airoldi mario s.c. oncologia medica 2 città della salute e

La salute dell’osso nelle pazienti in trattamento

adiuvante

Airoldi Mario - S.C. Oncologia Medica 2

Città della Salute e della Scienza di Torino

BONE STRENGTH

• OSTEOPOROSIS SKELETAL DISORDER COMPROMISING BS LEADING TO INCREASED RISK OF FRACTURE

• BS HAS TWO COMPONENTS: MICROARCHITECTURE (QUALITY) , BONE DENSITY (QUANTITY)

• BMDDXA (<2.5 T SCORE=OSTEOPOROSIS)

FRAX ALGORITHM

understimates AI effect

-1.3% and -2.9% - AXELSEN

Outcomes Extended Duration AI beyond 5 yrs

N

(% N+)

Duratio

n

ET/AI

DFS

Benefit

OS

Benefit

New BC

Benefit

MA-17R 1918

(53%)

10-15

5-10

Y* N Y

B-42 3966

(42%)

5-10

2-10

N N Y

IDEAL 1824

(74%)

7.5-10

2.5-10

N N Y

DATA 1912

(67%)

5-9

3-6

N N N

SOLE 4884

(99%)

5-10

5-10cont

N N ?

ABCSG16 3484

(31%)

7-10

2-10

N N N

AEs Extended Duration AI beyond 5 yrs

Arthalgia

AI/Plc

Hot Flashes

AI/Plc

Vaginal

Dryness

AI/Plc

Cardio

vascular

AI/Plc

Fractures

AI/Plc

MA-17R

53

50

38

37

11

10

12

10

14

9

B-42

5.4

4.8

IDEAL 14.7

13.2

13.1

10.5

5

2.8

DATA 60

54

15

14

10

8

SOLE 68

66

54

52

10

9

ABCSG1

6

6.3

4.7

ABCSG-18: study design

Gnant M, et al. Lancet 2015;386:433–43 (and supplementary appendix).

*5 patients withdrew consent to use their data; †Defined as having undergone a bilateral oophorectomy, ≥ 60 years of age, or < 60 years of age

but with follicle-stimulating hormone and oestradiol levels in the postmenopausal range;

‡Oral BP treatment if taken for 3 years or longer continuously or if taken for between

3 months and 3 years unless the patient had a washout period of at least 1 year

before randomisation, or any use during the 3 months before randomisation.

IV, intravenous; ECOG, Eastern Cooperative Oncology Group; ER, oestrogen receptor; Q6M, every 6 months;

PR, progesterone receptor; SC, subcutaneous; SERM, selective oestrogen receptor modulator.

Enrolled

N = 3425*

Denosumab

60 mg SC Q6M

n = 1711

Placebo

SC Q6M

n = 1709

R

A

N

D

O

M

I

S

A

T

I

O

N

Daily supplementation with calcium (500 mg) and vitamin D (≥ 400 IU) were

recommended throughout study treatment

Key inclusion criteria

• Postmenopausal women†

• Histologically confirmed non-metastatic ER+

and/or PR+ adenocarcinoma of the breast

• Receiving or due to receive adjuvant non-steroidal

AI therapy

• ECOG performance score: 0 or 1

Key exclusion criteria

• AI therapy for > 24 months before trial inclusion

• Previous or concurrent treatment with SERMs

• Evidence of metastatic disease

• Ongoing or previous IV BPs; oral BPs‡

• Previous denosumab therapy

• Known history of: Paget’s disease, Cushing’s disease,

hyperprolactinaemia, hypercalcaemia, hypocalcaemia or other

active metabolic bone disease

• Major surgery or traumatic injury < 4 weeks before

randomisation

• Exploratory endpoints were: the percentage change in total lumbar spine, total hip and femoral

neck BMD from baseline to Months 12 and 24 (at preselected sites); the percentage change in

total lumbar spine, total hip and femoral neck BMD from baseline to Months 12, 24 and 36 (at all

participating clinical sites); new† and new or worsening vertebral fractures† at Months 12 and 24

• Safety endpoints were: incidence of treatment-emergent adverse events (TEAEs); clinically

significant changes in laboratory values; anti-denosumab antibody formation

ABCSG-18: outcomes

Gnant M, et al. Lancet 2015;386:433–43.

*Defined as clinically evident fractures with associated symptoms, except for those of the

skull, face, fingers, and toes, which are typically not associated with osteoporosis; †Morphometric fractures identified from study radiographs and

clinical vertebral fractures confirmed by radiographs.

Time to first

clinical fracture*

• Percentage change in total lumbar spine,

total hip and femoral neck BMD from baseline

to Month 36

• Incidence of new vertebral fractures† at Month 36

• Incidence of new or worsening of pre-existing

vertebral fractures† at Month 36

• Disease-free survival (DFS)

• Bone metastasis-free survival (BMFS)

• Overall survival (OS)

Primary endpoint Secondary endpoints

ABCSG-18: denosumab significantly increased BMD

in the lumbar spine, total hip and femoral neck

vs placebo

Gnant M, et al. Lancet 2015;386:433–43.

*Note: these data represent an exploratory endpoint of the study; †Note: these data represent a secondary endpoint of the study. Error bars are 95% CIs.

5.75% difference at Month 12*

8.28% difference at Month 24*

10.02% difference at Month 36†

3.86% difference at Month 12*

5.85% difference at Month 24*

7.92% difference at Month 36†

3.30% difference at Month 12*

5.19% difference at Month 24*

6.51% difference at Month 36†

(n = 992) (n = 717) (n = 468)

Lumbar spine Total hip Femoral neck

Placebo

Denosumab

Ad

jus

ted

me

an

ch

an

ge

in B

MD

(%

)

Months since randomisation

(n = 986) (n = 725) (n = 475) (n = 995) (n = 723) (n = 469)

P < 0.0001 at all bone sites and time points

Do not copy or distribute.

Placebo: n = 84/775

Denosumab: n = 49/773

72 66 60 54 48 42 36 30 24 18 12 6 0

0

5

10

15

20

25

30

Ris

k o

f fr

ac

ture

(%

)

Months since randomisation

50

50

88

95

134

137

187

198

245

248

300

307

369

370

423

433

481

494

563

580

664

660

754

750

775

773

Number at risk

Placebo

Denosumab

ABCSG-18: denosumab significantly reduced the

incidence of clinical fractures vs placebo regardless

of baseline BMD

Percentage risk of fracture based on Kaplan–Meier time-to-event analysis

within each treatment group at 6-month intervals. The HR and P value were

calculated from a Cox model including treatment groups as the independent

variable and stratified by the randomisation stratification factors.

HR = 0.44 (95% CI: 0.31–0.64)

P < 0.0001

Normal BMD

(baseline T-score ≥ –1.0)

Overall cumulative incidence of first clinical fractures

HR = 0.57 (95% CI: 0.40–0.82)

P = 0.002

Overall cumulative incidence of first clinical fractures

Low BMD

(baseline T-score < –1.0)

Placebo: n = 92/934

Denosumab: n = 43/938

72 66 60 54 48 42 36 30 24 18 12 6 0

0

5

10

15

20

25

30

Ris

k o

f fr

ac

ture

(%

)

Months since randomisation

62

66

97

126

141

168

197

234

268

301

337

381

416

453

498

532

588

624

702

717

806

828

906

915

934

938

Number at risk

Placebo

Denosumab

Placebo

Denosumab

Gnant M, et al. Lancet 2015;386:433–43 (and supplementary appendix).