Adam M. Brufsky, MD, PhD Co-Director, Comprehensive Breast Cancer Center Magee-Women’s Hospital University of Pittsburgh Medical Center Pittsburgh, Pennsylvania Improving Bone Health in Patients With Early Breast 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 complications 1,2 –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 yr Final analysis RAN RRAANNDODOMMIIZZEEDDRRAANNDODOMMIIZZEEDDMIZED 3 yr1 yr Eligibility: ER+/PgR+ BCa PMW with T 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 Design Zometa 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 N-telopeptide (NTX) n 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 (L 1 –L 4 ) 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

Demographics Upfront GroupDelayed Group No. of patients enrolled301 No. of patients in ITT population300 Median age, yr60 Median age at start of menopause, yr49 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 GroupDelayed Group ECOG status, no. of patients (%) 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 > (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 Group No. of delayed group patients (%) who had initiated ZA 6-mo visit All patients29 (9.7) Per protocol*12 (4) 12-mo visit All patients42 (14) Per protocol*24 (8) Time to initiation of first ZA infusion in delayed group patients, mo Mean (SD)8.8 (4.7) Median6.3 Range0.03–24.2 *Because T score decreased to < -2 and/or clinical fracture.

Mean (SD) Percentage Change in BMD (g/cm 2 ) Lumbar SpineTotal Hip P< Month 6Month 12Month 6Month 12

Mean (-SD) T Scores P< P< Lumbar SpineTotal Hip Month 6Month 12BaselineMonth 6Month 12Baseline

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

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

Mean (SD) Percentage Change in Bone Markers From Baseline Bone Marker AssessmentUpfront GroupDelayed Group NTX, mean (SD) Baseline, nmol BCE/L Month 12, nmol BCE/L % change at month (6.3) 9.7 (3.6) (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 (7.7) 18.5 (5) -8.8 (26.5)* 24.4 (9.8) 26.9 (9.6) 24.3 (50.3) *P< BCE=bone collagen equivalent.

Mean (SD) Percentage Change in Mean NTX From Baseline P< Month 3 Month 6 Month 9Month 12

Mean (SD) Percentage Change in Serum BSAP From Baseline P< Month 3 Month 6 Month 9Month 12

Adverse Events Occurring in >5% of Patients Adverse Event No. of Pts (%) Upfront Group (n=300) Delayed Group (n=300) Arthralgia90 (30)87 (29) Hot flashes76 (25.3)77 (25.7) Fatigue52 (17.3) 46 (15.3) Myalgia38 (12.7)29 (9.7) Bone pain34 (11.3)12 (4) Headache27 (9)22 (7.3) Nausea24 (8) 17 (5.7) Pain in extremity24 (8)13 (4.3) Insomnia21 (7)16 (5.3) Depression17 (5.7)27 (9) Back pain18 (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

References 1.Pfeilschifter J, et al. J Clin Oncol. 2000;18: Heshmati HM, et al. J Bone Miner Res. 2002;17: Baum M, et al. Lancet. 2002;359: Coombes RC, et al. N Engl J Med. 2004;350: BIG 1-98 Collaborative Group. Breast. 2005;14:Suppl 1:S3. Abstract. 6.Reid IR, et al. N Engl J Med. 2002;346: Gnant M, et al. Presented at: SABCS; December 8-11, 2004; San Antonio, Tex. Abstract 6.

Questions and Answers

Acknowledgements  All women who participated in this study  Z-FAST principal investigators and study coordinators  PRA International  BioImaging Technologies, Inc.  CRL Medinet, Inc.  ClinPhone