NDA 20-498 / S012 CASODEX (bicalutamide) 150 mg

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NDA 20-498 / S012CASODEX (bicalutamide) 150 mg

• FDA Review
• Division of Reproductive and Urologic
• Drug Products (DRUDP)

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Outline of FDA Presentation

• Background and Review Issues
• Dan Shames, M.D., Director, DRUDP
• Review of Clinical Trial Data
• Scott Monroe, M.D., Medical Team Leader, DRUDP
• Summary of Review Issues and Introduction of
  Questions
• Dan Shames, M.D.

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Background

• Importance of current supplement on the public
  health
• Importance of adequate staging in the treatment
  of prostate cancer
• History of Casodex 150mg development

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Public Health Importance

• Would be first approved drug for non-metastatic
  prostate cancer
• Target population of hundreds of thousands
• Therapy not warranted in a proportion of patients
• Variable natural history of prostate cancer
• Side effects possible without drug benefit
• Drug could be used for years or decades

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Prediction of Prognoses of Prostate Cancer
Subpopulations

• Definition of Prostate Cancer Subpopulation
• Clinical/path stage
• Gleason Score
• measure of differentiation
• Gleason score assigned by improper methodology in
  non US studies
• PSA
• Partin, DAmico, etc.
• Gleason adds to precision of staging and prognosis

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History of CASODEX 150 Trials 306
307

• Randomized, parallel studies in Advanced
  carcinoma of prostate (1992)
• M0 T3/T4 , PSA 5 x ULN (N490)
• M1 bone mets (N960)
• Casodex 150 vs. castration (medical or surgical)
• Intent of study
• to show survival non-inferiority of Casodex
  compared to castration
• to show QOL advantage of Casodex compared to
  castration

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Trials 306 307

• DSMB stopped the trials for M1 patients
• Casodex compared to castration
• decreased survival
• increased progression
• in both trials
• Trials continued with M0 patients only
• Trial 306 (N128)
• Trial 307 (N352)

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Trials 306 307 (NDA 20-498 / S006)

• Submitted 2/25/00
• To compare in a combined analysis, the selected
  dose of Casodex 150mg with medical or surgical
  castration in terms of survival, time to
  progression and time to treatment failure, QOL
  and tolerability in patients with untreated,
  locally advanced prostate cancer (T3-4, Nx, Mo)

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Results of Trials 306 307Hazard Ratios for
Mortality (M0)

• At 56 overall mortality, median of 6.3 yrs
  follow-up
• Trial 306 (N128)
• HR (Casodex/Castration) 0.64 (0.39, 1.03)
• Trial 307 (N352)
• HR (Casodex/Castration) 1.25 (0.92, 1.71)
• Combined Analysis
• HR (Casodex/Castration) 1.05 (0.81, 1.36)
• Casodex failed to meet pre specified 1.25 to
  signify equivalence (Casodex could be no more
  than 25 worse than castration)

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Concerns Regarding Results of Trials 306 307

• In M1 patients, Casodex inferior to castration
  (stopped by DSMB)
• In M0 patients, Casodex had disparate results
• data from larger trial indicated decreased
  survival and increase progression compared to
  castration

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Additional Information Regarding Long Term Use of
Antiandrogens

• Ann Int Med, April 2000, Seidenfeld et al
• Issue of paradoxical antiandrogen stimulation
• occurs with all anti androgens
• receptor gene mutation?

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Review Issues for NDA 20-498 / S012

• Efficacy Concerns
• Duration of trials too short to demonstrate
  enduring benefit
• Invalid Gleason Scores
• trials 24, 25 Gleason score assigned by improper
  methodology
• inconsistencies of clinical stage/outcomes and
  pathology between US and Non US trials
• Data proposed to support efficacy in US patients
  based on retrospective subgroup analyses

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Review Issues for NDA 20-498 / S012

• Safety Concerns
• High discontinuation rates for adverse events
• High incidence of gynecomastia/breast pain
• Irreversible gynecomastia
• Liver toxicity

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Review Issues for NDA 20-498 / S012

• Other issues
• possible survival decrement with longer follow up
• paradoxical antiandrogen stimulation
• QOL/Sexual
• three trials with heterogeneous populations, and
  different treatments
• Non-US trials reflect different practice patterns
• imprecision of bone scan readings

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FDA Review of Efficacy and Safety

• NDA 20-498/s012
• Sponsors current indications for CASODEX 150 mg
• 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
• Medical Reviewer Scott Monroe MD

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Overview of Clinical Program for Early Prostate
Cancer
Trial 23
Trial 24
Trial 25
N3603
N1218
N3292
N8113
Casodex Ptsn4052
Placebo Ptsn4061
Withdrawn from Treatmentn1845
Treatment ongoing or completedn2207
Treatment ongoing or completedn2355
Withdrawn from Treatmentn1706
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Topics for Review and Presentation

• Presentation limited to
• Significant Clinical Review Issues
• Differences between Sponsor and Division
  regarding
• Study endpoints and data analyses
• Interpretation of clinical findings
• Findings of concern to the Division

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Disease Characteristics at Baseline
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Discordance between Gleason Scores and Disease
Progression

• Prostatectomy Patients

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Discordance between Gleason Scores and Disease
Progression

• Radiotherapy Patients

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Primary Endpoints and Analysis

• Sponsors primary analysis and endpoints
• Time to disease progression
• local or distant progression of disease confirmed
  by bone scan, x-ray, CT scan, MRI,
  ultrasonography, or biopsy
• death due to any cause in absence of progression
• FDA preferred analysis and endpoints
• Proportion of patients with progression within 2
  yrs post randomization
• positive bone scan
• death due to any cause in absence of progression

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Primary Endpoints and Analysis

• Rationale for FDA preferred endpoints and
  analysis
• Blinding not maintained because of gynecomastia
  and decrease in PSA in Casodex treated patients
• Specific criteria for local disease progression
  not provided in protocols
• No central, blinded review of events classified
  as progression
• All protocols mandated a bone scan at 2 yrs post
  randomization

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Disease Progression or Death (FDA Requested
Analysis)
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Original Indication (submitted with NDA)for
Treatment with Casodex 150 mg

• Immediate hormonal therapy or adjuvant therapy
  to treatment of curative intent in patients with
  non-metastatic prostate cancer

Clinical Stage of Prostate Ca
M0
M0
Adjuvant TxImmediate Tx
T1
T2
T3
T4

• Sponsor was asked to identify population treated
  by prostatectomy or radiotherapy in US who would
  benefit from adjuvant treatment
• Sponsor performed post hoc exploratory analyses
  that resulted in first of two changes to the
  proposed indication

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Sponsors First Revision to Proposed Indications
for Treatment with Casodex 150 mg

• First revision of Indication (submitted May 2002)
• 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 non-metastatic prostate
  cancer in patients for whom therapy of curative
  intent is not indicated

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Disease Progression in High Risk Patients
(T3/T4 and Detectable PSA Post-prostatectomy)
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Disease Progression in High Risk Patients
(T3/T4 and Pre-radiation PSA gt10 ng/mL
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Sponsors Revised Definition of High Risk for
Disease Recurrence in Adjuvant Patients

• Sponsors original definition of high risk for
  recurrence
• locally advanced (T3/T4) and one of the following
• detectable postsurgical PSA or
• preradiation PSA gt10 ng/mL
• Sponsors revised definition of high risk for
  recurrence
• locally advanced (T3/T4) and one of the following
• detectable postsurgical PSA, or presurgical PSA
  gt10 ng/mL, or Gleason score ? 7 or
• preradiation PSA gt4 ng/mL

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Disease Progression in High and Low Risk
Adjuvant-Treated Patients (Revised Definition)
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Disease Progression in High Risk Prostatectomy
Patients (Revised Definition of High Risk)
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Current (2nd) Revision to Proposed Indication for
Casodex 150 mg

• Adjuvant usage (unchanged)
• 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 or monotherapy usage (modified)
• Immediate treatment of localized (T1/T2)
  non-metastatic prostate cancer in patients for
  whom therapy of curative intent is not indicated

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Disease Progression in Immediate Therapy
(Monotherapy) T1/T2 (Localized Disease) Patients
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Disease Characteristics of Patients in Immediate
Treatment (Monotherapy) Group
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Discordance between Local and Central Bone Scan
Readings
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Number () of Deaths (Prostate Cancer-Related or
Other Causes
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Summary of Unresolved Efficacy Issues

• Maturity of studies
• Only 15.6 and 9.3 of pts had disease
  progression by Sponsor or FDA preferred analyses,
  respectively, across Trials 24 and 25
• Long-term benefit of treatment unclear in absence
  of survival and meaningful quality of life data
• Inability to identify those prostate cancer pts
  in US who would derive benefit from adjuvant
  therapy
• Post hoc subset analyses by Sponsor were
  inconclusive or nonsupportive
• Lack of valid Gleason scores in non-US trials
• What is the risk/benefit ratio for immediate
  therapy (monotherapy) in patients with localized
  disease

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Disposition of Patients
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Adverse Events with Incidence gt5 and More
Frequent in Casodex Patients
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Time to First Occurrence of Gynecomastia (All
Trials)
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Incidence of and Withdrawals due to Gynecomastia
or Breast Pain (All Trials)
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Persistence of Gynecomastia or Breast Pain
Posttreatment in Casodex Patients
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Maintenance of Sexual Function Relative to
Baseline (Trial 25)
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Clinically Relevant Changes in ALT, AST, and
Bilirubin Values (Combined Data)
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Summary of Significant Safety Findings in NDA
20-498/012

• A high percentage of patients reported
  antiandrogenic- or estrogenic-related adverse
  events
• 86 Casodex patients vs. 12 placebo patients
  reported gynecomastia or breast pain
• 16 Casodex patients vs. lt1 placebo patients
  withdrew because of gynecomastia or breast pain
• Gynecomastia persisted post-treatment in 50
  patients
• Life-threatening or fatal hepatotoxicity - rare
  and similar in both groups
• Clinically significant rises in ALT/AST and
  withdrawals due to hepatic AEs 2-3 fold greater
  in Casodex treated patients

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Summary of Not Approvable Letter

• Division wanted submission of more mature trial
  data
• Does progression advantage persist?
• R/O survival disadvantage compared to placebo
• Perform Gleason scores on Trials 24 25
• Choose well defined successful subgroup and
  perform well controlled prospective trial

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Review Issues for NDA 20-498 / S012

• Efficacy Concerns
• Duration of trials too short to demonstrate
  enduring benefit
• Invalid Gleason Scores
• trials 24, 25 Gleason score assigned by improper
  methodology
• inconsistencies of clinical stage/outcomes and
  pathology between US and Non US trials
• Data proposed to support efficacy in US patients
  based on retrospective subgroup analyses

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Review Issues for NDA 20-498 / S012

• Safety Concerns
• High discontinuation rates for adverse events
• High incidence of gynecomastia/breast pain
• Irreversible gynecomastia
• Liver toxicity

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Review Issues for NDA 20-498 / S012

• Other issues
• possible survival decrement with longer follow up
• paradoxical antiandrogen stimulation
• QOL/Sexual
• three trials with heterogeneous populations, and
  different treatments
• Non-US trials reflect different practice patterns
• imprecision of bone scan readings

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