# Presentation: 695709

## Raloxifene for the Reduction in the Risk of Invasive Breast Cancer  

**July 24, 2007****Eli Lilly and Company****Oncologic Drugs Advisory Committee****Presentation**

## Lilly’s Presentation

- Introduction	Gwen Krivi, PhD	Eli Lilly and Company
- Benefits and Risks of Evista
- MORE/CORE/RUTH	Steven R. Cummings, MD	Director, San Francisco Coordinating Center	Professor of Medicine and Epidemiology (emeritus)	CPMC Research Institute and UC San Francisco
- STAR	Larry Wickerham, MD	NSABP STAR Project Officer	National Surgical Adjuvant Breast and Bowel Project 	(NSABP)
- Conclusions	George Sledge, MD	Ballve Lantero Professor of Oncology	Indiana University School of Medicine

## Expert Participants

**Eli Lilly and Company**
**Bruce Mitlak, MD **(moderator)
**	****John Mershon, MD****	**
**	****Dan Masica, MD**
**	****Michelle McNabb, MS**
**	****Jingli Song, PhD**
**	****Matt Rotelli, PhD ****	**
**	****Dan Brady, PhD**
**	**
**	**

**Additional External Consultants**
**Joseph Costantino, DrPH**Director, NSABP Biostatistical CenterNational Surgical Adjuvant Breast and Bowel Project (NSABP)
**Norman Wolmark, MD**Chairman, NSABPNational Surgical Adjuvant Breast and Bowel Project (NSABP)

## Why Is Breast Cancer Risk Reduction Important?

- 2nd most common cause of cancer death in women
- 178,000 cases diagnosed annually
- 40,000 deaths annually
- Disease prevention remains an unmet need in breast cancer
- Identification of women at risk continues to improve
- Postmenopausal women need additional options to reduce risk of breast cancer

## Raloxifene is aSelective Estrogen Receptor Modulator

- Non-steroidal ligand of the estrogen receptor
- Has estrogen-like effects in some tissues
- Blocks estrogen effects in other tissues

- Evista® (raloxifene HCl 60 mg/day) is approved for the prevention and treatment of osteoporosis

## Raloxifene Development HistoryBreast Cancer (1982-1998)

- 1982-1990	IND for treatment of Breast Cancer opened with 	the Oncology Division
- 	IND for osteoporosis opened with Endocrine 	Division
- 	MORE study initiated (breast cancer – secondary 	endpoint)
- 	IND for invasive breast cancer risk reduction 	opened
- 		IND for STAR opened by NSABP
- 		RUTH study initiated (CV risk reduction)

## Raloxifene Development HistoryBreast Cancer (1999 – present)

- 	CORE study initiated (follow-up to MORE; 	invasive breast cancer – primary endpoint)
- 	RUTH protocol amended to add invasive breast 	cancer as a second primary endpoint
- 2005 	Pre-NDA meetings with the Oncology Division
- 2006	Invasive breast cancer risk reduction	NDA submitted

## Evista®:  Current Indication

**Proposed Additional Indication**

- The prevention and treatment of osteoporosis.** **

- The reduction in risk of invasive breast cancer in  postmenopausal women _with osteoporosis_.

## Evista®:  Current Indication

**Proposed Additional Indication**

- The prevention and treatment of osteoporosis.** **

- The reduction in risk of invasive breast cancer in  postmenopausal women _at high risk for breast cancer_.

## Studied in More Than 37,000 PostmenopausalWomen Across a Spectrum of Breast Cancer Risk

- Randomized active comparator trial
- Study of Tamoxifen and Raloxifene (STAR)
- Randomized placebo-controlled trials
- Raloxifene Use for The Heart Trial (RUTH)
- Multiple Outcomes of Raloxifene Evaluation (MORE)
- Placebo-controlled follow-up study of MORE participants
- Continuing Outcomes Relevant to Evista (CORE)

**76,000 patient years of exposure to raloxifene**

## 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****	****	**** **

**Memo: **

**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

- 0

- 1

- 2

- 3

- 4

- Year

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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

- 0

- 1

- 2

- 3

- 4

- 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)*

- 5

- 6

- 7

- 8

## Study Design  MORE Followed by CORE

- 0

- 1

- 2

- 3

- 4

- 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)*

*(N = 2725)*

- 5

- 6

- 7

- 8

## Study Design  MORE Followed by CORE:  8 Years

- 0

- 1

- 2

- 3

- 4

- 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:  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

- 20

- 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

- 6

- 8

- 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**

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

- N=674

- N=1475

- N=604

- N=1243

- 6

- 8

- 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

## Study of Tamoxifen and RaloxifeneSTAR

**Larry Wickerham, MD**
**NSABP STAR Project Officer**

## NSABP P1 Study

**                 ****# Events**
**Placebo****	****93**
**Tamoxifen****	****60****   **

**                 ****# Events**
**Placebo****	****250**
**Tamoxifen****	****145****   **

**50**

**40**

**30**

**20**

**10**

**0**

**Cumulative Rate/1000**

**Invasive **
**Breast Cancer**

**Noninvasive**
**Breast Cancer**

**Time to Breast Cancer (Years)**

**P < 0.0001**

**P= 0.008**

**NSABP P1 Study**

## Study DesignSTAR

- Age
- Gail Model Risk
- Race
- History of LCIS
- Hysterectomy

- Tamoxifen
- 20 mg/day
- x 5 years

**Study Design****STAR**

- Raloxifene
- 60 mg/day
- x 5 years

- Risk-Eligible Postmenopausal Women

## Inclusion and Exclusion CriteriaSTAR

_**Inclusion**_
- At least 35 years of age
- Postmenopausal
- Risk eligible
- 	Lobular carcinoma *in situ* or
- 	5-year Gail risk of breast cancer _>_1.66%

_**Exclusion**_
- History of:
- Invasive breast cancer
- Ductal carcinoma *in situ*
- DVT, PE
- CVA, TIA
- Uncontrolled diabetes, hypertension or atrial fibrillation

## Primary AimsSTAR

- The primary aim of the study was to determine which  of the following three statements is true:
- Compared to tamoxifen, raloxifene significantly reduces the incidence rate of IBC
- Compared to raloxifene, tamoxifen significantly reduces the incidence rate of IBC
- The statistical superiority of one of the treatments cannot be demonstrated and the choice of therapy should be based on benefit/risk considerations

## Primary ObjectiveSTAR

- Evaluate the effect of raloxifene versus tamoxifen in reducing the incidence of invasive breast cancer in postmenopausal women who are at increased risk.

## Secondary Objectives STAR

- Non-invasive breast cancer
- Endometrial cancer
- Ischemic heart disease
- Fractures of the hip, spine or wrist
- Toxicity and side effects

## Screening, Accrual and Follow-upSTAR

- Screened	184,460
- Eligible	96,368
- Randomized	19,747
- Woman-years of follow-up	79,173
- Average follow-up (years) 	4.06

## Baseline CharacteristicsSTAR

**Baseline Characteristics****STAR**

- Age (mean)	58.5
- Caucasian	93%
- Hysterectomy	51%
- First degree relative(s)with breast cancer	71%
- History of
- 	Lobular carcinoma *in situ*	9%
- 	Atypical hyperplasia	23%
- 5-year predicted Gail risk ofinvasive breast cancer (mean)	4.03%

## Effects on Invasive Breast Cancer STAR

**RR (95% CI) = 1.02 (0.82, 1.27)**

## Invasive Breast Cancer STAR

**168**

**173**

**325**

## Invasive Breast Cancer by 5-year Predicted RiskSTAR

## Invasive Breast Cancer Tumor CharacteristicsSTAR

|  | Tamoxifenn=168 | Raloxifenen=173 |
| --- | --- | --- |
| Estrogen Receptor Status |  |  |
| 	+ | 72% | 69% |
| 	- | 28% | 31% |
| Tumor Size |  |  |
| 	<1 | 29% | 39% |
| 	1.1-3 | 61% | 54% |
| 	>3.1 | 10% | 8% |
| Nodal Status |  |  |
| 	- | 74% | 80% |
| 	+ | 26% | 20% |

## Invasive Breast Cancer in Women with aHistory of LCIS or Atypical Hyperplasia STAR

**Invasive Breast Cancer in Women with a****History of LCIS or Atypical Hyperplasia ****STAR**

## Non-Invasive Breast Cancer STAR

## Non-Invasive Breast CancerSTAR

|  | Tamoxifen
(n) | Raloxifene
(n) | RR (95%CI) |
| --- | --- | --- | --- |
| DCIS | 
32 
 | 47 | 1.46 (0.91-2.37) |
| LCIS | 23  | 29  | 1.26 (0.70-2.27) |
| Mixed | 5  | 7  | 1.39 (0.38-5.57) |

## Uterine Cancer STAR

## Uterine Hyperplasia and HysterectomySTAR

|  | Tamoxifen(n) | Raloxifene(n) | RR (95% CI) |
| --- | --- | --- | --- |
| Hysterectomyduring study | 246 | 92 | 0.37 (0.28, 0.47) |
| Hyperplasia  | 100 | 17 | 0.17 (0.09, 0.28) |
| 	with atypia | 15 | 2 | 0.13 (0.01, 0.56) |
| 	w/o atypia | 85 | 15 | 0.17 (0.09, 0.30) |

**Uterine Hyperplasia and Hysterectomy****STAR**

##  Ischemic Heart Disease STAR

|  | Tamoxifen
(n) | Raloxifene
(n) | RR (95% CI) |
| --- | --- | --- | --- |
| Myocardial infarction | 53 | 39 | 0.73 (0.47-1.13) |
| Severe angina | 55 | 71 | 1.28 (0.89-1.86) |
| Acute ischemic syndrome | 17 | 28 | 1.64 (0.87-3.19) |
| Total | 125 | 138 | 1.10 (0.86-1.41) |

## Osteoporotic Fractures STAR 

| 
 | Tamoxifen
(n) | Raloxifene
(n) | RR (95% CI) |
| --- | --- | --- | --- |
| Hip | 28 | 26 | 0.92 (0.52-1.63) |
| Spine   | 58 | 58 | 0.99 (0.68-1.46) |
| Wrist | 27 | 27 | 0.99 (0.56-1.76) |
| Total* | 111 | 108 | 0.97 (0.73-1.27) |

- *Columns not additive because one patient may have had fractures at multiple sites.

## MortalitySTAR

|  | Tamoxifen(n) | Raloxifene(n) |  |
| --- | --- | --- | --- |
| Cancer | 52 | 52 |  |
| 	Breast cancer | 	5 | 	2 |  |
| Circulatory/vascular  | 25 | 21 |  |
| Other | 32 | 31 |  |
| Any cause | 109 | 104 | RR (95% CI) 0.95 (0.72-1.25) |

## Venous Thromboembolic EventsSTAR

## Cataracts and Cataract Surgery During Follow-upSTAR

## Summary STAR

- Compared with tamoxifen, raloxifene was:
- similar in decreasing the risk of invasive breast cancer
- not as effective at decreasing the risk of non-invasive breast cancer
- associated with fewer:
- adverse events related to uterus
- VTEs
- cataracts and cataract surgery

## Risk Benefit and Conclusions

**George Sledge, MD****Indiana University School of Medicine**

## Do We Need a New Chemoprevention Agent?

- Breast cancer continues to represent a major cause of morbidity and mortality
- Few women actually receive tamoxifen as chemoprevention for breast cancer
- Real toxicities (VTE, uterine cancer) limit its use
- Perception that it is a “cancer drug” with poor risk/benefit ratio

## Raloxifene Demonstrates Efficacyin Postmenopausal WomenAcross a Spectrum of Breast Cancer Risk

- 71%

- 56%

- 44**%**

- RR 1.02

## Confirmation of Raloxifene’s Effectiveness Relative to Tamoxifen in STAR

- STAR Non-inferiority Analysis
-  	Proportion retention of tamoxifen’s effect* (95% CI) = 97% (65%, 128%)

- STAR Primary Analysis
- RR (95% CI) = 1.02 (0.82, 1.27)

*** Tamoxifen’s effect based on women 50 years or older in P-1**

## Raloxifene as an Alternative to Tamoxifen: Benefit

- Similar efficacy with regard to prevention of invasive breast cancer
- Less effect on noninvasive cancers

## Non-Invasive Breast Cancerin Placebo-Controlled Studies MORE, CORE, RUTH

- 11/5044

- 5/5057

- 2/1274

- 5/2716

**(N=5133)**

**(N=3990)**

**(N=10,101)**

- 5/2576

- 3/2557

**SEER**

**SEER annual US incidence rate per 1,000 in white women ≥50 (2000 data) **

## Efficacy and Important Safety Outcomes STAR

**FAVORS RALOXIFENE**

**FAVORS TAMOXIFEN**

- Difference in Number of Events (95% CI) per 1000 Women/Yr

- P=0.055

- P=0.057

*****

*****

*****

*****

- *P < 0.05 vs. tamoxifen

## Differences in Outcomes forRaloxifene versus TamoxifenSTAR

**(RALOXIFENE VS. TAMOXIFEN)**

- Non-invasive breast cancer	3 more
- 	DCIS only		2 more
- Hysterectomy	40 fewer†
- Hyperplasia	20 fewer†
- Uterine cancer	4 fewer
- Venous thromboembolism	6 fewer†
-      Deep vein thrombosis		3 fewer
-      Pulmonary embolism		3 fewer
- Cataracts	10 fewer†
- 	Cataract surgery		9 fewer†

**Outcome**

- †P < 0.05

**Differences in Outcomes for****Raloxifene versus Tamoxifen****STAR**

## Invasive Breast Cancer Risk Reduction Compares Favorablywith Other Prevention Therapies

- 2MRC Working Party Br Med J 1992;304:405-412
- 3Berger JS et al. JAMA 2006;295:306-313
- 4Fisher B et al., J Natl Cancer Inst. 1998 Sep 16;90(18):1371-88.

**Invasive Breast Cancer Risk Reduction Compares Favorably****with Other Prevention Therapies**

| Therapy | Event | NNT* |
| --- | --- | --- |
| Atorvastatin1 | MI/CHD death	 | 294 |
| Antihypertensives2 | Strokes | 370 |
|  | Coronary event | 417 |
| Aspirin3 | MI | 753 |
| Tamoxifen4 | Invasive BrCa	 | 303 |
| Raloxifene (MORE) | Invasive BrCa	 | 323 |
| Raloxifene (CORE) | Invasive BrCa	 | 335 |
| Raloxifene (RUTH) | Invasive BrCa	 | 862 |

- *NNT = number of patients needed to treat for 1 year to prevent 1 outcome

## Postmenopausal women at high risk for breast cancer should now have a choice

## Well established, FDA approved agent for prevention and treatment of osteoporosis
Reduced risk of invasive breast cancer observed in MORE has been confirmed in RUTH and STAR
Clinically important benefit for these women

- Reduced risk of invasive breast cancer observed in MORE has been confirmed in RUTH and STAR
- Clinically important benefit for these women

**Raloxifene and Postmenopausal Women with Osteoporosis**

## Invasive Breast Cancer and Vertebral Fracture MORE and P-1

**Clinical Vertebral Fracture**
**(No. per 1000/yr)**

**Invasive Breast Cancer **
**(No. per 1000/yr)**

**0**

**2**

**4**

**6**

**8**

**10**

**12**

**0**

**2**

**4**

**6**

**8**

**10**

**12**

## Invasive Breast Cancer and Vertebral Fracture MORE and P-1

**Clinical Vertebral Fracture**
**(No. per 1000/yr)**

**Invasive Breast Cancer **
**(No. per 1000/yr)**

**0**

**2**

**4**

**6**

**8**

**10**

**12**

**0**

**2**

**4**

**6**

**8**

**10**

**12**

## Invasive Breast Cancer and Vertebral Fracture MORE and P-1

**(No. per 1000/yr)**

**Invasive Breast Cancer **
**(No. per 1000/yr)**

**MORE**

**Placebo**

**P-1 (age≥50)**

**Placebo**

**0**

**2**

**4**

**6**

**8**

**10**

**12**

**0**

**2**

**4**

**6**

**8**

**10**

**12**

**Raloxifene**

**3.1 fewer**

**3.6 fewer**

**Tamoxifen**

**0.5 fewer**

**5.2 fewer**

**Invasive Breast Cancer and Vertebral Fracture ****MORE and P-1**

## Postmenopausal women considering raloxifene for treatment of osteoporosis should be informed about the potential additional benefit on their risk of invasive breast cancer

**Slide Modified: **

**Memo: **

## Conclusion

- Since 1998 an estimated 22 million postmenopausal women worldwide have received raloxifene to prevent or treat osteoporosis.
- Clinical trials involving more than 37,000 postmenopausal women now provide information on the benefits and risks of the use of raloxifene to reduce the risk of invasive breast cancer.
- The benefit-risk is favorable in postmenopausal women at high risk for breast cancer and in postmenopausal women taking raloxifene for osteoporosis.

## Slide 93

## Time to Event Analysis of Stroke by Year All Randomized Patients RUTH

-        	N=5057	N=5044	Hazard Ratio
- Stroke	n (%)	 n (%)	 (95% CI)	p-Valuea
- 1 year 	35 (0.7)	40 (0.8)	1.14 (0.73, 1.80)	.5596
- 2 year 	73 (1.4)	82 (1.6)	1.12 (0.82, 1.54)	.4806
- 3 year 	118 (2.3)	124 (2.5)	1.04 (0.81, 1.34)	.7440
- 4 year  	148 (2.9)	167 (3.3)	1.12 (0.90, 1.39)	.3253
- 5 year 	187 (3.7)	216 (4.3)	1.14 (0.94, 1.39)	.1815
- 6 year 	221 (4.4)	242 (4.8)	1.08 (0.90, 1.30)	.3936
- 7 year	 224 (4.4)	249 (4.9)	1.10 (0.92, 1.32)	.3034

- ap-value obtained from log-rank test

**Time to Event Analysis of Stroke by Year ****All Randomized Patients ****RUTH**

## Stroke Across Studies 

- Incidence per 1000 woman-yrs

**(N=10,101)**

**(N=7705)**

**(N=19,487)**

**(N=8018)**

**P=0.19**

**P=0.30**

**P=0.82**

**P=0.04**

**Tamoxifen**

## Evista Label Update: Precautions and WarningsDeath Due to Stroke

**Section 5.3 Death Due to Stroke**
- In a clinical trial of postmenopausal women with documented coronary heart disease or at increased risk for coronary events, an increased risk of death due to stroke was observed after treatment with EVISTA.  During an average follow-up of 5.6 years, 59 (1.2%) EVISTA -treated women died due to a stroke compared to 39 (0.8%) placebo-treated women (22 versus 15 per 10,000 women-years; hazard ratio 1.49; 95% confidence interval, 1.00-2.24; p=0.0499). There was no statistically significant difference between treatment groups in the incidence of stroke (249 in EVISTA [4.9%] versus 224 placebo [4.4%]). EVISTA had no significant effect on all-cause mortality. The risk-benefit balance should be considered in women at risk for stroke, such as prior stroke or transient ischemic attack (TIA), atrial fibrillation, hypertension, or cigarette smoking *[see Clinical Studies (14.4)]*.

## Proportion of Tamoxifen Efficacy Retained by Raloxifene (Invasive Breast Cancer)Rothmann Analysis

**Source for Historical Effect Data**

**P-1 (>50)**

**P-1**

**Cuzick meta-analysis (>50)**

**Cuzick meta-analysis**

## Four Tamoxifen Breast Cancer Prevention TrialsStudy Design

| Trial | Study Population and Duration | Primary Endpoint | Enrollment Criteria | Use of ET (%)
During the Study |
| --- | --- | --- | --- | --- |
| Royal Marsden | N=2471
1986-1996
European Trial | Occurrence of breast cancer | High risk and family history of breast cancer | Yes, 26% |
| Italian | N=5408
1992-1997
European Trial | Occurrence of breast cancer and deaths from breast cancer | Normal risk and hysterectomy | Yes, not reported |
| P-1 | N=13,388
1992-1997
North American Trial | Occurrence of invasive breast cancer | 5 year risk of invasive breast cancer ≥1.66% or had a history of LCIS or atypical hyperplasia | No |
| IBIS-I | N=7139
1992-2001
European Trial | Occurrence of breast cancer including DCIS | Had risk factors for breast cancer with at least 2-fold relative risk | Yes, 40% |

**Four Tamoxifen Breast Cancer Prevention Trials****Study Design**