact, well-characterized, they?re
predictable, they are generally mild to moderate, and consistent, as
I?ve mentioned, with the known pharmacology of this product. The main
tolerability issues clearly are gynecomastia and breast tenderness.

Currently, many urologists, radiation oncologists and medical
oncologists use medical or surgical castration in patients with
non-metastatic prostate cancer. That is a quantum difference than what
we saw 10 or 15 years ago, when most of our patients, in fact, had
metastatic disease, and that?s where we used the androgen deprivation.
In fact, despite limited clinical trial data, the most common use of
LHRH analogs in the U.S. today are in patients with non-metastatic
prostate cancer; that is, the rising PSA.

Surgical or medical castration, as we know, is associated with a list of
adverse effects which significantly alter a patient?s quality of life.
And some of these adverse events are seen here, hot flashes often
requiring, certainly in my practice, additional treatment, erectile
dysfunction or impotence, loss of libido. Important one for men who are
vigorous, who have occupations, attorneys, physicians, accountants, et
cetera, is their cognitive function. And there is now emerging data that
typical forms of androgen deprivation; that is surgical or medical
castration alter this not insignificantly.

And something that I think will become more important over time is that
with increasing use, duration of androgen deprivation, particularly
again referring to the medical or surgical castration that we use, be it
orchiectomy or LHRH analog, there?s a progressive loss of bone mineral
activity, and thus, osteoporosis. And I think in the future, this is
going to be a major problem we?ll have to address.

Well, Casodex 150 is a different type of androgen deprivation. It is a
potent anti-androgen with a once-daily pill, and I think this is
important, one, for compliance having a once a day pill, but also
because it frees the patient?s schedule from having to go to the
physician every three or four months for that injection. It puts them a
little bit more in control. Since testosterone is maintained, there?s a
different side effect profile. And, in fact, sexual function and aspects
of bone mineral density are, in fact, retained with Casodex.

Now really quite forward looking, remember when this trial was designed,
the Scandinavian group decided for patients who had normal erectile
function going onto the trial that they would use a validated
questionnaire, and at regular intervals they would ask the men to fill
out this questionnaire. Now we say oh, that?s a natural, but this is
several years ago when they did this. And this looked at sexual function
and sexual frequency.

And if we look at the data on the next slide, and again, this is one of
the largest data sets asking these questions in men with prostate
cancer, I think you will note that there?s very little difference
between the Casodex 150 and placebo, and this is questions related to
sexual function.

Now again, those of you who are familiar with various forms of androgen
deprivation which lower testosterone, orchiectomy or LHRH analog, there
would be a very dramatic difference here. And the next slide shows in
the questions related to sexual frequency, again not much difference
between Casodex. It?s a little bit lower, but dramatically different
than one would expect if these patients had an LHRH analog, for example.

Next slide. Now there is emerging data, and this is one analysis, of men
who received an orchiectomy, comparing to age-matched patients in the
population, and they looked at the number of osteoporotic related
fractures. And as you can see, as time goes on, those number of
fractures increase on men who have had an orchiectomy. And there are
several publications now that corroborate that this is the case. And
these, of course, add to additional morbidity for these patients when
they occur.

To address this, AstraZeneca performed a prospective randomized study of
103 men who either had Casodex 150 or an LHRH analog, and used the
standard test dual emission x-ray absorption to monitor bone mineral
density at indicated times. And it?s actually pretty dramatic. If you
note that the LHRH analog group in the blue on the bottom, bottom
because their bone mineral density diminished over time. And by week 96,
there is a 5 percent loss. That?s already in week 96, two years. And the
level of minus 5 percent is where you start seeing osteoporotic
fractures.

In contrast, the men who took Casodex 150, they?re above the line and
retained the bone mineral integrity. And as I said, when we?re talking
about men who, if they elect androgen deprivation for rising PSA, they
may be on these ?- they may have orchiectomy or an LHRH analog for many
years. And I think in the future this is going to be a major problem.

Well, as a clinician who practices in the U.S., obviously, like many of
you, there are clinical scenarios for which I would like the opportunity
to discuss, and if I discuss, I would like the opportunity, of course,
to prescribe Casodex 150. Now this would include patients who have
received radiation therapy, who have had a radical prostatectomy, or who
may be electing watchful waiting. And by knowledge, by your knowledge,
by the patient?s knowledge, and patients are pretty sharp these days,
and you heard some of them earlier today, they are at high risk for
recurrence or progression of their disease. And I?m going to give you a
couple of examples from my practice, which I hope will bring this home.

This first gentleman is 68 years old. He had his cancer diagnosed, so
often common scenario. His PSA was elevated. It was 12.3. He had a
biopsy after the digital exam was noted to be abnormal. He was
classified as T3, so it was felt that the tumor was just outside the
prostate, probably into the capsule. Gleason Score on the biopsy 4 plus
3, and he elected to have external beam radiation therapy, 3-D conformal
therapy, which is a very reasonable alternative for him.

Not surprisingly as many of our patients, he was surfing the net and he
pulled up one of the nomograms which are, in fact, patients know them
more than I do at times, and he says, you know, Dr. Soloway, my clinical
recurrence rate is about 50 percent. And he said, \"Gee, I want
additional therapy. I?m not happy with that. But on the other hand, I
don?t want the side effect profile that I?m aware of with an LHRH
analog.\"

Well, based upon this information we heard today from the large, and I
think it?s quite large, EPC Program, we know that Casodex therapy will
reduce his risk of progression by 61 percent. I think given this
information, I, as a treating physician, would like the opportunity to
discuss this approach with him. And then, of course, discuss it. One
would want the opportunity to prescribe Casodex 150. He may or may not
elect to have it, but I think that opportunity, particularly with the
favorable side effect profile of this agent, should be reasonable and
available to the patients.

Now the next case is a more very recent gentleman, 65 years old,
recently treated I should say. His PSA was 8. He had a clinical T2
lesion, and I performed a bilateral pelvic lymph node dissection radical
prostatectomy, and then as we all do, I sat down with him and reviewed
his pathology. And he had a Gleason 7, 4 plus 3, and unfortunately, the
tumor extended into the left seminal vesicle.

Now from my database of over 1,100 radical prostatectomies and
databases, there are some people in the room that have similar
databases, this gentleman has a 50 to 70 percent chance that he will
initially have PSA, and then subsequently clinical recurrence. And as
we?ve heard today from the large Casodex 150 program, the EPC program,
he has a 47 percent less chance that he will progress over time if he
receives Casodex 150. And I think it is very important to provide the
information. The information is out there, and thus, allow the
opportunity, if he chooses, to have that agent.

The next patient is a little bit different scenario, and each case, of
course, is somewhat different. And I think this again highlights some of
the important variables that we have to deal with. This is a 77 year
old, very well known. He wouldn?t probably be known to many of you, talk
show host. And he deals with important personalities every day.

Well, he found out his PSA was 17. He had a biopsy and he has prostate
cancer. Now cognitive function is critical to this guy?s very
livelihood, and what he does every day. And parenthetically, he also has
a relatively young wife. Again, unfortunately, and not without much
discussion, he was said you need an LHRH analog. He was put on this, and
he was devastated.

Most importantly, his cognitive function within a couple of months
really was dramatically altered, and this bothered him tremendously. He
was almost clinically depressed. In his social life, his reaction with
his wife, also was altered. But on the other hand, he was smart enough
to know that he wanted treatment. His PSA was 17, and thus the dilemma.
And think Casodex 150 would be an excellent alternative for this agent,
again because of the possibility to retain some of the functions that
one would not have if his testosterone, as experienced already by this
gentleman, went to very low levels, castrate levels. Next slide.

Therefore, in clinical practice in the United States, Casodex I think is
a good alternative to watchful waiting, providing an option for those
patients who want that option. It is also a treatment option I think for
men with high risk locally advanced prostate cancer who have radiation
therapy, or radical prostatectomy.

From the data that you?ve heard today, and the adverse events safety
profile data, I would conclude that the benefit risk ratio for Casodex
is clearly favorable in patients who are at high risk for recurrence or
progression. And most of us, as oncologists, know who these people are,
and increasingly the patients know who they are. Right now there?s only
one systemic treatment option for them, and that is surgical or medical
castration. And many men simply do not want to tolerate the side effects
related to that, and that?s why they often choose, whether they have
radiation or surgery, much of it is based on the side effect profile.

Indeed, although gynecomastia and breast pain can be an issue in some
patients, there are ongoing approaches to management of this problem.
Casodex, over all, has a very well defined clinical benefit and risks
with proven efficacy, and a well tolerated safety profile. And this has
been demonstrated in the largest prospective randomized trial ever
performed in men with prostate cancer.

I think Casodex 150 does represent an important treatment option for the
patients we treat on a daily basis in the United States, and it fulfills
an unmet need. Thanks for your attention, and we?ll go back to Dr.
Kennealey.

DR. KENNEALEY:  Thank you, Mark.

You?ve seen an awful lot of data today, both efficacy data and safety
data, and I would like just to summarize, show the slide again, because
I think this slide gets to the heart of what we?re here to talk about
today.

Casodex clearly has reduced the risk of disease progression at a median
follow-up of three years. The overall reduction was 42 percent. For the
subgroups for which we are seeking approval, we have shown a 61 percent
reduction in risk in radiotherapy patients, a 47 percent reduction in
risk for radical prostatectomy patients, and a 35 percent reduction in
risk in localized watchful waiting patients.

This benefit persists at a follow-up of 4.2 years, and these data have
led to the approval of Casodex 150 milligrams as an option for men with
early prostate cancer in over 40 countries, including Canada just this
last month.

Dr. Hoberman has recently sent to all of you a statistical addendum
looking at the Early Prostate Cancer Program, and there?s some clear
agreement between AstraZeneca and the FDA on a number of these issues.
And I?ve put these areas of agreement on this slide. And they are,
Casodex 150 milligrams reduces the risk of progression regardless of
primary treatment. Dr. Hoberman has confirmed that patients in Trial 23
are at low risk for progression, and that PSA and stage are important
determinants of outcome. He has also noted that objective progression
may be suppressed in Trial 23 due to U.S. clinical practice. And he also
noted that the central re-read of the bone scans supported the
protocolled primary endpoint.

At this point, I would like to digress briefly into an area for which
there is some difference of opinion between AstraZeneca and the United
States FDA, and that is concerning Trials 306 and 307 that are mentioned
quite extensively in the FDA Briefing Document.

I?m going to ask my colleague, Dr. George Blackledge, who many of you
remember from September. Dr. Blackledge is the Global Vice President of
Oncology, and has been heavily involved in Trials 306 and 307, to give
you some information about these trials.

DR. BLACKLEDGE:  Thank you, Dr. Kennealey.

I think it?s worthwhile putting Trials 306 and 307 into context. If we
look here at the slide based on Dr. Scher?s presentation, we can see the
spectrum of prostate cancer from clinically localized disease right
through to clinical metastases. As is usual in oncology drug
development, we began our development at the more advanced end; namely,
in the presence of metastases, and that?s exactly what Trials 306 and
307 began to do.

In metastatic disease, it?s true that we fell short of our objective,
and we did not demonstrate equivalence with castration with metastatic
disease. We actually had a shortfall which was statistically significant
of 42 days in terms of median survival, so we did not feel that we could
progress with a metastatic claim at that point. However, as you can see,
this trial program also covered clinically locally advanced disease.

And this is the survival curve for Casodex and castration for local
advanced disease. You can see that the two survival curves are basically
indistinguishable. We tested this for non-inferiority, and we did not
quite achieve non-inferiority. We look for a 95 percent confidence limit
for non-inferiority. We only achieved a 91 percent confidence limit for
non-inferiority.

Nonetheless, these data and other data from trials carried out in Italy
and Spain, strongly suggest that in locally advanced disease, there is
no difference between Casodex and any form of surgical or medical
castration. But I would say that the overlap is very small between the
patient population here, and the patient population in the Early
Prostate Cancer Program.

You can see here the differences between the two populations. In Trials
306 and 307, the aim was palliative. In the EPC trial, patients chose
not to undergo therapy of curative intent. Castration was considered a
standard of care. It had to be for the randomization in Trials 306 and
307. There?s no standard of care for the patients entering the Early
Prostate Cancer Program.

You can see dramatic differences in the median PSA, and indeed, in the T
stages, with most of the patients in the Early Prostate Cancer Program
having T1 or T2. And these actually not being allowed in Trials 306 and
307. So the amount of overlap that there is between Trials 306 and 307,
and the Early Prostate Cancer is vanishingly small. And even in Trials
306 and 307, together with the accumulated body of data, there?s a
strong suggestion that there is really no difference between Casodex and
castration in terms of survival outcome. Over to you, Dr. Kennealey.

DR. KENNEALEY:  Thank you, George. And let me now go on to discuss the
questions that the FDA has posed, and they?re in your Briefing Document.
And I have shortened them in order to fit them on the slides.

The first question, in the absence of meaningful survival data or
quality of life benefits, are Trials 24 and 25 sufficiently mature to
conclude that patients treated with Casodex will derive clinically
significant long-term benefit? And the answer to that question is yes.
We have shown the data that Casodex has a clear benefit over placebo
with a median follow-up of three years in the overall protocolled
analysis, in the individual analysis of Trials 24 and 25, and in the FDA
requested analysis.

Additional analysis of these data with now a follow-up of 4.2 years has
confirmed this benefit. A substantial delay in disease progression is
truly a long-term clinical benefit. We can?t lose sight of the fact that
delaying progression to bony metastases is meaningful to men with
prostate cancer, nor lose sight of the fact that patients with
metastatic cancer face a lifetime without prospect of cure.

And the second question, do the lack of valid Gleason Scores allow for
the adequate definition of a patient population that can be extrapolated
from the non-U.S. studies to define groups of U.S. patients who will
benefit from Casodex therapy. Yes, patient clinical benefits from
Casodex can be predicted without standardized Gleason Scores.

In the literature, Gleason Score is a less predictive variable in
prostate cancer, and is not a fully independent variable. PSA and
disease stage are considered to be better indicators of patient outcome.
And the multi-variate analysis that we performed in the Early Prostate
Cancer Program showed that Gleason Score was not independently
predictive of outcome.

And the third question, what population of patients initially treated
with radical prostatectomy or radiation therapy with curative intent in
the United States would benefit from adjuvant treatment with Casodex?
And this is really an approval question.

Based on the literature that has been published since the close of
recruitment in 1998, we have defined the patients who are at highest
risk for recurrence following radiotherapy and radical prostatectomy.
For radiotherapy patients with locally advanced disease, and a
pre-radiation PSA of greater than 4, we have shown a 61 percent
reduction in the risk of progression. For radical prostatectomy patients
with locally advanced disease, and at least one of the following,
detectible post-operative PSA, pre-op PSA greater than 10, or Gleason
Score of 7 to 10, we have shown a 47 percent reduction in the risk of
progression.

These patients, as mentioned by Dr. Soloway, are seen in U.S. practice.
They progress in U.S. practice, and they need new and effective
treatment options. And based on these data, this is the indication we
are seeking. Casodex as adjuvant to primary therapy and men with locally
advanced disease defined according to the recent urologic literature.
And we ask your endorsement for this indication.

And finally, question 4. Has AstraZeneca demonstrated in Trials 24 and
25 that U.S. patients with localized non-metastatic prostate cancer who
are presently managed by watchful waiting would derive sufficient
benefit from Casodex to justify the associated adverse events. This is
actually the second approval question.

The data that we have shown support the benefit of Casodex as immediate
therapy in men with localized prostate cancer. The risk of progression
was reduced by 35 percent. We have demonstrated the relevance to U.S.
practice for nearly 20 percent of patients are currently treated
expectantly. We have shown that these patients are at significant risk
for progression, and that U.S. patients are well represented in Trials
24 and 25.

The longer follow-up data do support these findings, and the benefit of
delaying risk to metastatic disease clearly outweigh the side effect
profile in this patient population. Thus, we are seeking as an
indication Casodex 150 milligrams as immediate treatment of localized
non-metastatic prostate cancer for patients who do not receive therapy
of curative intent, and we ask your endorsement for this indication.

And my final slide, we have established the basis for approval for
Casodex 150 milligrams. We have shown that Casodex delays objective
progression in the patient subgroups for whom we are seeking
endorsement. The patients who will benefit are well characterized in the
presentations you have just heard. Casodex preserves sexual function,
sexual activity and bone mineral density. The safety profile is
favorable for the intended population, and Casodex fulfills an unmet
need, and provides an important treatment option for patients with
prostate cancer. Thank you.

CHAIRPERSON PRZEPIORKA:  Thank you, Dr. Kennealey. And at this time, I?d
like to ask if Dr. Schoenberg could come forward and take his seat,
because I think we want to have the Committee ask the sponsor questions
at this point. And I will actually open that question asking period with
questions for Dr. Kennealey or Dr. See.

Specifically, you have asked for approval for two specific indications,
and the data that I have seen demonstrates significance for these two
indication when data from three trials are pooled together. And in a
data fishing and data mining type of analysis, I always get concerned
that we may lose our reproducibility, or that a negative in one study
will be covered by a positive in another. So your first request is for
immediate treatment of patients with localized disease, watchful
waiting. In Trial 24 and 25, that subgroup in particular are the
endpoints positive in each trial separately?

DR. KENNEALEY:  The question is, are the ends for localized disease in
the watchful waiting patient group positive separately? And I?ll ask Dr.
Charles Morris, who is the Senior Director of Oncology for AstraZeneca
to respond to that question.

DR. MORRIS:  Charles Morris, AstraZeneca. Yes, the treatment effect as
we?ve seen for the localized watchful waiting group overall is
reproduced within Trials 24 and 25, as you can see on this slide, with
the 32 percent reduction in Trial 24, and 39 percent reduction in Trial
25.

CHAIRPERSON PRZEPIORKA:  And in parallel, you?ve asked for approval for
adjuvant treatment for locally advanced disease after radiotherapy or
prostatectomy. And are the endpoints significant in Trials 23, 24 and 25
individually for that subgroup of patients?

DR. KENNEALEY:  Dr. Morris, do you want to come back and address a
similar question with regards to the two other endpoints for which we
are seeking approval?

DR. MORRIS:  Yes. In your initial comment, you made the comment about
fishing expedition. What we actually did, based on the overall treatment
effect from the trial program was try to work with FDA to define the
benefits in patients more clearly. I apologize.

For the high risk patients on radical prostatectomy, what we see on this
particular slide is that the effects are seen within Trials 24 and 25,
but less of an effect is seen in Trial 23. This, as has been discussed
in Dr. See?s presentation, really seems to be consistent with some of
the events which have been going on in terms of U.S. clinical practice,
where the number of patients who received additional therapies at PSA
progression was actually much higher in the United States trial.

For the radiation therapy patients, which should be appearing on the
slide in a moment, there was once again, reproducible effects in both
Trial 24 and Trial 25. There were only a very small number of radiation
therapy patients meeting these criteria within Trial 23.

CHAIRPERSON PRZEPIORKA:  Dr. Martino.

DR. MARTINO:  I have two questions. The first relates to the intended
length of treatment in patients who did not have some evidence of
progression of disease. Do I understand correctly from the slides that
in the American trial, the intended length of treatment was two years,
but in the European trials it was five. Is that correct?

DR. KENNEALEY:  That is correct. Actually, the intended duration of
treatment in all three trials was initially two years. And as the two
year time point approached, the American principal investigators elected
to keep to the two year time frame because this was a true adjuvant
trial. And the investigators for the other two trials where a large
number of patients were watchful waiting, they elected to change the
endpoint.

At that point, we had amassed an enormous safety database, and they felt
comfortable extending the duration of treatment as a result of that
enormous safety database.

DR. MARTINO:  And that may become important, as you know from your work
in breast cancer with Tamoxifen.

DR. KENNEALEY:  That?s correct.

DR. MORRIS:  The length of time is important, so that?s why I wanted
those clarified. The other question that I have is, am I correct that
the withdrawal of patients on Casodex is 27 percent? Is that accurate?

DR. KENNEALEY:  The withdrawal of patients on Casodex is indeed 27
percent. That is accurate.

DR. MORRIS:  Now that, to me, is a striking number. Okay? That means
that nearly a quarter to a third of patients choose to come off because
of a side effect. Do we know ?- so that?s a problem in and of its own,
but the other question that follows that in my mind is, is that number
different in the U.S. versus in the non-U.S. studies? In other words, do
we have more patients in this country who came off because they
perceived toxicity?

DR. KENNEALEY:  Okay. I believe Dr. Tom Morris will come up and answer
this question. Dr. Morris is the Medical Director for AstraZeneca
Oncology in Europe.

DR. MORRIS:  Tom Morris, AstraZeneca.

The large part of that 27 percent withdrawal rate from Casodex is due
just to adverse effect, gynecomastia and breast pain, which account for
16 percent. When you take that out of the equation, there is no
difference between the Casodex response. If we look across the three
trials, we do see some differences in withdrawal rates, that?s true.

The withdrawal rate in Trial 23 is somewhat higher than in Trials 24 and
25, particularly with regard to gynecomastia and breast pain. With
regard to other adverse events, there?s very little difference in
withdrawal rates.

CHAIRPERSON PRZEPIORKA:  Dr. Hanno.

DR. HANNO:  I have a question with regard to the bone scans. Bone scans
are notoriously non-specific, and even in your re-reads, 27 percent of
the ones originally read as positive were thought to be negative, or at
least not positive. So how did you confirm the positive bone scan
findings indicating that these were true metastatic lesions, since so
much of your application is based on the positive bone scans?

DR. KENNEALEY:  I?d like to ask Mr. Kevin Carroll, our Statistician, to
respond to the question concerning bone scans and the bone scan re-read
that we performed.

MR. CARROLL:  Thank you. Kevin Carroll, Statistician. I think it?s
important to point out that the bone scan re-read exercise was designed
to assess whether there was any bias in the local reading of scans. And
in concordance with the review provided by Dr. Hoberman, the re-reads
indeed showed no evidence of any bias in the local reading of bone scans
between Casodex and placebo treated patients. And, therefore, the time
progression endpoint as defined in the trial protocol at the outset, is
fully supported by the re-read results. Thank you.

DR. HANNO:  My question is though, if in reality half ?- there are
studies that show that in cancers where the bone scan turns positive
when it?s been negative, only about 14 percent may be true positives,
and people do MRIs, they do KUBs, they do other studies to see if
there?s a reason for this. Even if it?s the same in both groups, if the
actual number of true positive bone metastatic events is half of what
you have in the study, how would that affect your results?

DR. KENNEALEY:  Let me ask Dr. Charles Morris to respond to that.

DR. MORRIS:  I think we need to point out that the incidence of bone
scans was not purely on with the two year, if you like, screening bone
scan. The majority of the bone scan events that we have seen occurred
when a patient either developed pain, or the patient had a rising PSA,
so around about 80 percent of those events are actually based on a
clinical indication for the bone scan. So no, we did not perform
additional radiographic confirmations, but it did fit into the clinical
scenario that we see within prostate cancer.

CHAIRPERSON PRZEPIORKA:  Dr. Blayney.

DR. BLAYNEY:  I have two questions. One relates to the, if you will, bad
things that happen with androgen deprivation, either chemical or
surgical castration. We saw some reassuring data that your compound does
not lead to osteoporosis. Dr. Soloway, in his vignette, talked about the
cognitive, essentially debilitating cognitive function loss with LHRH
agonist. Do you have any data with Casodex to be reassuring in that
regard?

DR. KENNEALEY:  We have not specifically examined cognitive function
with regard to Casodex.

DR. BLAYNEY:  Secondly, a large measure of your indication hinges on
what you call watchful waiting in Europe. And as a medical oncologist in
this country, we do get a fair amount. I?d like to get some sense,
perhaps from one of your European investigators, what actually happened
during your investigation. Were there patient ?- during your clinical
trial. Were there patients who were prevalent, if you will, or who were
being followed in clinic, and then all of a sudden the next time they
appeared their physician said, \"Oh, we have this potentially new drug.
Would you like to be involved?\" Or was there some triggering event that
said, \"Now is the time for you, sir, to be involved in this clinical
trial.\" Because those are, I think, two different iatrogenic stimuli,
if you will.

DR. KENNEALEY:  I?d like to ask Dr. John Anderson, who is one of the
investigators in the European trial, to respond to the treatment
practices concerning watchful waiting.

DR. BLAYNEY:  And this trial, Dr. Anderson, you were in the European or
in the Scandinavian?

DR. ANDERSON:  John Anderson. I?m a urologist from the U.K. I was
involved in Trial 24. The scenario you described is exactly the case. We
have a number of patients who elect to go on watchful waiting in the
U.K. They are more concerned about the potential morbidity that goes
with radical prostatectomy, or radical radiotherapy, and elect to sit on
a watchful waiting program.

Nonetheless, these men remain concerned, and obviously when they come to
clinic, the first thing we do is check their PSA, and we can?t get away
from the rising PSA story. The patient?s disease may not have changed,
but he starts to see something alter. Along comes a trial where we?re
exploring a new agent, and we offer the patient to be randomized into
this trial to see if it?s going to make a difference for him. I?m a
great believer in sharing that information with patients explaining the
limitations of the treatment, but also illustrating the potential
benefits, and many patients with a rising PSA on a watchful waiting
program were keen to be enrolled in this study.

DR. BLAYNEY:  So I?m given to understand that the stimulus to enroll in
this study was some action perceived on the part of the patient, not a
new trial opening in your or other centers.

DR. ANDERSON:  Not at all. It was a shared concern between clinician and
patient.

DR. KENNEALEY:  Let me ask Dr. Peter Iverson, who was the principal
investigator of the Scandinavian trial to respond to your question, as
well.

DR. IVERSEN:  With regard to your questions about whether some of these
patients were prevalent patients, I can inform you that in the
Scandinavian trial, actually most of them were newly diagnosed patients,
the median time from diagnosis to enrollment in the trial was three
months.

DR. BLAYNEY:  Was three months, you say?

DR. IVERSEN:  Three months.

DR. BLAYNEY:  Thank you.

CHAIRPERSON PRZEPIORKA:  Dr. Kelsen.

DR. KELSEN:  There?s been a considerable discussion about the Gleason
Score, so I have a technical question, and then a question about some of
your conclusion slides. Was there a central pathology review of the
European pathology slides to address the issue of Gleason stage, or was
this determined by the local pathologist?

DR. KENNEALEY:  This was determined by the local pathologist.

DR. KELSEN:  Is there any particular reason that you elected not to have
a central pathology review?

DR. KENNEALEY:  Let me ask Dr. Charles Morris to respond to our reasons
in deciding against central pathology review.

DR. MORRIS:  You remember that the primary intent of the trial was to
demonstrate an effect overall in patients with early prostate cancer,
irrespective of radical prostatectomy, radiation therapy, or watchful
waiting. There was no specific requirement or entry criteria based on
Gleason Sum, nor was there any a priori intent to analyze results in
terms of ?- in relation to Gleason Sum, so we did not see a need
prospectively to define a central pathology review.

DR. KELSEN:  So if I just follow that up, in CC-7, in your conclusion
slide to partly address this, you made the point that Gleason was not an
independent variable, and was not an important part of making a decision
regarding treatment, so I?m curious how on CC-9, one of your requests
for patients who derive greatest benefit is radical prostatectomy
patients who have locally advanced disease and any one of several
criteria. And as I read this, maybe I?m reading it wrong, it?s one or
the other.

DR. KENNEALEY:  One or the other, in addition to having locally advanced
disease.

DR. KELSEN:  Right.

DR. KENNEALEY:  That?s correct.

DR. KELSEN:  And one of those is a Gleason Sum of 7 to 10.

DR. KENNEALEY:  Yes, that?s correct.

DR. KELSEN:  So it?s not an independent variable, but it can be chosen
to choose a patient population.

DR. KENNEALEY:  Absolutely. We clearly believe that a Gleason Score is
important and continues to be used by clinicians and pathologists, but
in our review of the literature, and in a review of our own database, it
came out to be less predictive than tumor stage and PSA.

CHAIRPERSON PRZEPIORKA:  Dr. Brawley.

DR. BRAWLEY:   A couple of questions. First off, if AstraZeneca can
start bringing up CE-37 while I ask both AstraZeneca and the FDA, is
there any drug in LHRH agonist perhaps that is currently approved for
these indications for adjuvant therapy?

DR. KENNEALEY:  You?re asking for CE ?-

DR. BRAWLEY:  37.

DR. KENNEALEY:  37. These are the three indications ?- is that the
slide?

DR. BRAWLEY:  The first question is about the LHRH agonist. Are they
approved for ?- it?s my impression that there is currently not any drug
approved for these indications. AstraZeneca ?-

DR. KENNEALEY:  Dr. Charles Morris will respond to that.

DR. MORRIS:  In the indications we are seeking, there are currently no
specific indications in the adjuvant setting. There is neo-adjuvant
indication for radiation therapy patients, LHRH agonist, combined
androgen blocking.

DR. BRAWLEY:  Okay. One of the things that I frequently worry about is
truth in advertising, and whenever I want to argue something, I usually
use relative risk. And whenever I want to argue against something, I
usually use absolute risk. Let?s look at 42 percent there overall, and
please tell me if I?m wrong. I believe that refers to slide CE-13, and
if we can go to CE-13.

DR. KENNEALEY:  It?s the reduction, the relative reduction in risk.

DR. BRAWLEY:  Yeah. Now the way I read that, and perhaps you
statisticians can correct me, is if we treat 100 men with Casodex for
five years, 4.8 will benefit. Is that correct?

DR. KENNEALEY:  I?ll ask our statistician, Mr. Carroll, to respond to
that. But I?d also preface his remarks by mentioning that this reduction
in relative risk is in line with or actually exceeds the reduction in
relative risk seen with Tamoxifen ?-

DR. BRAWLEY:  But that?s for mortality.

DR. KENNEALEY:  ?- in the breast cancer studies. Both for time to
objective progression and for mortality.

DR. BRAWLEY:  Yeah. But see, my problem ?- I?ll already play my hand. My
problem is, Tamoxifen has been shown to reduce mortality at these rates,
and you?re showing that there?s a reduction in disease recurrence at
these rates. There?s a difference between recurrence and death.

DR. KENNEALEY:  Clearly, reduction in objective progression is important
because it means the delay in development of metastatic disease.

DR. BRAWLEY:  Okay. I?d much rather see you in your insert if you did
this indication, not say there?s a 42 percent reduction, but say that 5
percent of the guys getting this drug benefit.

DR. KENNEALEY:  Let me ask Dr. Scott, Head of Regulatory Affairs, and
one of our statisticians to respond to that.

DR. SCOTT:  Mark Scott, AstraZeneca. You?re correct that the reduction
in risk for Tamoxifen, there was a survival benefit, but the original
approvals for Tamoxifen were based on a reduction risk of time to
progression.

DR. BRAWLEY:  All right. Can we go to CE-26 now? Now there you said
there was a 61 percent reduction. By my calculations that means if you
treat 100 men, 15.6 benefit at five years, or at four years. Excuse me.
Is that correct?

DR. KENNEALEY:  That is correct, but let me ask Dr. Blackledge to
amplify on the data on the slide.

DR. BLACKLEDGE:  George Blackledge, AstraZeneca. I think we have to be
quite careful about making absolute differences, because this is
actually summing the data for the whole population. And actually, you
could have an effect for every single patient, a smaller effect for
every single patient actually making this up, so we cannot talk in terms
of having to treat a hundred patients to benefit 27 or 13, or whatever
it is. You can actually be getting the benefit, as we believe we do in
breast cancer in the adjuvant setting, across the whole population, so I
think it?s probably inadvisable to be talking about treating so many
people to get so much benefit, because you can actually be benefitting
the whole target population to a greater or lesser extent.

DR. BRAWLEY:  Then I?d actually prefer to see median days increase
disease free survival as the way that you present the data. But again,
bear with me again. CE-29, by my way of presenting the data, instead of
a 47 percent decrease in risk, 6 percent of men who were treated with
this drug actually end up benefitting at four years. That?s how I
actually would prefer to think of it, and on CE-33, instead of a 35
percent decrease in risk, I?d prefer to say that 5 percent of men
treated over four years benefit. And I think that by doing my 5 percent
in the percent, I?m actually statistically averaging over the population
where I?m talking to one individual man, very much in the same way you
were talking, Dr. Blackledge. Thank you.

CHAIRPERSON PRZEPIORKA:  Dr. Carpenter.

DR. CARPENTER:  I want to disagree pretty strongly with that
interpretation of the data. These absolute risks are on the order of
magnitude absolute which you?ve seen with Tamoxifen, you get a much more
informative effect of the therapy by looking at a difference in the
medians as you suggested. If you discuss it with patients, you also get
very different reactions, and this has been done both ways.

It?s likely that you get a benefit across most patients, and the ?- if
you analyze the curves the other way, you probably do get a sum of
benefit. If you look at your progression free survival median
differences, which are not presented here but which actually be quite ?-
you couldn?t use medians but you have to cut it perhaps the 75^th^
percentile because it?s early. You?d see very dramatic differences which
have spread through the population. And the vertical difference greatly
under-estimates the population benefit.

DR. BRAWLEY:  Perhaps I didn?t say it clearly. I wish they had presented
the data by progression free. I?m wondering why it wasn?t. And I still
have a very open mind as to whether this should be favorably moved upon
or not, but I wonder one, why not the progression free analysis. And
two, why spend so much time talking about the relative risk and not
talking about absolute?

DR. CARPENTER:  Well, the absolute risk is on the same order of
magnitude as I?ve seen with treatment of node negative pre-menopausal
breast cancer, which this situation has a lot of ?-

DR. BRAWLEY:  For survival, not for recurrence. Correct? Now if this
were survival, if these numbers were in survival, I?d say this is a slam
dunk. This is easy.

DR. CARPENTER:  Yes. It?s too early to present this for survival. In
general, the survival benefit has been in breast cancer about half that.
The absolute differences seen in recurrence fairly consistently across
the board in the overview. We don?t know if that?s what?s going to
happen in this population because there?s not any long experience to
make a judgment on that. But the ?- even the magnitude of reduction in
the lapses on this order of magnitude in young women with node negative
breast cancer.

CHAIRPERSON PRZEPIORKA:  And just to add here, if you want to talk about
the breast cancer patients, many of them will say no to Tamoxifen
adjuvant therapy when they know that the absolute risk is very small,
and the incidence of side effects is larger than their absolute risk of
relapse. And with a 25 percent withdrawal rate because of toxicity from
this drug, I think Dr. Brawley makes a good point. Dr. George.

DR. GEORGE:  I wasn?t going to comment on that, but since Dr. Brawley
brought it up, I?ll mention it. Both are correct ways to look at things.
It is a difference in emphasis. The relative risk is an average over
time in these time to event things, but may translate into a very small
absolute risk at the end of the day. But I have a couple of questions.

One is, I can?t help asking since I haven?t ?- we?ve heard a good
explanation of how these studies differed with respect to the patient
populations. I had a question as to why, not that it might affect the
decision today, but it?s just ?- it?s a question left hanging for me.
Why were the studies designed this way? Why didn?t you try to get more
comparability among the studies, watchful waiting patients from the
U.S., lower risk patients from the other countries. Is there some
explanation for this?

DR. KENNEALEY:  Sure. Let me start by answering the final part of the
question first. The U.S. trial was actually designed as a true adjuvant
study, and therefore, watchful waiting patients were not entered into
the U.S. trial. And the overall objective of the trial program was to
get patients over the entire continuum of prostate cancer, and that?s
why there were different entry criteria over the three trials.

DR. GEORGE:  Yeah, but am I missing something here? Wouldn?t it have
been nice to have ?- at this point to have had watchful waiting patients
from the U.S. on this study to sort of add to the evidence?

DR. KENNEALEY:  It would take one question off the list, certainly. But
we did set it up, indeed, in 1995 as an adjuvant. That was a question
that was thought to be very important for the U.S. investigators.

DR. GEORGE:  All right. I don?t want to beat that. It was just something
bothering me.

Now the other question has to do with something I?m concerned about, is
the follow-up information, the length of follow-up.

DR. KENNEALEY:  Yes.

DR. GEORGE:  One sub-part of that is the ?- you mentioned it was a
meeting of three years, I think, follow-up.

DR. KENNEALEY:  Yes.

DR. GEORGE:  And then you said that everything remains the same at 4.2
years, but have we seen that data, or is that just what you?re saying?

DR. KENNEALEY:  The data ?- the three year median follow-up data was
part of the original submission. The four month safety update was
submitted to the FDA more recently than the submission, and that
included data up to 4.2 years for safety. At the request of regulatory
agencies outside the United States, we?ve looked at that data, and the
efficacy data have not changed.

DR. GEORGE:  And the ?- but we?re just taking your word for it, I mean.

DR. KENNEALEY:  We\'d be happy to show you that data if you wish.

DR. GEORGE:  Okay. And the data presented, if I?m looking at it right,
overall, if you just take all the studies together, about 11 percent of
the patients have progressed, and the primary endpoint is time to
progression. I?m just adding up all the studies. And it?s strikingly
different, of course, by study. In the U.S. only about 5 percent. And
this is over a time frame that I would just guess, although it wasn?t
presented, what the median time to progression, again over all the
studies, would probably be something on the order of 7 years, sort of a
median time. So all those things put together, I mean, this is pretty
early. Even though you?ve got some strong differences in the 24 and 25
study, this is early in this ?-

DR. KENNEALEY:  This slide shows the progression of events over the
entire clinical program at the 4.2 year median follow-up, and we?re now
up to about 17 percent progression rate. Again, the hazard ratio and the
statistical significance is really substantial. At the three year median
follow-up, there were 14 zeroes after the decimal point. There?s a few
less now, but I mean, it?s still very statistically significant. And
despite the fact that there are less than 20 percent progression events,
it?s our belief that these data are unlikely to change.

DR. GEORGE:  And you will ?- you are still following the patients.

DR. KENNEALEY:  All patients continue to be followed for progression and
survival in this trial, but again, the data are so compelling at this
point from a statistical and clinical standpoint, that we believe
they?re unlikely to change.

CHAIRPERSON PRZEPIORKA:  Dr. Shames, did you have something to clarify?

DR. SHAMES:  Yes. WE have now reviewed the 4.2 year data that was not in
the supplement we?re talking about today at all. It was the earlier
data. We actually, just to explain what happened, we offered the sponsor
the option to resubmit this with the later data, and they elected to go
this route instead, so we have not reviewed that data. And actually,
it?s other information I see this morning that we have not had a chance
to review.

DR. KENNEALEY:  Yes. And that is why those data were not in the primary
presentation. The four month safety update, however, has been submitted
to the agency.

CHAIRPERSON PRZEPIORKA:  Dr. Albertsen.

DR. ALBERTSEN:  In Trial 23, you mentioned that the initiation of
anti-androgen therapy has confounded the likelihood that a patient would
reach one of the primary endpoints. Could you tell me exactly how
patients in each arm of Trial 23 were withdrawn because of this
condition, and what criteria were used to have them start on
anti-androgen therapy?

DR. KENNEALEY:  Okay. I?m sorry. I didn?t hear the final portion of your
question. What criteria were used for ?-

DR. ALBERTSEN:  In other words, what made the patient drop out? Was it
patient volunteerism? Was there a criteria they had to have a rise in a
PSA, or was it just the patients who chose to drop out because they
thought their PSA was rising?

DR. KENNEALEY:  So the question is criteria for withdrawal. I have to
apologize. I am directly under the blower so it?s sometimes difficult
for me to hear, so if I ask to repeat the question, that?s why.

DR. ALBERTSEN:  The criteria, and the absolute number of patients in
each arm.

DR. KENNEALEY:  Okay. I?ll ask Dr. Charles Morris to respond to that.

DR. MORRIS:  The number of patients who had additional therapies
introduced within Trial 23 was 10 percent on the ?- or 9.5 percent on
the placebo arm, and 7 percent on the Casodex arm. The information that
we have suggests that that was in response to a rise in their PSA. The
intent of the trial, as you know, was to follow until clinical objective
progression.

DR. ALBERTSEN:  So that?s 9.5 percent of 1,000, are you telling me, of
the 1,645, or ?-

DR. MORRIS:  Yeah. Approximately 1,600 patients. Yes.

DR. ALBERTSEN:  So you?re telling me roughly 164 patients were withdrawn
from the placebo arm, and slightly less from the Casodex arm because of
a potential rise in the PSA, or some other explanation that would
justify additional therapy.

DR. MORRIS:  That?s correct.

DR. ALBERTSEN:  Thank you.

CHAIRPERSON PRZEPIORKA:  Dr. Krist.

DR. KRIST:  One of the things that I?m interested in is the
generalizability of studies 24 and 25 to the U.S. And I?m interested
somewhat from the other end. I?m a family physician, and we?re part of a
practice-based research network. And within our group, most of our 50 to
70 year old patients, about 70 percent of them opt to get screened for
prostate cancer.

DR. KENNEALEY:  Sure.

DR. KRIST:  And when looking at the characteristics of the patients with
prostate cancer in Trial 24 and 25 versus 23, 24 and 25 look more
advanced. I?m interested in what some of the screening and diagnosis
practices are in the countries for 24 and 25, and how that differs from
the U.S. And then what component of how ?- what?s been presented here is
that Trial 23 was designed to look at earlier prostate cancer, but I?m
interested in what component of Trial 23 showing earlier prostate cancer
is more a reflection of different practices in different countries.

DR. KENNEALEY:  Let me start by asking Dr. Anderson to respond to
screening practices in the United Kingdom.

DR. ANDERSON:  Thank you very much. There are clearly Transatlantic
differences in terms of early detection for prostate cancer. Whilst
there are well-established recommendations for screening in the U.S.A.
from the American Cancer Society, I understand, the American Urological
Association, in the U.K. that is not the case. It was only very, very
recently that the National Cancer Plan was instituted. It?s now advised
that patients over the age of 50 can ask their family practitioner to
have their PSA checked. The family practitioner is instructed not to
raise the subject with the patient if he doesn?t.

DR. KENNEALEY:  Dr. Iversen, do you want to expand on what happens in
Scandinavia?

DR. IVERSEN:  Yeah. With regard to the part of your question addressing
whether there?s a difference in the way the disease appears across the
Atlantic, I would say that there?s absolutely no evidence of a
Transatlantic difference in tumor biology. An aggressive PSA-based
detection strategy in the U.S., combined with a long natural history of
the disease has introduced a lead time with more small tumors being
detected in this country. However, the more than 30,000 American
patients dying from the disease, and the more patients suffering from
the morbidity, pass through exactly the same stages and phases of the
disease as European patients do. And it is my belief that these
patients, as their European counterparts needs and deserves all the best
treatment options possible.

DR. KENNEALEY:  Thank you. Does that answer your question?

DR. KRIST:  Well, it does. And certainly there is a component of a lead
time bias. There?s also probably a component though of a prognostic bias
if you?re having higher screening than that.

DR. IVERSEN:  Yes.

DR. KRIST:  You?re going to find more clinically insignificant cancers.
Once again, I?m interested some if the difference in the tumor
characteristics between 24 and 25 versus 23, was more relation to the
inclusion/exclusion criteria.

DR. KENNEALEY:  Okay. Sure. I?m going to ask Dr. See to come up to the
podium in just a moment. I think what we need to explain more fully is
the difference in the patient population who are candidates for Trial
23, and the totality of patients with prostate cancer who are treated
surgically or with radiation therapy in the United States. It?s actually
a bigger group, and that matches 24 and 25 quite well. Let me ask Dr.
See to expand on his practice.

DR. SEE:  I think that the differences that we?ve observed in the risk
profile, if you will, across the overall clinical trial program are
driven by enrollment criteria. But in fact, those enrollment criteria
were intended to capitalize upon differences, if you will, that existed
in 1995 across the different nations participating in this clinical
trial program.

CHAIRPERSON PRZEPIORKA:  Dr. Martino.

DR. MARTINO:  In the three studies, was there a frequency at which the
PSA was to be measured, and was that frequency constant throughout the
three trials? Question number one. And if, in fact, they were measured,
was there some behavior that was recommended in the protocols as to what
was to be done when the PSA would rise?

DR. SEE:  Okay. The PSA was measured in all three trials every three
months, and we looked at the differences among ?- we looked at each of
the three trials to see if there was a difference in frequency that
might create some bias, and there was neither a difference in frequency
across the trials, or between the arms in the trial. And there was no
recommendation from the protocol as to what action to take upon the
finding ?- upon the results of the PSA measurement. A PSA rise was not
considered to be ?- for the sake of the protocol was not considered to
be evidence of objective progression, because the FDA did not and does
not recognize that as a valid endpoint.

CHAIRPERSON PRZEPIORKA:  Dr. Redman.

DR. REDMAN:  A follow-up to some of the points. Specifically, Dr. See?s
Slide 18, where there was a difference in the median going to another
line of therapy. And the question I have with that is that since
survival isn?t a question, what was the difference between the Casodex
arms across the trials and on each trial, the Casodex arm going onto an
alternative form of therapy, and the patients who were not on the
placebo going onto an alternative form of therapy. What is the median
difference in that time in months?

DR. KENNEALEY:  So the question you?re asking is the median ?- again, I
apologize.

DR. REDMAN:  The difference in the medians and months between going onto
an alternative therapy on the Casodex arm, going to alternative therapy
on the placebo arm.

DR. KENNEALEY:  Okay. Let me ask Dr. Charles Morris to answer your
question.

DR. MORRIS:  As you see from the slide, the median point in time has not
actually been reached to this point, so the number of the events and the
relative reduction in the risk of the events is demonstrated on this
particular slide.

DR. REDMAN:  But you have no ?- forget the median then. You have no
difference in months? Any idea?

DR. MORRIS:  Well, at this point in time, obviously, we haven?t reached
a median time to event. No.

DR. REDMAN:  Okay. One other follow-up question. For U.S. in watchful
waiting, of the 20 percent or so of patients who go on watchful waiting,
is there a sense of how many of those is a physician?s decision based on
the fact that definitive therapy would not affect survival, and the
patient?s request to do that?

DR. KENNEALEY:  Let me ask Dr. David Paulson to respond to that
question.

DR. PAULSON:  Watchful waiting as it?s practiced clinically among
urologists in the United States is largely a patient-driven initiative.
It?s a patient-driven initiative based upon their own assessment of the
risk of their disease, and also driven by their assessment of a need for
lifestyle maintenance.

DR. KENNEALEY:  I think that?s one of the important reasons why we are
looking to seek an indication in watchful waiting, because there?s a
clear difference in the tolerance of Casodex, versus as Dr. Soloway
mentioned, what is sometimes used in this setting, which is an LHRH
analog.

CHAIRPERSON PRZEPIORKA:  Dr. Schoenberg.

DR. SCHOENBERG:  Yeah, I think this is a follow-up, actually, to a
number of previously asked questions, but I?m curious about the
definition of the population in the studies performed of patients who
would be candidates for watchful waiting, because I think in contrast to
some of the remarks that have been made today, my understanding in U.S.
practice is that watchful waiting is offered to a very specific group of
individuals. It is, although clearly impacted upon by patient
preference, not solely driven by patient decision-making. I wonder if
you could illuminate that for me? I have another smaller question after
that.

DR. KENNEALEY:  Okay. Dr. Paulson I think would be the best to answer
that.

DR. PAULSON:  Clearly, there are patients who have significant competing
risks of death, who would be dissuaded from choosing some form of active
therapy because it would be felt that their lifetime ?- their life
expectancy from competing risks would not be affected. And we usually
use, as you know, the ten year interval before we choose a therapy of
curative intent. Physicians, I think, may very well sway patients one
way or the other, but at least in our practice when we discuss watchful
waiting, it?s largely a patient-driven decision.

DR. SCHOENBERG:  Well, perhaps while Dr. Paulson is still up there, let
me just ask this as the meat of the question. My understanding of
watchful waiting is, it is a therapy designed for patients for whom we
assess the biology of their prostate cancer to not be life threatening.
And that it is not a matter simply of trying to avoid some other
catastrophic outcome from active therapy, but it is a choice for
patients for whom therapy may not be necessary at all. I wonder how that
figures into the indication here.

DR. KENNEALEY:  I guess I?d have to say we would like to be able to do
that, but the practice of medicine has not advanced far enough to say
with certainty what the biology of a prostate cancer, what the
biological progression of the prostate cancer is going to be based on a
single point in time, so it?s not quite as easy to address it that way.
We?re simply not quite smart enough. Let me ask Dr. Paulson to elaborate
on that.

DR. PAULSON:  There certainly have been a series of risk factors
identified which would indicate that the patient is at minimal risk for
dying of their disease within a ten year frame. And Dr. Albertsen?s
group published some very nice data on that showing that if your PSA ?-
I mean, if your Gleason Sum is 6 or less, that your probability of dying
of prostate cancer within a ten year span is relatively small.

Unfortunately, I?m not quite sure how many of those patients
subsequently went on to have some form of castration-based therapy to
extend their life span during that interval.

DR. KENNEALEY:  To help answer your question, let me just show you the
slide again from patient progression on watchful waiting in the United
States. And this is at two years, and at five years, and this is based
on PSA. And even in patients with a low PSA, the percentage of patients
who do go on to require some form of therapy is substantial. Certainly
not zero.

DR. SCHOENBERG:  So the final question actually is a small one related
to the Gleason Score discussion. How did you decide based on current
understanding of clinical biology to group Gleason 7 with 8, 9, and 10,
because clearly, I think at least in U.S. practice, those Gleason Sums
are not normally lumped together.

DR. KENNEALEY:  Okay. Dr. Paulson will respond to the grouping of
Gleason Scores.

DR. PAULSON:  As you?ve correctly brought up, Dr. Schoenberg, there is
an intermediate grade or an intermediate survival expectation for
patients that have Gleason Sum 7 disease. There?s a fair amount of
controversy as to whether if it?s Gleason 4-3 or 3-4, depending upon the
predominant volume of disease, the relative risk. However, the data in
radical prostatectomy series would state that if you have margin
positive disease with Gleason Sum 7 as your pathology, you have, I
believe it?s about a 50 percent probability of having a PSA failure
within five to seven years. And the survival data subsequently with
secondary therapies I believe has pushed that to somewhere around 14 to
15 years. But with margin positive disease, that?s a different risk
group than just Gleason 7 that is organ confined, as you know very well
from the data at Hopkins.

CHAIRPERSON PRZEPIORKA:  Dr. Brawley.

DR. BRAWLEY:  Yeah. I?m somewhat motivated by the old data via early
versus late prostate cancer treatment papers in metastatic disease. Do
you plan on continuing to follow these groups to determine the overall
survival and mortality rates of people who were treated early with
Casodex versus those who had delay therapy because they were randomized
to get the placebo?

DR. KENNEALEY:  We have information on all patients on first treatment
following ?- first treatment for prostate cancer following withdrawal
from therapy. We don?t have information on subsequent therapies beyond
that, and we will be following all patients for initial progression,
initial objective progression and survival.

DR. BRAWLEY:  Thank you.

CHAIRPERSON PRZEPIORKA:  Dr. Blayney.

DR. BLAYNEY:  The analogy has been made to breast cancer, and also your
again stimulus for watch and wait treatment was a rising PSA. In breast
cancer, it seems to me the ?-

DR. KENNEALEY:  I?m sorry. Go ahead.

DR. BLAYNEY:  We heard in Scandinavia that when patients had an event,
and often it sounded like rising PSA was what triggered the enrollment
in this trial. The analogy would be the rising tumor marker in breast
cancer. And to my understanding, rising tumor markers in CA15-3 or 27-29
in breast cancer have not been useful in prolonging survival, when
treatment is inaugurated based on a rising tumor marker, so I think your
?- I hope that you?re correct in that there is going to be some clinical
benefit and some survival benefit to inaugurating in the watch and wait
population treatment with your drug based on a rising PSA. But I think
the analogy in breast cancer ?- the analogy to breast cancer remains to
be proven.

Secondly, the issue of gynecomastia, which was ?- and breast pain was a
big issue for treatment withdrawal. When I was trained many years ago
before I had all this gray hair, there was breast radiation to men who
were going on castration as a preventative measure for gynecomastia. And
I don?t know if any of your experts have any experience on low dose
breast radiation to prevent that.

DR. KENNEALEY:  Yeah. Let me ask Dr. John Anderson from the United
Kingdom to respond to how he looks at gynecomastia in his practice.

DR. ANDERSON:  Thank you very much. I?ve been using Casodex both in the
trial setting, and also in my clinical practice in the U.K. for some
years. You?re right to raise the issue of gynecomastia, and it?s
something we address with the patients early-on. We?ve seen the figures.
We?ve seen that it occurs.

In my experience, it?s not a major problem, and we do not see patients
withdraw once they know the benefits of treatment. I think the high
withdrawal rate we see, the EPC data, reflects unknown efficacy of the
drug, but recognized toxicity.

What I see in my clinical practice is a different thing. I see patients
who we address up front with gynecomastia is an expected event in
someone who?s on Casodex, but it?s manageable, and it should not cause a
problem. If the patient has an issue, then irradiation of the breast
tissue before we start treatment is something we would discuss with
them. We re-address the issue once they?re stabilized on treatment, and
withdrawal of treatment is always an option. But what I?m absolutely
persuaded by is the benefits that the patient perceives in terms of
delaying disease progression far outweighs his concerns about the
potential toxicity of the treatment. And I feel, therefore, that in my
practice it?s very important to have that option to offer the patient,
and involve him in the discussion of the relative benefits of delaying
disease progression against possible side effects. He should have the
option.

DR. BLAYNEY:  I agree with the involvement of discussion. Finally, Dr.
Kennealey, in your slide CI-10, which was the chronology of development,
there?s a compound and it may come up later in the morning or earlier
afternoon about your dealings with the FDA. Were you meaning to imply
that there was a change in the rules or the change in the parameters
which you used, or you were required to use to develop this compound?

DR. KENNEALEY:  We were asked by the FDA to look at an alternate
endpoint of time to disease progression after the close of recruitment.
And we, indeed, did that, and that showed that the results of that were
congruent with the results from the primary, the initial endpoint.

DR. BRAWLEY:  Can we see those results?

DR. KENNEALEY:  You want to see the results of the FDA ?- the endpoint
of time to bone scan progression? Yes, let me just bring that up for
you. This slide shows the bone scan progression, the endpoint requested
by the FDA. As with the primary analysis, there is an overall benefit in
favor of Casodex with a reduction of 37 percent. That was seen primarily
in Trials 25 and 24, as was ?- you know, this really parallels the
primary analysis, and actually confirms that analysis.

CHAIRPERSON PRZEPIORKA:  Dr. Hanno.

DR. HANNO:  I have a question with regard to indication number two. I
know you pick your words very carefully when you go for an indication,
and here the indication is localized non-metastatic prostate cancer in
patients for whom therapy of curative intent is not indicated. To me,
and I think to a lot of urologists, that would mean patients who don?t
have a ten year life expectancy, because therapy of curative intent
would be indicated in the other people, whether or not they chose to
accept it.

My question is, would it be better to change that to not planned, and
are you looking for therapy in patients who have locally advanced
disease, and that?s why they don?t have therapy of curative intent
planned, or they don?t have a life expectancy to warrant it, because
those are two very different groups.

DR. KENNEALEY:  Sure.

DR. HANNO:  And there are standard therapies for the other group.

DR. KENNEALEY:  Yes. We?d love to ?- we submitted the original
indication last year, and as we reviewed our data and reviewed our plans
towards coming here, it became very clear that indicated was not the
right word. And that intended, either by the patient or physician, would
be a much more appropriate word in our indication. And that would be
something that we would want to change.

CHAIRPERSON PRZEPIORKA:  Dr. Martino.

DR. MARTINO:  I want to add something to this comparison of breast
cancer to prostate cancer, and it?s in reference to the use of tumor
markers. There actually is a trial that was reported and done in Europe.
It was presented in poster form at it was either ASCO or San Antonio
about five years ago. It was a patient population that was being
followed by tumor marker, and the tumor marker used was a 15.3.

At the time that the patient had a rising tumor marker, and had no
involvement that could be seen by clinical exam or x-ray, so in other
words, the tumor marker appeared to be the only sign that something
might be going on, the patients were randomized to either observation
further or to Tamoxifen. And a survival advantage was seen in the
Tamoxifen treated arm. It was a small trial. It was abstract, and with
all respects to our European colleagues it was from Europe, and so I
think that it was somewhat ignored. Nevertheless, it does exist in the
literature, and may be somewhat of a model to this PSA issue.

CHAIRPERSON PRZEPIORKA:  Dr. Brawley.

DR. BRAWLEY:  Two quick questions. Were there any formal studies, a
wonderful presentation looking on side effects and quality of life. But
were there any formal studies to look at state of well-being of men on
Casodex versus placebo?

DR. KENNEALEY:  There were no formal studies that looked at state of
well-being in men on Casodex versus placebo. The only quality of life
study are studies that were presented by Dr. Soloway.

DR. BRAWLEY:  I mean, granted, and I accept that it?s very likely that
knowing that your PSA is down improves your quality of well-being. I
accept that. The other question is, and again, I?m heavily influenced by
Dave Byers? studies that showed that early treatment had no greater
effect on survival than later treatment granted in a different group of
individuals or different patient population. And it was 30 years ago
with different drugs, but I?m wondering do you have any data on response
to LHRH agonists in men who progressed after being on Casodex?

DR. KENNEALEY:  Yes. Let me ask Dr. Anderson, who has extensive European
experience, to address that.

DR. ANDERSON:  I have been using Casodex long enough to see men
progress, and standard practice for me would be to institute them on an
LHRH analog. Response rate is about a third as measured by PSA response,
and I think that?s in keeping with any other first line hormone
treatment where the patient escapes hormone control.

I don?t know of any sequential studies to say that one sequence is
better than another, but where I draw reassurance is when I look back at
the 306-307 data, where patients were either treated with Casodex, or
with castration. Now in those studies, both patients progressed in
either arm. They were treated with alternative second line treatments,
and we know that there are no major survival differences for the two
groups, so I?m reassured that there?s no difference in the biology of
the tumor after the patient has been treated with Casodex.

CHAIRPERSON PRZEPIORKA:  A follow-up question while you?re standing,
sir. Did I understand you to say that when you had patients on Casodex,
you would start them on second line salvage therapy on the basis of a
PSA, and follow the PSA only?

DR. ANDERSON:  I?m sorry. Could you repeat the question? It is noisy
here.

CHAIRPERSON PRZEPIORKA:  For your patients on Casodex, did I hear you
say that you would start them on the LHRH antagonist on the basis of a
rising PSA only, and then follow the PSA?

DR. ANDERSON:  No, you did not hear me say that. When a patient fails
hormone treatment, it?s a full clinical picture. The patient either
becomes symptomatic, he has a rapidly rising PSA or has changes perhaps
on his bone scan that would indicate treatment. It would just ?- it
would not just be on a PSA progression.

CHAIRPERSON PRZEPIORKA:  Any other questions from the Committee? Dr.
Albertsen.

DR. ALBERTSEN:  Just a quick follow-up on Dr. Brawley?s question, again
to help me understand some of the British data. In England, on Trial 24
when you started patients on Casodex, and when they failed Casodex, they
moved on to anti-androgen therapy, was the length of time of response on
anti-androgen therapy equivalent to what might have been perceived had
they started initially on anti-androgen therapy and run the whole way?
Basically, what I?m trying to get at, was there additional response time
by sequencing the drug, rather than starting initially on anti-androgen
therapy and just waiting to see what happened?

DR. KENNEALEY:  Let me just clarify. You meant after Casodex, you mean
LHRH. You didn?t mean anti-androgen therapy?

DR. ALBERTSEN:  Right. I meant LHRH. Correct.

DR. KENNEALEY:  Okay. Thank you.

DR. ANDERSON:  I don?t have any personal data to support that, neither
do I know of any studies that would support it either. It?s relatively
early to be able to answer that question confidently, but I do reflect
back to the 306-307 data, where those sequences occurred in each arm
where there were no differences.

DR. ALBERTSEN:  Where I?m coming from is, it would strike me from a
clinical perspective that Casodex in this country would probably
substitute in many instances for LHRH agonist therapy very early on in
the practice. And so what I?m trying to grasp is, are we likely to see
an extension of survival which we haven?t seen certainly in Trial 23.
And I?m not saying you have data here. What I?m getting at as you?re
talking about your clinical practice. Is this ?- because what you?re
quoting is the survival on Casodex versus standard castration therapy.
There was no survival difference, so what?s striking me is that Casodex
becomes a substitute, but doesn?t increase survival. Is that a wrong
conclusion?

DR. ANDERSON:  Well, I think that?s probably accurate. There?s probably
?- there?s no evidence to suggest one way or the other to my mind.

CHAIRPERSON PRZEPIORKA:  Other questions? Hearing none, what I?d like to
do is take a break for 15 minutes, be back here at 10 minutes after 11.
Thank you.

(Off the record 10:55:28 - 11:14:04 a.m.)

CHAIRPERSON PRZEPIORKA:  Okay. We?ll start with the FDA Presentation.
Dr. Daniel Shames.

DR. SHAMES:  Good morning. I?m Dan Shames. I?m the Director of the
Division of Reproductive and Urologic Drug Products at the FDA. Before I
start my remarks, Dr. Hoberman, our statistician, has asked to make a
few comments.

DR. HOBERMAN:  Thanks, Dr. Shames. In retirement, I thought I could be
quiet as a mouse, but unfortunately not. The Sponsor made comments about
statements I made in my review, and I just wanted to clarify a couple of
them because they were made out of context, and I want to provide the
full context for the record. Also, I do want to make it clear that I?m a
statistician, I?m not a clinician.

The first statement they made was they concluded from my review that
Casodex reduces the risk of progression regardless of primary treatment.
That was true in Europe, but I wish they had made it clear that I don?t
think that there?s a shred of evidence data that supports efficacy in
the United States.

The second point is that patients in Trial 23 are at low risk for
progression. I think that was a consensus that we all had that what they
failed to mention was that I did do an analysis which tried to account
for the lack of treatment difference in Europe, in the United States,
based on the different distributions of prognostic variables. And for
reasons unknown to me, was unable to account for that difference. So
even though that I understand that in the clinical community, I guess
it?s sort of common wisdom that one of the reasons that the response
rates were so low in the United States in comparison to Europe was that
the course ?- where the patients were in the course of their disease,
statistical methods surprisingly couldn?t confirm that, and I was
disappointed.

The other thing that they quoted was, ?Objective progression may be
surpressed in Trial 23 due to U.S. clinical practice.? I have no
business saying that as a statistician, except as in the context of the
review, it was one of a litany of different things that might have
accounted for the differences between Europe and the United States. And
one of the reasons I mention that is because I was involved in the
application of Rilutek, the only treatment on the market for ALS, in
which there was evidence of efficacy in Europe, but there wasn?t a shred
of evidence of efficacy in combined Canadian and North American trials,
so I want to make that clear.

There are a couple of very quick things that I would like to point out
also for the record, that I want to emphasize, although I know that Dr.
Monroe is going to refer to these. One is that when the sponsor showed
the slide about the results of 306 and 307, they combined the results
and showed that they didn?t make a confidence interval for equivalence
or non-inferiority. But the whole point of that was that the FDA decided
that those trials could not be combined because of positive results in
one, negative results in the other. And when you put them together,
there was a wash, and that?s important to point out.

The only other thing I wanted to point out is that this business about
the modeling in order to find a subgroup in which there would be
efficacy in a high risk subgroup, that modeling exercise is, in a sense,
a reasonable thing to do, but I think you ought to keep in mind that
when labeling the drug, it?s a very risky business when you?re talking
about what are going to be the cut-offs in the prognostic factors, which
have been identified in the model. So it may be that they can find a
difference in a subgroup when restricted to certain risk variables like
PSA end stage, but how the Gleason Score came up, how the PSA score came
up as the boundary for who should be eligible for Casodex 150 is
certainly not clear, and those cut points must be due to a degree of
data dredging that comes from the model that was used to find the
prognostic factors.

Thank you very much for the opportunity for me to correct the record.

DR. SHAMES:  Hello. I?d like to first thank the Division of Oncologic
Drug Products for the close cooperation and advice we?ve had from them
during the course of our reviews of the various applications for Casodex
150. And I also appreciate ODAC for taking the time to advise us
regarding this challenging issue being presented before us today.

I would say that whatever differences any of us have we, I?m sure, all
agree that these issues ?- the general issue of prostate cancer and the
specific issue before us today is extremely challenging.

The FDA?s presentation will consist of the following. I?m going to
discuss background and review issues. Dr. Monroe, who is the medical
team leader for this product, will review the clinical trial data, and
then I?ll come back and summarize the review issues, and introduce the
questions.

As far as background, my background comments will include mention of the
importance of the issues before us this morning. We heard some of that.
A brief discussion of the critical role staging plays in the treatment
of prostate cancer, and a few remarks regarding the relevant history of
the development of Casodex 150.

The issues being considered today regarding the use of pharmacological
therapy for non-metastatic prostate cancer impact a large segment of the
U.S. prostate cancer population, as we all know. Casodex 150 would be
the first approved therapy for non-metastatic prostate cancer. The
target population could include hundreds of thousands of patients that
would take the drug for years, or perhaps decades.

However, because of the variable nature of cancer of the prostate many
patients, including those who remain asymptomatic throughout their lives
might be exposed to unnecessary risk.

As you all know, prostate cancer is a disease that can exist along a
very wide continuum, from microscopic clinically inapparent, to advanced
hormonally insensitive disease. For many elderly men, the disease exists
in our bodies for many years until they die of something else.
Therefore, the treatment for prostate cancer must take into account the
dictum ?primum non nocere?, or first do no harm.

We must be careful not to expose patients with early prostate cancer to
unnecessary toxicity without proven benefit. Recent evidence indicates
that the most precise method to predict a patient?s disease stage and,
therefore, decide on appropriate therapy, such as surgery, radiotherapy
and others are outlined in the trial, which I will mention further.

It should be noted that Gleason Scores, which are based on glandular
patterns of tumor under low power magnification is essentially the most
accepted method of pathologic grading in the United States, were not
used in the non-U.S. trials. Traditional pathologic grading was used in
the studies outside the U.S., and the results were extrapolated into
Gleason Scores. It was more than ?- really there was no central
laboratory. The pathology was translated into Gleason Scores, and
someone did make the comment about the translation of 7 versus 7, 8, 9,
10, and we also had that problem.

From my reading of the literature, it appears that the best way to ?- at
the moment to define cancer sub-populations are the clinicals, the
Gleason Score and the PSA. It is true that they all are independent
predictors, but the papers that we read tell us that the three together
are the best predictors, and add the most precision to the staging and
prognosis paradigm.

We do need to talk a little about Trials 306 and 307. Casodex 150, as
you know, has been previously studied in a population of patients with
advanced prostate cancer. The information derived from those studies is
important when evaluating the potential use of Casodex for earlier forms
of prostate cancer. These were randomized parallel studies in advanced
carcinoma starting in 1992. The definitions of the populations are seen
on the slides.

There were M0 patients, as defined, and M1 patients who were defined
with bone mets. These trials involved Casodex 150 versus castration,
medical or surgical castration. The intent of the study was to show
survival non-inferiority of Casodex compared to castration, and to show
a quality of life advantage of Casodex compared to castration.

The Data Safety Monitoring Board stopped the trials for M1 patients
because Casodex compared to castration had decreased survival, and
increased progression at the time in both trials independently. The
trials continued after that with M0 patients only, and these are the
numbers that were in the two trials, and you see Trial 307 is maybe
twice as large, or perhaps even larger than Trial 306.

The data, the information from the M1 patients in Trial 306 and 307 were
submitted to our division as supplement 06 of this NDA in February of
2000, and the purpose was to compare a combined analysis, the selected
dose of Casodex 150 with medical or surgical castration in terms of
survival, time to progression and time to treatment failure, quality of
life, and tolerability in patients with untreated locally advanced
prostate cancer defined as you see before you. And these are the results
of the M0 patients. And these are hazard ratios for mortality.

In the smaller trial, the hazard ratio indicated that Casodex treated
patient had reduced mortality compared to the patients treated with
castration. However, in the larger trial, which was more than twice the
size, the Casodex treated patients experienced increased mortality
compared to the patients treated with castration.

The results from the sponsor?s combined analysis revealed that Casodex
failed to meet the pre-specified parameter to declare non-inferiority
castration. In other words, demonstrate non-inferiority to castration in
terms of survival. Casodex was to be no more than 25 percent worse than
castration with respect to survival. However, the combined analysis as
previously shown the confidence interval was 36 percent.

As previously mentioned in M1 patients, the Casodex was inferior to
castration in terms of survival and progression. In M0 patients, the
Casodex trials had disparate results. The data from the larger trial
indicated decreased survival and increase progression compared to
castration.

Our experience with this particular trial in the various patient groups
caused us to have concern. Because of these results, the FDA had
concerns about overall mortality being adversely affected in M0 patients
possibly, and perhaps even earlier patients, or even the overlap
patients, so we found some additional information that might support our
concern.

In recently published large meta analysis of single therapy androgen
suppression in men with advanced prostate cancer which was published in
April of 2000, the author stated, ?The evidence from eight trials
involving 2,700 patients suggests that non-steroidal anti-androgens were
associated with a lower overall survival compared to castration. The
data from the Casodex trials in the meta analysis, especially

The data from the Casodex trials in the meta analysis, especially since
there may be a biologically plausible explanation for the survival
disadvantage of Casodex compared to castration in men with advanced
prostate cancer.

Those who treat patients with prostate cancer are familiar with the
phenomenon of anti-androgen withdrawal syndrome, which is a paradoxical
anti-androgen stimulation of prostate cancer, perhaps resulting from
prostate cancer receptive gene mutation. I don?t think we?re absolutely
sure. A similar mechanism could be in operation to explain the survival
disadvantage of Casodex compared to castration in patients with advanced
prostate cancer.

Now, it is true that the Trial 306 and 307 were on more advanced
patients, and there was only some overlap. But, quite frankly, we don?t
know what long-term treatment of Casodex is going to have ?- the effect
is going to have on survival because we?re very early in the process
here. And considering the data we have, this is an issue of great
concern to us.

I?m going to now tell you what the review issues that Dr. Monroe is
going to speak about in just a minute or two. Our efficacy concerns have
to do with the fact that the trials are really not long enough to
demonstrate enduring efficacy as we have defined them. The Gleason
Scores are ?- we consider invalid in Trials 24 and 25, not only for the
technical reasons I told you, but also \-- as Dr. Monroe will point out
\-- there were inconsistencies between the clinical stage and outcomes
and pathology between the U.S. and the non-U.S. trials.

Also, the data proposed to support efficacy in the U.S. is based on a
retrospective subgroup analysis. As far as safety, there is a very high
discontinuation rate from adverse events, a high instance of
gynecomastia and breast pain. And as you will learn, for many of these
people the gynecomastia is irreversible. There?s also some concern about
liver toxicity.

Additional review issues were the issue I just discussed, which is
questionable. We?re not sure about long-term survival, even in this
patient group. We do not believe it?s been demonstrated that there?s a
quality-of-life or sexual advantage clearly demonstrated, especially a
quality-of-life advantage regarding Casodex. And the three trials that
we are presented are heterogeneous populations with different
treatments. And the non-U.S. trials reflect different practice patterns.

In addition, we did find in our review what we felt to be some
imprecision regarding the bone scans. Dr. Scott Monroe will now report
on the details and data for Trials 23 and 24, which were submitted to
support Casodex 150 for non-metastatic prostate cancer.

DR. MONROE:  Hi. I?m Dr. Scott Monroe from the Division of Reproductive
and Urologic Drug Products. I was originally going to start by saying
\"good morning,\" but we?ve almost reached noontime because of the
lengthy \-- but I think very important \-- discussions that we?ve had
prior to this time. Earlier this morning, the sponsor presented their
data and their interpretation of these data that were submitted in
support of the two indications for Casodex that you see showing on the
screen in front of you. In support of these indications, as you?ve
heard, the sponsor conducted three multi-center randomized
placebo-controlled clinical trials.

Trial 23, as you know by now, was conducted almost entirely in the U.S.,
and to a lesser extent in Canada, and neither Trials 24 or 25 enrolled
any patients in the U.S. Trial 23 enrolled only patients with prostate
cancer who had previously been treated by either a radical prostatectomy
or radiotherapy. These patients have been referred to as the adjuvant
treatment groups.

Trial 24 and 25 enrolled similar patients, but also enrolled patients
that had not undergone any prior treatment. And these have been referred
in your background documents, as well as in our presentations today, as
the \"watchful waiting\" group, the \"immediate therapy\" group or
\"monotherapy\" group, all referring to the same group of patients.

One of the most important characteristics of all patients across all
trials was that they were all supposed to be negative as far as bone
scans. That?s a very important unifying characteristic that crossed all
of the trials. An important difference was that treatment in Trial 23
was limited to two years, while treatment in both Trials 24 and 25
continues. And this also applies to the adjuvant patients in Trials 24
and 25, so you can see there is a difference between these trials. It?s
not just whether they?re watchful waiting or not, but a decision was
made in one adjuvant group treatment would be discontinued, while in the
other two trials which also have adjuvant therapies, treatment is
ongoing.

Since the sponsor has reviewed the overall design of these clinical
trials, their similarities and differences, and the overall efficacy and
safety findings, I will avoid re-reviewing these topics. Rather, I?ll
try to limit my presentation to significant clinical review issues. And
these review issues include differences between the sponsor and the
division regarding study endpoints and data analyses, and interpretation
of clinical findings.

I will also review findings of concern to the division. Now, not having
had the benefit of knowing exactly what the sponsor was going to
present, I will, however, have some duplication, but hopefully we can go
over those areas quickly.

Early in the review process, we noted an inconsistency between the
Gleason Grades or Scores in the clinical stage of tumor stage and
pre-treatment PSA values across the trials. Note that in Trial 23, the
U.S. trial, there is a much higher proportion of patients that were
characterized as having poorly differentiated tumors, and whether or not
this was based on a proper Gleason Score or not, there is a difference,
at least in terms of how the pathology or the histopathology of these
tumors was assessed.

You could say almost half the patients in the U.S. were considered to
have poorly differentiated tumors, where only a quarter and just a
little bit over 10 percent were classified as having similar tumors in
the non-U.S. trials. However, if you look at the clinical stage, you can
see that patients enrolled in the U.S. had least advanced disease. They
had the smallest percentage of patients in Clinical Stages 3 and 4, and
we had the highest percentages or higher percentages in both of the two
European trials.

This discordance is also apparent when we look at tumor differentiation
and pre-treatment PSA values. And once again, we can see \-- looking at
median PSA values at the bottom of that slide \-- they?re lowest in the
U.S., highest in the non-U.S. studies, and this is going exactly the
opposite than what was determined to be the histopathology of these
tumors.

There is also a discordance between the baseline histopathology or
Gleason Scores and disease progression. On this slide, we?ve listed for
you, for each of the trials, the percentages of patients in the
prostatectomy group who had Gleason or tumors reported as poorly
differentiated, or Gleason Scores of 7 or greater. And whether we?re
talking about 7s or 8s, I don?t want to belabor that point. We have to
go with the data as it was presented to us by the sponsor. But I think
the important point I?m trying to make here is that there is less tumor
dedifferentiation, at least as assessed by the pathologists in the
various trials in the non-U.S. studies; namely, those were better
differentiated tumors, yet we can see that the incidence of disease
progression as assessed by a positive bone scan was much higher in the
non-U.S. trials. And this certainly was problematic for us in terms of
interpretation of the baseline disease characteristics of these
patients.

Similar data was observed when we look at the subgroup of patients
treated by radiotherapy across the three trials. Once again, we see that
the percentage of patients with high Gleason Scores or poorly
differentiated tumors is highest in Trial 23. Yet, it is these patients
that have the lowest or the least disease progression as assessed by
positive bone scans.

Although the sponsor and the division met on many occasions throughout
the development of this program, both prior to its onset, as well as
while the studies were ongoing, the sponsor and the division never fully
reached closure on what the primary study endpoints and analyses should
be.

We discussed this somewhat earlier this morning. I?d like to expand on
that just a little bit here. The sponsor preferred a time-to-disease
progression endpoint, where progressive events were based either on
local or distant events of disease progression confirmed by bone scan,
x-ray, CT, MRI, ultrasonography, or biopsy, or death due to any cause in
absence of progression.

The FDA, on the other hand, preferred an analysis and endpoints based on
the proportion of patients with progression within two years
post-randomization, where events of progression would be limited to
positive bone scans, or death due to any cause in the absence of disease
progression.

The rationale for the FDA?s preferred endpoints and analysis was based
on concern acknowledged by the sponsor that blinding could not be
maintained because of the anticipated high incidence of gynecomastia and
decreases in serum PSA in the Casodex-treated patients. We felt that the
inability to maintain blinding could result in significant assessment by
us. In addition, specific criteria for local disease progression did not
appear to be provided in the study protocols, and there was no central
blinded review of events classified as progression, whether they be
bone-scan-documented or otherwise. Because all the protocols mandated a
bone scan at two years post- randomization, it was believed that this
endpoint, along with death, would be least subject to possible
assessment bias.

On this slide are listed the results from the three clinical trials in
which events and analyses are based on the FDA preferred endpoints;
namely, a positive bone scan or death, in this case, actually within two
and a half years of randomization. And the time interval was extended
from two to two and a half years to allow for inclusion of the patients
whose bone scans would be delayed for a small period of time.

In each of Trials 24 and 25, there was statistical evidence that
treatment with Casodex delayed disease progression. In Trial 23, however
\-- the only trial that enrolled patients in the U.S. \-- there was no
significant difference between the two treatment groups. And as you saw
earlier this morning, the same conclusions regarding the effect of
Casodex treatment on disease progression were obtained using the
sponsor?s preferred endpoints and analyses.

The sponsor?s original proposed indication for Casodex 150 milligrams
was immediate hormonal therapy, or adjuvant therapy to treatment of
curative intent, patients with non-metastatic prostate cancer. Such an
indication would encompass virtually all patients with non-metastatic
prostate cancer, and was not, in our opinion, supported by the submitted
data.

Because of the negative outcome of Trial 23, the division also concluded
that adjuvant treatment in patients with early disease would be of
little, if any, benefit. The division was also unable to characterize
\-- based on data in the NDA submission \-- the population of patients
in the U.S. who would likely benefit from Casodex adjuvant therapy.

The sponsor was asked to identify populations treated by a prostatectomy
or radiotherapy in the U.S. who would likely benefit from adjuvant
therapy, based on the actual data provided in their submission. In
response to this request, the sponsor performed post-talk exploratory
analyses that resulted in the first of two changes to the proposed
indication.

The first revision to the indication concerned the use of adjuvant
therapy. That will be our focus for the moment. Based on these analyses
of the indication for adjuvant therapy was limited, as you heard
earlier, to patients with locally advanced non-metastatic prostate
cancer who have a high risk for disease progression.

This modification of the indication was presumably based on analysis
performed by the sponsor on their data set, which showed that patients
with stage three or four disease and a detectible post-prostatectomy PSA
value, or a pre-radiation PSA value of greater than 10, were most likely
to have disease recurrence.

The data supporting this change for the adjuvant treated patients, based
on the FDA preferred endpoints, are shown on this slide. And what we can
see here \-- and let?s focus primarily on Study 23 \-- that by this
criteria, there were very few patients in the U.S. who had disease
progression, as assessed either by a positive bone scan or death within
the two-year period after randomization. As you can see, there are only
four in the Casodex group, six in the placebo group, and clearly these
were too small to make any conclusions regarding the potential benefit
of Casodex in this group.

On this slide we can see similar data for patients who were initially
treated by radiation, had a pre-radiation PSA value of 10 or greater.
Once again, you can see in the U.S. population, there were very few
patients who met this criteria, and the number of events were one in
each of the two treatment groups. Once again, not supporting the benefit
of this therapy in U.S. patients. You can see there were numeric
advantages for Casodex in the radiotherapy patients in both Trials 24
and 25.

We noted during our review of the sponsor?s background document that the
definition of a patient of high risk for disease recurrence appears to
have expanded somewhat, and this new expanded definition is listed in
the lower portion of the slide. These patients remain those with locally
advanced stage T3-4 disease and detectible post-surgical PSA values, but
also include pre-surgical PSAs of greater than 10, or a Gleason of 7 or
greater. And the criteria for a patient treated by radiation has been
loosened somewhat, so that a pre-radiation value of 4 would qualify an
individual for being at high risk for recurrence or disease progression.

Earlier today, the sponsor showed you a number of Kaplan-Meier curves
based on these definitions. And I want to first bring to your attention
that the prostatectomy and radiotherapy labels are reversed on this
slide. The data in the upper half of the slide are from the radiotherapy
group, those in the lower portion from the prostatectomy group. And we
agree with the Kaplan-Meier curves that you saw earlier, if you accept
the sponsor?s endpoints, that in the high risk group of patients as
defined \-- as I showed you just a moment ago \-- there were
statistically significant reductions in the proportion of patients who
had disease progression.

But throughout our review, our concern has really focused on the
findings in Trial 23. And you did see a slide showing a breakdown of
these patients, at least for the radical prostatectomy group earlier,
and here I show you those data once again. And you can see the benefit
of Casodex in that combined analysis that we just previously showed was
driven entirely by the results of Trials 24 and 25. And one could ask if
it was even appropriate to combine all trials together, but that again
is really not the issue.

The issue is that if you apply criteria that sponsor has determined to
identify patients at high risk for disease recurrence, and apply those
criteria to the population in the U.S., we just at this point do not see
any benefit of Casodex treatment. We see a proportion of patients with
progression of 6.8 percent in the Casodex group, and 6.4 in the placebo
group.

Now the earlier analyses were based on very small numbers, and their
significance is questionable. But here, presumably we have 712 patients
that are at high risk for disease progression, yet we don?t see any
benefit at this stage of Casodex therapy. And this, again, underlies the
concern of the division that logic would say you could just transfer
these data and information from the European studies to the U.S.
studies, but it just hasn?t worked out when we apply them, or the
sponsor in this case has applied them to the actual data.

I do not have a slide for the radiotherapy patients. The sponsor
actually showed one, I believe, earlier where they showed that in Trial
23, using the definition of high risk for recurrence, there were only
four events \-- I believe \-- in the U.S. trial, if I remember. And if I
also remember correctly, of those four events, two occurred in the
Casodex group, two in the placebo group. So once again, I?d say there is
a problem as to what is happening with the U.S. patients.

Now subsequent to the division?s not approving the NDA for Casodex 150
milligrams, the sponsor revised the proposed indication for the
\"watchful waiting\" or monotherapy group. And in the revised
indication, as you?ve heard this morning, the sponsor now recommends
that immediate treatment or monotherapy be limited to patients with
localized Stage T1/T2 non-metastatic prostate cancer. It?s our
understanding that this modification was made because of the concerns of
the division that Stage 3 and 4 patients were very similar to those in
the previous studies, where there were concerns about survival in the
Casodex-treated patients.

Sponsor has also shown or at least told you that the effects of Casodex
treatment in these earlier stage patients was statistically significant,
and that we do agree with that based on the sponsor?s endpoints and
time-to-event analysis. But if you apply to these patients the endpoints
and analyses that the FDA feels are more appropriate because of the
concerns about assessment bias, we can see that there are certainly
strong trends in support of Casodex, but that the upper bound of the 95
percent confidence limits for the odds ratios for both of the studies
extend above one. Whether these will drop down below one or whether they
have in your more mature data which you?ve not seen, we just don?t know.
But at least on the data that we?ve had a chance to review, neither of
these studies would have crossed the bound that would have met the
criteria for statistical significance.

It also was of interest to us that the majority of events that were
classified as disease progression were actually deaths in this
population, but that of these deaths, only about 10 percent, or perhaps
a little under 10 percent, are actually due to prostate cancer.

These are the baseline disease characteristics for the patients in the
T1/T2 \"watchful waiting\" groups in Trials 24 and 25. And at first
glance, one would say these Gleason scores look like those that are seen
for U.S. patients that frequently are managed by surveillance. But our
concern is that, based on the data where we could compare tumor
histopathology across the European or the non-U.S. studies and the U.S.
studies, we felt that these patients had under-reporting for poorly
differentiated tumors. Clearly, there was a difference in reporting, so
that even though these Gleason scores would be very comparable, I
believe, to what type of patient might be a candidate for \"watchful
waiting\" presently in the U.S., we believe that these scores are
unreliable and, therefore, we can?t conclude that these patients had the
same type of tumors as those patients that are frequently given the
option, or at least advised that watchful waiting would be a reasonable
option for them.

Although we agree that there was no assessment bias in the bone scans
\-- in that if you look at the number of positive scans that were read
as other than positive, it was the same in both the Casodex and placebo
groups \-- we are concerned over the fact that at least in this re-read,
27 percent of the scans have read as positive in the Casodex, and
placebo group were read as something other than positive. This causes us
to have some concerns about the actual accuracy of the measurements. And
bone scans, like all other indices of disease progression, were not
re-reviewed centrally, nor by an independent panel.

The last efficacy topic that I?d like to review with you this morning
relates to survival. And what I?ve summarized on this slide are the
percentage of deaths related either to prostate cancer or other in each
of the three trials. The data in the upper half of the slide are those
data that were submitted at the time of the initial submission as part
of the efficacy component of the application. And they had a data
cut-off date of June in 2000. With the safety update, we received
additional survival data, which had a cut-off date of September, 2001,
represented in the lower portion of the slide, and I think we ought to
focus on those numbers since they are more current.

If we look just at prostate cancer-related deaths, we can see that there
are small numeric decreases in both of Trials 24 and 25, but that in
Trial 23, we see just the opposite. There?s a small numeric increase. I
think the conclusion is that there?s probably no impact on survival at
this time in patients with prostate cancer.

And similarly, if we look at other events we again see a little increase
or a decrease, depending on which study we?re referring to. And if we go
to the bottom, the data represented in yellow, we can see that the
differences within any study tend to be very small. And we would concur
with the sponsor that at this time there isn?t any evidence that
treatment with Casodex is having any impact on survival either way.

So, to summarize what we?ll call unresolved efficacy issues, we can lump
these into perhaps three broad categories. The first category concerns
the maturity of the studies, and since only 15.6 percent of the patients
using the sponsor?s endpoints and analysis, or 9.3 percent using the
FDA?s preferred endpoints, have had an event of disease progression, we
think that these are early studies. The results from these studies are
quite early. And that the long-term benefit of treatment at this time is
unclear in the absence of survival data, or a survival difference, or
meaningful quality of life data.

The second category relates to the inability of the division to identify
those prostate cancer patients in the U.S. who would derive benefit from
adjuvant therapy. Post-talk subset analyses by the sponsor were
inclusive or not supportive, and we also remain concerned about the lack
of valid Gleason scores, which has made it impossible for us to fully
characterize those patients involved in the non-U.S. trials.

The third area is what is the risk benefit ratio for immediate therapy
or monotherapy in patients with localized disease. This time I?d like to
spend just a little bit of my presentation to go over some of the safety
observations. This slide shows the disposition of patients in each of
the trials. And as you can see, the percentage of patients who
terminated prematurely exceeds probably 30 percent or more in all of the
trials. And in some trials, the percentage is higher in the Casodex, in
others it?s higher in the placebo group.

If we look at Trial 23, the U.S. trial, we can see that the patient
terminations due to adverse events in the Casodex group far exceeded
those in the placebo group. What the reason for this imbalance is, we
don?t know, except for the development of those adverse events, which
we?ll discuss in a moment. And actually, adverse events exceeded in the
Casodex group was a greater cause for premature withdrawals in all the
studies. However, as you can see in the European studies, disease
progression was a more common cause for withdrawal in the placebo
patients than in the Casodex-treated patients.

The most common adverse events, as you heard earlier, are those related
to the pharmacology of the drug, its anti-androgenic or its estrogenic
activity. And as a result of the drug?s pharmacology, 73 percent of the
patients across all the trials reported breast pain, and 67 percent
reported gynecomastia. You can compare these to the much lower incidence
in the placebo groups of 7 and 8 percent respectively.

Because of the high incidence of breast pain and gynecomastia, I?d like
to focus on this adverse event in somewhat greater detail. The figure
that I?ve taken from the sponsor?s integrated summary of safety in which
the proportion of patients without event, in this case gynecomastia, are
represented as a function of time. And, as you can see, that by
approximately one year or so after the onset of treatment, about
two-thirds of the patients have developed gynecomastia. This percentage
increases slightly, but most of this occurs certainly within the first
year of treatment.

A very high proportion, as I?ve mentioned to you earlier, of patients do
experience gynecomastia or breast pain. We can see that across the
studies, this was a complaint reported by 86 percent of the patients.
And patients withdrew from the study because of gynecomastia in what we
believe is a significant number. Across all the studies, 16 percent of
patients withdrew because of gynecomastia or breast pain in the Casodex
groups, compared to less than 1 percent in the placebo groups. And in
the U.S. trial, I believe this number was approximately 20 percent, even
slightly greater.

The sponsor was able to follow a significant number of patients for
resolution of gynecomastia. And what this slide does is summarize the
number of patients, or list for us the number of patients who had
gynecomastia at the end of treatment, and who also had post-treatment
follow-up. There were approximately 1,500 of these patients, and in
approximately half of these patients, some degree of gynecomastia
persisted at the last follow-up exam. Breast pain, on the other hand,
resolved almost entirely, and the percentage of patients that had
residual breast pain was quite low.

We?ve heard earlier this morning about quality-of-life issues, and in
these particular trials there wasn?t any effort to really assess
quality-of-life in any systematic manner. There was very limited
quality-of-life data. There was data on maintenance of sexual function
in the study that was conducted in Sweden. And I have to confess, I?m
personally a little bit befuddled by these data, because the data that I
show before you here, I thought I had taken directly out of the
sponsor?s integrated summary of safety again, and this would suggest
that in these patients, both in the placebo and Casodex patients,
there?s a very significant diminution of sexual function over time. And
in the bar graphs that we saw earlier, they didn?t give this impression
at all, so perhaps we have misinterpreted these data. Perhaps you could
explain the difference.

But if we interpret these data correctly, it appears that in both groups
in this particular population as assessed by this instrument, there was
significant decrease in sexual function over time. Whether one can put
any credence on these data we don?t know, because of the rapid fall
within 12 weeks of treatment onset in both treatment groups.

In these studies, the incidence of life-threatening or fatal
hepatotoxicity was similar in both the Casodex and placebo treatment
groups. However, as shown on this slide, there was an increase in what
was defined as clinically relevant changes in ALT or AST or bilirubin
levels in the Casodex patients relative to the placebo patients. And
roughly anywhere from two ?- this difference was two- to four-fold
higher in the Casodex patients relative to the placebo patients. There
was also a greater percentage of Casodex patients who withdrew due to
liver-related adverse events, perhaps two- to three-fold greater in the
Casodex group, as well.

So in conclusion, a high percentage of patient reported anti-androgenic
or estrogenic related adverse events, 86 percent of Casodex patients
versus 12 percent of placebo patients reported gynecomastia or breast
pain. Sixteen percent of Casodex patients versus less than 1 percent of
placebo patients withdrew because of gynecomastia or breast pain. And
gynecomastia persisted post-treatment in almost half of the patients.

Life-threatening or fatal hepatotoxicity was rare and similar in both
treatment groups. However, clinically significant or clinically relevant
\-- to use the sponsor?s terminology \-- arises in ALT or AST values,
and withdrawals due to hepatic adverse events were two- to three-fold
greater in Casodex-treated patients.

At this time, I?d like to return the presentation to Dr. Shames, who
will summarize our concerns about this particular application.

DR. SHAMES:  Thanks, Scott. First, I want to tell you where we are in a
regulatory sense. We issued a non-approvable letter for this supplement
involving Trials 23, 24, 25, and in that letter, we stated that we
wanted to see more mature trial data to find out ?- to answer some of
the questions that we have before us today. We also asked that, if it
were possible for the sponsor to get the slides from the foreign studies
and really do Gleason scores, but we believed that the essential issue
was that these were sort of post hoc subgroup analyses, and that there
was hypothesis testing, and they should choose well-defined successful
subgroups, and perform well-controlled trials after the results that
they?ve seen currently.

I just would like to take time to discuss ?- clear up an issue regarding
the interaction of the FDA with the sponsor regarding these endpoints.
In the notes that I can see as far back as it goes, there was
disagreement regarding the ?- what we consider an objective endpoint,
the protocol-driven bone scan as opposed to the more investigator-driven
endpoints, which the sponsor used. That disagreement appears right from
the very beginning, because we were concerned about the possible
unblinding, probable unblinding, perhaps, of gynecomastia, and the fact
that Casodex in some variable way in itself will reduce PSA.

Now let?s go on to the review issues, which are the core of the concerns
that we?ll discuss in the questions. We are concerned about the small
number of progression events, and even fewer survival events after three
years, to draw conclusions about long-term use of Casodex 150. As
mentioned several times, one of the key parameters used in the U.S. for
disease staging \-- the Gleason score \-- was improperly used in the
non-U.S. trials. In addition, there was disturbing inconsistencies
between the pathology and clinical outcomes between the three trials.

The data proposed to support use of Casodex 150 in the U.S. patients is
based on retrospective subgroup analyses. As far as safety concerns,
there was a high discontinuation rate, and Scott discussed the
gynecomastia, possibly irreversible liver toxicity.

Certainly on the face of it, you would, you know, consider that sexual
function will be decreased in people who are ?- men that are castrated.
But on the other hand, we have other issues when we?re using Casodex.
And in fact, it?s very unclear whether \-- when we?re dealing with
quality-of-life \-- we improve it with Casodex versus castration, or
placebo. As a matter of fact, in the paper that I mentioned before in
[The Annals of Internal Medicine]{.underline}, April 2000, which looked
at a large amount of analysis of androgen monotherapy in advanced
prostate cancer, the authors concluded that treatment withdrawal, the
most reliable indicator of adverse effects are less with LHRH agonists
versus non-steroidal anti-androgens.

The review regarding safety is particularly concerned because this drug
has the potential for being used in a very wide population. We had some
other review issues. There is concern over the potential, as we?ve
talked about, survival detriment is too early to tell, and we feel there
may be evidence for us to be concerned about that, and there is some
biological plausibility.

There is a question, as I just mentioned, whether Casodex has any
quality-of-life advantage over placebo or castration. And Trials 23, 24
and 25 are trials which studied heterogenous populations with different
treatments that reflect differing practice patterns in various global
locations. Finally, although not a key issue, bone scan readings appear
to be imprecise.

That?s the end of our presentation, and thank you.

CHAIRPERSON PRZEPIORKA:  Thank you, Dr. Shames. And the floor is now
open for the Committee to ask questions to the FDA. And I?ll start by
asking, could you explain briefly, please, why you would not accept
x-ray results or biopsies as an endpoint for this study?

DR. SHAMES:  Well, I think you mean ?- well, because I think they were
?- some of those were investigator-driven, and we?re concerned that
there may been some selection bias. You mean, x-ray ?- you mean a
precipitation of the x-ray, or the biopsy occurred because of some
change in PSA or knowledge of what the control ?- what the arm was.

DR. MONROE:  I guess I?ll expand on that just a little. The
documentation for these other events was very inconsistent in the
application. They weren?t assembled by the sponsor in any way that you
could actually determine, in most cases, exactly what was going on. They
were reported just as having occurred, and it was not possible to really
decipher what these were. Some of these were local events, and some were
distant events. And without having had more documentation as to the
nature of these other events \-- forgetting about whether they were
driven by factors or not \-- we just couldn?t place any reliability on
them. And I did address the fact that there was no central review of
these. There was no clear criteria in the protocols defining what some
of these events needed to be. I believe some of these events may well
have been enlargement of the prostate, perhaps, for those patients in
the \"watchful waiting\" group. Yet, we couldn?t find anything that said
it had to be an enlargement by a specific size or not. It seemed to be
driven only by the assessment of the investigator that an event of
progression had occurred.

CHAIRPERSON PRZEPIORKA:  Dr. Cheson.

DR. CHESON:  Well, I can see the issue that you?re raising about the
size of the prostate, but a positive biopsy is a positive biopsy. No
matter what drives it, it?s evidence of progression. And even a positive
x-ray is a positive x-ray, but that raises the other point, which
troubles me no end, that there wasn?t any central review of the x-rays.
And I really find that hard to believe.

If I could ask one question which sort of came to me, because often we
miss therapeutic leads because they?re hidden in toxicities and
whatever. Did either the agency or the company look to see if there was
any correlation between the development of gynecomastia and outcome,
because this may tip you off as to whether this is really a biological
effect, and may be a plus instead of its being a minus. But I?m agreeing
with Donna, that it?s sort of bothersome that you?d sort of write off
things which are not subjective, and are purely objective, like positive
biopsies and things, which I think, you know, in all fairness probably
are evidence of progression.

CHAIRPERSON PRZEPIORKA:  Dr. Krist.

DR. KRIST:  Going on the theme about the sponsor\'s versus the FDA?s
endpoints, to a certain extent I disagree. I mean, I do think an
objective result is an objective result. There?s a higher risk of
missing those objective results in the placebo patients because you
might not look for it. But that?s something that I think is a difficult
thing to think about.

I?m curious, though. You presented data showing that if you looked at
just Trial 25 in the \"watchful waiting\" group, and looked at low-risk
people by FDA endpoints, that there was no benefit. And then you also
showed in 24 looking at the prostatectomy group who are high risk, and
by sponsor?s endpoints, that there was a benefit. I?m curious for Trial
24, if you were to believe in the FDA endpoint, if high-risk FDA
endpoint and prostatectomy, if there was a relative difference, I didn?t
see that number.

DR. MONROE:  I think I?m going to have to ask you to go through that
step by step, please, and then I can address each piece of it.

DR. KRIST:  The big question I had was that you showed a slide doing the
subgroup analyses, and you showed that on Trial 24, in the patients who
had locally advanced or the high-risk disease, who had prostatectomy,
and you went by sponsor?s endpoints, that there was a difference in
outcome between Casodex and placebo. And I?m interested in Trial 24 for
that same group, instead of going by sponsor?s endpoint, but by FDA
endpoint, for Trial 24 who are a high risk, who had prostatectomy ?-

DR. MONROE:  We?re talking about the adjuvant treatment prostatectomy
patients.

DR. KRIST:  Yes. Right.

DR. MONROE:  Okay. And on the slide that I showed, and we?re not set up
to immediately go back, but I believe on that slide, which is ?- let me
just find that for you so you can all look at it here. Were you talking
about Slide 26, perhaps? Could you refer me to the slide on the
handouts? That was the high risk prostatectomy FDA analysis. Is that the
one you?re referring to?

DR. KRIST:  Yeah. Is there a confidence interval for that? Is that
statistically significant?

DR. MONROE:  Well, there?s clearly nothing there. We could show you what
those data look like if you use the sponsor?s analysis, if you wished.
In other words, you would find events due to this category of other
objective events, which would have an impact on the absolute numbers. Is
that what you?re asking?

If you want to go to the backup slides, Randy. Okay. That?s the same
data, I believe, but using the looser definitions where you would
include all events. And you would see, we have more events, and we see
that there are some numeric differences, only one of which by this
analysis has a confidence interval that is less than one. But if you go
to the next slide and look at what?s driving these, I think this may
answer your question. That?s Study 23 at the top, so we can see there?s
actually one more positive bone scan in the Casodex group than in the
placebo group. There were two more other objective events, and I can?t
tell you precisely what those were at this moment. And there appeared to
be four deaths, but those deaths, three of the four had nothing to do
with prostate cancer. So it seems that as you go into these subset
analyses deeper and deeper with small numbers, you can come out with
almost any kind of an outcome. And that is what?s being driven by these.

I think perhaps the most compelling data were those of the sponsors
using the criteria that they are now using for high risk, where we have
a lot of events occurring, but yet there was no difference between the
two groups. And if we could go back to slide \-- I guess it?s 30. And
here we don?t have to bicker over whether we should or should not
include these other objective events. This includes all of those other
non-bone scan driven events, and there is just no difference in the
ratios between the Casodex and placebo treated patients in Trial 23.

CHAIRPERSON PRZEPIORKA:  Dr. Cheson, did you have a follow-up?

DR. CHESON:  I was ?- this is just probably not even a very smart
question, but I just want a point of clarification. There were those
patients in the ?watchful waiting group?, who were treated on the basis
of the PSA that went up, which have been alluded to as, perhaps,
protocol violations. How did you handle them in the analysis? Did you
include them? Were they censored at some point, and does that make any
difference?

DR. MONROE:  Neither we nor the sponsor handled them any differently.
This question of whether or not they should have been included was not
addressed at all in the sponsor?s original submission. And because of
the fact that our basic analysis had not yet shown \-- or maybe never
would show \-- that there was a statistical difference in at least the
\"watchful waiting\" local patients, it wasn?t pursued further. If he
were to look at all of the watchful waiting patients, Stages 1, 2, 3 and
4, as a group, they do show a statistical effect as a consequence of
Casodex treatment, but those ?- but one has to remember that there are
many more events occurring in the T3 and T4 patients, and once those are
removed, you have many less events to assess whether the change is
statistically significant or not. And that is what we saw with our
analysis based on the low risk component of the \"watchful waiting\"
population.

CHAIRPERSON PRZEPIORKA:  Dr. Albertsen.

DR. ALBERTSEN:  My question drives to the choice of endpoints for these
trials. In some respect, it?s almost an artificial construct in
contemporary urologic and oncologic practice, in the sense that a bone
scan and a survival are really downstream endpoints, to the point of 10
years and almost 15 years later when you look at some of the data in the
literature. And my concern is: by excluding PSA progression as a
potential endpoint, don?t we potentially run the risk of missing a
benefit, in the sense that if patients \-- specifically in Trial 23 \--
move on to LHRH agonist therapy when they have PSA progression, this
happens before they even have a chance to achieve the endpoint the FDA
is looking for. And, therefore, asking for more mature data, while very
valid, probably puts that off until about 10 years from now. And I?d
like your comment on that.

DR. SHAMES:  Well, as you know, that?s sort of a controversial issue,
and we have yet to have the hard data that we felt we needed to use PSA
as a surrogate endpoint essentially. So we have not yet accepted that. I
mean, that?s still being debated internally and externally, as you know.
It?s a somewhat difficult issue. I think the ?- okay. Go ahead.

DR. ALBERTSEN:  But the whole decision before us rests on that very
decision, because the trial is clearly too short to demonstrate an
effect from anti ?- at least in my opinion \-- to direct an effect from
a hormone therapy given over two years, given the lead time of five
years. At a minimum lead time of five years that PSA testing has
achieved, we are identifying patients in the U.S. considerably earlier
than our European and Scandinavian colleagues. We?re operating on them,
so an adjuvant trial based on those patients given for only two years, I
think at virtually any endpoint you select, it would be difficult to
demonstrate the difference.

So the trial, as constructed, is stacked heavily in favor of not
demonstrating efficacy, unless you ran that trial for a period of ten
years. And I?m not sure if the FDA or the sponsor were prepared to do
that up front, and we?re stuck now deciding what do you do with the
information at hand.

DR. SHAMES:  Well, I mean, we grapple with this issue daily because
prostate cancer has this particular problem. We do trials regarding
prevention of prostate cancer. And so, you know, perhaps if we had had
?- the problem that we have ?- the essential problem we have here is how
to communicate who these people are that we can ?- that physicians will
prescribe medication. And basically, although there are certain aspects,
there are certain data here that shows a difference, there?s no question
about it. We could?- we?re not able with the data before us to, we feel,
adequately communicate to prescribers who exactly is supposed to get
this medication, and make sure that we weren?t giving it to patients too
early, and they were taking this for years and years, you know, without
?- we don?t know, perhaps possible adverse events \-- or giving them
later where they might overlap with the patients that might have some
survival disadvantage.

So that, you know, as you?ve seen in the questions, and we?ll discuss
the questions. That?s part of our basic difficulty here.

DR. ALBERTSEN:  If I can follow up, I think realistically were this
drug, if it were to take ?- if FDA were to give its approval, I doubt it
would be used as the indications are listed. Realistically, I think what
would happen is most urologists and oncologists would give this drug to
patients who demonstrate aggressive PSA doubling time. Specifically, if
you refer to the Pound data from JAMA, anyone with a doubling time
greater than ten months is at great risk of disease progression.

I suspect this drug is going to be used as a substitute for another drug
that is not indicated for use in early prostate cancer, but is uniformly
used in this country, specifically an LHRH agonist. The risk factors for
them is the potential for osteoporosis, and all the other complications
we all grapple with. So, therefore, the average clinician is going to
try to weigh the complications of one drug that?s not indicated with
another drug that?s not indicated. Realistically, that?s what?s going to
happen. And I kind of scratch my head looking at the data presented, and
feel I?m kind of an artificial construct, or an Alice in Wonderland
scenario. In fact, what we?re discussing bears little resemblance to
what will happen the minute this drug gets approved. Your comments on
that.

DR. SHAMES:  All right. Well, that happens all the time. That?s part of
the problem we have here, actually. Part of my concern is that the drug
will not be used the way it should be used. And we will have ?- and I
did say we might have hundreds of thousands of men using this drug, in
either late stage, early stage, in-between, when we have some indication
that there might be in some people a survival disadvantage, you know.
And so that?s right, absolutely. That is absolutely one of our concerns.
It?s always one of our concerns, but in this case, given the huge
potential population that could be using this drug, we?re concerned
about it not being used in the right population. And that?s why \--
since we had a lot of difficulty determining who exactly this should be
used in \-- that?s why we?re not ?- one of the reasons we didn?t approve
it. We couldn?t rely ?- conceptually, of course, we realize people in
Europe and Sweden are not biologically different than the U.S. I mean,
obviously that wasn?t the problem. The problem was, the data were
difficult for us. You know, we didn?t understand the problem with the
pathology, you know, the internal inconsistencies.

The thing with the Gleason score, you know, was difficult. That?s one of
the reasons we asked the sponsor to perhaps, if it?s at all possible, to
get the slides, and better define the population. That?s what we?re
trying to ask there.

CHAIRPERSON PRZEPIORKA:  Dr. George.

DR. GEORGE:  I had a question about the further follow-up, and I guess
it?s related to the definition of the primary endpoint, as well. How
would you ?- if you do further follow-up, which is, I think, certainly
needed \-- if you do that, what are you going to gain unless you expand
the endpoint some to ?- if you?re going to include bone scan only,
you?re going to have some issues there with people who have clearly
progressed, but just didn?t have a bone scan yet. And you?re going to
have also issues of requiring a bone scan at future times. Have you
thought about that, I mean, beyond the two years? I mean, if you just
said two years, then there?s not much point in following up beyond two
years, if that?s what your major endpoint would be. DR. SHAMES:  Well,
quite frankly, I was ?- I wonder if I?ll often see what happened to
survival ultimately. I mean, that was one of my main reasons for asking
for follow-up. I?m not sure there?s going to be a tremendous difference.

DR. GEORGE:  Well, one of the things that was presented in the FDA
presentation was, further confirm that the durations of the
time-to-progression information is maintained, and that?s more than just
survival. I mean, I agree certainly with the survival, but the ?- you?re
going to have to think hard about ?- that endpoint thing is not going to
go away just with further follow-up.

DR. MONROE:  If I could just comment. The sponsor has indicated that
these protocols do require bone scans at two-year intervals, so
objectively they should be done in any patient who has not had
documented objective progression at years four and six, as well. So that
should provide us with additional evidence of disease progression or
lack thereof in a relatively unbiased fashion.

DR. GEORGE:  That?s good. Would you do a bone scan in someone who
clearly has progression, I mean, that you already know has progression?
Is at advanced stage and, you know, you just didn?t do the bone scan.
You did other things.

DR. MONROE:  You?d have to ask the sponsor exactly what they?ve told
their investigators. It was our impression that these were supposed to
be confirmed by bone scan to address the concerns about not being able
to maintain blind, but they would need to address that.

DR. CARROLL:  Kevin Carroll, AstraZeneca Statistician, just to answer
the question. If you could just repeat that question. The shock just
confused me for a moment.

DR. GEORGE:  I was just concerned, I guess if bone ?- it says that bone
scans are supposed to be done every two years. If you didn?t do a bone
scan because a patient had had clearly advanced disease because of other
markers, and maybe died even of ?- I guess the death would be the
endpoint, but you still would have had ?- presume if you had done a bone
scan earlier you would have spotted it, but you didn?t. And I just
wonder if there are going to be patients that you?re going to end up not
counting as progression that were clearly progressions?

DR. CARROLL:  Thank you for the clarification. What the protocol
required was that in patients who had not previously progressed, then a
bone scan was scheduled at every two years. There was no intention to ?-
for a patient who progressed, say, at three years, to then do a bone
scan at four years if that would not be clinically indicated.

DR. GEORGE:  Right. But that then gets to be a problem in the FDA. Okay.
If it were ?- but it wouldn?t have been picked up as via a bone scan. It
would have been a rising PSA or something, I think, what they?re talking
about.

DR. MONROE:  It was clear from the beginning that both the sponsor and
the FDA said a rise in PSA would not qualify. There was never any issue
that PSA increases would be considered objective progression.

CHAIRPERSON PRZEPIORKA:  Dr. Redman.

DR. REDMAN:  Just to reiterate on the endpoint, and really just ask the
FDA directly, if I was coming to them with a trial of an intervention in
this setting, you?ve agreed that PSA is not valid. You?ve shown data
that you don?t accept bone scan because of the inherent error in bone
scan that all of us who practice are well aware of, that it?s very
difficult to read a bone scan that?s not attached to a patient and
interpret it. So I guess other than survival, overall survival, what
endpoint is acceptable if you ask the sponsor to redo the trial,
narrowly define the patient population. What is the end point going to
be?

DR. SHAMES:  We showed some of the problems with bone scan, but I don?t
think we said we wouldn?t accept that as a protocol defined bone scan in
everybody. A situation where we ?- in this particular case, and perhaps
some of the advisors can comment on this \-- we were concerned about,
particularly with Casodex because of this unblinding issue. So there?s
some issues that are particular here that may not be relevant to, you
know, other trials with other drugs we?re not as concerned about
unblinding.

The unblinding in the question of what the effect of Casodex is perhaps
on PSA, and that kind of thing. What exactly the effect is, you know. Is
it a variable effect? Does it change its effect over time, you know,
things like that. So I think that this particular drug has particular
issues, which might not be in other drugs.

CHAIRPERSON PRZEPIORKA:  Dr. Kelsen.

DR. KELSEN:  This is a follow-up to the comment that was made about
patients who have a rapidly rising PSA, have the option right now. They
get an LHRH antagonist, but Casodex is commercially available in the
United States at a 50 milligram tablet, and I?m pointing at the open
form. At least one patient who is taking 150 milligrams a day. This is a
question to the urologists, either here or from the sponsor. How
frequently is this therapy being used now in this area? Do we know
anything about that at all?

DR. ALBERTSEN:  I?ll just make an anecdotal comment. I know it?s
beginning to make its way into the medical community. How pervasive it
is, I think, depends on how close you are to a center that?s promoting
it, or to an individual person who might be promoting it. But I think
the very real issue is, as the long term concerns over LHRH agonists,
which have become the de facto treatment for men with rising PSAs, could
Casodex be the substitute? And that?s the reality that?s playing out on
the street. But I have no idea how prevalent it is yet.

DR. KELSEN:  I understand. My question was, it seemed like that might be
a default position, and certainly, we need to address the indication
issue.

CHAIRPERSON PRZEPIORKA:  Mr. Ohye.

MR. OHYE:  Thank you. I have a rather fundamental question about the
change in endpoints. Some people say I?m older than dirt because I?ve
been attending ?- before I retired I?ve been attending End-of-Phase-2
meetings, dozens upon dozens of them. And at the conclusion of the
End-of-Phase-2 meeting, the sponsor generally goes away with a good idea
of what would be needed to register the drug.

If I look at the history of this product, they had that End-of-Phase-2
meeting in 1995, and \-- was this division in existence in 1995? It was
not. It was the Metabolic and Endocrine Division then. I believe the
practice then was to allow the sponsor to carry away key elements of
agreements made, and then they would come back with a protocol based on
the agreements made, sort of a quasi contract with the division. And it
appears to me from the record, that they did that. And over the course
of the next three years, they completed enrollment. And then a year
later, the target was moved, and I think it would be very instructive
for me as a representative of industry to find out how the heck that
happened. Because, you know, these studies ?- you?re talking about a
huge study here, costs millions of dollars. I?m sure you all are
operating on good faith, but this moving target is quite troublesome to
me personally, and I?m quite sure to others. I have other questions, if
I may, but this is just a fundamental procedural question.

DR. SHAMES:  You?re absolutely right, in that when people come for an
End-of-Phase-2 meeting we do everything we can to make sure that
everything is appropriate so they can do their trials, and we?re all in
agreement. You know, we ?- there was disagreement about a lot of these
issues since we?ve been here maybe the last three or four years, so I
cannot say if we would have ?- those of us here would have agreed to all
of this, you know, the three different trials with the totally
heterogeneous groups and that kind of thing. And certain other ?- we
would have advised perhaps about Gleason scores, or central readings,
things like that. So it was pretty much after the fact that we got here
and looked at the trials and found the problems.

Now it brings us ?- and I agree that it ?- the overall procedure should
be that we stick to the ?- what we say at the end of Phase 2, and then
we let them go and then evaluate it.

Now sometimes people don?t ?- and I don?t know if that?s the case here.
Sometimes that doesn?t happen anyway. You know, we can?t stop trials for
sign problems. However, we are faced with this situation at it occurs
now. I agree with your point and, you know, the only thing I can say is
perhaps the people that reviewed it had a different view than we did,
you know. It was before our division even was assembled.

But the issue before us is what we have to deal with right now, so
that?s, you know ?-

MR. OHYE:  But nevertheless, we deal ?- as sponsors we deal with the
agency as an entity, and as not just individuals? opinions, but we deal,
you know, with the FDA as a whole.

DR. SHAMES:  Your point is very well taken, and I absolutely agree that
the procedure should be that we come to agreements at the end of Phase
2, and hold to those agreements unless there?s some scientific reason
that comes up later that causes us to have a problem.

MR. OHYE:  I think we all agree if there?s an overwhelming scientific
reason to change prior commitments, but if we deal as sponsors deal with
the agency as an entity, then we should be able to rely on prior
commitments.

I have a question for Dr. Monroe. I?m sure you weren?t implying \-- and
I just want to make this clear \-- that there is anything wrong with the
sponsor proposing a change in indication, because that goes on, you
know, frequently during the development of a product. I just want to
make sure that I understood that right.

DR. MONROE:  Well, the need to change an indication does come up not
infrequently, where an indication has to be modified to best reflect
what the data are. What we were, I think, trying to convey to you is
that, in an effort to identify who would best be served by the use of
this drug as we reviewed it and brought up these issues, the indication
was changed on multiple occasions, because the data clearly didn?t
support certain things. Adjuvant issues in early disease, and we were
surprised that the application even came in with such a broad
indication, because there was just no data to support that. When those
issues were brought forth, the sponsor acknowledged that and made these
changes which perhaps could have come in initially.

And that I think it?s also a reflection that I don?t believe that we or
the sponsor \-- I shouldn?t really speak for the sponsor \-- has
adequately characterized who would benefit by adjuvant therapy. On that
last slide I showed, we pretty much took aside all of the issues about
what the endpoint should be. And those data I showed, they showed
absolutely no effect of Casodex in U.S. Trial 23, based on the sponsor?s
present definition of high risk. And it?s our concern that \-- let? say
the drug were to be labeled as that, and you say high risk. Well, are
you going to define what high risk is, or are you going to leave it to
each practitioner? I don?t know.

But if you use criteria that I think are generally accepted, as we use
our high Gleason score, post-operative PSA, and a high pre-operative
PSA, we didn?t see any benefit of the drug. And that?s our dilemma. We
just don?t know who would be served well by taking this drug.

MR. OHYE:  I beg the Committee?s indulgence. I have two short questions,
if I may continue. I believe I heard the conclusion that some of the
data didn?t support a clinical benefit when you were making reference to
some of your slides. This may be useful for deliberation when we
discussed the questions. Are there data likely to predict clinical
benefit?

DR. SHAMES:  Let me go ?- first, I would like to go back to the other
issue, because Dr. Hirsch reminded me that in 1995, because he looked
this up, we did not ?- we discussed the issue of the endpoints and did
not totally agree with the endpoints actually, and the endpoints were ?-
and as I said, you know, we can?t stop trials for design problems. We
can only stop them for safety problems. Can you repeat the question,
because I ?-

MR. OHYE:  I was making reference ?-

CHAIRPERSON PRZEPIORKA:  I?m sorry. Before you go on, can I just address
that, please. Just switch hats as a former member of an IRB, and to
encourage you to re-look at that issue specifically, because from the
IRB point of view, to put a patient on a trial which will not give you
an answer is a safety concern.

DR. HIRSCH:  The issue is one of bias, of limiting bias. In 1995, the
company was informed that there was a high likelihood that there would
be a high incidence of gynecomb in the treatment group, and that that
might unbias the trial. That was clearly stated and acknowledged by the
sponsor, and it did come to pass. And in an effort to reduce bias, we
discussed with the sponsor alternative endpoints that might be less apt
to bias. And that was, to the best of our knowledge, one bone scan that
was done in everyone at year two, so at end of Phase 2, we held these
discussions with the sponsor.

DR. BRAWLEY:  Can I ask, was there an ?- pardon me for interrupting. Was
there an agreement between the FDA and AstraZeneca about what relevant
endpoints would be for these studies that would lead to approval?

DR. SHAMES:  Since my ?- I have been there in various capacities \-- we
could not totally agree. We knew what the endpoints were, but we did not
agree about these other endpoints, the objective progression endpoints.

MR. OHYE:  I?m afraid I?m taking too much time, but one last question,
if I may. I was trying to ask \-- I remember hearing the conclusion that
the data didn?t support the finding of a clinical benefit. My question
was, and I thought this might be useful when we go into our own
deliberation, were there any data likely to predict a clinical benefit?

DR. SHAMES:  I think an objective ?- however we defined it, an objective
progression would be information that we would consider clinically
important, or delaying objective progression in a way that was not
biased.

DR. MONROE:  Well, if I could add a little bit to that. The question of
accepting the bone scan data is really not a question. I raised the
concern that there is an inherent lack of accuracy in these methods, and
we are concerned that a degree of inaccuracy needs to be considered when
you?re looking at small absolute differences between treatment groups in
trials that show very few events. We?re not saying that the bone scans
are not acceptable as an assessment. We think that was a very valid
endpoint, and would be done in a way that would be subject to minimum
bias.

I think we would accept other possibly objective endpoints if they had
been well documented, and had been confirmed by some type of a central
reading, as is frequently done in oncology trials. And all of that was
lacking in this particular trial.

MR. OHYE:  I?d like to reserve my comments for the general discussion.
Thank you.

CHAIRPERSON PRZEPIORKA:  Dr. Blayney.

DR. BLAYNEY:  I have two things. One gets to the issue of bias, as you
put it, or this unblinding effect by Casodex, or unblinding effect. When
you?re treating a patient, was your concern that gee, Mr. Smith, you
have gynecomastia. You must be getting the active drug, and we?re going
to ignore this urinary retention, or this new bone pain, or this rising
PSA. Whereas, in somebody who is not having gynecomastia, they?re
treating investigator would jump on a similar symptom in some
differential manner.

DR. SHAMES:  I think it?s the general issues that we?re concerned about,
regarding bias. You know, whatever ?- if you know that 80 percent of the
patients ?- if the trial is essentially unblinded, then it?s not the
kind of trial that gives us the same kind of data as a blinder trial,
and we were trying to get the best data possible.

DR. BLAYNEY:  I mean, the endpoints you showed seemed to be very
unsubjective. I mean, death, bone scan progression or some other PSA
progression seemed to be uninfluenced by observer interpretation. So I
think the suspicion or the concern that you had in setting an endpoint
that gynecomastia or some clue that a patient was getting active
treatment turns out to be ?-

DR. SHAMES:  Well, it?s true that death and bone scan are ?- we accepted
death and bone scan. And PSA is a separate issue which, you know, needs
other discussion. We don?t have the data right now to use it as a
surrogate endpoint, and many of the other events were driven by the
investigators.

DR. BLAYNEY:  But I?m saying that I don?t see that an investigator would
have that ?- would be biased by the ?- he?d do the same ?- an
investigator is likely to do the same thing, regardless of whether he
thinks the patient is getting active treatment or not.

DR. SHAMES:  Well, I guess I would disagree about that.

DR. BLAYNEY:  Fair enough. The last thing, I think, you?re asking us to
make a judgment here basically on subset analysis since 1995 and this
inauguration of the trial. You said well, wait a minute. Let?s now
retrospectively or encouraged the sponsor to retrospectively define a
group of men whom they thought might benefit based on a retrospective
subset analysis. That?s something that has been looked at askance at
this committee level, and I?d like to hear why you would want to do
that.

DR. SHAMES:  Why we did subset analyses?

DR. BLAYNEY:  No. Why you would encourage the sponsor to bring forward
an application for an indication based on a ?-

DR. SHAMES:  No, it was not a sub ?- what they brought ?- their original
indication was essentially everybody in this trial. Their original
indication was everybody. Everybody who doesn?t have metastatic disease
was the original indication. We didn?t think that was reasonable.
However, the data supported it. And we?d said that and they went and
tried to find the appropriate subgroups. And, you know, we are ?- you
know that?s what happened.

DR. BLAYNEY:  And based on that, you know, we might as well just go
home, because they haven?t demonstrated that. But I think there?s
efficacy there that we need to ?- I would encourage you all to find a
way to take care of ?-

DR. SHAMES:  Actually, the advice we?re looking for here, I mean, quite
frankly, we are ?- you know, I said this to the sponsor. We could not
figure out how to communicate who these people are to be treated with
this medication. That was our basic problem, because there were various
trial design problems, aside from the pathologic problems, et cetera, et
cetera. And that?s reflected in the questions, and we certainly didn?t
want to go approving this for everybody since this is not a totally
benign drug, at least what we know about it.

DR. BLAYNEY:  I think Dr. Albertsen?s comments are right on point. It?s
likely to be a drug that is used as a substitute for another
non-approved drug. And this is going to be an expensive drug that
patients will have to put that into their and their physician?s
calculus.

CHAIRPERSON PRZEPIORKA:  Dr. Brawley, do you have another question? Dr.
Hanno.

DR. HANNO:  Just two very quick points. One is, since the bone scan data
is so critical in this, I really think that some confirmation of which
of the bone scans are truly positive would be helpful in at least
calculating the absolute risk, because it may be much lower than it
appears in these data. And there are plenty of studies that show how
bone scan data is kind of unreliable. Even though it may be the same
unreliability in both sides, it doesn?t mean that the risk is
significant.

Second, aren?t we ultimately talking about if we?re going to use delay
in objective progression as the endpoint and agree to that, don?t you
really need an answer on whether immediate hormonal therapy versus
delay, versus intermittent hormonal therapy? Which of those ?- is there
a problem between them? I mean, that?s really the underlying issue here
that we don?t have an answer to, and that we?re sort of skating around,
I think. And in the absence of that, you?re really looking at survival
and quality of life data.

CHAIRPERSON PRZEPIORKA:  Dr. Brawley.

DR. BRAWLEY:  Yeah. Seeing that there was someone from AstraZeneca that
wanted to respond to one of the questions I asked earlier, is that
allowable?

DR. SCOTT:  Ask the question again, please.

DR. BRAWLEY:  Well, I was asking what was the FDA and AstraZeneca?s
agreement back in 1995. And it just seems somebody had gotten up ?- I
just saw him out of the corner of my eye, and they weren?t allowed to
speak.

DR. SCOTT:  Mark Scott, AstraZeneca. If you ?- the interpretation of the
minutes is there were a couple of different endpoints that were under
debate. We designed the Casodex clinical trial program as one large
program, where the analysis we proposed was based on objective
progression as we defined it in each trial. The difference really was
whether you would need to have two clinical trials to support that
indication, if in fact it was time to progression.

The overall analysis could be done if survival was the endpoint of
interest, but we focused on clinical progression as the primary
endpoint. And we agree that we did have the conversations about the
potential for unblinding, but I believe that we?ve demonstrated in the
application that blinding was not ?- or the unblinding was not present
due to the frequency of the assessments being similar between treatment
groups, and across studies.

CHAIRPERSON PRZEPIORKA:  Dr. Hoberman.

DR. HOBERMAN:  I have two points. One is that I agree with the sponsor
that the issue of blinding is probably not a substantial issue in these
trials. The results are quite robust in Europe, whether or not you take
into account time to event or incidence of objective progression. The
other thing has escaped my mind. I must have gotten a shock from this.

Oh, yes. I was just struck by lightning. One of the ?- and I?m very
sympathetic to what Dr. Blayney said, because once we ask the sponsor to
go back and find a subgroup in which there would efficacy, it was
practically doomed to failure from the beginning, and the reason is that
the U.S. trial was a null trial. There was no room for anybody to get
true benefit. And so what happened was that the sponsor went back and
did what they could, and had a very, very small subgroup, which showed a
leaning towards results that were similar in Europe. The problem is that
it was based on so few results, so few patients that it simply wasn?t
reliable, and it was hard to take seriously.

The slide that Dr. Monroe showed, which happened when you took into
account more patients to try to increase the size of this high risk
population, the whole thing blows up in your face. You?re including more
people in a null trial, and the hazard ratio goes right back to one, so
it?s sort of like a rubber band. You pull it out, and it?s going to snap
back. So I think that in this data is futile to try to go back and try
to find a believable subgroup of patients in the United States who
actually benefitted from the drug. And we?re in this problem because we
have something in Europe that is trying to be extrapolated to the U.S.

CHAIRPERSON PRZEPIORKA:  Thank you. Dr. Martino.

DR. MARTINO:  This is terribly reminiscent of breast cancer. The real
problem that I see here has to do with the fact that the gentlemen who
were enrolled in America actually did too well to show you much of a
difference if there could be one. It really comes down to that simple
problem, which is in no way unheard of in adjuvant therapies. And I
really think that?s at the gut of all of this, that the patients did so
well that there?s no way, at least with this length of follow-up and
this volume of relapse, which we?re really in the range of what, 5
percent or so for that one trial. In all fairness, how could you expect
that there would be much of a difference unless you had a true miracle.
And you can turn that data inside out and upside down, and it?s not
going to change unless either you add more patients or more time passes.

The other issue is, you lost a third of the patients. Remember that they
actually withdrew, which further reduces your number, so the real
problem is unfortunately, or fortunately, how you choose to look at it,
that the Americans did well.

CHAIRPERSON PRZEPIORKA:  Other comments. Okay. Then before we break for
lunch, we have two more individuals who want to respond at the open
public hearing after hearing all the data, so I?d like to call to the
podium first, Mr. John Page from Us Too! International.

MR. PAGE:  My name is John Page. I?m President and CEO of Us Too!
International. We are a 501(c)(3) prostate cancer education and support
group. As a matter of disclosure we do, in fact, get funding from a
number of sources. One of them is AstraZeneca, but do not interpret that
to mean that someone has paid me to come here and make the comments that
I am about to make, because any people that know me, know that that is
probably the farthest thing that could be from the truth here. And
unfortunately, I have not been in this kind of a situation before, so if
some of my comments come out as too aggressive, please forgive me.

I am not, by the way, a prostate cancer patient, but I do work with
them, have over the last three years on a daily basis, and so I speak
really more as a patient advocate, as opposed to some of the gentlemen
this morning we who have spoken really from the heart, and having to
deal with this full on. I have had access to the data over the course of
the last year, and so I?ve had a good opportunity to look at it.

I am also someone who has worked in healthcare for the last 30 years
almost, and have a science and engineering background, so I do have an
appreciation for statistics and dealing with research, but I do not
consider myself, thankfully, simply a researcher or statistician, so I?m
really addressing you really from the human perspective. And in dealing
with that from the human perspective, I think I look at this as trying
to define do patients deserve the information that is contained in these
studies.

I hear the FDA talking about their determination of who should get this
drug, and perhaps it?s just a generation that I have, but I find that
not what I would hope the FDA would be looking at. I enjoy the FDA
protecting me from bad things, and I enjoy the FDA giving me information
that I can rely on, but I would hope that people would recognize that as
a patient, it?s really up to the patient and his or her physician to
determine what course of action is best for them. I don?t know that
anyone in this room who?s not having to make that decision on a personal
level should be excluding information given to the patient. And I think
that?s really the crux of what I see us talking about here, is will you
allow information about this trial to be provided to physicians and
patients, and have them make a determination about whether or not this
treatment option should even be considered.

I enjoyed the comments about the real world perspective, and whether or
not you are setting up an Alice in Wonderland reality, but from all
intents and purposes from a patient perspective, PSA rise is, in fact, a
de facto standard that a patient uses to determine whether or not his
disease is progressing. Whether we want to argue about that in theory
and in research terms, the reality of the practice is a patient goes to
his physician when he sees a PSA rise and says I?m afraid my disease is
progressing, and I want to have another treatment. Good or bad, that?s
the reality of the situation.

And I think the risk benefit equation can only be, and can best be
determined by that patient and his family and his caregivers, because
when it comes down to it, and you look at the NIH mandate that a patient
be responsible for his or her care and the decisions thereof, the
patient can?t make that determination unless they are given information.
And there is no information that can be given unless this drug is
approved. And so I find that by cutting off, prospectively cutting off
even the discussion of potential benefit, and I think what I?m hearing
after reviewing the data for a good number of months, and in listening
to the FDA and AstraZeneca today, what I?m hearing is that there is
definitely benefit coming ?- we?re trying to determine what group of
patients that is, but there seems to me benefit, substantial benefit.
Depends on how you define that, but at relatively small risk, and I
think as long as the patient is informed up front about what those risks
are, there seems to me very clear, and one of the gentleman from the
U.K. who talks to his patient about expecting gynecomastia or breast
pain. I think that that?s really what should happen. The patient should
be fully informed.

Whether or not that happens is really a clinical decision, but when
you?re looking at 40 to 60 percent reduction in progress of this
disease, to me from a patient?s perspective, that would be very
significant. And when the risks are identifiable, potentially
manageable, and this is not an irreversible ?- I mean, the patient can
go off this if he chooses, or if he decides that it?s not something he
wants to do, I think that that?s really a patient decision. And again,
as a patient advocate, my point is empower the patient with the
information to make that decision.

I will use one statistic, I guess, because I think that it?s important.
There were at one time more than 100 men in this room. If we use
statistics, my guess is 20 men in this room will come down with prostate
cancer. If I use further statistics about recurrence, 5 to 10 of those
men will have a recurrence and potentially be seeking treatment options
for which they have, at this point, limited or no treatment option
availability.

Would you, if you were one of those five or ten men, want to
prospectively eliminate a potential option with known risks. I guess
that?s the question I leave you with, because as a patient advocate, a
patient is really looking at options that are out there. When there are
no options out there, and currently for a subset of patients, there are
no treatment options out there, this represents a viable treatment
option if they and their caregiver chooses to do it. And again, I think
that?s the most empowering thing you can do today, is allow the patient
to have the information upon which to make a decision that affects their
life. Thank you very much.

DR. BRAWLEY:  May I ask him a question?

CHAIRPERSON PRZEPIORKA:  Yes, Dr. Brawley. Mr. Page.

MR. PAGE:  Yes.

DR. BRAWLEY:  Did I mishear you. Are you saying that the FDA is keeping
doctors and patients from discussing this data currently, and keeping
doctors from prescribing this drug as an adjuvant therapy at present? Is
that what you were saying?

MR. PAGE:  Right now, Casodex 150 is not an approved drug, and it is not
available, widely available. As a result, if it?s not approved, it
really doesn?t even come up in conversation except as an off-label
indication. And I think that if you are assuming that it is okay for us
to continue to treat patients routinely in off-label activities, then I
say by all means. I mean, you cannot approve this, but I think if you?re
going to be open and honest, and the reality of the situation is,
patients are looking for something that may give, as the data indicated,
perhaps a two year disease progression free life, that?s a quality of
life indicator that a lot of men are going to accept.

DR. BRAWLEY:  Have we seen data that show that there?s a two year
progression free interval with this drug?

MR. PAGE:  I looked at the data that is presented, and if you look at
the Casodex versus the placebo, there is a ?-

DR. BRAWLEY:  Really.

MR. PAGE:  It may be one year, it may be two years, it may be three
months. There is certainly what appears to be ?- and again, I?m going
based on what the data is. The data does not appear to be contradicted
by the FDA. There does appear even in the FDA analysis to be a benefit
in time to progression. Their time to progression does not include PSA,
but I can tell you, and Dr. Brawley, you probably know from your own
practice, that a patient PSA rise is, in fact, a standard that a patient
uses, whether the FDA or researchers choose to use that or not. It is,
in fact, the de facto patient standard.

CHAIRPERSON PRZEPIORKA:  Thank you very much, Mr. Page. Next is Mr. Ben
Fay from the Wellness Community Delaware.

MR. FAY:  I?m sorry to say good afternoon. I have no conflict of
interest, but when I offered to come and say a few words here,
AstraZeneca did agree to reimburse me for my out-of-pocket expenses.

I?m a retired chemical engineer from Wilmington, Delaware. In February,
I?ll be a six year survivor of T4 node positive prostate cancer and I
watched my father die a horrible and degrading death from prostate
cancer. I?m the community coordinator for the Wellness Community
Delaware. I?m a Director and Secretary of the First State Prostate
Cancer Support Group, and I also volunteer at the American Cancer
Society and Christiana Cares, the principal health provider in northern
Delaware. And as part of Christiana Care?s Cancer Outreach Program, I
volunteer with a group of African American men to promote prostate
cancer awareness and screening.

In these roles I know and speak to dozens and dozens of men who have or
are at risk of having prostate cancer. I think I can speak realistically
about how men at the grass roots level feel about prostate cancer. And I
will tell you, and I can speak very confidently of this, there are three
concerns that men have related to prostate cancer, other than survival.
The first concern is number one on everybody?s list, loss of sexual
activity. Number two on just about everybody?s list is incontinence, and
number three, is hot flashes. Rarely hear any mention or concern of
gynecomastia, and that?s a fact.

I?m simply going to build on what John said, and skip some of the
things. I agree with everything he said virtually word for word. I?d
like to talk about the African American community where I really am
familiar. There are many men there who refuse to be screened or who
avoid, or delay treatment after diagnosis of prostate cancer, because
they fear loss of sexual ability. These men represent a self-selected
and I think largely unidentified de facto group of watch and waiters. If
these men had the 150 milligram dose of Casodex available with its very
low level of adverse effects, adverse sexual side effects, they would
elect earlier intervention, and thereby distinctly improving their
likelihood of living longer and better.

And delay or avoidance of treatment is not limited to the African
American community. Many Caucasian men who have had definitive treatment
for prostate cancer, radiation therapy or radical prostatectomy, and who
now find themselves with a rising PSA, and this is a phenomenon clearly
regarded by both the men and their physicians as a sure sign that their
prostate cancer is progressing. Delay taking the next step, which is
chemical or physical castration, and I meant to tell you that if I
stumble during the presentation you can chalk it up to cognitive
dysfunction or whatever you called that earlier, because as part of my
treatment, I had an orchiectomy almost six years ago. And they do this,
they delay the treatment because of the horror stories they hear about
hot flashes, or because they fear losing whatever sexual function they
still have.

These fears extend across the whole male spectrum. I?d like to give you
three quick examples. Dr. Soloway talked about some patients from the
doctor?s perspective. I?m going to talk to you about them from the
patient?s perspective, and from my perspective. And I?m going to talk to
you about three men that I know personally, that are friends, that I
talk to. At the Wellness Community we deal with the emotional aspects of
cancer. We talk, like you never heard men talk. There is no secret
unbarred in our discussions, but anyhow, one is an African American man.
He delayed additional treatment when he had a rising PSA following
radiation out of fear of hot flashes, just that, hot flashes. He allowed
his prostate cancer to progress until it was untreatable, and he died, I
think prematurely.

George, a Caucasian has a Gleason Score of 6 and a PSA varying between
15 and 20. He?s gambling on watchful waiting because he does not want
the side effects of any currently used treatment. Lou is a 76 year old
Caucasian who has radiation. On Monday night at our support group
meeting at the Wellness Community, he was in tears as he described the
pressure he gets from his 78 year old wife, new bride, when he loses his
ability to have an erection following injection of an LHRH agonist, so
he stops taking the injection. His erectile dysfunction, his erectile
function returns. I did stumble, and his PSA rapidly climbs to 80 before
he panics and resumes the injections and the devastating cycle restarts.

These men need the option of taking the 150 milligram dose of Casodex,
and they need it now, not years from now when every I is dotted, and
every T is crossed. The risk of taking it, as I read the data, is very
small, and the potential benefit is great. Give us, the patients, the
opportunity to make the choice. I beg you. I beg you to approve today?s
application. Thanks.

CHAIRPERSON PRZEPIORKA:  Thank you very much, Mr. Fay. Is there anyone
else who has a comment to make? In that case, I want to actually thank
both Mr. Page and Mr. Fay for their courage to do this after the
presentations, and really address the data from a patient?s perspective,
and come here to do that. Thank you.

We?ll break now and return at a quarter to 2. Actually, I?m sorry, 2:00,
but Dr. Templeton-Somers wants to make an announcement first.

DR. TEMPLETON-SOMERS:  One of the big advantages of holding an open
advisory committee meeting is that discussions like these take place in
an open forum. It?s unusual for this particular committee to have a
lunch break in the middle of an application, and I?d like to put forth a
gentle reminder to everyone in the room that discussions of this
application with the Committee should wait until this afternoon when our
open meeting resumes and everyone can hear and participate. Thank you.

CHAIRPERSON PRZEPIORKA:  So please return here at 2:00.

(Whereupon, the proceedings in the above-entitled matter recessed for
lunch at 1:20 and resumed at 1:59

p.m.)

A-F-T-E-R-N-O-O-N S-E-S-S-I-O-N

(1:59 P.M.)

CHAIRPERSON PRZEPIORKA:  Dr. Shames, you gave a very nice introduction
to the questions earlier today, so unless there?s anything burning that
you wish to add, I will dive right into it. Fine, let us dive. So we?re
going to discuss Casodex for adjuvant therapy to radical prostatectomy
and radiotherapy of curative intent in patients with locally advanced
non-metastatic prostate cancer who have a high risk for disease
recurrence or immediate treatment of localized non-metastatic prostate
cancer in patients for whom therapy of curative intent is not indicated.

We?ll go through the questions one by one, ask if anybody has any
comments, and then call the question and take the vote, except for the
essay questions, which I don?t think we have today.

Number one, across ongoing Trials 24 and 25, only 15.6 percent of
patients using sponsored preferred endpoints, and 9.3 percent of
patients using FDA requested endpoints had objective progression of
prostate cancer or died from any cause in the absence of disease
progression. At the time of data cut-off, June, 2000, median follow-up
was 2.6 years in Trial 24, and three years in Trial 25. In the absence
of meaningful survival data or quality of life benefits, are these
studies sufficiently mature to conclude with a reasonable level of
confidence that patients treated with Casodex in these trials will
derive clinically significant long term benefit? If not, what additional
information is needed? Dr. Krist.

DR. KRIST:  Well, I ?- looking overall, it?s kind of tricky for me
hearing both perspectives. I have some reservations with the subgroup
analyses. I have reservations with combining the data on the studies,
and my inclination is to say it seems like there?s some form of a
benefit, but I can?t put my finger on as to who it is. And I also think
that whether that conveys into a survival benefit, there is some room
for question with that, particularly with U.S. patients, because I think
that the populations treated and diagnosed in the U.S. probably are very
different than those treated in other countries.

CHAIRPERSON PRZEPIORKA:  Any other discussion of this question? Dr.
Kelsen.

DR. KELSEN:  I think this is a question again to the urology, the
advisers at the table. My impression is that although the 23 Trial in
the U.S. focused on a different population, people undergoing curative
therapy, that many patients in the United States are seen with the same
stage of disease as patients seen in Trials 24 and 25. And it?s not that
we don?t have patients in the United States who present with these
states of disease or rapidly develop them, but we just didn?t ?- they
just weren?t studied in this particular cohort. Am I correct?

DR. HANNO:  I think you are correct. I think some of these patients get
treated with the LHRH analogs, and I think that it would be more
appropriate to compare it to that than to placebo, because a lot of
these patients don?t get treated with placebo when they?re in that
stage, or at least have that in the mix.

DR. KELSEN:  But the population exists in the states.

DR. SCHOENBERG:  Well, I think we should just have the caveat that
although that?s true, we see a very significantly declining number of
the more advanced stage disease, precisely because of the very proactive
approach that the American medical community and patients have taken
toward early diagnosis.

DR. ALBERTSEN:  My concern in the indication is the term adjuvant, and
then moving on to define high risk. I don?t think the data I?ve seen
convinced me that true adjuvant use of this drug is sufficient since
Trial 23 basically showed no difference. Where I begin to hedge a little
bit is the question of high risk patients. And indeed, those are more
easily identified post surgery, when you begin to see a rising serum
PSA. Unfortunately, they?re not the subjects of any of the trials, and
they?re the ones of most interest to the urologists. As a consequence,
I?m struggling on how best to interpret the trials of the more advanced
disease, because I believe they do show efficacy. But then you have the
question, are the European population sufficiently generalizable to the
American population? I think they are, but I think the American
population has just been identified a good five to seven years earlier,
implying that you probably need to have people on this drug for at least
five to seven years before you see the true survival differences, or at
least the efficacy differences that you see in the European trials.

CHAIRPERSON PRZEPIORKA:  Dr. George.

DR. GEORGE:  I think it?s ?- the problem here is a follow-up issue,
particularly on 23. And I think we do need further follow-up to be sure
of what we?re getting. And one of the things in saying that, we?re in a
situation where we would like to have the answer faster. I mean, we
would like to have fast answers, but we?re in a setting where it?s very
difficult to do. It?s a long time before recurrence, and certainly
before we have much information about survival. And that?s just a tough
situation.

We?d like to have very good surrogate markers that would spot all this,
but we don?t have them. And so my take on this is, these are very
interesting results, but follow-up is a big issue.

CHAIRPERSON PRZEPIORKA:  Dr. Redman.

DR. REDMAN:  I guess the point here is significant long-term benefit. I
think, you know, following patients in 23 for the next 20 years isn?t
going to really answer because of the patient population. But if you
look at the two European trials, I don?t think 2.6 or three years is
adequate follow-up to say that there?s a long-term benefit versus a
potential short-term benefit. I mean, it?s a quandary in oncology, do we
treat you now with toxicity, and there is toxicity to this drug, more so
than no treatment. Or do we wait until you develop symptomatic
progression and treat you at that time for ?- you know, overall survival
is a long-term benefit.

CHAIRPERSON PRZEPIORKA:  Dr. Brawley.

DR. BRAWLEY:  I would agree that the issue of long-term benefit is the
real problem here, that just two to three years doesn?t do it. If there
was a trial that showed that there was a survival benefit, that would
be, in my mind, a slam dunk and very easy to recommend approval. But we
haven?t even really proven that we make the patients feel better. We?ve
shown some indications that show that maybe some of the patients feel
better. And we?ve also shown that, at best, 85 to 90 percent of the
patients who would be treated wouldn?t even need therapy to begin with,
and 30 percent of folks are going to drop off, so I guess I have some
real problems and reservations here.

CHAIRPERSON PRZEPIORKA:  Dr. Martino.

DR. MARTINO:  I think I have a different reaction to this than what I?m
hearing around the table. These are patients where the word adjuvant, I
think, does apply. They are patients without obvious distant metastases,
and we?re looking at their first suggestion that they have metastatic
distant disease. Okay? That is the adjuvant setting. And what you
normally see when you do adjuvant trials is you don?t see survival
advantage until years later. You tend to see that there?s a difference
in terms of when patients have their first evidence of recurrence.

I think that?s what you?re seeing in Studies 24 and 25. You?re not
seeing that in Study 23. Many of us could have almost predicted that you
wouldn?t see it this quickly in that particular U.S. trial. So for me,
there really is nothing here that disagrees with what I recognize is a
basic principle, that this is a hormonal disease where hormonal therapy
to a small degree, which is the problem with all of our adjuvant trials.
It is that 2, 3, 4 percent if you?re lucky, that you see a difference
between a treated and untreated group. So I think for me, there is value
to this therapy in the patients that were treated with it, which is what
the question states. The issue of whether that can be translated to the
American population is a different issue for me.

CHAIRPERSON PRZEPIORKA:  And I think I want to echo what Dr. Martino
says. If you do look at the curves, they do separate. And if you follow
the curves long enough, eventually all the curves will go to zero, and
so we have to figure out what does long-term really mean in the life of
an elderly patient or a young prostate patient. And so some of the
curves were very definitive, in not just P-value but size difference,
the interval difference between the placebo group and the treatment
group. Dr. Brawley.

DR. BRAWLEY:  Yeah. That gets back to an earlier point. The reason why
we don?t see median time to progression in the two arms is neither arm
has actually lived to median time to progression yet. That really means
that we?re not treating very much at this juncture. I mean, if there is
a benefit, and the advocates really need to understand this. You know,
if you?re talking to that black guy up in Connecticut, you need to tell
him there?s a one out of 25 chance that this pill may help you, and a
one in three chance that you?re going to drop off the pill because of
side effects. You really need to tell him that.

CHAIRPERSON PRZEPIORKA:  Other discussion? Then I?ll call the question
once again. Across Trials 24 and 25, only 15.6 percent of patients or
9.3 depending on endpoints had objective progression of cancer or died.
At the time of cut-off median follow-up was 2.6 and 3.0 years. In the
absence of meaningful survival data or quality of life benefits, are
these studies sufficiently mature to conclude with a reasonable level of
confidence that patients treated with Casodex in these trials will
derive clinically significant long-term benefits? Dr. Redman.

DR. REDMAN:  No.

DR. BLAYNEY:  No.

DR. GEORGE:  No.

DR. CHESON:  No.

DR. ALBERTSEN:  No.

DR. REDMAN:  No.

DR. KELSEN:  Yes.

CHAIRPERSON PRZEPIORKA:  Yes.

DR. KRIST:  No.

MR. ANDERSON:  No.

DR. SCHOENBERG:  No.

DR. BRAWLEY:  No.

DR. HANNO:  No.

DR. PELUSI:  No.

DR. MARTINO:  Yes.

DR. ALBERTSEN:  No.

CHAIRPERSON PRZEPIORKA:  That?s three yes and 13 no. Question two, do
the data that is clinical stage PSA level and lack of valid Gleason
Score from Trials 24 and 25 allow for the adequate definition of a
patient population that can extrapolated from the non-U.S. studies to a
defined group of U.S. patients who will derive significant benefit from
Casodex therapy?

DR. CHESON:  Point of order, there?s a second part to the first question
that wasn?t addressed. If not.

CHAIRPERSON PRZEPIORKA:  Oh, sorry. Thank you. If not, what additional
information is needed. Yes, thank you. Would you care to take that? Dr.
George.

DR. GEORGE:  I?m the one who noticed that. He?s the aggressive one who
spoke up, but I had ?- I thought we were going to address that because
that was an important part if we did say no.

CHAIRPERSON PRZEPIORKA:  Yes.

DR. GEORGE:  And to me, again getting back to the follow-up issue, and
it?s still the ?- what are these types of information we can maybe talk
about later I guess, number two, and so forth, but the key with respect
to follow-up is to follow-up until the number of events is higher, the
percentage of events. I won?t go through all that again, but it?s still,
even in the ones like 025, it?s still a low percentage of overall
events. And events I?m talking about here are either death, bone scan
progression, or even this other progression. You just add them all up,
especially in the death category, of course, but in the others as well.
The overall percentage is still low enough to be disturbing - not
disturbing, but to be unreliable with respect to the long-term issues.
Even though I agree that unless you change definitions of endpoints, the
early results aren?t going to change. But we do need to know the
long-term, even granted that everybody either dies or progresses
eventually. You still want to see what happens later, and have more
reliable answers. So the kind of information I would say we need first
and foremost, is a higher percentage of events in all these categories.

CHAIRPERSON PRZEPIORKA:  Dr. Cheson.

DR. CHESON:  Yeah. And just all kidding aside here, I want to agree my
friend Otis over there, in that you have to look at long-term in the
context of the natural history of the disease. So whereas, you?re saying
it?s going to be two years, three years, four years, five years, you
have to recognize what the median survival is, and look at these events
that Steve was talking about in relationship to that sort of a time
point.

CHAIRPERSON PRZEPIORKA:  Dr. Albertsen.

DR. ALBERTSEN:  In terms of additional information needed, even though
the FDA does not accept PSA progression as an endpoint, I would, for
one, like to have seen the data presented with that as an endpoint,
because one of the problems with the way that studies are currently
constructed is that a valid endpoint to show efficacy is so far out in
the future, that I feel as currently constructed, you have no other way
of addressing the answer but saying no, because of the way the problem
is framed. Therefore, reframing the endpoint and adding some more, a two
or three year follow-up I think might, in fact, lead us to a better feel
for how this drug is truly working.

So two pieces of information. One, a new endpoint which has not been
thrown on the table yet, and a little more time.

CHAIRPERSON PRZEPIORKA:  Any other comments? Okay. Now on to question
two. Do the data from these trials allow for adequate definition of
patient population that can be extrapolated from the non-U.S. studies to
a defined group of U.S. patients who will derive significant benefit
from Casodex therapy. Dr. Schoenberg.

DR. SCHOENBERG:  This is ?- you?re calling for comments. Correct? I?m
concerned because I think the groups of patients are very significantly
not comparable. And that doesn?t mean, as I think people have noted
previously, that there aren\'t interesting and compelling data to be
derived from the European trials, but the U.S. population is very
different, the one that was studied. And because of the confounding
problem of identifying exactly which pathologic entities were being
studied in 24 and 25, I?m particularly concerned that we?re going to
have difficulty identifying who?s going to benefit. And I am very
concerned as this particularly touches upon the issue of watchful
waiting, so I am very concerned about those two particular problems.

CHAIRPERSON PRZEPIORKA:  Can I ask if you can give your opinion on the
subgroup separately? I hear that for the localized disease group with
watchful waiting you don?t believe that the subgroups, that the two
groups are comparable, but what about the high risk group? Would they be
more comparable, or not comparable at all?

DR. SCHOENBERG:  Well, as I think we?ve discussed previously briefly,
the problem, and this may be reflective of an issue, a Transatlantic
practice difference, is that I think the groups that were studied in 24
and 25 are not ?- if not vanishing, substantially diminished in U.S.
practice. And it?s not that those people don?t exist, but they are
substantially less common. So I think yes, there are compelling data in
the higher risk groups, but again, we do have problems with definition.
And I believe one of the issues we\'ve discussed previously was the
lumping of 7 with 8, 9, and 10. That is, to my mind, very problematic,
so yes, I?m intrigued by that population, but I think more information
will be necessary to extrapolate this to the U.S. population.

CHAIRPERSON PRZEPIORKA:  Other comments? Dr. Blayney.

DR. BLAYNEY:  I would take a contrary-wise point of view. I think for
men who don?t want radiation, but who might have localized disease
discovered at surgery, the data from 24 and 25 might be useful in
helping them and their physicians make some decisions. For men who may
have a very high Gleason Score of 8 or 9, who would otherwise fit ?- be
much like the 24 and 25, I think in my practice in my community, that
would be ?- that data would help in decision making, so I would say ?-
my answer to this question would be yes.

DR. SCHOENBERG:  Actually, can I just ask a question?

CHAIRPERSON PRZEPIORKA:  Sure.

DR. SCHOENBERG:  Could you be very specific about how it will aid in
decision making? I?m just curious.

DR. BLAYNEY:  Some men don?t want radiation after a positive surgical
margin is discovered. Traditionally, those people are recommended, and
there may be some benefit to survival to salvage radiation. If they
don?t want radiation, this is an ?- I think there?s data that this
treatment might be an option for them.

CHAIRPERSON PRZEPIORKA:  Dr. Albertsen.

DR. ALBERTSEN:  In my mind, the data from Trials 24 and 25 do provide
evidence of efficacy for men with more advanced disease. The question
then becomes how do you interpret advanced disease in the context of a
U.S. population. Even though this wasn?t test tried, I think the
physician community is treating patients with rapidly rising or high
doubling time PSAs as men at high risk of failing. That probably can?t
be incorporated in the labeling of this drug, but in terms of how do you
do the walk across the Atlantic. In my mind, that?s how it would be
done. So, therefore, I do believe the data support efficacy in men with
more advanced, or as they say, high risk disease, and I would define
these, as I think people do in clinical practice, as people with rapid
doubling times.

CHAIRPERSON PRZEPIORKA:  Dr. Brawley.

DR. BRAWLEY:  Earlier there was discussion of subset analysis and how
subset analysis should be avoided. I just want to weigh in and reiterate
that subset analysis really should be avoided. It is my feeling that the
groups defined in 24 and 25, especially in Trial 25, can be
extrapolatable, and you can find people like that in the United States.
Although they are few and far between, I think you can find folks, so I
?- it might seem contrary to my first vote in the previous statements,
but I do believe that you can extrapolate from the foreign trials to
find similar patients in the United States.

CHAIRPERSON PRZEPIORKA:  And I think like Dr. Brawley, I also believe
that we?ve seen positive results here, and that there are probably
patients in the U.S. who would fit the same criteria as in the U.S.
trial. Where I would disagree also is that the statistical analysis that
was presented was not the most eloquent I?ve ever seen for looking for
subsets of populations and risk factors for regression, and whether or
not the treatment arm gives benefit, so I would disagree and say that
the data as presented are probably not adequate enough to define the
population very well. Other comments? Dr. George.

DR. GEORGE:  There was the ?- Dr. Hoberman, if he?s still here. He is
here, that he had done a number of analyses with respect to trying to
adjust for factors to see if the great discrepancies between all these
studies could be reconciled in certain ways; that is, to use the 24 and
25 data and see if you could predict some of the things that were
observed on the 23 study. And if I?m interpreting this right, I think
the answer was you couldn?t really do it. Maybe you?d like to elaborate
on that a little bit.

DR. HOBERMAN:  Yeah, I did it, and the numbers didn?t come out right. I
was not able to close the gap that should have been closed in the U.S.
by doing that progression projection from Europe. I?m not sure exactly
how this fits into the question that was being asked, but ?-

DR. GEORGE:  I?m just using that as an example, and why I?m kind of
reluctant in this area, because what ?- you know, if you assume ?- in
general, it?s not a problem that you have studies with markedly
different distributions of variables, as long as you have enough
patients treated in groups that you can use statistical procedures to
kind of adjust for that. In this case, it didn?t seem to work out right;
that is, something wasn?t right, either the variables weren?t measured
properly, the models that were being applied didn?t fit, and the
European studies didn?t seem to apply to the U.S. for some reason. It
would take a lot more looking at this issue to convince me that the
results from 24 and 25 could be used.

CHAIRPERSON PRZEPIORKA:  Dr. Redman.

DR. REDMAN:  I got a little confused by Dr. Albertsen?s comments. You
state that you wanted to somehow define a high risk population in a
population that wasn?t in these studies. Somebody with a doubling PSA,
so nine months after they?ve had the surgery, the PSA ?- or radiation
therapy, the PSA is doubling. These studies, if I?m correct, looked at
you had your radiation therapy. We?re not going to wait for PSA
doubling. You?re either going to go on Casodex, or you?re going to go on
observation, so I don?t know how that high risk population fits into
what these studies showed.

DR. ALBERTSEN:  That?s why I made the comment as the way I did. When I
looked at the data, the only patients that I can determine have any
benefit are the ones who are high risk, i.e., the European patients, who
in general have a disease that?s more advanced, precisely because they
don?t do or have not been doing in 1995 aggressive PSA testing as we do
in this country. So in 1995, you had a lead time introduced for most
American patients which you didn?t have in Europe. And that?s why, in my
mind, these two populations aren?t comparable.

When you use this drug very early on in the course of disease, it plays
out over 10 or 15 years. You?re not expecting, and I would be astounded
to see any benefit in the first five years. Hence, if this company were
to run the trial for 15 years, I think we might see a difference, so
that remains to be tested. But if I had to guess one population that
might be most likely to achieve, and again, this is a bit of a leap of
faith, it?s the very patients who we see failing radical prostatectomy
or radiation therapy. And we know from the Pound data published in JAMA
about two years ago, that men with PSA doubling times less than 10
months will generally progress to metastatic disease within 8 years, and
will die from their disease within 13 years. But that?s the time frames
we play out here. And again, it?s a bit of a leap of faith, but when
asked the way the question was structured, if I could identify a
population, considering the tools I have in 2003, that?s probably the
best way I could estimate such a population.

CHAIRPERSON PRZEPIORKA:  Dr. Kelsen.

DR. KELSEN:  I asked a question earlier about groups of patients in the
United States because we recently met with hospitals dealing with
minority populations in the New York area, and I was struck by the
comment of the physicians who worked in that area, of the large number
of patients that they see with prostate cancer who present with locally
advanced inoperable disease because of late diagnosis. And I wondered
whether or not that would not be an example of a population in the
United States that was very close to the European population.

I haven?t got a clue as to what those numbers are. I was wondering if
our urologist did, and I gather it?s hard to extrapolate those numbers.
But I think there is a population in this country that doesn?t get
screened, that does present late, and that might well mimic the European
population. It would be exactly what you?d be looking for. And they
don?t go on clinical trials, so there?s no data for it. I actually don?t
think 23 applies to this question at all. Twenty-three is a different
issue, totally a different study. Just because the trial was done in
Europe does not mean it doesn?t apply to American patients.

CHAIRPERSON PRZEPIORKA:  Dr. Brawley.

DR. BRAWLEY:  Yeah. David, you can perhaps correct me if I?m wrong.
Grace Lu-yao showed that 30 to 40 percent of men who get radical
prostatectomy in this country relapse by PSA within five years, many of
them within two years. And it is now very common that those individuals
get off-label LHRH agonist. I think a growing population will probably
get Casodex off-label, despite what one of the advocates said a little
earlier. But AstraZeneca is actually to be congratulated for doing
studies looking at these populations right after initial therapy. I wish
we had similar data with the other drugs that are being used in them,
but one possible place for Casodex and one study that still does need to
be done is in that 30 to 40 percent of Americans who after radical
prostatectomy, or after ?- I don?t know the percentage after radiation
therapy, who have a rising PSA. And unfortunately, that trial if it is
powered for survival, is going to be a 15 year trial. But I must point
out that AstraZeneca has presented data, very elegant data looking at
Tamoxifen at 10 and 15 years of data, so we just need to do the
equivalent in prostate cancer. And in Tamoxifen, they show the survival
benefit which may or may not be available if we use Casodex as an
adjuvant.

CHAIRPERSON PRZEPIORKA:  Dr. Albertsen.

DR. ALBERTSEN:  Yeah. Otis, I agree with you. If I had to just pick the
trial that I?d want to see today to make the decision, it?s basically
men who have rising PSAs following radiation or surgery, who now face a
choice, or face the problem of what do you do. What?s happening is most
of them are getting LHRH agonist with the associated risks of libido,
hot flashes and osteoporosis. They?d like an alternative, something that
avoids those risks. However, ultimately I?m not sure which the better
therapy is. What troubles me about the data is that Casodex 150 was not
as good as castration in the M1 trials. Therefore, with an alternative
that clearly works better in advanced stages, but it comes at a price of
quality of life much earlier on. And since we?re dealing with a chronic
disease, the question is what?s the appropriate choice.

The trial that needs to be done is in men with progression following
surgery or radiation. Is it best to give LHRH agonist, Casodex or
placebo? I suspect no one is going to fund such a trial. It will take
too long to sort out, so instead we?re grappling with the data that?s
being handed to us.

CHAIRPERSON PRZEPIORKA:  Dr. Schoenberg.

DR. SCHOENBERG:  Yeah. I think this is sort of a more general comment
echoing some of the things that Peter has just said. AstraZeneca, as is
everyone who works on prostate cancer and works on it seriously, is to
be congratulated for doing difficult trials, but the disease is what it
is. And if it takes a long time to get an answer, that?s the ball game.
And at least from a practical clinical perspective, it?s very hard to
accept intermediate endpoints that have not been validated, that are of
questionable value within the context of a given study. And I think one
thing we need to keep in the back of our minds, probably everyone here
is thinking about it, is that while it is great to offer patients
choices, and all of us want to do that, I think that at some level it is
unethical to represent that a choice, any choice is a good choice. And
part of our job, obviously, is to make sure that drugs that we recommend
or don?t recommend get that recommendation for a reason. And I think the
strength of the data here make it problematic for, at least for an
American urologist like myself, to weigh in strongly and say sure,
there?s clear evidence that this will be beneficial.

I think what we can say is that it may be in a very small and defined
segment of a population, which really requires a much longer study,
unfortunately. That?s the ball game we?re playing here.

CHAIRPERSON PRZEPIORKA:  Other comments. Mr. Ohye.

MR. OHYE:  I?d like to reserve a comment after the vote between this
question and the next, if I may.

CHAIRPERSON PRZEPIORKA:  Then I will call the question. Number two then
is, do the data from Trials 24 and 25 allow for adequate definition of a
patient population that can extrapolated from the non-U.S. to the U.S.
patients who will derive a significant benefit from Casodex? Dr.
Albertsen.

DR. ALBERTSEN:  Yes.

DR. MARTINO:  Yes.

DR. PELUSI:  Yes.

DR. HANNO:  No.

DR. BRAWLEY:  Yes.

DR. SCHOENBERG:  No.

MR. ANDERSON:  No.

DR. KRIST:  No.

CHAIRPERSON PRZEPIORKA:  No.

DR. KELSEN:  Yes.

DR. REDMAN:  Yes.

DR. CARPENTER:  Yes.

DR. CHESON:  No.

DR. GEORGE:  No.

DR. BLAYNEY:  Yes.

DR. REDMAN:  No.

CHAIRPERSON PRZEPIORKA:  I?m sorry to tell you, eight yes, eight no. Mr.
Ohye, which may actually give us the deciding vote.

MR. OHYE:  As you know, I?m non-voting. However, I think the FDA in
their wisdom under Subpart H in the regulations, have provided a way out
for us here, because if we were to change this question to read and I?ll
only refer to the last line of the question. Change it as follows,
?Define groups of U.S. patients who are likely to derive a clinical
benefit from Casodex therapy?, we?re talking about using the provisions
of Subpart H or accelerated approval as we did yesterday, where you have
data that is likely to show, likely to provide a clinical benefit. And
then we have the burden of the sponsor to show at a subsequent time,
later data, could be more mature data from this study, because this is
certainly not a failed study. We?re not trying to save a failed study.
This was a good study. It was carried out pursuant to the agreements
reached by FDA at the End of Phase 2 Meeting.

As you heard from Dr. Albertsen, we know that this drug is going to be
used, available. We know the drug is going to be imported from Canada. I
can go on the web site as soon as it?s available in he Canadian market.
I can go on my computer and get it, and FDA has made an announcement
that they?re not going enforce importation of use of drugs for
individual patients, so this cries out for, I think, the sponsor and the
agency to provide adequate directions for use, and to move forward with
this drug under the provisions of Subpart H. Thank you.

CHAIRPERSON PRZEPIORKA:  Question three, based on the findings in Trial
23 as of June, 2000 data cut-off, it appears that Casodex does not offer
a significant benefit for men with early prostate cancer who initially
are treated by radical prostatectomy or radiation therapy with curative
intent. In light of this observation, what population of patients, if
any, who were initially treated by radical prostatectomy or radiation of
curative intent in the U.S. would benefit from adjuvant therapy with
Casodex? Dr. Hanno.

DR. HANNO:  I don?t think it?s clear basically if any would. I don?t
think we know, and we would just be guessing. And I think the key
missing element in this whole discussion is, is there data that
immediate hormone therapy improves survival? I mean, if it does, then a
lot of this ?- then Casodex may turn out to be a great drug. In the
absence of that data from any trials on any type of hormonal therapy, we
are really in the dark about this, and we?re just sort of guessing, so I
would just say it?s not clear if any would.

CHAIRPERSON PRZEPIORKA:  Could you just repeat then, what additional
data would you require to allow you to conclude that Casodex would
provide a clinically significant benefit? Part C of Question Three.

DR. HANNO:  Part C of Question Three. I?d like to see either survival
data, or quality of life data suggesting that early treatment in
preventing the onset of metastatic lesions improves the quality of life,
regardless of effects on survival, compared to treating when PSA rises
or bone metastases appear. And my concern is that this indication in the
U.S. for Casodex would imply that Casodex improves survival of all
patients after definitive therapy. And it would become ?- there would be
widespread use of adjuvant Casodex in virtually everyone who gets a
radical prostatectomy or radiation therapy. And I?m not sure that would
be warranted, but I think that might well happen.

CHAIRPERSON PRZEPIORKA:  Dr. Martino.

DR. MARTINO:   I don?t think it?s fair to say that this trial, number
23, does not show a benefit. See, that implies that we know the future,
and we don?t. The reality is that this is a trial where the relapse rate
is quite small at this point in time in a patient population where that
could have easily been anticipated to be the case, so the question
implies that we understand that even in this population, there can never
be a benefit. I think that?s an assumption on our part.

CHAIRPERSON PRZEPIORKA:  And actually, if I recall the data, and I wrote
it down from 23 specifically, the patients who had radiotherapy had a
significant improvement or a significant lack of progression being
reduced from 40 percent to 28 percent. It was the prostatectomy patients
who had no benefit and no progression, as you had pointed out earlier,
so I think you?re correct. And I would echo what you said about we?re
not there long enough, although the radiotherapy patients certainly look
like they derive benefit. Other comments regarding 3(a)? Dr. Albertsen.

DR. ALBERTSEN:  I agree with Dr. Hanno. Ultimately, the use of hormonal
therapy has not yet been demonstrated to increase longevity. And the sad
part is, I see any window of opportunity to prove this in a clinical
trial as probably beginning to draw to a close, so I?ll address number
C. Given the group of patients we know that are high risk for disease
progression and death from prostate cancer, are those men with rapid PSA
doubling times following a definitive therapy. That?s the population
that?s key, and whether ?- and how much Casodex or any hormonal therapy
alters that natural history is debatable. But that is a group that
requires further study, and that?s the group that if we are
extrapolating from Trial 24, you?d be extrapolating to.

CHAIRPERSON PRZEPIORKA:  Other comments? So, Dr. Shames, I think the
answer to ?- this was an essay question for A is, we can?t define a
population based on what we have now. We would like longer follow-up
data.

Moving on to question 4 then. In the U.S. trial, Trial 23, there was no
watchful waiting treatment group. (A) Has the sponsor demonstrated in
trials 24 and 25 that U.S. patients with localized non-metastatic
prostate cancer who are presently managed by surveillance would derive
sufficient benefit from Casodex monotherapy, or immediate treatment to
justify the adverse events that would be associated with such treatment?
Dr. Albertsen.

DR. ALBERTSEN:  I?d answer no to that.

CHAIRPERSON PRZEPIORKA:  And what additional data would you require to
allow you to conclude that monotherapy would provide clinically
significant benefit to the U.S. patients presently managed by
surveillance?

DR. ALBERTSEN:  That?s defining who is getting watchful waiting in this
country, because usually the persons getting watchful waiting in this
country are people who are felt to be at low risk for disease
progression. It?s precisely those patients that you?re going to have the
least amount of efficacy from Casodex. The ones who have a high
probability of progression are the ones who might benefit, and that?s
why I voted no.

CHAIRPERSON PRZEPIORKA:  Would you consider patients who you are waiting
and watching their PSAs rise as a potential group?

DR. ALBERTSEN:  I think a potential group are those patients who elect
not to have surgery or radiation, yet who have clear progression of PSA.
I?m dealing with a gentleman in my community I just saw yesterday who?s
been watching himself for five years. He?s 65 years old, and he just
does not want to have surgery or radiation. His PSA is now up to 16. I
know eventually he?s going to die from this disease. He?d be the perfect
candidate to put on something like this, so I think there?s a group out
there, but I think it?s small. But to a blanket statement of all
patients who choose watchful waiting, that I think is inappropriate
because most of the patients who choose watchful waiting are usually men
in their late 70s and early 80s whose natural history is such that they
are going to most likely die of a competing hazard, rather than their
prostate cancer. So, therefore, treating them with Casodex just gives
them the morbidity from the treatment. It is unlikely to achieve any
benefit for them.

CHAIRPERSON PRZEPIORKA:  Dr. Martino.

DR. MARTINO:  I guess I?m unsure now as to ?- particularly in Trial 25,
the Scandinavian trial, where I thought I had seen that about 80 percent
of the patients in that trial were of this population. I guess I?m not
sure why it is that those patients are so different from the American
population. I remember the gentleman who addressed the nature of the
patients, making the statement that the patients that went into Trial 25
were men who had a time from diagnosis to entry in trial of three
months, so how is that so different from what might happen in this
country? I?m very confused on this patient selection issue.

CHAIRPERSON PRZEPIORKA:  Dr. Albertsen.

DR. ALBERTSEN:  Yeah. I think the issue has to do with PSA screening in
this country. The U.S. populations were probably comparable in 1990, but
are no longer in 2003. Maybe in 2005, as the Europeans begin to more
aggressively screen PSA, you?ll see a congruence. But right when this
study was done in 1995, you probably had the most disparity from what
was being done in this country compared to what was being done in
Europe, so therefore, the pool of patients who are slated to be enrolled
in Trials 24 and 25, by and large had more advanced disease than their
American counterparts. So again, it goes down to the lead time
associated with this disease. And if we?re talking about a lead time of
at least five years, and possibly longer as a result of PSA screening,
when you make a new diagnosis of someone who?s in their mid to late 70s,
who has at best a 10 year survival, you could see where the benefits
begin to get very marginal.

DR. MARTINO:  I understand the basic concept, and I agree with the basic
concept. I think what I?d like is, I?d like to hear from the PI from the
Scandinavian trial that in fact, when they entered patients on this,
that they really were not selected from the point of view of being
diagnosed, screened based on PSA that ?- the impression is that these
were gentlemen in Europe who actually were symptomatic, and therefore,
diagnosed. I?d like to know if that?s correct or not.

CHAIRPERSON PRZEPIORKA:  So the question to the PI on the Scandinavian
trial is, are the patients who were placed on this protocol part of the
screening population, or patients who came in for a reason?

DR. IVERSEN:  In response to your question, I can inform you that at
that time in Scandinavia, screening with PSA was not practiced.

CHAIRPERSON PRZEPIORKA:  Dr. Shoenberg.

DR. SCHOENBERG:  Yeah. I mean, just as a follow-up to Dr. Albertsen?s
comments, and to clarify this. There are guidelines in the U.S. for
recommending watchful waiting to patients with prostate cancer. Not
everybody follows them. Clinicians are accorded a relatively broad
degree of latitude in advising patients about the problem, but this
population is, I believe, by definition substantially different than the
U.S. watchful waiting population. Using the criteria of PSA density, the
amount of biopsy material that is actually positive for carcinoma, and
the Gleason Score, which by definition should be less than 6, or
equivalent to 6 but not greater, so I suspect they?re really very
different populations.

CHAIRPERSON PRZEPIORKA:  Dr. Krist.

DR. KRIST:  I agree with all the statements made. I mean, the other
thing that concerns me too with the watchful waiting group is it seems
like there?s a narrow window of potential benefit, where there?s a group
of patients who really aren?t going to derive any benefit from treatment
with Casodex, just due to the nature of their disease, and would be
better off with just watchful waiting, and no therapy. And then even on
the other end of the spectrum with us seeing in Trial 306 and 307,
there?s the other end of the spectrum where there?s a potential group
with more advanced disease who might opt for watchful waiting, who would
be better off with LRHR analog, or medical castration instead.

CHAIRPERSON PRZEPIORKA:  Yes.

DR. HOBERMAN:  I simply have a point of information. You made a
statement about in 23, radiotherapy patients having an efficacy
advantage. And I?m curious where that is coming from.

CHAIRPERSON PRZEPIORKA:  I copied that off an additional slide that the
sponsor placed in response to a question that I had asked.

DR. HOBERMAN:  Was that among the high risk group, or was that including
the total sample?

CHAIRPERSON PRZEPIORKA:  Just the high risk group, specifically in Trial
23.

DR. HOBERMAN:  That doesn?t square.

DR. MONROE:  I believe you were shown percentages, but I think the
number of events were only like four total, and so you have maybe some
very ?- the data by looking at percentages I don?t think are
appropriately represented. I just want to bring that up, that if one
looks at actual number of events, I think by looking at percentages, you
get a wrong impression as to what really occurred.

CHAIRPERSON PRZEPIORKA:  Thank you for clarifying that. Other comments?
Dr. Shames, do you want us to take a vote on 4(a), or what I?m hearing
is that essentially we don?t believe that the patient population in 23
and 24 is something that we frequently see in the U.S., but there is a
population in the U.S. who really does need to be studied, whom we would
predict would have benefit from this, to answer Part C, which means
another study.

DR. SHAMES:  Essentially no, but we would prefer to have another study
to see this. Okay. Thank you.

CHAIRPERSON PRZEPIORKA:  Any other comments from the Committee? Dr.
Shames, any other questions from the FDA?

DR. SHAMES:  No, I appreciate this a great deal.

CHAIRPERSON PRZEPIORKA:  Thank you. I call this meeting adjourned.

(Whereupon the proceedings in the above-entitled matter adjourned at
2:47 p.m.)