# Presentation: 837018

## Multiple Outcomes of Raloxifene EvaluationMORE Continuing Outcomes Relevant to EvistaCORE Raloxifene Use for The Heart Trial RUTH

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**Source:  Silvana Martino Oral Presentation at ASCO 2004****	****	**** **

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**Steven R. Cummings, MD**
**Director, San Francisco Coordinating Center**
**Professor of Medicine and Epidemiology (emeritus)**
**CPMC Research Institute and UC San Francisco**

## Study DesignMORE

- International multicenter, double-blind, placebo-controlled
- 7705 postmenopausal women with osteoporosis; excluded women with a history of breast cancer
- Raloxifene 60 mg, 120 mg, or placebo daily
- 3 years with 1 year extension
- Primary objectives: radiographic vertebral fracture, bone mineral density

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## Secondary ObjectivesMORE

- All fractures
- Cardiovascular health
- Breast cancer
- Endometrial cancer
- Cognitive function and dementia
- Health outcomes

## Ascertainment and Validation of Invasive Breast Cancer

- Mammograms or ultrasound required at baseline
- Mammograms were performed at years 2, 3, & 4
- All investigator-reported breast cancers were reviewed and adjudicated by a board of breast cancer specialists
- blinded to treatment assignment
- not employed by Lilly

## Baseline CharacteristicsMORE

|  | N=5133* |
| --- | --- |
| Mean age | 66.9 years |
| Caucasian | 95.9% |
| Family history of breast cancer | 12.5% |
| Hysterectomy | 23.1% |
| Previous hormone therapy | 29.3% |

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- * Placebo and raloxifene 60 mg/day only

## Raloxifene Is Approved for the Preventionand Treatment of OsteoporosisMORE

- Clinical vertebral fracturesper 1000 woman-yrs

- 5.2 fewer fractures per 1000/yr

- HR = 0.57 (95% CI, 0.42-0.78)

- 43% decreased risk

## Invasive Breast CancerMORE

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**Invasive Breast Cancer****MORE**

**3.1 fewer cases per 1000/yr**

## Invasive Breast CancerMORE

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**Invasive Breast Cancer****MORE**

## Invasive and Non-Invasive Breast CancersMORE

## Invasive Breast Cancer by ER StatusMORE

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**Invasive Breast Cancer by ER Status****MORE**

## Study DesignCORE

- Double-blind, placebo-controlled continuation of MORE
- Does raloxifene continue to reduce the risk of breast cancer after 4 years?
- 1° endpoint: invasive breast cancer
- 4011 women from MORE continued in CORE

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## Study Design  MORE Followed by CORE:  8 Years

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*Placebo*

*Raloxifene 60 mg/day*

*Raloxifene 120 mg/day*

**Study Design **** MORE Followed by CORE:  8 Years**

## Study Design  MORE Followed by CORE

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- Year

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*Placebo*

*Raloxifene 60 mg/day*

*Raloxifene 120 mg/day*

*Placebo*

*Raloxifene 60 mg/day*

**Study Design **** MORE Followed by CORE**

*(N = 1286)*

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## Study Design  MORE Followed by CORE

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*Placebo*

*Raloxifene 60 mg/day*

*Raloxifene 120 mg/day*

*Placebo*

*Raloxifene 60 mg/day*

**Study Design **** MORE Followed by CORE**

*(N = 1286)*

*(N = 2725)*

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## Study Design  MORE Followed by CORE:  8 Years

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*Placebo*

*Raloxifene 60 mg/day*

*Raloxifene 120 mg/day*

*Placebo*

*Raloxifene 60 mg/day*

**Study Design **** MORE Followed by CORE:  8 Years**

*(N = 1286)*

*(N = 2725)*

- 5

- 6

- 7

- 8

- 4 more years

## Breast Cancer AssessmentsCORE

- Baseline: 5-year risk of breast cancer by Gail Model
- Annual clinical breast exams
- Mammograms required at baseline and years 2 and 4
- Reports of breast cancer adjudicated by 3 breast cancer specialists
- who were blinded to patient treatment assignment
- who were not employed by Lilly

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## 5-Year Predicted Risk of Breast Cancer by Gail ModelCORE

|  | Placebo
N=1286 | Raloxifene
N=2725 |
| --- | --- | --- |
| Average 5-year predicted risk | 1.94% | 1.94% |
| Percent with 5-year predicted risk ≥1.66% | 53% | 54% |

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## Invasive Breast Cancer Risk ReductionCORE

**Invasive Breast Cancer Risk Reduction****CORE**

- HR, 0.44
- (95% CI  0.24-0.83)
- p = 0.009

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- 19

**Placebo**
**N=1274**

**Raloxifene**
**N=2716**

**3.0 fewer cases per 1000/yr**

## Raloxifene Reduced the Incidence of InvasiveBreast Cancer in Women with High or Low RiskCORE

- N=674

- N=1475

- N=604

- N=1243

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- 14

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- HR 0.35(95% CI, 0.16-0.78)

- HR 0.65(95% CI, 0.23-1.87)

- <1.66%

- ≥1.66%

- 5-year Predicted Invasive Breast Cancer Risk by Gail Score

**1.2 fewer cases per 1000/yr**

**4.6 fewer cases per 1000/yr**

## Raloxifene Reduced the Incidence of InvasiveBreast Cancer in Women with High or Low RiskCORE

- N=674

- N=1475

- N=604

- N=1243

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- 14

- 11

- HR 0.35(95% CI, 0.16-0.78)

- HR 0.65(95% CI, 0.23-1.87)

- <1.66%

- ≥1.66%

- 5-year Predicted Invasive Breast Cancer Risk by Gail Score

**1.2 fewer cases per 1000/yr**

**4.6 fewer cases per 1000/yr**

- Interactionp = 0.37

## Invasive Breast CancerRaloxifene 60 mg vs. Placebo

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**Invasive Breast Cancer****Raloxifene 60 mg vs. Placebo**

- In women assigned to raloxifene 60 mg or placebo in both MORE and CORE over 8 years:
- 	60% decrease: HR 0.40 (95% CI = 0.21-0.77)

## Raloxifene Use for The Heart Trial RUTH

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## Background  RUTH

- RUTH began enrollment in June, 1998
- It was believed that estrogen may reduce risk of CHD by improving lipoproteins and vascular function
- Raloxifene improved lipoproteins and fibrinogen
- Hypothesis: Treatment with raloxifene would reduce the risk of CHD events.

## Study DesignRUTH

- Randomized, double-blind, placebo-controlled
- Raloxifene 60 mg or placebo daily
- 10,101 postmenopausal women at high risk for coronary heart disease
- Primary Outcome
- Coronary heart disease events (CHD death, nonfatal MI, hospitalized acute coronary syndrome besides MI)

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## Study DesignRUTH

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- Randomized, double-blind, placebo-controlled
- Raloxifene 60 mg or placebo daily
- 10,101 postmenopausal women at high risk for coronary heart disease
- Primary Outcome
- Coronary heart disease events (CHD death, nonfatal MI, hospitalized acute coronary syndrome besides MI)
- Invasive breast cancer

**Study Design****RUTH**

## Baseline CharacteristicsRUTH

| Characteristic |  |
| --- | --- |
| Age | 67.5 years |
| Caucasian | 84.0% |
| BMI | 28.8 kg/m2 |
| Current smoker | 12.4% |
| Previous estrogen use | 14.0% |
| Previous estrogen/progestin | 6.1% |
|  |  |

**Baseline Characteristics****RUTH**

## Baseline Breast Cancer RiskRUTH

| Characteristic | Total(N=10,101) |
| --- | --- |
| Mean 5-yr estimated breast cancer risk | 1.73% |
| Percent with 5-yr risk ≥1.66% | 41.4% |
| Family history of breast cancer | 9.8% |
| Prior breast biopsy | 8.8% |
| Diagnosis of atypical hyperplasia | 1.7% |
|  |  |

**Baseline Breast Cancer Risk****RUTH**

## No Effect on Coronary Events*RUTH 

- *First occurrence of non-fatal MI,  hospitalized ACS or coronary death

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## Significant Reduction inInvasive Breast Cancer IncidenceRUTH

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**1.2 fewer cases per 1000/yr**

## Raloxifene Reduces the Incidence of Invasive Breast Cancer in Women with High or Low Gail Risk RUTH

**Raloxifene Reduces the Incidence of Invasive Breast Cancer in Women with High or Low Gail Risk ****RUTH**

- 34

- 17

- 35

- 23

- HR 0.65(95% CI, 0.38-1.09)

- HR 0.49(95% CI, 0.28-0.88)

- <1.66%

- ≥1.66%

- 5-year Predicted Invasive Breast Cancer Risk

**1.1 fewer cases per 1000/yr**

**1.2 fewer cases per 1000/yr**

## Raloxifene Reduces the Incidence of Invasive Breast Cancer in Women with High or Low Gail Risk RUTH

**Raloxifene Reduces the Incidence of Invasive Breast Cancer in Women with High or Low Gail Risk ****RUTH**

- 34

- 17

- 35

- 23

- HR 0.65(95% CI, 0.38-1.09)

- HR 0.49(95% CI, 0.28-0.88)

- <1.66%

- ≥1.66%

- 5-year Predicted Invasive Breast Cancer Risk

**1.1 fewer cases per 1000/yr**

**1.2 fewer cases per 1000/yr**

- Interactionp-value = 0.50

## SummaryReductions in Invasive Breast Cancer

- 71%

- 56%

- 44%

**Summary****Reductions in Invasive Breast Cancer**

## Raloxifene Safety

## Adverse EventsMORE – 4 Years

**Adverse Events****MORE – 4 Years**

|  | Percent (%) |  |  |
| --- | --- | --- | --- |
|  | Placebo
(n=2576) | Raloxifene
(n=5129) | p-value |
| Thromboembolic disease | 17 (0.7) | 64 (1.3) | 0.017 |
|    - deep vein thrombosis | 8 (0.3) | 44 (0.9) | 0.005 |
|    - pulmonary embolism | 4 (0.2) | 22 (0.4) | 0.060 |
| Death | 36 (1.4) | 64 (1.2) | 0.584 |

## Adverse EventsMORE – 4 Years

**Adverse Events****MORE – 4 Years**

|  | Percent (%) |  |  |
| --- | --- | --- | --- |
|  | Placebo
(n=2576) | Raloxifene
(n=5129) | p-value |
| Vaginal bleeding* | 74 (3.7) | 220 (3.7) | 0.977 |
| Endometrial hyperplasia* | 5 (0.3) | 11 (0.3) | 0.846 |
| Endometrial cancer* | 5 (0.3) | 8 (0.2) | 0.707 |
| Cataracts | 141 (5.5) | 257 (5.0) | 0.386 |
| Hot Flushes | 151 (5.9) | 512 (10.0) | <.001 |
| Leg Cramps | 150 (5.8) | 443 (8.6) | <.001 |
| Peripheral edema | 134 (5.2) | 340 (6.6) | 0.014 |

- *In participants with a uterus

## Balance of Efficacy and Safety OutcomesMORE

**FAVORS RALOXIFENE**

**FAVORS PLACEBO**

## Balance of Efficacy and Safety OutcomesMORE

**FAVORS RALOXIFENE**

**FAVORS PLACEBO**

## Endometrial and Uterine CancerRUTH, MORE, CORE

- Including only women with a uterus

## Safety SummaryRUTH

- Compared to placebo, raloxifene was associated with:
- Increased risk of VTEs
- No effect on all-cause mortality
- No effect on all strokes
- Increased risk of death due to stroke
- Reduced risk of clinical vertebral fractures

## Safety Information in Evista Label

- Based on the osteoporosis prevention and treatment trials, MORE and CORE, the safety profile in the label includes:
- VTEs
- Hot flushes, leg cramps, peripheral edema
- Based on the RUTH trial, the label also states:
- Evista should not be used for the primary or secondary prevention of cardiovascular disease.
- Increased risk of death due to stroke occurred in a trial in postmenopausal women with documented coronary heart disease or at increased risk for major coronary events.  No increased risk of stroke was seen.  Consider risk-benefit balance in women at risk for stroke.

## RUTH

**Overall benefit risk profile is neutral in women****at high risk of cardiovascular disease**

## An Additional Benefit for Women with Osteoporosis

- Raloxifene is indicated for osteoporosis
- Postmenopausal women considering Evista for osteoporosis should be informed about its effect on risk of breast cancer