Transcript Toremifene - Clinicians Channel&#174

Are All SERMs the Same?
William H. Catherino, MD, PhD
Research Director
Department of Obstetrics and Gynecology
Uniformed Services University of the Health Sciences
Director of Reproductive Endocrinology (Intramural)
National Institute of Child Health & Human Development, NIH
Bethesda, Maryland
and
Régine L. Sitruk-Ware, MD
Executive Director, Research and Development
Rockefeller University and Population Council
New York, New York
Promise of Hormone Replacement
Therapy (HRT)
Circa 1990’s

Alleviates climacteric symptoms

Protects bone

Protects heart

Protects endometrial lining

No effect on breast cancer
HRT in the New Millennium

Alleviates hot flashes

Protects bone

Neutral to negative cardiovascular
effects, depending on age

Neutral to negative endometrial
effects

Neutral to negative breast effects
HRT Use Before and After Publication of
the Women’s Health Initiative (WHI)
40
30
Pre-WHI
21.3%
20
Post-WHI
9.1%
10
0
n = 61
n = 55
Noncarriers of BRCA1/2
Reprinted from Dorval M, et al. Cancer Epidemiol Biomarkers Prev. 2007;16:157,
with permission from the American Association for Cancer Research.
The Promise of Selective Estrogen
Receptor Modulators (SERMs)1,2

Estrogenic activity tissue dependent

Compounds direct estrogenic function
to tissues that benefit from estrogen
exposure

Same compounds act as anti-estrogens in
tissues harmed by estrogen exposure
1. Gajdos C, et al. Clin Breast Cancer. 2002;2:272. 2. Jordan VC. Clin Cancer Res. 2006;12:5010.
SERM Development Timeline
Fulvestranta
DT56a
HMR 3339
Tamoxifena
DES
Raloxifenea
Lasofoxifene
Arzoxifene
Bazedoxifene
Toremifene
Droloxifene
MER 25
Clomiphene
Ospemifene
Idoxifene
1930
1940
1950
1960
1970
aFDA-approved.
Graphic courtesy of William H. Catherino, MD, PhD.
1980
1990
2000
2010
Tamoxifen
Climacteric
symptoms
Hot flashes increased1
Bone
↓ fractures2
BMD preserved3
Breast
↓ cancer incidence1,4
Endometrium
↑ cancer 2.4-fold4
CV
↓ MI risk5
↑ VTE risk 2.5-fold5
Chemical structure available at: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=168097.
CV = cardiovascular; BMD = bone mineral density; MI = myocardial infarction; VTE = venous thromboembolytic event.
1. Fisher B, et al. J Natl Cancer Inst. 1998;90:1371. 2. Fisher B, et al. J Natl Cancer Inst. 2005;97:1652. 3. Love RR, et al.
N Engl J Med. 1992;326:852. 4. Cuzick J, et al. Lancet. 2003;361:296. 5. McDonald CC, et al. BMJ. 1995;311:977.
Tamoxifen Analogs in
Clinical Development
“Triphenylethylenes”

Toremifene

Droloxifene

Idoxifene

Lasofoxifene

Ospemifene
Toremifene
Climacteric
symptoms
Comparable to tamoxifen1
Bone
BMD comparable to
placebo, inferior to
tamoxifen2
Breast
Comparable to
tamoxifen1,3,4
Endometrium
Fewer cases of cancer1,4
CV
↓ LDL , ↑ VTE,
comparable to tamoxifen5
Chemical structure available at: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=193362.
1. Pyrhönen S, et al. Breast Cancer Res Treat. 1999;56:133.
2. Erkkola R, et al. Breast Cancer Res Treat. 2005;93:277. 3. Holli K, et al. J Clin Oncol. 2000;18:3487.
4. Milla-Santos A, et al. Breast Cancer Res Treat. 2001;65:119. 5. Gylling H, et al. J Clin Oncol. 1995;13:2900.
Droloxifene
Climacteric
symptoms
Undefined
Bone
Undefined
Breast
Less effective than
tamoxifen1
Endometrium
Undefined
CV
↓ LDL, total
cholesterol, and
coagulation factors2
Chemical structure available at: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=199578.
1. Buzdar A, et al. Br Cancer Res Treat. 2002;73:161. 2. Herrington DM, et al. Arterioscler Thromb Vasc Biol.
2000;20:1606.
Idoxifene
Climacteric
symptoms
Comparable to
tamoxifen1
Bone
Same as placebo2
Breast
Same as tamoxifen3
Endometrium
↑ thickness4
CV
No change in LDL1
Chemical structure available at: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=47206344.
1. Johnston SR, et al. Cancer Chemother Pharmacol. 2004;53:341. 2. van Rietbergen B, et al. Clin Miomech. 2002;17:81.
3. Arpino G, et al. Ann Oncol. 2003;14:233. 4. Fleischer AC, et al. J Ultrasound Med. 1999;18:503.
Lasofoxifene
Climacteric
symptoms
Undefined
Bone
↑ BMD1
Breast
Undefined
Endometrium
Undefined
CV
↓ LDL1
Chemical structure available at: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=789595.
1. McClung MR, et al. Menopause. 2006;13:377.
Ospemifene
Climacteric
symptoms
↓ vaginal atrophy1,2
Bone
↓ turnover,3 similar to
raloxifene4
Breast
Undefined
Endometrium
No effect1
CV
No change in LDL5
Chemical structure available at: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=725813.
1. Voipio SK, et al. Maturitas. 2002;43:207. 2. Rutanen EM, et al. Menopause. 2003;10:433. 3. Komi J, et al. Gynecol
Endocrinol. 2004;18:152. 4. Komi J, et al. J Bone Miner Metab. 2006;24:314. 5. Ylikorkala O, et al. Menopause. 2003;10:440.
Raloxifene
Climacteric
symptoms
Does not alleviate hot
flashes1
Bone
Breast
↓ Vertebral fractures,2,6
↑ BMD1,2
↓ Invasive cancer3-6
Endometrium
No effect3
CV
No effect on CHD,6
↑ VTE3,4,6
Chemical structure available at: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=5035.
1. Delmas PD, et al. N Engl J Med. 1997;337:1641. 2. Ettinger B, et al. JAMA. 1999;282:637.
3. Cummings SR, et al. JAMA. 1999;281:2189. 4. Cauley JA, et al. Br Cancer Res Treat. 2001;65:125.
5. Vogel VG, et al. JAMA. 2006;295:2727. 6. Barrett-Connor E, et al. N Engl J Med. 2006;355:125.
Raloxifene Analogs
in Clinical Development
“Benzothiophenes”

Arzoxifene

Bazedoxifene
Arzoxifene
Climacteric
symptoms
↑ hot flashes1
Bone
Undefined
Breast
Inferior to tamoxifen2
Endometrium
No effect1
OCH3
CV
Undefined
Chemical structure available at: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=46519464.
1. Münster PN, et al. J Clin Oncol. 2001;19:2002. 2. Deshmane V, et al. J Clin Oncol. 2007;25:4967.
Bazedoxifene
Climacteric
symptoms
Comparable to
placebo1
Bone
↓ bone loss1
Breast
Undefined
Endometrium
No effect2
CV
Undefined
CH3
Chemical structure available at: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=787914&10c=ec_rcs.
1. Miller PD, et al. J Bone Miner Res. 2008;23:525. 2. Ronkin S, et al. Obstet Gynecol. 2005;105:1397.
3rd-Generation SERMs

Fulvestrant

HMR 3339

DT56a
Fulvestrant
Climacteric
symptoms
Hot flashes same as
anastrozole1,2
Bone
Undefined
Breast
Same as anastrozole2
Endometrium
Undefined
CV
VTE same as anastrozole1-3
HO
Chemical structure available at: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=682160.
1. Osborne CK, et al. J Clin Oncol. 2002;20:3386. 2. Robertson JFR, et al. Cancer. 2003;98:229.
3. Howell A, et al. J Clin Oncol. 2002;20:3396.
HMR 3339
Climacteric
symptoms
Undefined
Bone
Undefined
Breast
Undefined
Endometrium
Undefined
CV
↓ total
cholesterol and
LDL1
Reprinted from Vogelvang TE, et al. Drugs. 2006;66:191, with permission from Wolters Kluwer Health.
1. Vogelvang TE, et al. Fertil Steril. 2004;82:1540.
DT56a
Climacteric
symptoms
↓ hot flashes1
Bone
↑ BMD2
Breast
Undefined
Endometrium
Undefined
CV
Undefined
Soy
Extract
1. Yoles I, et al. Clin Exp Obstet Gynecol. 2004;31:123. 2. Yoles I, et al. Menopause. 2003;10:522.
Human Studies
SERM
aFDA
#
PRPCT
Climacteric
symptoms
Bone
Breast
↑
↑
↔
↑
↑
↑
↑
↑
?
?
Endometrium Cardiovascular
Tamoxifena
>100
Raloxifenea
> 50
Toremifene
3
Ospemifene
3
↓
↓
↓
↑
Bazedoxifene
2
?
Idoxifene
2
↓
↔
Droloxifene
2
?
?
↑
↓
Lasofoxifene
1
?
?
Fulvestranta
1
↓
↑
?
?
?
↔
?
HMR 3339
1
?
?
?
?
Arzoxifene
1
?
↓
↑
↑
↑
↓
↑
↔
?
DT56a
0
↑
?
?
?
↓
↑
approved
PRPCT = prospective randomized placebo-controlled trial.
Graphic courtesy of William H. Catherino, MD, PhD.
↓
↑
↓
↑
↔
↓
↓= Negative effect
↑= Positive effect
+/-
↓
+/-
↑
↔
↔ = No difference
? = Unknown
Combination Therapy


Raloxifene + estradiol published data
–
Vasomotor symptoms and endometrial safety1
–
Vaginal atrophy2,3
Bazedoxifene + conjugated estrogen clinical trials
–
Vasomotor symptoms (completed Feb 2007)4
–
Vulvar/vaginal atrophy (completed Mar 2007)5
–
Endometrial hyperplasia and osteoporosis (to be
completed in Aug 2008)6
1. Stovall DW, et al. Menopause. 2007;14:510. 2. Pinkerton JV, et al. Menopause. 2003;10:45. 3. Parsons
A, et al. Obstet Gynecol. 2003;101:346. 4. Clinicaltrials.gov Identifier: NCT00234819. 5. Clinicaltrials.gov
Identifier: NCT00238732. 6. Clinicaltrials.gov Identifier: NCT00242710.
SERMs in Men

Toremifene
– ↓Prostate cancer in high-risk men1
– ↑BMD in men receiving a gonadotropinreleasing hormone agonist (GnRHa)2

Raloxifene
– ↑BMD in GnRHa-treated men3
– ↓ total cholesterol4
1. Price D, et al. J Urol. 2006;176:965. 2. Smith MR, et al. J Urol. 2008;179:152. 3. Smith MR, et al. J Clin
Endocrinol Metab. 2004;89:3841. 4. Duschek EJ, et al. Eur J Endocrinol. 2004;150:539.
Effect of Raloxifene on ALL CV Events in
Women at Increased Risk
% Women with CV Event
4-Year Data from MOREa Trial
n = 1035
20
P <.03b
15
12.9%
10
7.8%
Raloxifene
60 mg/d
Raloxifene
120 mg/d
5
0
Placebo
aMultiple
bvs
7.8%
Outcomes of Raloxifene Evaluation.
placebo.
Barrett-Connor E, et al. JAMA. 2002;287:847.
Risk of Thrombosis
Raloxifene1
Estrogen, oral2

VTE OR: 1.62 (1.25–2.09)

VTE HR: 1.32 (0.99–1.75)

DVT OR: 1.54 (1.13–2.11)

DVT HR: 1.47 (1.06–2.06)

PE OR: 1.91 (1.05–3.47)
DVT = deep venous thrombosis; PE = pulmonary embolism; VTE = venous thromboembolism.
1. Adomaityte J, et al. Thromb Haemost. 2008;99:338. 2. Curb JD, et al. Arch Intern Med. 2006;166:772.
SERMs in Postmenopausal Women

Women with osteoporosis

Women with high risk of breast cancer

Women without risk factors for VTE
Patient Profile 1

Woman, 45 years of age
– Ovariectomy–hysterectomy
– Hot flashes
– Mother had myocardial infarction at age 65

Clinical needs
– Treatment of hot flashes
– Possible cardiovascular disease protection

Early treatment = ESTROGEN
Patient Profile 2

Woman, age 60 years
– With uterus
– No symptoms; never treated
– Traumatic fracture at age 58 years
– Sister diagnosed with breast cancer; her
X-ray normal

Clinical needs
– Prevention of further fractures
– No need for symptoms therapy
– Possible breast cancer risk

Treatment = SERM
Current Recommendations
aBeware
Climacteric
Symptoms
No SERM
recommendation
Breast Cancer
Protection
Raloxifenea
Tamoxifenb
Bone
Maintenance
Raloxifenea
Tamoxifenb
Endometrial
Protection
No SERM
recommendation
Cardiovascular
Benefit
No SERM
recommendation
VTE/stroke; bBeware VTE and endometrial cancer.
Graphic courtesy of William H. Catherino, MD, PhD.
Conclusions

After WHI, compounds with selective
estrogen activity are in great
demand

SERM development has resulted in
significant therapeutic advances

Future SERMs may have a
therapeutic profile that can be
tailored to specific patient
populations, including men