**Overview for Oncology Drugs Advisory Committee**

**December 18, 2002 Meeting**

**NDA 20-498/s012**

**Drug**

**Established name** Bicalutamide

**Trade name** Casodex

**Applicant** AstraZeneca Pharmaceuticals LP\
PO Box 8355\
Wilmington, DE 19803-8355

**Proposed Indication** *Original Indication (Submitted 20 December 2001
with NDA)*\
Immediate hormonal therapy or adjuvant therapy to treatment of curative
intent in patients with non-metastatic prostate cancer

*First Revision of Indication (Submitted 10 May 2002)*\
Part 1: 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

Part 2: Immediate treatment of non-metastatic prostate cancer in
patients for whom therapy of curative intent is not indicated

*Second Revision of Indication (Submitted 10 May 2002)*\
Part 1: (Unchanged from 10 May 2002 submission)

Part 2: Immediate treatment of [localized]{.underline} non-metastatic
prostate cancer in patients for whom therapy of curative intent is not
indicated

**Dosing Regimen** One 150 mg tablet daily

# Background 

Casodex at a daily dose of 50 mg in combination with medical or surgical
castration is registered world-wide for the palliative treatment of
advanced prostate cancer. In some markets, the mode of castration is
limited to one or the other method. The product was approved in the US
in 1995 for the treatment of metastatic prostate cancer (Stage D2) in
combination with GnRH analog therapy.

In February 2000, AstraZeneca submitted an efficacy supplement (NDA
20-498/s006) for the treatment of locally advanced, non-metastatic
(Stages T3-T4, NX, M0) prostate cancer with Casodex monotherapy (150
mg/d). Two pivotal trials were submitted in support of the application.
The trials were similar in design but conducted in different geographic
locales. Both were open-label, active comparator trials that compared
Casodex monotherapy to medical or surgical castration. The studies
originally included patients with metastatic disease (Stage M1) as well
as non-metastatic (M0) disease. Based on an interim analysis of
survival, the Data Safety Monitoring Board (DSMB) recommended that
Casodex treatment be discontinued in M1 patients. The data at the time
of their recommendation indicated that the risk of death was 25% and 31%
higher in the Casodex M1 groups compared to the castration M1 groups in
Trails 0306 and 0307, respectively. The trials continued thereafter with
only patients who had Stage M0 disease at the time of entry.

Survival in the M0 Casodex-treated patients, compared to that in the
patients treated by castration, differed across the Trials. In Trial
0306 (n = 140 M0 patients), the risk of death was calculated as 36%
lower in the Casodex group while in Trial 0307 (n = 352 M0 patients),
the risk of death was calculated as 25% higher in the Casodex group.
Both the primary medical reviewer and statistical reviewer recommended
that the application not be approved for several reasons that included
(1) the conflicting trial results with the larger trial demonstrating a
survival disadvantage in the Casodex treatment group for M0 patients,
and (2) a combined statistical analysis that (a) did not fully meet the
Sponsor's original definition of noninferiority and (b) was considered
to be statistically inappropriate. Upon learning that the application
would not be approved, AstraZeneca withdrew the supplemental NDA in
December 2000.

# Regulatory History of NDA 20-498/s012

AstraZeneca first met with the FDA in 1995 to discuss their proposed
clinical program for the use of Casodex monotherapy (150 mg/d) for the
treatment of patients with "early prostate cancer (the EPC Program)."
The Sponsor indicated that several clinical trials would be conducted
under the EPC Program. Efficacy of Casodex monotherapy would be assessed
in terms of time-to-progression (TTP) and survival. A combined analysis,
based on the findings across all of the studies also was proposed. At
the meeting. the FDA concurred with the overall design of the clinical
program but raised concerns for potential unblinding due to anticipated
differences in the incidence of gynecomastia and reduced PSA levels in
the Casodex treatment groups relative to the placebo groups. The FDA
agreed with the Sponsor that a meta-analysis for survival was
acceptable; however, if a time-to-progression endpoint was the only
endpoint, 2 trials would be required.

The differences between the Sponsor and the FDA regarding the choice of
primary efficacy endpoints and the primary efficacy analyses persisted.
The Sponsor's preferred, protocol-defined primary endpoints continued to
be (1) *objective disease progression* defined as local or distant
progression of disease *confirmed by bone scan, x-ray, CT scan, magnetic
resonance imaging, ultrasonography, or biopsy* and (2) *death* due to
any cause in the absence of objectively confirmed progression. The
Sponsor's preferred, protocol-defined primary efficacy analyses were
time to objective progression or death. Because of continuing concern
about the potential for assessment bias due to the adverse effects of
Casodex treatment, the FDA requested that the primary efficacy endpoints
be limited to (1) the events of (a) *bone scan documented disease
progression* and (b) *death* due to any cause in the absence of bone
scan confirmed progression and (2) *events that occurred within 2 years
of randomization.* The 2-year endpoint was selected because all study
protocols required that a bone scan be performed at Year 2 unless
objective progression had previously been documented. Minutes from the
final communication between the sponsor and the Division of Reproductive
and Urologic Drug Products in May 2001 stated: "... disagreements remain
between the sponsor and the Agency; the Division will need to review the
data to determine approvability of the sNDA." NDA 20-498 was submitted
on 20 December 2001 and was assigned priority review status.

# Overview of the Clinical Trials

The Sponsor submitted data from 3 placebo-controlled, randomized,
double-blind, parallel-group clinical trials that enrolled men with
local or locally advanced non-metastatic prostate cancer. The trials
were conducted in (1) North America, predominantly the US \[Trial 23\],
(2) Europe (other than Scandinavia), South Africa, Israel, Mexico, and
Australia \[Trial 24\], and (3) Scandinavia \[Trial 25\]. Patients were
randomized in a 1:1 ratio to treatment with either Casodex 150 mg per
day or matching placebo. In all 3 trials, Casodex was investigated as
adjuvant therapy in patients who had had previous therapy for their
prostate cancer (i.e., radical prostatectomy or radiation therapy). In
Trials 24 and 25 (but not Trial 23), Casodex also was investigated as
monotherapy (i.e., in patients who had had no prior therapy and whose
prostate cancer would otherwise be managed by watchful waiting or
surveillance).

A total of 8,113 patients were randomized to therapy (the
intent-to-treat population) with 3292, 3603, and 1218 patients
randomized to Trials 23, 24, and 25, respectively. Median patient-years
of follow up for disease progression and survival (efficacy analyses)
were 3.2 years (Trial 23), 2.6 years (Trial 24) and 3.0 years
(Trial 25). In general, baseline patient characteristics across
Trials 24 and 25 were similar but differed somewhat from those in Trial
23 in that patients in Trial 23 tended to be younger by several years,
weighed slightly more, and had lower serum PSA values.

# Overview of Efficacy Findings

The percentages of patients with disease progression or death in the
absence of disease progression in each of the trials (based on the
Sponsor's preferred protocol-defined endpoints) are summarized in Table
A. ). There was no evidence of benefit from Casodex treatment in Trial
23 (the only trial conducted in the US).

Table A Disease Progression or Death (Based on Sponsor's Preferred
Endpoints)

  -------------- ---------- -------- ---- ----------- ---------- -------- ----------- ---------- ------------ --------- ---------- ------------ -------- ---------- ------------ --------- ---------- ------------
                 Number                                                                                                                                                                               
                 (per cent)                                                                                                                                                                           
                 of                                                                                                                                                                                   
                 patients                                                                                                                                                                             
                 with event                                                                                                                                                                           

  Event          Study 23                                                             Study 24                                                           Study 25                                     

                 Casodex\                             Placebo\                        Casodex\                          Placebo\                         Casodex\                          Placebo\   
                 (N = 1647)                           (N = 1645)                      (N = 1798)                        (N = 1805)                       (N = 607)                         N = 611)   

  Positive bone             21            (1.3)                  15       (0.9)       60         (3.3)        116                  (6.4)        32                  (5.3)        95                   (15.5)
  scan                                                                                                                                                                                                

  Other                              10   (0.6)                  17       (1.0)       25         (1.4)        85                   (4.7)        19                  (3.1)        40                   (6.5)
  objective                                                                                                                                                                                           
  events ^1^                                                                                                                                                                                          

  Death in                  52            (3.2)                  55       (3.3)       96         (5.3)        92                   (5.1)        48                  (7.9)        44                   (7.2)
  absence of                                                                                                                                                                                          
  progression                                                                                                                                                                                         

  **Total (%)               **83**        **(5.0)**              **87**   **(5.3)**   **181**    **(10.1)**   **293**              **(16.2)**   **99**              **(16.3)**   **179**              **(29.3)**
  Patients**                                                                                                                                                                                          
  -------------- ---------- -------- ---- ----------- ---------- -------- ----------- ---------- ------------ --------- ---------- ------------ -------- ---------- ------------ --------- ---------- ------------

^1^ Documented by magnetic resonance imaging, computerized tomography,
sonography, or biopsy.

The percentages of patients with objective disease progression or death
in the absence of objective progression within 2.5 years of
randomization (FDA-requested endpoints) are presented in Table B.

Table B Disease Progression or Death (Based on FDA Requested Endpoints)

  -------------- ---- --------------- -------- ----------- ---------- -------- ----------- --------- ---------- ----------- --------- ---------- ----------- -------- ---------- ------------ --------- ---------- ------------
                      Number (per                                                                                                                                                                                  
                      cent) of                                                                                                                                                                                     
                      patients with                                                                                                                                                                                
                      event within                                                                                                                                                                                 
                      2.5 yr. of                                                                                                                                                                                   
                      randomization                                                                                                                                                                                

  Event               Study 23                                                                       Study 24                                                         Study 25                                     

                      Casodex\                             Placebo\                                  Casodex\                         Placebo\                        Casodex\                          Placebo\   
                      (N = 1647)                           (N = 1645)                                (N = 1798)                       (N = 1805)                      (N = 607)                         N = 611)   

  Positive bone  14                            (0.9)                  11       (0.7)       42                   (2.3)       98                   (5.4)       22                  (3.6)        72                   (11.8)
  scan                                                                                                                                                                                                             

  Death in       25                            (1.5)                  37       (2.2)       70                   (3.9)       70                   (3.9)       41                  (6.8)        33                   (5.4)
  absence of                                                                                                                                                                                                       
  progression                                                                                                                                                                                                      

  **Total (%) of                      **39**   **(2.4)**              **48**   **(2.9)**   **112**              **(6.2)**   **168**              **(9.3)**   **63**              **(10.4)**   **105**              **(17.2)**
  patients**                                                                                                                                                                                                       
  -------------- ---- --------------- -------- ----------- ---------- -------- ----------- --------- ---------- ----------- --------- ---------- ----------- -------- ---------- ------------ --------- ---------- ------------

The total number and percentage of deaths due to prostate cancer or
other causes in each of the trials at the data cutoff for the efficacy
analyses (2 June 2000) and the data cutoff for the safety update
(28 September 2001) are listed in Table C. There were no significant
differences in the percentage of patients who died, either of prostate
cancer or of other causes, in the Casodex and placebo groups within each
of the trials.

Table C Total Number and (%) of Deaths due to Prostate Cancer or Other
Causes

  ------------ ---------- ----------- --------- ----------- -- ---------- ------------ --------- ------------ -- ---------- ------------ ---------- ------------
  Cause of\    Study 23                                        Study 24                                          Study 25                           
  Death                                                                                                                                             

               Casodex\               Placebo                  Casodex\                Placebo                   Casodex\                Placebo\   
               N= 1647                N=1645                   N= 1798                 N=1805                    N= 607                  N= 611     

               n          (%)         n         (%)            n          (%)          n         (%)             n          (%)          n          (%)

  Prostate     8          (0.5)       3         (0.2)          26         (1.4)        38        (2.1)           24         (4.0)        28         (4.6)
  cancer                                                                                                                                            

  Other        54         (3.3)       58        (3.5)          97         (5.4)        99        (5.5)           45         (7.4)        42         (6.9)

  **Total      **62**     **(3.8)**   **61**    **(3.7)**      **123**    **(6.8)**    **137**   **(7.6)**       **69**     **(11.4)**   **70**     **(11.5)**
  ^1^**                                                                                                                                             

  Prostate     14         (0.9)       6         (0.4)          56         (3.1)        66        (3.7)           49         (8.1)        56         (9.2)
  cancer                                                                                                                                            

  Other        91         (5.6)       93        (5.7)          168        (9.4)        161       (9.0)           67         (11.1)       50         (8.2)

  **Total      **105**    **(6.5)**   **99**    **(6.1)**      **224**    **(12.5)**   **227**   **(12.7)**      **116**    **(19.2)**   **106**    **(17.4)**
  ^2^**                                                                                                                                             
  ------------ ---------- ----------- --------- ----------- -- ---------- ------------ --------- ------------ -- ---------- ------------ ---------- ------------

> 1\. Data cutoff of 2 June 2000 (efficacy population). 2. Data cutoff
> of 28 September 2001 (safety population).

**Summary of Efficacy Findings**. The Sponsor has provided statistically
significant evidence in two non-US clinical trials (Trials 24 and 25)
that treatment with Casodex 150 mg per day, compared to treatment with
placebo, in men with non-metastatic prostate cancer at entry delayed
progression of disease as assessed by the appearance of new bone scan
confirmed metastases or death in the absence of objective disease
progression. In Trial 23 (the only trial conducted in the US and the
trial most relevant to patients in the US), there was no evidence that
treatment with Casodex delayed disease progression. The relevance of
benefit from treatment with Casodex in the 2 non-US trials for men with
prostate cancer in the US who might be treated with Casodex adjuvant
therapy or Casodex monotherapy is unknown. There was no evidence that
treatment with Casodex improved survival in any of the trials or in the
combined analysis. Evidence of improved survival, however, was not
anticipated as the survival data were expected to be immature.

# Unresolved Review Issues

## General Issues

The following issues were identified during the review of this NDA.
Input from the Oncology Drugs Advisory Committee is sought regarding
these unresolved issues.

Across ongoing Trials 24 and 25, only 15.6% of patients
(Sponsor-preferred endpoints) and 9.3% of patients (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 cutoff
(June 2000), median follow up was 2.6 years (Trial 24) and 3.0 years
(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 will
derive clinically significant long-term benefit?

There was a lack of correlation between Gleason scores and preprocedure
PSA values. Patients in Trial 23 had higher Gleason scores (more severe
disease) than patients in Trials 24 and 25 but lower PSA values.
Patients in Trial 23 also had less progression of disease (unexpected
with higher Gleason scores) than patients in Trials 24 and 25. Due to
the failure to standardize Gleason scores (and the questionable validity
of the Gleason scores in Trials 24 and 25), it was not possible to
adequately characterize the patients in Trials 24 and 25. This
deficiency contributed to the Division's inability to identify those
patients in the US who might derive significant benefit from Casodex
treatment.

The relevance of the findings in Trials 24 and 25 to men with prostate
cancer in the US who would be treated with Casodex (either adjuvant
therapy or monotherapy) was not clear to the Division.

## Issues Related to Casodex Adjuvant Therapy 

Based on the data submitted by the Sponsor, patients similar to those
enrolled in Trial 23 who are initially treated by radical prostatectomy
or radiotherapy in the US would derive no benefit from Casodex adjuvant
therapy. A supplemental analysis by the Sponsor, based on a subset of
patients in Trial 23, also did not show convincing evidence of efficacy
for Casodex adjuvant therapy. As described previously, it was not
possible (1) to adequately characterize the patients in Trials 24 and 25
because of lack of standardized Gleason scores and (2) to extrapolate
the data from patients in Trials 24 and 25 to Trial 23 to identify US
patients who might benefit from Casodex adjuvant therapy.

## Issues Related to Casodex Immediate Treatment or Monotherapy.

A watchful waiting (immediate treatment) subgroup was not included in
Trial 23. The proposed indication did not adequately identify the
population of prostate cancer patients in the US who might derive
sufficient benefit from Casodex monotherapy to warrant the risks of
treatment.

**For local or early disease**. The Sponsor did not provide sufficient
evidence that the findings in Trials 24 and 25 are relevant to prostate
cancer patients in the US who are currently managed by watchful waiting
or surveillance. In particular, the Sponsor did not provide data
demonstrating that prostate cancer-related morbidity or mortality in
patients with localized prostate cancer occurs with a sufficiently high
incidence that the potential benefits of Casodex treatment will out
weight the adverse effects of treatment (e.g., gynecomastia, breast
pain, and possible liver toxicity).

**For locally advanced disease.** Trials 24 and 25 were not conducted in
accordance with present standards of care for patients with locally
advanced, non-metastatic prostate cancer in the US. Since the comparator
in these trials was placebo and not active therapy (i.e., medical or
surgical castration), it was not possible to adequately address the
efficacy of Casodex monotherapy. This is a critical issue since survival
may be shortened in patients with locally advanced prostate cancer
treated with Casodex monotherapy instead of by medical or surgical
castration (the present standard of care in the US for such patients).
This concern has been addressed, in part, by the Sponsor's second
revision to the proposed indication for Casodex immediate therapy that
was submitted on 22 October 2002. The second revision states that
Casodex immediate treatment is indicated for the treatment of
"[localized]{.underline} non-metastatic prostate cancer in patients for
whom therapy of curative intent is not indicated."