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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, D’Amico, 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 (N=490)

› M1 = bone mets (N=960)

• 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 (N=128)› Trial 307 (N=352)

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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 (N=128)› HR (Casodex/Castration) = 0.64 (0.39, 1.03)

• Trial 307 (N=352)› 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

› Sponsor’s 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 25N=3292 N=3603 N=1218

N=8113

Casodex Ptsn=4052

Placebo Ptsn=4061

Withdrawn from Treatment

n=1845

Treatment ongoing or completed

n=2207

Treatment ongoing or completed

n=2355

Withdrawn from Treatment

n=1706

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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 Percentage of patients

Characteristic Trial 23 Trial 24 Trial 25Clinical Stage

T1 10 25 21T2 63 40 39T3 27 32 38T4 <1 3 2

Gleason Grade (Score)Well different. (2 to 4) 5 31 43Mod. different. (5 to 6) 48 41 44Poorly different. (7 to 10) 47 26 12

PSA (median) ng/mLPretreatment 7.1 11.7 16.1

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Discordance between Gleason Scores and Disease Progression

Percentage of patients with finding 1

Trial No. Gleason Score7 or greater

PositiveBone Scan 2

23 (US) 51 0.624 33 3.325 16 8.8

1. Patients in placebo treatment group.2. Positive scans within 2.5 yrs of entry.

• Prostatectomy Patients

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Discordance between Gleason Scores and Disease Progression

Percentage of patients with finding 1

Trial No. Gleason Score7 or greater

PositiveBone Scan 2

23 (US) 29 0.924 24 8.625 12 23.1

1. Patients in placebo treatment group.2. Positive scans within 2.5 yrs of entry.

• Radiotherapy Patients

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Primary Endpoints and Analysis

• Sponsor’s 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)

Number (%) of patients with eventStudy 23 Study 24 Study 25

Event Caso.n=1647

Plac.n=1645

Caso.n=1798

Plac.n=1805

Caso.n=607

Plac.n=611

Positive bone 14 11 42 98 22 72

scan (0.9) (0.7) (2.3) (5.4) (3.6) (11.8)

Death without 25 37 70 70 41 33 progression (1.5) (2.2) (3.9) (3.9) (6.8) (5.4)

Total 39 48 112 168 63 105

(%) (2.4) (2.9) (6.2) (9.3) (10.4) (17.4)

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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”

T1

Clinical Stage of Prostate CaM0 M0

T2 T3 T4Adjuvant TxImmediate Tx

• 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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Sponsor’s 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)

Number pts with progression1Trial TotalPts (n)

High RiskPts (n) Casodex Placebo

23 2647 158 4 of 83 6 of 7524 1648 277 13 of 133 14 of 144

25 159 74 2 of 33 6 of 41

1. FDA preferred endpoint and analysis

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Disease Progression in “High Risk” Patients (T3/T4 and Pre-radiation PSA >10 ng/mL

Number pts with progression1Trial TotalPts (n)

High RiskPts (n) Casodex Placebo

23 645 8 1 of 5 1 of 324 660 199 8 of 102 15 of 97

25 65 28 1 of 17 5 of 11

1. FDA preferred endpoint and analysis

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Sponsor’s Revised Definition of High Risk for Disease Recurrence in Adjuvant Patients

• Sponsor’s original definition of high risk for recurrence › locally advanced (T3/T4) and one of the following

– detectable postsurgical PSA or – preradiation PSA >10 ng/mL

• Sponsor’s revised definition of high risk for recurrence› locally advanced (T3/T4) and one of the following

– detectable postsurgical PSA, or presurgical PSA >10 ng/mL, or Gleason score 7 or

– preradiation PSA >4 ng/mL

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Disease Progression in “High and Low Risk” Adjuvant-Treated Patients (Revised Definition)

Treatment Risk Number pts with progression1 HRGroup Group Casodex Placebo (95% CI)

Radiotherapy High 20 of 148 39 of 134 0.39(13.5%) (29.1%) (0.22-0.67)

Low 55 of 551 64 of 537 0.781(10.1%) (11.9%) (0.54-1.12)

Prostatectomy High 59 of 722 100 of 702 .534(8.2%) (14.2%) (0.39-0.74)

Low 56 of 1514 70 of 1516 0.80(3.7%) (4.6%) (0.56-1.13)

1. Sponsor’s preferred endpoint and analysis

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Disease Progression in “High Risk” Prostatectomy Patients (Revised Definition of “High Risk”)

Number pts with progression1

Trial N2 n Casodex Placebo HR (95% CI)

23 2647 712 25 of 367 22 of 345 1.09 (0.61-1.93)(6.8%) (6.4%)

24 1648 617 29 of 312 66 of 305 0.37 (0.24-0.58)(9.3%) (21.6%)

25 159 96 5 of 44 12 of 52 0.53 (0.18-1.56)(11.4%) (23.1%)

1. Sponsor’s preferred endpoint and analysis

2 = Total number of pts in prostatectomy group

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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

No. pts with progression1 Odds RatioTrial Event Casodex Placebo (95% CI)24 All events 35 of 475 52 of 521 0.72

(7.4%) (10.0%) (0.46-1.13)Bone scan pos 8 16All deaths 27 36

PC deaths 2 3

25 All events 29 of 304 39 of 327 0.76(9.5%) (11.9%) (0.45-1.27)

Bone scan pos 8 22All deaths 21 17

PC deaths 1 21. FDA preferred endpoints and analysis

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Disease Characteristics of Patients in Immediate Treatment (Monotherapy) Group

Characteristic Trial 24 Trial 25T1 59% 39%T2 41% 61%

Gleason Grade (Score)Well different. (2,3,4) 48% 55%Mod. different. (5,6) 35% 37%Poorly different. (7 to 10) 14% 8%

PSA>0.2-4 23% 13%>4-10 26% 26%>10-20 24% 25%>20 22% 34%

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Discordance between Local and Central Bone Scan Readings

Central reread result

Number (%) of scans in categoryTreatmentGroup

LocalResult Positive Negative Indeterminate

Casodex Pos 73(73%) 22(22%) 5 (5%)Neg 31 (6%) 443(87%) 34 (7%)

Placebo Pos 144(73%) 36(18%) 18 (9%)Neg 22 (5%) 359(84%) 45(11%)

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Number (%) of Deaths (Prostate Cancer-Related or Other Causes

Study 23 Study 24 Study 25Cause ofDeath

Caso.N=1647

Plac.N=1645

Caso.N=1798

Plac.N=1805

Caso.N=607

Plac.N=611

Prostate CA 8 3 26 38 24 28Other 54 58 97 99 45 42

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

Prostate CA 14 6 56 66 49 56Other 91 93 168 161 67 50

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

1. Cut off date of 2 June 20002 . Cut off date of 28 September 2001

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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

Percentage of Patients

Study 23 Study 24 Study 25Disposition Caso.

(1627)Plac.

(1627)Caso.(1790)

Plac.(1795)

Caso.(605)

Plac.(609)

Premature termination 38 20 47 45 37 54Death <1 <1 3 3 5 3

Disease progression <1 <1 4 13 11 32Adverse event 31 9 27 9 17 7Non-compliance <1 <1 <1 <1 <1 <1Patient’s decision 5 5 9 8 4 5Other 1 <1 4 3 11 1 51. Includes increase in PSA, need for other therapy, investigator decision.

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Adverse Events with Incidence >5% and More Frequent in Casodex Patients

Number (%) of patients reporting event

Casodex PlaceboAdverse Event N=4022 N=4031

Breast pain 2937 (73) 296 (7)

Gynecomastia 2700 (67) 325 (8)

Asthenia 427 (11) 303 (7)

Vasodilation 364 (9) 211 (5)

Impotence 362 (9) 250 (6)

Alopecia 239 (6) 31 (1)

Weight gain 231 (6) 115 (3)

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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)

Number (%) of patients

Casodex PlaceboCategory (n=4022) (n=4031)

Patients reporting

Gynecomastia or breast pain 3467 (86) 501 (12)Patients withdrawing due to

Gynecomastia 418 (10) 15 (0.4)Breast pain 498 (12) 15 (0.4)Gynecomastia or breast pain 649 (16) 25 (0.6)

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Persistence of Gynecomastia or Breast Pain Posttreatment in Casodex Patients

Category Number (%) ofpatients (n=4022)

Gynecomastia

Ongoing at end of treatment withposttreatment follow up 1 1572

Not resolved posttreatment 775 (49)Breast pain

Ongoing at end of treatment withposttreatment follow up 1 1729

Resolution posttreatment 134 (8)1. Follow up information available from about 85% of patients.

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Maintenance of Sexual Function Relative to Baseline (Trial 25)

Weeks post-randomizationWk 12 Wk 24 Wk 36 Wk 48Sexual function

domain % of pts maintaining baseline function 1

Frequency

Casodex 45 42 36 31

Placebo 62 55 47 48

Potency

Casodex 50 44 40 35

Placebo 62 58 60 53

1 Assessed by the Golombok Rusk Inventory of Sexual Satisfaction(GRISS) questionnaire.

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Clinically Relevant Changes in ALT, AST, and Bilirubin Values (Combined Data)

Number (%) of patientsCasodex (N=4022) Placebo (N=4031)

Parameter Baseline Pts. withchange

Baseline Pts. withchange

AST 3745 65 (1.7) 3770 27 (0.7)

ALT 3660 60 (1.6) 3685 13 (0.4)

Bilirubin 3530 29 (0.8) 3558 18 (0.5)

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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. <1% 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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