1. STAR

2. 2 NSABP P-1 Trial Results: Age > 50 Category TamoxifenPlacebo ARD RR(95% CI) n 4010 IR n 4008 IR Breast Cancer Invasive Invasive Non-invasive Non-invasive51253.211.58107326.802.04+3.59+0.46 0.47 (0.33,0.67) 0.77 (0.44,1.35) C V Fractures 201.25281.76+0.51 0.71 (0.38,1.31) Death513.19593.70+0.51 0.86 (0.58,1.28) Stroke Death 30.1920.13-0.06 1.50 (0.17,17.91) Stroke352.20201.26-0.94 1.75 (0.98,3.20) DVT241.51140.88-0.63 1.71 (0.85,3.58) PE161.0050.31-0.69 3.19 (1.12,11.15) Endometrial Ca 273.0570.76-2.29 4.01 (1.70,10.90)

3. 3 STAR Study Design Randomized, Phase 3, multinational, double- blind in 19,747 women Two Arms: Evista and Tamoxifen for 5 years Stratified by Stratified by age, race, history of LCIS, prior hysterectomy and absolute risk of invasive breast cancer within 5 years Not designed to show non-inferiority

4. 4 Women Eligibility Postmenopausal and the projected 5 year probability of developing breast cancer was at least 1.66% or Postmenopausal and they had a history of LCIS treated by excision only

5. 5 Exclusion Criteria Prior hx of invasive breast cancer DCIS LCIS (mastectomy, radiation, adjuvant therapy) DVT Pulmonary embolus Documented cerebral vascular accident or TIA Current use of coumadin Uncontrolled diabetes or hypertension Atrial Fibrillation

6. 6 Primary Endpoint Occurrence of Invasive Breast Cancer

7. 7 Efficacy and Important Safety Outcomes Event TamoxifenRaloxifeneRR (95%CI) (95%CI) nIRnIR All Breast cancers 2285.852566.54 1.12 (0.93,1.34) Invasive1684.301734.40 1.02 (0.82,1.27) Non-invasive601.54832.12 1.38 (0.98,1.95)

8. 8 Efficacy and Important Safety Outcomes Event TamoxifenRaloxifene ARD RR (95%CI) (95%CI) nIRnIR Breast cancers All All Invasive Invasive Non-invasive Non-invasive228168605.854.301.54256173836.544.402.12+0.69+0.10+0.58 1.12 (0.93,1.34) 1.02 (0.82,1.27) 1.38 (0.98,1.95) Deaths Stroke Deaths 10972.760.1810452.620.13-0.14-0.05 0.95 (0.72,1.25) 0.71 (0.18,2.60) Stroke561.42541.36-0.06 0.96 (0.65,1.42) C. V. Fractures 581.47581.46-0.01 0.99 (0.68,1.46) DVT922.35671.69-0.66 0.72 (0.52,1.00) PE581.47380.96-0.51 0.65 (0.42,1.00)

9. 9 Continuation Efficacy and Important Safety Outcomes Event TamoxifenRaloxifene ARD RR (95%CI) (95%CI) nIRnIR Breast cancers All All Invasive Invasive Non-invasive Non-invasive228168605.854.301.54256173836.544.402.12+0.69+0.10+0.58 1.12 (0.93,1.34) 1.02 (0.82,1.27) 1.38 (0.98,1.95) Endometrial Ca 371.99231.21-0.78 0.61 (0.34,1.05) Ovarian Ca 140.52180.66+0.14 1.27 (0.60,2.76) Cataracts43513.1934310.34-2.85 0.78 (0.68,0.91) Hysterectomy24613.25924.84-8.71 0.37 (0.28,0.47) Hot Flashes 7170181.716748169.41-12.30 0.94 (0.90,0.97) Leg Cramps 5999152.035373135.29-16.74 0.89 (0.86,0.92) Edema66416.8374118.66+1.83 1.11 (1.00,1.23)

10. 10 Tamoxifen: A higher incidence of DVT, PE endometrial cancer, cataracts, hysterectomy, hot flashes and leg cramps. Raloxifene: A higher incidence of ovarian cancer and edema.

11. 11 STAR trial did not show superiority of raloxifene compared to Tamoxifen for reducing risk of invasive breast cancer. A non-prespecified non-inferiority analysis was conducted to demonstrate efficacy

12. 12 Requirements to Demonstrate NI Active control (Tamoxifen) has efficacy – Tamoxifen is approved for this indication Active control effect size can be estimated based on meta-analysis of historical randomized studies – to estimate tamoxifen effect only one randomized study (P-1) which included the current study population as a subset is available Pre-specified percent of active control effect size to be retained – no pre-specified retention

13. 13 NSABP P-1 Trial Data Estimate of Tamoxifen effect size in subjects 50 years or older Event TamoxifenPlacebo RR (95% CI) nIRnIR Breast Cancer Invasive 513.211076.800.47(0.33,0.67) Non-Invasive 251.58322.040.77(0.44,1.35)

14. 14 Non-inferiority Analysis for invasive breast cancer The analysis indicated that raloxifene retained at least 65% (may lose up to 35%) of the control effect of tamoxifen prevention of invasive breast cancer Point estimate = 97% 95% CI (65%, 128%)

15. 15 In the adjuvant breast cancer setting, the FDA requires at least a 75% retention of an active control effect for an efficacy claim based on non-inferiority. In a prevention trial, it is not clear what the minimum percent retention of an active control effect should be for an efficacy claim based on non-inferiority.

16. 16 Non-inferiority Analysis for all breast cancer The analysis indicated that raloxifene retained at least 53% (may lose up to 47%) of the control effect of tamoxifen prevention of all breast cancers Point estimate = 85% 95% CI (53%, 109%)

17. 17 Important Issues STAR Trial STAR trial did not show superiority of raloxifene compared to Tamoxifen for reducing risk of invasive breast cancer. A non-inferiority analysis shows that raloxifene could lose up to 35% of the Tamoxifen effect in reducing risk of invasive breast cancer A non-inferiority analysis shows that raloxifene could lose up to 47% of the Tamoxifen effect in reducing the risk of all breast cancer Fewer non-invasive breast cancers in the tamoxifen group (60) than the Evista group (83)

18. 18 When compared to Raloxifene, Tamoxifen has increased DVTPE Endometrial cancer HysterectomyCataracts Hot flashes Leg Cramps

19. 19 STAR Trial Question Does the benefit of raloxifene (invasive breast cancer reduction of at least 65% of Tamoxifen effect, without a reduction in the risk of non-invasive breast cancer) outweigh the risk of adverse events?

20. 20 Summary of the Evista ® (raloxifene HCL) Application

21. 21 FIRST INDICATION Reduction in risk of invasive breast cancer in postmenopausal women with osteoporosis Balance of benefits versus risks: Benefits: –Reduced risk of ER + invasive breast cancer compared with placebo Risks: –Increased risk of DVT, PE and possibly stroke deaths compared with placebo

22. 22 SECOND INDICATION The reduction in risk of invasive breast cancer in postmenopausal women at high risk for breast cancer Balance of benefits versus risks: Benefits: –The size of the benefit is uncertain when compared to tamoxifen Risks: –Generally less risks compared with Tamoxifen.