General Principles of Endocrine Therapy Etienne GC Brain, MD PhD

Medical Oncology Hôpital René Huguenin / Institut Curie

Saint-Cloud, France

www.siog.org

Differences

• Chemotherapy

1. Focus on proliferation

2. Fast action when works

3. Side effects

• Alopecia

• Nausea vomiting

• Haematological

• Cardiac

• Mucositis

4. Route

• IV >> PO

• Endocrine treatment

1. Need hormonal

dependance (receptors,

body source)

2. Slow action when works

3. Side effects

• Lipds and cholesterol

• Endocrine

• Metabolic

• Cardiovascular

• Bone

• Endocrine sensitive tissue

4. Route

• PO >>> IM/SC

Breast

compounds

settings

(metastatic, adjuvant, extended)

future

Endocrine treatment

• Pioneer of targeted treatments

– 20 May1896 Edinburgh

• Sir George Thomas Beatson (1848-1933) demonstrates the

efficacy of bilateral ovariectomy on metastatic breast cancer

Beatson. Lancet 1896

1947 ER 1958 Albert Lasker Award for Basic Medical Research

Elwood V Jensen

Compounds

• Anti-oestrogen

– Tamoxifen (PO)

– Fulvestrant (IM)

• Castration

– Surgery, XRT, LHRH

analogs

• Aromatase inhibitors

– Non steroidal

• Letrozole (PO)

• Anastrozole (PO)

– Steroidal

• Exemestane (PO)

• Progestatives

Metastatic setting

www.abc-lisbon.org

AI and TAM: global response rate

• Statistical significant benefit AI > TAM

– ORR (OR, 1.56; 95% CI, 1.17-2.07; P .002)

– Clinical benefit (OR, 1.70; 95% CI, 1.24-2.33; P .0009)

Hong-Bin Xu et al. Clinical Breast Cancer 11 (4); 246, 2011

AI and TAM: overall survival

• Non significant trend favouring AI

– OS (OR, 1.95; 95% CI, 0.88-4.30; P .10)

Hong-Bin Xu et al. Clinical Breast Cancer 11 (4); 246, 2011

Robertson JF et al. Breast Cancer Res Treat (2012) 136:503

Randomized phase II

205 patients

SoFEA

• 03/2004-08/2010

• 723 patients

• Median PFS

– Fulverstrant anastrozole 4·4 (3·4-5·4)

– Fulvestrant placebo 4·8 (3·6-5·5) vs

– Exemestane 3·4 (3·0-4·6) p NS

Johnston et al. Lancet Oncol 2013

PFS

Adjuvant setting

Sch

iavo

n.

Bre

ast

Can

cer

Res 2

014

TAM 5 yr & BC recurrence & mortality

EBCTCG. Lancet 2011

RR 0·53 [SE 0·03] yr 0–4 [2p<0·00001]

RR 0·68 [SE 0·06] yr 5–9 [2p<0·00001]

RR 0·97 [SE 0·10] yr 10–14

RR 0·71 [SE 0·05] yr 0–4

RR 0·66 [SE 0·05] yr 5–9

RR 0·68 [SE 0·08] yr 10–14, all p<0·0001

A high proportion of patients receiving TAM 5 yr can be potentially cured

EBCTCG. Lancet 2011

Schema of included trials.

Burstein H J et al. JCO 2010;28:3784-3796

©2010 by American Society of Clinical Oncology

• TAM / 0

15 10 5

60 %

50 %

40 %

30 %

20 %

10 %

rech

ute

26,5

38,3

45,0

24,7

15,1

33,2

control

TAM 5A

• AI / TAM

Reduction of

risk of relapse

Absolute benefit

at 10 years

ER+ 41 % 13,6 %

Reduction of

risk of relapse

Absolute benefit

at 10 years

ER+

Post-

MP

20 % 5 %

AI 5A

DFS and adjuvant trials w/ AI

Study

Patients

(N)

Follow-up

(mth)

DFS HR

(95% CI)

Absolute ≠

(%)

Time to distant M+

HR (95% CI)

ATAC 6186 68 0.87 (0.78-0.97) 5-yr difference: 2.5 0.84 (0.70-1.00)

BIG 1-98 8010 25.8 0.81 (0.70-0.83) 5-yr difference: 2.6 0.73 (0.60-0.88)

IES 4742 58 0.76 (0.66-0.88) 5-yr difference: 3.4 0.83 (0.70-0.98)

ARNO 95

ABCSG 8 3224 28 0.60 (0.44-0.81) 3-yr difference: 3.1 0.61 (0.42-0.87)

ITA 448 36 0.35 (0.18-0.68) 3-yr difference: 5.3 0.49 (0.22-1.05)

MA.17 5187 30 0.58 (0.45-0.76) 4-yr difference: 4.6 0.60 (0.43-0.84)

COMPLIANCE

is the issue!!!

TAM AI

Neurocognition

Sexuality

Hot flushes

Thrombosis & embolism

Uterus cancer

Gynecological tractus

Vaginal discharge

Cataract

Arthralgias & myalgias

Osteoporosis

Fractures

Dryness

Cardiovascular

Lipid profile

?

TAM risks

• Overall non-BC mortality little affected,

• Small absolute increases in thromboembolic and

uterine cancer mortality

– Both only in women ≥ 55 yo

– Uterine cancer risk

• < 55 yo ~ 0%

• 55-69 yo 3.8% vs 1.1% (RR 2.4, p = 0.00002)

EBCTCG. Lancet 2011; Jordan. Annu Rev Pharmacol Toxicol 1995

Fractures

Trial

Follow up

(mth)

Years

w/TAM

AI

(%)

Comparator

(%) p

ATAC 68 0 ANA (11.0) TAM (7.7) < 0.0001

ATAC 33 0 ANA (5.9) TAM (3.7) < 0.0001

ARNO 95

ABCSG 8 28 2-3 ANA (2) TAM (1) 0.015

BIG 1-98 25.8 0 LET (5.6) TAM (4.0) < 0.001

IES 55.7 2-3 EXE (7.0) TAM (4.9) 0.003

MA.17 30 4-6 LET(5.3) Placebo (4.6) 0.25

And up to 80% of arthralgia….

(20.3% vs 12.3%, p < 0.001 BIG 1-98)

Copyright © American Society of Clinical Oncology

Morales, L. et al. J Clin Oncol; 26:3147-3152 2008

Getting a grip on aromatase inhibitor–associated arthralgias

Dawn L. Hershman

Figure 4 Fracture rates in the full study population Numbers at risk differ in some cases from those provided in the 100-month

analysis<ce:cross-ref refid="bib3"> 3 </ce:cross-ref> because of additional follow-up data.

Jack Cuzick , Ivana Sestak , Michael Baum , Aman Buzdar , Anthony Howell , Mitch Dowsett , John F Forbes

Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial

The Lancet Oncology, Volume 11, Issue 12, 2010, 1135 - 1141

http://dx.doi.org/10.1016/S1470-2045(10)70257-6

Extended ("post adjuvant")

Annual hazard rate curves (%) for distant recurrence according to risk group and scores (all

split at the median) (TRANSATAC)

Sestak I et al. JNCI J Natl Cancer Inst 2013;105:1504-1511

© The Author 2013. Published by Oxford University Press.

IHC4 = ER, PgR, HER2, Ki67

None of the IHC4 markers provided

statistically significant prognostic

information in yr 5-10, except for N and T

ROR gave the strongest prognostic

information in yr 5-10

These results may help select patients

who could benefit most from hormonal

therapy beyond 5 yr of treatment

Signatures ? Endopredict (ABCSG-6 & 8)

Dubsky. Br J Cancer 2013

The EP test provides additional prognostic information for the identification of early and late DM beyond what can be achieved by combining the

commonly used clinical parameters. The EPclin reliably identified a subgroup of patients who have an excellent long-term prognosis after 5 years of

endocrine therapy. The side effects of extended therapy should be weighed against this projected outcome.

Rechute

Davies. Lancet 2013

Mortalité

A carry-over effect!!

Davies. Lancet 2013

Resistance to endocrine treatment everolimus

palbociclib

BOLERO-2: Everolimus + Exemestane in HR+ Advanced BC

Key Endpoints:

• Primary: PFS (local assessment)

• Secondary: OS, ORR, QOL, safety, bone markers, PK

Everolimus 10 mg/day+

Exemestane 25 mg/day (n = 485)

Placebo+

Exemestane 25 mg/day (n = 239)

R2:1

N = 724• Postmenopausal ER+

• Unresectable locally

advanced or metastatic

BC

• Recurrence or

progression after

letrozole or anastrozole Stratification

• Sensitivity to prior hormonal therapy

and presence of visceral metastases

Baselga J, et al. N Engl J Med. 2012;366(6):520-529.

PFS + 4.6-6.9 mths (x 2)

BOLERO-2 (18-ms FU): PFS Local

1

EVE 10 mg + EXE

PBO + EXE

Number of patients still at risk

0

20

40

60

80

100

Time (week)

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108 114 120

485 436 366 304 257 221 185 158 124 91 66 50 35 24 22 13 10 8 2 1 0

239 190 132 96 67 50 39 30 21 15 10 8 5 3 1 1 1 0 0 0 0

Censoring times

EVE 10 mg + EXE (n/N = 310/485)

PBO + EXE (n/N = 200/239)

HR = 0.45 (95% CI: 0.38-0.54)

Log-rank P value: <.0001

Kaplan-Meier medians

EVE 10 mg + EXE: 7.8 months

PBO + EXE: 3.2 months

Pro

bab

ilit

y (

%)

of

Ev

en

t

Piccart M, et al. ASCO 2012. Abstract 559.

BOLERO-2 (18-ms FU): PFS Central

2

EVE 10 mg + EXE

PBO + EXE

Number of patients still at risk

HR = 0.38 (95% CI: 0.31-0.48)

Log-rank P value: <.0001

Kaplan-Meier medians

EVE 10 mg + EXE: 11.0 months

PBO + EXE: 4.1 months

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108

485

239

427

179

359

114

292

76

239

56

211

39

166

31

140

27

108

16

77

13

62

9

48

6

32

4

21

1

18

0

11

0

10

0

5

0

0

0

Censoring times

EVE 10 mg + EXE (n/N = 188/485)

PBO + EXE (n/N = 132/239)0

20

40

60

80

100

Pro

bab

ilit

y (

%)

of

Ev

en

t

Time (week)

Piccart M, et al. ASCO 2012. Abstract 559.

Baselga N Engl J Med 2012

Everolimus (Afinitor®)

Most Common Adverse Events (AEs) Fatigue Stomatitis Rash Anorexia Diarrhea Less frequent but clinically relevant: Hyperglycemia Pneumonitis: Rare but potentially fatal

Clinical Management Strategy Patient awareness and early intervention

Well defined management & dose reduction/delay/discontinuation guidelines

(they exist for stomatitis, pneumonitis, hyperglycemia)

Significant % (about

20%) of EVE–treated

patients required a dose

reduction

PD 0332991 (Palbociclib CDK 4/6 inh) + letrozole

vs letrozole (randomized phase II) PFS x 3

PFS

PD 0332991 + Letrozole (n = 84)

Letrozole (n = 81)

HR

(95% CI) P Value

Events, n (%) 21 (25) 40 (49)

Median PFS, mos (95% CI) 26.1

(12.7-26.1) 7.5

(5.6-12.6)

0.37

(0.21-0.63) < .001

Finn RS, et al. SABCS 2012. Abstract S1-6

Prostate Cancer

Prostate cancer is known to be androgen sensitive and

responds to inhibition of androgen receptor signalling

Despite low or even undetectable levels of serum androgen,

androgen receptor signalling continues to promote disease

progression

Stimulation of tumour cell growth via the androgen receptor

requires nuclear localization and DNA binding

Androgen Deprivation Therapy side effects

• Hot flashes

• Decreased libido, erectile

dysfunction

• Increase of cardiovascular risk

• Lipid changes

• Increase of metabolic syndrome

• Risk of osteoporosis

– Increases the risk of fractures up

to 45% long-term

– Requires an assessment mineral

bone density if other osteoporosis

risk factors are associated

– Prescribe supplemental calcium

and vitamin D

– Bisphosphonates may be

prescribe if osteoporosis

confirmed

• Sarcopenia and increase in fat

mass

• Risk factor for falls, loss of

autonomy

• Mood impact

• Cognitive impact suspected but

unproven (to be included in the

benefit / risk balance in case of

pre-existing disorder)

Careful evaluation of benefit /

risk balance at the time of initial

prescription

Encourage lifestyle changes

Abiraterone acetate + prednisone Zytiga®

• Abiraterone acetate (ZYTIGA) is converted in vivo to abiraterone, an

androgen biosynthesis inhibitor

• Specifically, abiraterone selectively inhibits the enzyme 17α-

hydroxylase/C17,20-lyase (CYP17)

• This enzyme is expressed in and is required for androgen biosynthesis in

testicular, adrenal and prostatic tumour tissues

• CYP17 catalyses the conversion of pregnenolone and progesterone into

testosterone precursors, DHEA and androstenedione, respectively, by 17α-

hydroxylation and cleavage of the C17,20 bond

• CYP17 inhibition also results in increased mineralocorticoid production by

the adrenals

Abiraterone acetate side effects

• "mineralo corticosteroids": arterial tension+++

• Corticosteroids

• Cardiac

• Metabolic interactions

Enzalutamide

• Potent androgen receptor signalling inhibitor that blocks several steps in the

androgen receptor signalling pathway

• Competitively inhibits binding of androgens to androgen receptors

• Inhibits nuclear translocation of activated receptors and inhibits the

association of the activated androgen receptor with DNA even in the setting

of androgen receptor overexpression and in prostate cancer cells resistant

to anti-androgens

• Decreases the growth of prostate cancer cells and can induce cancer cell

death and tumour regression

• In preclinical studies enzalutamide lacks androgen receptor agonist activity