BACKGROUND INFORMATION ONLY

NOT THE PRIMARY SUBJECT OF PRESENT ODAC MEETING

(REVIEW OF EARLIER SUPPLEMENTAL NDA SUBMISSION)

Deputy Division Director/ Team Leader Memorandum

**NDA** 20-498 **SE1**-006

**Date NDA submitted**: February 25, 2000

**Date NDA received**: February 25, 2000

**Draft review completed**: December 15, 2000

**Revisions completed**:

**Sponsor**: AstraZeneca Pharmaceuticals LP

> 1800 Concord Pike
>
> Wilmington, DE 19850

**Drug**: **Generic**: Bicalutamide

**Proposed** **Trade**: CASODEX

> **Chemical**: propanamide. N-\[4-cyano-3-(triflouromethy)-phenyl\]- 3-
> \[(4-flourophenyl)sulfonyl-2-hydroxy-2-methy-, (+-)

**Route**: Oral

**Dosage form**: Tablets

**Strength**: 150 milligrams

**Proposed indication**: Treatment in locally advanced, non-metastatic
(Stages T3- T4, NX, **M0**) prostate cancer

# REGULATORY BACKGROUND

On October 18, 1989, Zeneca met with the Division of Metabolic and
Endocrine Drug Products and presented the concepts for two "pivotal"
clinical trials. These trials would compare CASODEX 50 mg daily
monotherapy with castration (medical or surgical) in patients with
locally advanced (M0) or known bone metastases (M1). The two trials
would be conducted outside the United States.

On July 1, 1992, the sponsor returned for an interim guidance meeting
and informed the Division that they had concluded that the 50 mg dose
"did not produce the expected efficacy" as monotherapy. Therefore,
trials had begun testing doses of 100 mg and 150 mg. Several months
after the trials began, the sponsor decided that 150 mg was the more
efficacious dose because of a robust PSA reduction with the higher dose.
Thereafter the trials (0306,0307) were conducted with the higher dose.

In addition, at the July 1, 1992 meeting, the sponsor informed the
Division of their plan to move ahead with a ["combination" therapy
program]{.underline}, comparing LHRH agonist + CASODEX 50 mg to LHRH
agonist + flutamide 250 mg TID. On October 4, 1995, CASODEX received
accelerated approval as "combination therapy" for advanced prostate
cancer. On December 12, 1997, CASODEX 50 mg received full approval.

During the conduct of these trials, it became apparent to the Data
Monitoring Safety Committee that there was a qualitative interaction
between survival and stage of disease (reduced survival of M1 patients
in the CASODEX group compared to the castration group). Accordingly, all
M1 patients were withdrawn from both trials on April 1995. The trials
continued with M0 patients only.

On June 16, 1997, the sponsor met with DRUDP in a Pre-sNDA meeting for
the 150 mg monotherapy indication. The survival data in the M0 patients
from 0306 and 0307 indicated disparate results. At that time, the
Division informed the sponsor that "**the inconsistencies in the results
between the two studies in the M0 subgroup presents a major review
challenge**". The Division recommended that the sponsor should allow the
data to mature and "perhaps, the data would become more consistent over
time.

On September 23, 1997, the Division again met with the sponsor to
discuss the 150 mg monotherapy program. At that time, the Division
stated that "**the study results for trials 0306 and 0307 for M0
patients should not be combined if the results are in opposite
directions (cannot pool the results)**."

On November 16, 1999, the sponsor met again with DRUDP and informed the
Division of their continued desire to submit this data as an sNDA. The
application was submitted on February 25, 2000.

# NDA CLINICAL BACKGROUND AND INFORMATION

**Scientific Rational:** Currently, the approved treatment for patients
with advanced prostate cancer is medical castration using an LHRH
agonist alone or in combination with an antiandrogen. Medical castration
at this time is approved only as "palliative" treatment in these
patients. However, there is evidence that early testosterone ablation of
patients with advanced prostate cancer provides clinical benefit,
including a survival benefit.

However, castration (whether medical or surgical) is associated with
several well-recognized adverse effects. These include the development
of hot flushes, reduced libido, impotence, asthenia, bone
demineralization and the potential for bony fracture. Chronic injections
of LHRH agonists can be inconvenient. Surgical castration is often
rejected by patients due to concerns related to bodily disfigurement and
self-image.

The sponsor's hypothesis was that CASODEX monotherapy would be as
efficacious in the treatment of advanced prostate cancer as castration
but that it would obviate many of the recognized adverse effects. The
sponsor intended to prove this hypothesis by conducting two identical
trials ([0306 and 0307]{.underline}) in the appropriate patient
population.

**Conduct of Clinical Trials (0306 and 0307):** They were multicenter,
randomized, open-label trials which compared castration with CASODEX
monotherapy in terms of time to death, time to treatment failure and
time to objective progression. In addition, a comparison of
quality-of-life questionnaires and adverse events were also undertaken.
Although the trials would be conducted in different geographic locales,
(Trial 0306 in Scandinavian countries only and Trial 0307 in other
European countries, South Africa and Australia) they were otherwise
identical.

The majority of patients in the castration group selected medical
castration with ZOLADEX. The initial phase of each trial was designed to
compare the "PSA response" of 100 mg and 150 mg doses. The sponsor
selected the 150 mg dose after it was recognized that the percent PSA
reduction was significantly less with 100 mg than with the 150 mg dose.
Once the 150 mg dose was selected, the trials continued with the
long-term endpoints. Trial 0306 began recruitment in May 1992 and the
last patient entered the trial in June 1993. Trial 0307 began
recruitment in January 1992 and the last patient entered the trial in
June 1993. Both trials are ongoing. However, the data cutoff for this
NDA was June 1, 1999.

The sample size was selected to demonstrate that CASODEX was no more
then 25% worse than castration in terms of time to death. The sponsor
believed that they could demonstrate "equivalent "efficacy and improved
"quality of life". A total of 1453 patients were randomized in both
trials and of those, 492 were classified as M0. Trial 0307 contained 352
M0 patients and Trial 0306 contained 140 M0 patients.

**Efficacy Results:** As previously mentioned, the results reported for
each trial demonstrated a statistically significant disadvantage for
time to death in the CASODEX group compared to castration in M1
patients. The data submitted by the sponsor indicated that the risk of
death was 25% and 31% higher in the CASODEX M1 groups compared with the
castration M1 groups, in Trials 0306 and 0307, respectively.

In the M0 groups, the results of Trials 0306 and 030 were disparate. In
**0306** (N=140, M0 patients), the hazard ratio (HR) for risk of death
in the CASODEX group compared to castration group was calculated as
being 0.65 (upper bound 1-sided 95% CI **0.96**), while the HR in
**0307** (N=352, M0 patients) was 1.25 (upper bound 1-sided 95% CI
**1.63**). When the M0 subgroups from both trials are combined, the
results reveal a hazard ratio of 1.05, with and an upper one-sided
confidence interval of **1.31**. The sponsor concluded that in the
pooled M0 population, survival was not meaningfully different between
CASODEX and castration, although they acknowledged that 1.31 was outside
the pre-determined limit of 1.25.

The sponsor also argues that data from a quality-of-life questionnaire
from approximately one third of the M0 patients who successfully
submitted a questionnaire at baseline and at Week 52 demonstrate a
benefit for CASODEX in terms of preservation of libido and "physical
capacity".

Finally, the sponsor argues that a single assessment of bone mineral
density in 29 patients at a median follow-up of 5.5 years demonstrated
significant differences between the CASODEX and the castration groups.

**Safety Results:** Over 4800 patients received CASODEX at doses of 100
mg daily or greater. The majority of these received 150 mg daily.
Approximately 200 patients received doses of at least 200 mg daily. In
the "pivotal trials", 570 patients received at least 6 months of
therapy, 435 patients received at least one year of therapy, 326
patients received at least 2 years of therapy, and 127 patients received
at least 4 years of therapy.

Overall, the total exposure in the pivotal trial alone was estimated as
1924 patient-years.

The sponsor studied an appropriate population for the proposed
indication as documented by the mean age, weight, and concomitant
medical conditions.

The major risks are those related to male breast enlargement and breast
pain, several episodes of jaundice or hepatic dysfunction, and the
potential for interactions with drugs metabolized by the cytochrome P450
3A4, 2C9, 2C19 and 2D6 enzymes. This drug/drug interaction potential
would be particularly important for concomitantly administered drugs
with a narrow therapeutic index.

# INTERGRATED COMMENTS ON SAFETY AND EFFICACY

1\. The sponsor failed to provide substantial evidence that CASODEX 150
monotherapy provides an equivalent survival advantage compared to
castration in M0 patients with prostate cancer.

-   The individual trials (0306,0307) indicate disparate results with
    the larger trial demonstrating a survival disadvantage for CASODEX.

-   The pooled results do not demonstrate statistical equivalence
    between the CASODEX and castration groups but the sponsor claims
    they are "clinically" equivalent. The sponsor had been informed in
    September 1997 that that pooling is inappropriate when the results
    are in opposite directions. In addition, the statistical reviewer
    makes a compelling argument against using the combined results as
    evidence of efficacy.

**2. It is of great concern that the M1 patients who took CASODEX had a
significant survival disadvantage. It is difficult to imagine a
mechanism whereby M1 patients who take CASODEX have a survival
disadvantage while M0 patients have an advantage. In addition, the
diagnosis of M0 and M1 patients is not precise in these trials. Because
of the high PSA levels in the M0 patients, one can conclude that many of
them actually were M1.**

3\. There was insufficient QOL, adverse event or bone density data to
conclude that CASODEX would provide an improved quality of life to
prostate cancer patients even if survival benefit had been demonstrated
to be equivalent to castration.

4\. The adverse effects to the breast and liver might prove to be of
significant concern in larger populations as well as the for drug/drug
interactions. In fact, it is of great concern that the adverse event of
death was more common in the CASODEX treated patients and the cause of
this increased mortality is unknown.

**Therefore, I agree with the primary medical reviewer's recommendation
of non-approval of this supplemental NDA.**

**NDA PHARMACOTOXICOLOGY INFORMATION**

CASODEX is an approved drug. Therefore, the only action that would be
required is modification of the label in the carcinogenesis and
pregnancy sections to reflect lower multiples of the animal/human
exposure ratios.

Reviewer's comment: Since no label will be finalized, these changes are
not required at the time of this action. I agree with the comments of
the Pharmtox. team.

**NDA CHEMISTRY INFORMATION**

From A CMC point of view, the supplement may be approved. The EER was
found to be acceptable on 12/12/00. The tradename CASODEX 150 mg is
acceptable.

**Reviewer's comment: I agree with the recommendation of the chemistry
team.**

**NDA CLINICAL PHARMACOLOGY INFORMATION**

The biopharmaceutics reviewer recommended approval of this supplement.
Recommendations regarding dissolution specifications should be conveyed
to the sponsor at the appropriate time. Labeling modifications regarding
potential drug/drug interactions should be conveyed at the sponsor.

Reviewer's comment: I agree with the recommendations of the
biopharmaceutics team.

DSI INSPECTIONS

Two sites were inspected. At both sites, there were similar findings
including deviations from protocol, failure to maintain adequate records
and inadequate informed consent procedures. The DSI reviewer believed
these problems were unlikely to significantly impact on the date
generated. The primary clinical reviewer concurs with this opinion

Reviewer's comment: I agree with opinion of the DSI and medical reviewer
that the deficiencies observed at the clinical sites probably do not
have a significant effect on the clinical (especially mortality)
evaluation.

REGULATORY RECOMMENDATION

I recommend non-approval of NDA 20-498 SE1-006.

The following reasons (deficiencies) for non-approval should be conveyed
in a regulatory letter:

1\. The sponsor failed to provide substantial evidence that CASODEX 150
monotherapy provides an equivalent survival advantage compared to
castration in M0 patients with prostate cancer.

-   The individual trials (0306,0307) indicate disparate results with
    the larger trial demonstrating a survival disadvantage for CASODEX.

-   The pooled results do not demonstrate statistical equivalence
    between the CASODEX and castration groups but the sponsor claims
    they are "clinically" equivalent. The sponsor had been informed in
    September 1997 that that pooling is inappropriate when the results
    are in opposite directions. In addition, the statistical reviewer
    makes a compelling argument against using the combined results as
    evidence of efficacy.

2.  **It is of great concern that the M1 patients who took CASODEX had a
    significant survival disadvantage. It is difficult to imagine a
    mechanism whereby M1 patients who take CASODEX have a survival
    disadvantage while M0 patients have an advantage. In addition, the
    diagnosis of M0 and M1 patients is not precise in these trials.
    Because of the high PSA levels in the M0 patients, one can conclude
    that many of them actually were M1.**

**3. There was insufficient QOL, adverse event or bone density data to
conclude that CASODEX would provide an improved quality of life to
prostate cancer patients even if survival benefit had been demonstrated
to be equivalent to castration.**

**RECOMMENDATION TO CORRECT DEFICIENCIES**

The sponsor should provide substantial evidence from new clinical trials
that CASODEX 150 mg provides an equivalent survival benefit compared to
castration while providing improved safety, tolerability and "quality of
life" in patients with advanced prostate cancer. The Division would
cooperate with the sponsor in the design of these trials

Daniel A. Shames MD

Deputy Division Director

DRUDP, HFD-580

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