Adam M. Brufsky, MD, PhD Co-Director, Comprehensive Breast Cancer Center

Magee-Women’s HospitalUniversity of Pittsburgh Medical Center

Pittsburgh, Pennsylvania

Improving Bone Health in Patients With EarlyBreast Cancer: 12-Month Bone Mineral

Density Results – The Z-Fast Trial

Background Further reduction or elimination of estrogen activity by AIs in PMW with

BCa may result in bone loss and bone-related complications1,2

– Anastrozole has been associated with greater incidence of fractures vs tamoxifen in PMW with primary BCa (5.9% vs 3.7%; P<0.0001)3

– Exemestane, following 2–3 yrs of tamoxifen therapy, has been associated with greater incidence of osteoporosis vs tamoxifen in PMW with primary BCa (7.4% vs 5.7%)4

– Letrozole has been associated with greater risk of bone fractures vs tamoxifen in PMW with primary BCa (5.8% vs 4.1%, P=0.0006).5

An effective therapy that will prevent bone loss associated with AIs in PMW with BCa is needed

Background (cont’d)

In clinical trials, zoledronic acid (ZA) increased bone mineral density (BMD) vs placebo or no ZA.6,7

– In PMW with low BMD, ZA (4-mg single dose) increased lumbar spine (LS) BMD by 4.3%–5.1% and femoral neck BMD by 3.1%–3.5% compared with placebo at 12 mo (P<0.001 for both).6

– In premenopausal women with BCa receiving anastrozole or tamoxifen with goserelin, LS BMD at 36 mo was higher in patients receiving ZA (4 mg q 6 mo) compared with patients not receiving ZA (P<0.0001).7

ZA = zoledronic acid

Study Design and Objectives

0 5 yrFinal analysis

RRAANNDDOOMMIIZZEEDD

3 yr1 yr

Eligibility:ER+/PgR+ BCaPMW withT score ≥ -2

Stratification:- Adjuvant chemo

(yes or no)- T score (> -1 or

between -1 and -2 )

*Plus daily calcium (1,000–1,200 mg) and vitamin D (400–800 IU).†Initiation determined by a postbaseline T score < -2, any clinical fracture, or an asymptomatic fracture at 36 mo.

Z/ZO-FAST Trial DesignZometa Femara Adjuvant Synergy Trial

+ Letrozole 2.5 mg/d*

UPFRONT Zoledronic acid 4 mg q 6 mo

+ Letrozole 2.5 mg/d*

DELAYED† Zoledronic acid 4 mg q 6 mo

Accrual complete: ZO-FAST: N = 1066; ZFAST: N = 602

Study Objectives

Primary objective

– % change in LS BMD at 12 mo

Secondary objectives

– % change in LS BMD at 2 yr, 3 yr, 5 yr

– % change in total hip (TH) BMD at 12 mo, 2 yr, 3 yr, 5 yr

– Changes in biochemical markers of bone turnover at 12 mo, 2 yr, 3 yr, 5 yr N-telopeptide (NTX) Bone-specific alkaline phosphatase (BSAP)

– Incidence of fractures at 3 yr

– Time to disease progression

– Rate of decrease in LS and TH BMD

Eligibility Criteria

PMW with stage I–IIIa ER+ and/or PgR+ BCa

Baseline LS and TH T score ≥ -2

ECOG PS between 0 to 2

Serum creatinine level < 3 mg/dL

Adjuvant CT, if administered, must have been completed before randomization

No evidence of existing fracture in LS or TH

Prior oral bisphosphonate therapy allowed but must have been discontinued at least 3 weeks before baseline evaluation

Methods

Study Assessments BMD

– DXA used to measure BMD of LS (L1–L4) and TH at baseline, 6, 12, 24, 36, and 48 mo and at final visit

– DXA machines cross-calibrated and films analyzed by central reader

Biochemical Markers (NTX and BSAP)– Evaluated in subset of ~150 patients– At baseline, every 3 mo for year 1, then every 6 mo up to 48 mo and final visit.– Analyzed by central laboratory

Fractures– X-ray at baseline to exclude patients with existing fractures– Additional x-rays and/or bone scans at discretion of investigator to confirm clinical

fracture throughout study and at 36 mo

Adverse Events (AEs)/Disease Progression– Evaluated every 6 mo– AEs graded using NCI Common Toxicity Criteria, version 2.0

DXA = Dual-energy x-ray absorptiometry

Statistical Analysis ITT population—all randomized pts who received

1 dose of letrozole or ZA and had 1 postbaseline assessment

Safety population—all randomized pts who received 1 dose of letrozole or ZA

Sample size and power considerations

– 250 pts per arm—90% power to detect 3% change in BMD and a common SD of 9% with a significance level of .05 and a 25% dropout rate

Enrollment closed December 2003 with 602 patients accrued at 93 sites in the US and Canada.

Results

DemographicsUpfront Group Delayed Group

No. of patients enrolled 301 301

No. of patients in ITT population 300 300

Median age, yr 60 60

Median age at start of menopause, yr 49 49

Race, no. of patients (%)

White

Black

Other

280 (93)

9 (3)

12 (4)

269 (89.4)

14 (4.7)

18 (5.9)

*One patient each in the upfront and delayed groups were randomized in error.

Demographics (cont’d)Upfront Group Delayed Group

ECOG status, no. of patients (%) 0

1 2 Unknown

253 (84.1)44 (14.6)

1 (0.3)3 (1)

248 (82.4)46 (15.3)

1 (0.3)6 (2)

Stratification factors, no. of patients

Prior adjuvant chemotherapy

No prior adjuvant chemotherapy

T score between -1 and -2

T score > -1

137 (45.7)*

163 (54.3)*

84 (27.9)

217 (72.1)

143 (47.7)*

157 (52.3)*

85 (28.2)

216 (71.8)

*One patient each in the upfront and delayed groups were randomized in error.

ZA Initiation in Delayed GroupNo. of delayed group patients (%) who had initiated ZA

6-mo visit

All patients 29 (9.7)

Per protocol* 12 (4)

12-mo visit

All patients 42 (14)

Per protocol* 24 (8)

Time to initiation of first ZA infusion in delayed group patients, mo

Mean (SD) 8.8 (4.7)

Median 6.3

Range 0.03–24.2

*Because T score decreased to < -2 and/or clinical fracture.

Mean (SD) Percentage Change in BMD (g/cm2)

Lumbar Spine

Total Hip

-8%

-6%

-4%

-2%

0%

2%

4%

6%

% C

han

ge

in B

MD

Upfront Group

Delayed Group

P<0.0001

P<0.0001

Month 6 Month 12 Month 6 Month 12

Mean (-SD) T Scores

-2.0

-1.5

-1.0

-0.5

0.0

0.5

Mea

n T

Sco

re

Upfront Group

Delayed Group

P<0.0001

P<0.0004

Lumbar Spine

Total Hip

Month 6 Month 12Baseline Month 6 Month 12Baseline

Shift in LS T-Score Distribution at 12 Months in Patients With Normal Baseline BMD

At 12 months

0%

20%

40%

60%

80%

100%

Baseline Upfront Delayed

Pa

tie

nts

(%

)

Normal Osteopenic Osteoporotic Missing

Shift in LS T-Score Distribution at 12 Months in Patients With Osteopenic Baseline BMD

At 12 months

0

20

40

60

80

100

Baseline Upfront Delayed

Pa

tien

ts (

%)

Normal Osteopenic Osteoporotic Missing

Mean (SD) Percentage Change in Bone Markers From Baseline

Bone Marker Assessment Upfront Group Delayed Group

NTX, mean (SD)

Baseline, nmol BCE/L

Month 12, nmol BCE/L

% change at month 12

14.2 (6.3)

9.7 (3.6)

-15.1 (70.9)*

13.5 (6)

13.9 (5.2)

19.9 (66.2)

BSAP, mean (SD)

Baseline, µg/L

Month 12, µg/L

% change at month 12

22.1 (7.7)

18.5 (5)

-8.8 (26.5)*

24.4 (9.8)

26.9 (9.6)

24.3 (50.3)

*P<0.0001.BCE=bone collagen equivalent.

Mean (SD) Percentage Change in Mean NTX From Baseline

-140

-120

-100

-80

-60

-40

-20

0

20

40

60

80

100

120

140

Ba

seli

ne

Va

lue

(%

)Upfront Group Delayed Group

P<0.0001

Month 3 Month 6 Month 9 Month 12

Mean (SD) Percentage Change in Serum BSAP From Baseline

-140

-120

-100

-80

-60

-40

-20

0

20

40

60

80

100

120

140B

ase

lin

e V

alu

e (

%)

Upfront Group Delayed Group

P<0.0001

Month 3 Month 6 Month 9 Month 12

Adverse Events Occurring in >5% of Patients

Adverse Event

No. of Pts (%)

Upfront Group(n=300)

Delayed Group(n=300)

Arthralgia 90 (30) 87 (29)

Hot flashes 76 (25.3) 77 (25.7)

Fatigue 52 (17.3) 46 (15.3)

Myalgia 38 (12.7) 29 (9.7)

Bone pain 34 (11.3) 12 (4)

Headache 27 (9) 22 (7.3)

Nausea 24 (8) 17 (5.7)

Pain in extremity 24 (8) 13 (4.3)

Insomnia 21 (7) 16 (5.3)

Depression 17 (5.7) 27 (9)

Back pain 18 (6) 17 (5.7)

Additional Safety Results Renal disorders

– No grade 3-4 renal disorders reported

– 1 patient with a grade-1 increase in serum creatinine level in the upfront group

Jaw disorders

– No osteonecrosis of the jaw reported

– 3 patients reported grade 1-2 jaw pain in the upfront group

Cardiac disorders

– Grade 3-4 cardiac disorders reported in < 2.5% of patients

– None were related to study drugs

Serious adverse events (SAEs) reported

– 16.7% of patients (upfront group), 18.7% of patients (delayed group)

Treatment discontinued due to SAEs

– 1.3% of patients (upfront group), 1% of patients (delayed group)

Conclusions Based on 12-mo data, upfront ZA (4 mg IV q 6 mo) prevents CTIBL in

PMW with early-stage BCa receiving adjuvant letrozole

– Primary endpoint of LS BMD was statistically significant in favor of the upfront ZA group

– TH BMD was also statistically significant in favor of the upfront ZA group

– 4% and 8% of patients in the delayed group experienced a decrease in BMD at 6 and 12 months, respectively, and required initiation of ZA

Bone markers were significantly decreased in patients receiving upfront ZA vs delayed ZA

Additional follow-up is needed to fully define the long-term benefit of ZA combined with AIs in PMW with early-stage BCa

References1. Pfeilschifter J, et al. J Clin Oncol. 2000;18:1570-1593.

2. Heshmati HM, et al. J Bone Miner Res. 2002;17:172-178.

3. Baum M, et al. Lancet. 2002;359:2131-2139.

4. Coombes RC, et al. N Engl J Med. 2004;350:1081-1092.

5. BIG 1-98 Collaborative Group. Breast. 2005;14:Suppl 1:S3. Abstract.

6. Reid IR, et al. N Engl J Med. 2002;346:653-661.

7. Gnant M, et al. Presented at: SABCS; December 8-11, 2004; San Antonio, Tex. Abstract 6.

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