1 raloxifene for the reduction in the risk of invasive breast cancer july 24, 2007 eli lilly and...
TRANSCRIPT
1
Raloxifene for the Reduction in the Risk of Invasive Breast Cancer
July 24, 2007
Eli Lilly and Company
Oncologic Drugs Advisory CommitteePresentation
2
Lilly’s Presentation
• Introduction Gwen Krivi, PhDEli Lilly and Company
• Benefits and Risks of Evista
– MORE/CORE/RUTH Steven R. Cummings, MDDirector, San Francisco Coordinating CenterProfessor of Medicine and Epidemiology
(emeritus) CPMC Research Institute and UC San Francisco
– STAR Larry Wickerham, MDNSABP STAR Project OfficerNational Surgical Adjuvant Breast and Bowel
Project (NSABP)
– Conclusions George Sledge, MDBallve Lantero Professor of OncologyIndiana University School of Medicine
3
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, DrPHDirector, NSABP Biostatistical CenterNational Surgical Adjuvant Breast and Bowel Project (NSABP)
Norman Wolmark, MDChairman, NSABPNational Surgical Adjuvant Breast and Bowel Project (NSABP)
4
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
5
Raloxifene is aSelective 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
6
Raloxifene Development HistoryBreast Cancer (1982-1998)
1982-1990 IND for treatment of Breast Cancer opened with the Oncology Division
1992 IND for osteoporosis opened with Endocrine Division
1994 MORE study initiated (breast cancer – secondary endpoint)
1998 IND for invasive breast cancer risk reduction opened
IND for STAR opened by NSABP
RUTH study initiated (CV risk reduction)
7
Raloxifene Development HistoryBreast Cancer (1999 – present)
1999 CORE study initiated (follow-up to MORE; invasive breast cancer – primary endpoint)
2000 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 reductionNDA submitted
8
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.
9
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.
10
Studied in More Than 37,000 PostmenopausalWomen 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
11
Multiple Outcomes of Raloxifene EvaluationMORE
Continuing Outcomes Relevant to EvistaCORE
Raloxifene Use for The Heart Trial RUTH
Steven R. Cummings, MDDirector, San Francisco Coordinating Center
Professor of Medicine and Epidemiology (emeritus)CPMC Research Institute and UC San Francisco
12
Study DesignMORE
• 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
13
Secondary ObjectivesMORE
• All fractures
• Cardiovascular health
• Breast cancer
• Endometrial cancer
• Cognitive function and dementia
• Health outcomes
14
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
15
Baseline CharacteristicsMORE
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%
* Placebo and raloxifene 60 mg/day only
16
Raloxifene Is Approved for the Preventionand Treatment of Osteoporosis
MOREC
linic
al v
erte
bral
frac
ture
spe
r 10
00 w
oman
-yrs
5.2 fewer fractures per 1000/yr
HR = 0.57 (95% CI, 0.42-0.78)
43% decreased risk
17Year
0 1 2 3 4
Cum
ulat
ive
inci
denc
e pe
r 10
00 w
omen
0
5
10
15
20
25
30Placebo (n=38)Raloxifene 60 mg (n=11)
RR = 0.29 (95% CI = 0.15-0.56)p-value <0.0001
Invasive Breast CancerMORE
3.1 fewer cases per 1000/yr
18Year
0 1 2 3 4
Cum
ulat
ive
inci
denc
e pe
r 10
00 w
omen
0
5
10
15
20
25
30Placebo (n=38)Raloxifene 60 mg (n=11)Raloxifene 120 mg (n=9)
Invasive Breast CancerMORE
19
Invasive and Non-Invasive Breast CancersMORE
Invasive Non-Invasive Invasiveness
Inci
denc
e pe
r 10
00 w
oman
-yrs
0
1
2
3
4
5
PlaceboRaloxifene 60 mg
38
11
13
HR 0.29(95% CI=0.15-0.56)
53
HR 0.59(95% CI=0.14-2.47)
unknown
20
Invasive Breast Cancer by ER StatusMORE
ER+ ER- ER unknown
Inci
denc
e pe
r 10
00 w
oman
-yrs
0
1
2
3
4
5
Placebo Raloxifene 60 mg
29
65
0
HR 0.20(95% CI=0.08-0.49)
4 5
HR 1.23(95% CI=0.33-4.60)
21
Study DesignCORE
• 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
22
0 1 2 3 4Year
Placebo
Raloxifene 60 mg/day
Raloxifene 120 mg/day
Study Design MORE Followed by CORE: 8 Years
MORE(N=7705)
CORE(N=4011)
23
0 1 2 3 4Year
Placebo
Raloxifene 60 mg/day
Raloxifene 120 mg/day
Placebo
Raloxifene 60 mg/day
Study Design MORE Followed by CORE
(N = 1286)
MORE(N=7705)
CORE(N=4011)
GapCORE
Screening
5 6 7 8
24
0 1 2 3 4Year
Placebo
Raloxifene 60 mg/day
Raloxifene 120 mg/day
Placebo
Raloxifene 60 mg/day
Study Design MORE Followed by CORE
(N = 1286)
(N = 2725)
MORE(N=7705)
CORE(N=4011)
GapCORE
Screening
5 6 7 8
25
0 1 2 3 4Year
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)
MORE(N=7705)
CORE(N=4011)
GapCORE
Screening
5 6 7 8
4 more years
26
Breast Cancer AssessmentsCORE
• 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
27
5-Year Predicted Risk of Breast Cancer by Gail Model
CORE
PlaceboN=1286
RaloxifeneN=2725
Average 5-year predicted risk 1.94% 1.94%
Percent with 5-year predicted risk ≥1.66%
53% 54%
28
0
1
2
3
4
5
6
7
Inci
den
ce p
er 1
000
wo
man
-yrs
Invasive Breast Cancer Risk ReductionCORE
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
29
Raloxifene Reduced the Incidence of InvasiveBreast Cancer in Women with High or Low Risk
CORE
0
1
2
3
4
5
6
7
8
Inci
den
ce p
er 1
000
wom
an-
yrs
Placebo
Raloxifene
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
30
Raloxifene Reduced the Incidence of InvasiveBreast Cancer in Women with High or Low Risk
CORE
0
1
2
3
4
5
6
7
8
Inci
den
ce p
er 1
000
wom
an-
yrs
Placebo
Raloxifene
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
31
Invasive Breast CancerRaloxifene 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)
32
Raloxifene Use for The Heart Trial RUTH
33
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.
34
Study DesignRUTH
• 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)
35
• 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 DesignRUTH
36
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 CharacteristicsRUTH
37
CharacteristicTotal
(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 RiskRUTH
38
No Effect on Coronary Events*RUTH
*First occurrence of non-fatal MI, hospitalized ACS or coronary death
39
Significant Reduction inInvasive Breast Cancer Incidence
RUTH
1.2 fewer cases per 1000/yr
40
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
41
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
42
RUTH MORE CORE
Inci
denc
e pe
r 10
00 w
oman
-yrs
0
1
2
3
4
5
6PlaceboRaloxifene
71%
56%
44%
SummaryReductions in Invasive Breast Cancer
43
Raloxifene Safety
44
Adverse EventsMORE – 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
45
Adverse EventsMORE – 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
46
Balance of Efficacy and Safety OutcomesMORE
Difference in No. of Events per 1000/yr
-10 -9 -8 -7 -6 -5 -4 -3 -2 -1 0 1 2 3
Ovarian ca
Endo ca
VTE
Stroke
Death due to stroke
Death
Vert fx
NIBC
IBC
FAVORS RALOXIFENE FAVORS PLACEBO
47
Balance of Efficacy and Safety OutcomesMORE
Difference in No. of Events per 1000/yr
-10 -9 -8 -7 -6 -5 -4 -3 -2 -1 0 1 2 3
Ovarian ca
Endo ca
VTE
Stroke
Death due to stroke
Death
Vert fx
NIBC
IBC
FAVORS RALOXIFENE FAVORS PLACEBO
48
Endometrial and Uterine CancerRUTH, MORE, CORE
0
0.25
0.5
0.75
1
1.25
1.5
RUTH MORE CORE
Inci
de
nce
pe
r 1
00
0 w
om
an
-yrs
Placebo
Raloxifene
5
8
17
21 3
4
(N=5959) (N=3146)(N=7782)
Including only women with a uterus
49
Safety SummaryRUTH
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
50
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.
51
RUTH
Overall benefit risk profile is neutral in womenat high risk of cardiovascular disease
52
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
53
Study of Tamoxifen and RaloxifeneSTAR
Larry Wickerham, MD
NSABP STAR Project Officer
54
0 1 2 3 4 5 6 7 0 1 2 3 4 5 6 7
# EventsPlacebo 93Tamoxifen 60
50
40
30
20
10
0
# EventsPlacebo 250Tamoxifen 145
50
40
30
20
10
0
Cu
mu
lati
ve R
ate/
1000
Invasive Breast Cancer
NoninvasiveBreast Cancer
Time to Breast Cancer (Years)
P < 0.0001
P= 0.008
NSABP P1 Study
55
STRATIFICATION• Age• Gail Model Risk• Race• History of LCIS• Hysterectomy
Tamoxifen20 mg/dayx 5 years
Study DesignSTAR
Raloxifene60 mg/dayx 5 years
Risk-Eligible Postmenopausal Women
56
Inclusion and Exclusion CriteriaSTAR
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
57
Primary AimsSTAR
• 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
58
Primary ObjectiveSTAR
Evaluate the effect of raloxifene versus tamoxifen in reducing the incidence of invasive breast cancer in postmenopausal women who are at increased risk.
59
Secondary Objectives STAR
•Non-invasive breast cancer
•Endometrial cancer
•Ischemic heart disease
•Fractures of the hip, spine or wrist
•Toxicity and side effects
60
Screening, Accrual and Follow-upSTAR
Screened 184,460
Eligible 96,368
Randomized 19,747
Woman-years of follow-up 79,173
Average follow-up (years) 4.06
61
Baseline CharacteristicsSTAR
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%
62
Effects on Invasive Breast Cancer STAR
Time Since Randomization (months)
0 6 12 18 24 30 36 42 48 54 60 66 72Cu
mu
lati
ve in
cid
ence
per
100
0 w
om
en
0
5
10
15
20
25
30Tamoxifen (n=168)Raloxifene (n=173)
RR (95% CI) = 1.02 (0.82, 1.27)
63
Invasive Breast Cancer STAR
0
2
4
6
8
10
12
Gail Model Expectedif Untreated
Tamoxifen Raloxifene
Inci
denc
e pe
r 10
00 w
oman
-yrs
168 173
325
64
Invasive Breast Cancer by 5-year Predicted RiskSTAR
0
2
4
6
8
10
12
≤3% 3.01 - 5% ≥5.01%
Predicted 5-year Risk
Inci
denc
e pe
r 10
00 w
oman
-yrs
Tamoxifen
Raloxifene
33
63
72
4449
80
65
Invasive Breast Cancer Tumor CharacteristicsSTAR
Tamoxifenn=168
Raloxifenen=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%
66
0
3
6
9
12
Inci
den
ce p
er 1
000
wo
man
-yrs Tamoxifen
Raloxifene
LCISN=1783
Atypical Hyperplasia N=4429
34 35
4741
Invasive Breast Cancer in Women with aHistory of LCIS or Atypical Hyperplasia
STAR
67
Non-Invasive Breast Cancer STAR
Time Since Randomization (months)
0 6 12 18 24 30 36 42 48 54 60 66 72Cu
mu
lati
ve
in
cid
en
ce
pe
r 1
00
0 w
om
en
0
5
10
15
20
25
30
Tamoxifen (n=60)Raloxifene (n=83)
RR (95% CI) = 1.38 (0.98-1.95)
68
Non-Invasive Breast CancerSTAR
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)
69
Uterine Cancer STAR
Time Since Randomization (months)
0 6 12 18 24 30 36 42 48 54 60 66 72Cu
mu
lati
ve in
cid
ence
per
100
0 w
om
en
0
5
10
15
20
25
30Tamoxifen (n=37)Raloxifene (n=23)
RR (95% CI) = 0.61 (0.34, 1.05)
70
Tamoxifen(n)
Raloxifene(n)
RR (95% CI)
Hysterectomyduring 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 HysterectomySTAR
71
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)
72
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.
73
MortalitySTAR
Tamoxifen(n)
Raloxifene(n)
Cancer 52 52
Breast cancer 5 2
Circulatory/vascular 25 21
Other 32 31
Any cause 109 104RR (95% CI)
0.95 (0.72-1.25)
74
Venous Thromboembolic EventsSTAR
Time Since Randomization (months)
0 6 12 18 24 30 36 42 48 54 60 66 72Cu
mu
lati
ve
in
cid
en
ce
pe
r 1
00
0 w
om
en
0
5
10
15
20
25
30Tamoxifen (n=150)Raloxifene (n=105)
RR (95% CI) = 0.69 (0.53, 0.90)
75
Cataracts and Cataract Surgery During Follow-upSTAR
0
2
4
6
8
10
12
14
Cataracts Cataract Surgery
Incid
en
ce p
er
1000 w
om
an
-yrs Tamoxifen
Raloxifene435
295
343
240
RR = 0.78(95% CI = 0.68–0.91)
RR = 0.81(95% CI = 0.68–0.96)
76
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
77
Risk Benefit and Conclusions
George Sledge, MDIndiana University School of Medicine
78
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
79
Raloxifene Demonstrates Efficacyin Postmenopausal Women
Across a Spectrum of Breast Cancer Risk
RUTH MORE CORE STAR
Inci
den
ce p
er 1
000
wom
an-y
rs
0
1
2
3
4
5
6PlaceboTamoxifenRaloxifene
71%
56%
44%
RR 1.02
80
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%)
Time Since Randomization (months)
0 6 12 18 24 30 36 42 48 54 60 66 72Cu
mu
lati
ve i
nci
den
ce p
er 1
000
wo
men
0
5
10
15
20
25
30Tamoxifen (n=168)Raloxifene (n=173)
STAR Primary AnalysisRR (95% CI) = 1.02 (0.82, 1.27)
* Tamoxifen’s effect based on women 50 years or older in P-1
81
Raloxifene as an Alternative to Tamoxifen: Benefit
• Similar efficacy with regard to prevention of invasive breast cancer
– Less effect on noninvasive cancers
82
Non-Invasive Breast Cancerin Placebo-Controlled Studies
MORE, CORE, RUTH
0
0.25
0.5
0.75
1
1.25
1.5
MORE CORE RUTH
Inc
ide
nc
e r
ate
pe
r 1
00
0 w
om
an
-yrs
PlaceboRaloxifene
11/50445/50572/1274 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)
83
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
84
Difference in # of events per 1000treated per 5 years
(RALOXIFENE VS. TAMOXIFEN)
Non-invasive breast cancer 3 moreDCIS 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 forRaloxifene versus Tamoxifen
STAR
85
1Sever PS et al., Lancet. 2003 Apr 5;361(9364):1149-582MRC Working Party Br Med J 1992;304:405-4123Berger JS et al. JAMA 2006;295:306-3134Fisher 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
86
Postmenopausal women at high risk for breast cancer should now have a choice
87
• 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
Raloxifene and Postmenopausal Women with Osteoporosis
88
Invasive Breast Cancer and Vertebral Fracture MORE and P-1
Clinical Vertebral Fracture
(No. per 1000/yr)
Inva
siv
e B
reas
t C
an
cer
(No
. pe
r 1
000
/yr)
MORE
Placebo
P-1 (age≥50)
Placebo
0
2
4
6
8
10
12
0 2 4 6 8 10 12
89
Invasive Breast Cancer and Vertebral Fracture MORE and P-1
Clinical Vertebral Fracture
(No. per 1000/yr)
Inva
siv
e B
reas
t C
an
cer
(No
. pe
r 1
000
/yr)
0
2
4
6
8
10
12
0 2 4 6 8 10 12
P-1 (age≥50)
Placebo
Tamoxifen
3.6 fewer
MORE
Placebo
Raloxifene
3.1 fewer
90
Clinical Vertebral Fracture
(No. per 1000/yr)
Inva
siv
e B
reas
t C
an
cer
(No
. pe
r 1
000
/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
91
Postmenopausal women considering raloxifene for treatment of osteoporosis should be informed about the potential
additional benefit on their risk of invasive breast cancer
92
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.
94
Placebo RLX 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
95
Stroke Across Studies
0
2
4
6
8
10
12
RUTH MORE STAR P-1 (age ≥50)
Placebo
Raloxifene
Inci
denc
e pe
r 10
00 w
oman
-yrs
(N=10,101) (N=7705) (N=19,487) (N=8018)
P=0.19
P=0.30
P=0.82
P=0.04
Tamoxifen
96
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)].
97
Proportion of Tamoxifen Efficacy Retained by Raloxifene (Invasive Breast Cancer)
Rothmann Analysis
% Tamoxifen Effect Retained (95% CI)
0 20 40 60 80 100 120 140 160 180
Source for Historical Effect Data
P-1 (>50)
P-1
Cuzick meta-analysis (>50)
Cuzick meta-analysis
98
Trial Study Population and Duration
Primary Endpoint Enrollment Criteria Use of ET (%)During the Study
Royal Marsden
N=24711986-1996European Trial
Occurrence of breast cancer
High risk and family history of breast cancer
Yes, 26%
Italian N=54081992-1997European Trial
Occurrence of breast cancer and deaths from breast cancer
Normal risk and hysterectomy
Yes, not reported
P-1 N=13,3881992-1997North 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=71391992-2001European 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 TrialsStudy Design