# Presentation: 664404

## STAR

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

| Category | Tamoxifen |  | Placebo |  | ARD | RR(95% CI) |
| --- | --- | --- | --- | --- | --- | --- |
|  | n 4010 | IR | n 4008 | IR |  |  |
| Breast Cancer
   Invasive
   Non-invasive | 
51
25 | 
3.21
1.58 | 
107
32 | 
6.80
2.04 | 
+3.59
+0.46 | 
0.47 (0.33,0.67) 
0.77 (0.44,1.35) |
| C V Fractures | 20 | 1.25 | 28 | 1.76 | +0.51 | 0.71 (0.38,1.31)  |
| Death | 51 | 3.19 | 59 | 3.70 | +0.51 | 0.86 (0.58,1.28)  |
| Stroke Death  | 3 | 0.19 | 2 | 0.13 | -0.06 | 1.50 (0.17,17.91)  |
| Stroke | 35 | 2.20 | 20 | 1.26 | -0.94 | 1.75 (0.98,3.20)  |
| DVT | 24 | 1.51 | 14 | 0.88 | -0.63 | 1.71 (0.85,3.58)  |
| PE | 16 | 1.00 | 5 | 0.31 | -0.69 | 3.19 (1.12,11.15)  |
| Endometrial Ca | 27 | 3.05 | 7 | 0.76 | -2.29 | 4.01 (1.70,10.90)  |

## STAR Study Design

- Randomized, Phase 3, multinational, double-blind in 19,747 women
- Two Arms: Evista  and Tamoxifen for 5 years
- 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

## 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

## 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

## Primary Endpoint

- Occurrence of Invasive Breast Cancer

## Efficacy and Important Safety Outcomes

| Event | Tamoxifen |  | Raloxifene |  | RR
 (95%CI) |
| --- | --- | --- | --- | --- | --- |
|  | n | IR | n | IR |  |
| All Breast cancers | 228 | 5.85 | 256 | 6.54 | 1.12 (0.93,1.34) |
| Invasive | 168 | 4.30 | 173 | 4.40 | 1.02 (0.82,1.27) |
| Non-invasive | 60 | 1.54 | 83 | 2.12 | 1.38 (0.98,1.95) |

## Efficacy and Important Safety Outcomes

| Event | Tamoxifen |  | Raloxifene |  | ARD | RR
 (95%CI) |
| --- | --- | --- | --- | --- | --- | --- |
|  | n | IR | n | IR |  |  |
| Breast cancers
     All
     Invasive
     Non-invasive | 
228
168
60 | 
5.85
4.30
1.54 | 
256
173
83 | 
6.54
4.40
2.12 | 
+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 | 109
7 | 2.76
0.18 | 104
5 | 2.62
0.13 | -0.14
-0.05 | 0.95 (0.72,1.25)
0.71 (0.18,2.60) |
| Stroke | 56 | 1.42 | 54 | 1.36 | -0.06 | 0.96 (0.65,1.42) |
| C. V. Fractures | 58 | 1.47 | 58 | 1.46 | -0.01 | 0.99 (0.68,1.46) |
| DVT | 92 | 2.35 | 67 | 1.69 | -0.66 | 0.72 (0.52,1.00) |
| PE | 58 | 1.47 | 38 | 0.96 | -0.51 | 0.65 (0.42,1.00) |

## Continuation Efficacy and Important Safety Outcomes

| Event | Tamoxifen |  | Raloxifene |  | ARD | RR
 (95%CI) |
| --- | --- | --- | --- | --- | --- | --- |
|  | n | IR | n | IR |  |  |
| Breast cancers
    All
    Invasive
    Non-invasive | 
228
168
60 | 
5.85
4.30
1.54 | 
256
173
83 | 
6.54
4.40
2.12 | 
+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 | 37 | 1.99 | 23 | 1.21 | -0.78 | 0.61 (0.34,1.05) |
| Ovarian Ca | 14 | 0.52 | 18 | 0.66 | +0.14 | 1.27 (0.60,2.76) |
| Cataracts | 435 | 13.19 | 343 | 10.34 | -2.85 | 0.78 (0.68,0.91) |
| Hysterectomy | 246 | 13.25 | 92 | 4.84 | -8.71 | 0.37 (0.28,0.47) |
| Hot Flashes | 7170 | 181.71 | 6748 | 169.41 | -12.30 | 0.94 (0.90,0.97) |
| Leg Cramps | 5999 | 152.03 | 5373 | 135.29 | -16.74 | 0.89 (0.86,0.92) |
| Edema | 664 | 16.83 | 741 | 18.66 | +1.83 | 1.11 (1.00,1.23) |

- 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.

## 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

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

## 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

## NSABP P-1 Trial Data Estimate of Tamoxifen effect size in subjects 50 years or older

| Event | Tamoxifen |  | Placebo |  | RR (95% CI) |
| --- | --- | --- | --- | --- | --- |
|  | n | IR | n | IR |  |
| Breast Cancer
Invasive | 51 | 3.21 | 107 | 6.80 | 0.47(0.33,0.67) |
| Breast Cancer
Non-Invasive | 25 | 1.58 | 32 | 2.04 | 0.77(0.44,1.35) |

## 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%)

- 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.

## 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%)

## 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)

## When compared to Raloxifene, Tamoxifen has increased

- DVT
- PE
- Endometrial cancer
- Hysterectomy
- Cataracts
- Hot flashes
- Leg Cramps

## 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?

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

## 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

## 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.