STARSTAR

22

NSABP P-1 Trial Results: Age NSABP P-1 Trial Results: Age >> 50 50

CategoryCategoryTamoxifenTamoxifen PlaceboPlacebo

ARDARD RR(95% CI)RR(95% CI)n 4010n 4010 IRIR n 4008n 4008 IRIR

Breast CancerBreast Cancer

InvasiveInvasive

Non-invasiveNon-invasive

5151

2525

3.213.21

1.581.58

107107

3232

6.806.80

2.042.04

+3.59+3.59

+0.46+0.46

0.47 (0.33,0.67) 0.47 (0.33,0.67)

0.77 (0.44,1.35)0.77 (0.44,1.35)

C V FracturesC V Fractures 2020 1.251.25 2828 1.761.76 +0.51+0.51 0.71 (0.38,1.31) 0.71 (0.38,1.31)

DeathDeath 5151 3.193.19 5959 3.703.70 +0.51+0.51 0.86 (0.58,1.28) 0.86 (0.58,1.28)

Stroke Death Stroke Death 33 0.190.19 22 0.130.13 -0.06-0.06 1.50 (0.17,17.91) 1.50 (0.17,17.91)

StrokeStroke 3535 2.202.20 2020 1.261.26 -0.94-0.94 1.75 (0.98,3.20) 1.75 (0.98,3.20)

DVTDVT 2424 1.511.51 1414 0.880.88 -0.63-0.63 1.71 (0.85,3.58)1.71 (0.85,3.58)

PEPE 1616 1.001.00 55 0.310.31 -0.69-0.69 3.19 (1.12,11.15) 3.19 (1.12,11.15)

Endometrial CaEndometrial Ca 2727 3.053.05 77 0.760.76 -2.29-2.29 4.01 (1.70,10.90) 4.01 (1.70,10.90)

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STAR Study DesignSTAR Study Design

Randomized, Phase 3, multinational, double-Randomized, Phase 3, multinational, double-blind in 19,747 womenblind in 19,747 womenTwo Arms: Evista and Tamoxifen for 5 yearsTwo Arms: Evista and Tamoxifen for 5 yearsStratified by Stratified by age, race, history of LCIS, prior hysterectomy and absolute risk of invasive breast cancer within 5 yearsNot designed to show non-inferiorityNot designed to show non-inferiority

44

Women EligibilityWomen Eligibility

Postmenopausal and the projected 5 year Postmenopausal and the projected 5 year probability of developing breast cancer probability of developing breast cancer was at least 1.66%was at least 1.66%

oror

Postmenopausal and they had a history of Postmenopausal and they had a history of LCIS treated by excision onlyLCIS treated by excision only

55

Exclusion CriteriaExclusion Criteria

Prior hx of invasive breast cancerPrior hx of invasive breast cancerDCISDCISLCIS (mastectomy, radiation, adjuvant therapy)LCIS (mastectomy, radiation, adjuvant therapy)DVTDVTPulmonary embolusPulmonary embolusDocumented cerebral vascular accident or TIADocumented cerebral vascular accident or TIACurrent use of coumadinCurrent use of coumadinUncontrolled diabetes or hypertensionUncontrolled diabetes or hypertensionAtrial FibrillationAtrial Fibrillation

66

Primary EndpointPrimary Endpoint

Occurrence of Invasive Breast CancerOccurrence of Invasive Breast Cancer

77

Efficacy and Important Safety OutcomesEfficacy and Important Safety Outcomes

EventEventTamoxifenTamoxifen RaloxifeneRaloxifene RRRR

(95%CI)(95%CI)nn IRIR nn IRIR

All Breast cancersAll Breast cancers 228228 5.855.85 256256 6.546.54 1.12 (0.93,1.34)1.12 (0.93,1.34)

InvasiveInvasive 168168 4.304.30 173173 4.404.40 1.02 (0.82,1.27)1.02 (0.82,1.27)

Non-invasiveNon-invasive 6060 1.541.54 8383 2.122.12 1.38 (0.98,1.95)1.38 (0.98,1.95)

88

Efficacy and Important Safety OutcomesEfficacy and Important Safety Outcomes

EventEventTamoxifenTamoxifen RaloxifeneRaloxifene

ARDARD

RRRR

(95%CI)(95%CI)nn IRIR nn IRIR

Breast cancersBreast cancers

AllAll

InvasiveInvasive

Non-invasiveNon-invasive

228228

168168

6060

5.855.85

4.304.30

1.541.54

256256

173173

8383

6.546.54

4.404.40

2.122.12

+0.69+0.69

+0.10+0.10

+0.58+0.58

1.12 (0.93,1.34)1.12 (0.93,1.34)

1.02 (0.82,1.27)1.02 (0.82,1.27)

1.38 (0.98,1.95)1.38 (0.98,1.95)

DeathsDeaths

Stroke DeathsStroke Deaths

109109

77

2.762.76

0.180.18

104104

55

2.622.62

0.130.13

-0.14-0.14

-0.05-0.05

0.95 (0.72,1.25)0.95 (0.72,1.25)

0.71 (0.18,2.60)0.71 (0.18,2.60)

StrokeStroke 5656 1.421.42 5454 1.361.36 -0.06-0.06 0.96 (0.65,1.42)0.96 (0.65,1.42)

C. V. FracturesC. V. Fractures 5858 1.471.47 5858 1.461.46 -0.01-0.01 0.99 (0.68,1.46)0.99 (0.68,1.46)

DVTDVT 9292 2.352.35 6767 1.691.69 -0.66-0.66 0.72 (0.52,1.00)0.72 (0.52,1.00)

PEPE 5858 1.471.47 3838 0.960.96 -0.51-0.51 0.65 (0.42,1.00)0.65 (0.42,1.00)

99

Continuation Efficacy and Important Safety OutcomesContinuation Efficacy and Important Safety Outcomes

EventEventTamoxifenTamoxifen RaloxifeneRaloxifene

ARDARD

RRRR

(95%CI)(95%CI)nn IRIR nn IRIR

Breast cancersBreast cancers

AllAll

InvasiveInvasive

Non-invasiveNon-invasive

228228

168168

6060

5.855.85

4.304.30

1.541.54

256256

173173

8383

6.546.54

4.404.40

2.122.12

+0.69+0.69

+0.10+0.10

+0.58+0.58

1.12 (0.93,1.34)1.12 (0.93,1.34)

1.02 (0.82,1.27)1.02 (0.82,1.27)

1.38 (0.98,1.95)1.38 (0.98,1.95)

Endometrial CaEndometrial Ca 3737 1.991.99 2323 1.211.21 -0.78-0.78 0.61 (0.34,1.05)0.61 (0.34,1.05)

Ovarian CaOvarian Ca 1414 0.520.52 1818 0.660.66 +0.14+0.14 1.27 (0.60,2.76)1.27 (0.60,2.76)

CataractsCataracts 435435 13.1913.19 343343 10.3410.34 -2.85-2.85 0.78 (0.68,0.91)0.78 (0.68,0.91)

HysterectomyHysterectomy 246246 13.2513.25 9292 4.844.84 -8.71-8.71 0.37 (0.28,0.47)0.37 (0.28,0.47)

Hot FlashesHot Flashes 71707170 181.71181.71 67486748 169.41169.41 -12.30-12.30 0.94 (0.90,0.97)0.94 (0.90,0.97)

Leg CrampsLeg Cramps 59995999 152.03152.03 53735373 135.29135.29 -16.74-16.74 0.89 (0.86,0.92)0.89 (0.86,0.92)

EdemaEdema 664664 16.8316.83 741741 18.6618.66 +1.83+1.83 1.11 (1.00,1.23)1.11 (1.00,1.23)

1010

Tamoxifen: A higher incidence of DVT, PE Tamoxifen: A higher incidence of DVT, PE endometrial cancer, cataracts, endometrial cancer, cataracts, hysterectomy, hot flashes and leg cramps.hysterectomy, hot flashes and leg cramps.

Raloxifene: A higher incidence of ovarian Raloxifene: A higher incidence of ovarian cancer and edema.cancer and edema.

1111

STAR trial did not show superiority of STAR trial did not show superiority of raloxifene compared to Tamoxifen for raloxifene compared to Tamoxifen for reducing risk of invasive breast cancer.reducing risk of invasive breast cancer.

A non-prespecified non-inferiority analysis A non-prespecified non-inferiority analysis was conducted to demonstrate efficacywas conducted to demonstrate efficacy

1212

Requirements to Demonstrate NIRequirements to Demonstrate NI

Active control (Tamoxifen) has efficacy – Active control (Tamoxifen) has efficacy – Tamoxifen is approved for this indicationTamoxifen is approved for this indication

Active control effect size can be estimated Active control effect size can be estimated based on meta-analysis of historical randomized based on meta-analysis of historical randomized studies – to estimate tamoxifen effect only one studies – to estimate tamoxifen effect only one randomized study (P-1) which included the randomized study (P-1) which included the current study population as a subset is availablecurrent study population as a subset is available

Pre-specified percent of active control effect size Pre-specified percent of active control effect size to be retained – no pre-specified retentionto be retained – no pre-specified retention

1313

NSABP P-1 Trial Data Estimate of NSABP P-1 Trial Data Estimate of Tamoxifen effect size in subjects 50 Tamoxifen effect size in subjects 50

years or olderyears or older

EventEventTamoxifenTamoxifen PlaceboPlacebo

RR (95% CI)RR (95% CI)nn IRIR nn IRIR

Breast CancerBreast Cancer

InvasiveInvasive5151 3.213.21 107107 6.806.80 0.47(0.33,0.67)0.47(0.33,0.67)

Breast CancerBreast Cancer

Non-InvasiveNon-Invasive2525 1.581.58 3232 2.042.04 0.77(0.44,1.35)0.77(0.44,1.35)

1414

Non-inferiority Analysis for invasive Non-inferiority Analysis for invasive breast cancerbreast cancer

The analysis indicated that raloxifene The analysis indicated that raloxifene retained at least 65% (may lose up to retained at least 65% (may lose up to 35%) of the control effect of tamoxifen 35%) of the control effect of tamoxifen prevention of invasive breast cancerprevention of invasive breast cancer

Point estimate = 97%Point estimate = 97%

95% CI (95% CI (65%65%,, 128%) 128%)

1515

In the adjuvant breast cancer setting, the In the adjuvant breast cancer setting, the FDA requires at least a 75% retention of FDA requires at least a 75% retention of an active control effect for an efficacy an active control effect for an efficacy claim based on non-inferiority. claim based on non-inferiority.

In a prevention trial, it is not clear what the In a prevention trial, it is not clear what the minimum percent retention of an active minimum percent retention of an active control effect should be for an efficacy control effect should be for an efficacy claim based on non-inferiority. claim based on non-inferiority.

1616

Non-inferiority Analysis for all Non-inferiority Analysis for all breast cancerbreast cancer

The analysis indicated that raloxifene The analysis indicated that raloxifene retained at least 53% (may lose up to retained at least 53% (may lose up to 47%) of the control effect of tamoxifen 47%) of the control effect of tamoxifen prevention of all breast cancersprevention of all breast cancers

Point estimate = 85%Point estimate = 85%

95% CI (53%, 109%)95% CI (53%, 109%)

1717

Important Issues STAR TrialImportant Issues STAR Trial

STAR trial did not show superiority of raloxifene STAR trial did not show superiority of raloxifene compared to Tamoxifen for reducing risk of invasive compared to Tamoxifen for reducing risk of invasive breast cancer. breast cancer.

A non-inferiority analysis shows that raloxifene could A non-inferiority analysis shows that raloxifene could lose up to 35% of the Tamoxifen effect in reducing risk of lose up to 35% of the Tamoxifen effect in reducing risk of invasive breast cancerinvasive breast cancer

A non-inferiority analysis shows that raloxifene could A non-inferiority analysis shows that raloxifene could lose up to 47% of the Tamoxifen effect in reducing the lose up to 47% of the Tamoxifen effect in reducing the risk of risk of all breast cancerall breast cancer

Fewer Fewer non-invasive breast cancersnon-invasive breast cancers in the tamoxifen in the tamoxifen group (60) than the Evista group (83) group (60) than the Evista group (83)

1818

When compared to Raloxifene, When compared to Raloxifene, Tamoxifen has increasedTamoxifen has increased

DVTDVT

PEPE

Endometrial cancerEndometrial cancer

HysterectomyHysterectomy

CataractsCataracts

Hot flashesHot flashes

Leg CrampsLeg Cramps

1919

STAR Trial QuestionSTAR Trial Question

Does the benefit of raloxifene (invasive Does the benefit of raloxifene (invasive breast cancer reduction of at least 65% of breast cancer reduction of at least 65% of Tamoxifen effect, without a reduction in Tamoxifen effect, without a reduction in the risk of non-invasive breast cancer) the risk of non-invasive breast cancer) outweigh the risk of adverse events?outweigh the risk of adverse events?

2020

Summary of the EvistaSummary of the Evista®® (raloxifene HCL) Application(raloxifene HCL) Application

2121

FIRST INDICATIONFIRST INDICATIONReduction in risk of invasive breast Reduction in risk of invasive breast

cancer in postmenopausal women with cancer in postmenopausal women with osteoporosisosteoporosis

Balance of benefits versus risks:Balance of benefits versus risks:

Benefits: Benefits: – Reduced risk of ER + invasive breast cancer Reduced risk of ER + invasive breast cancer

compared with placebocompared with placebo

Risks: Risks: – Increased risk of DVT, PE and possibly stroke Increased risk of DVT, PE and possibly stroke

deaths compared with placebo deaths compared with placebo

2222

SECOND INDICATIONSECOND INDICATIONThe reduction in risk of invasive breast The reduction in risk of invasive breast cancer in postmenopausal women at cancer in postmenopausal women at

high risk for breast cancerhigh risk for breast cancer

Balance of benefits versus risks:Balance of benefits versus risks:

Benefits: Benefits: – The size of the benefit is uncertain when The size of the benefit is uncertain when

compared to tamoxifencompared to tamoxifen

Risks: Risks: – Generally less risks compared with Generally less risks compared with

Tamoxifen.Tamoxifen.