ATAC Trial. 10 year median follow-up data. Approval Code: AZT-ARIM-10005

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Debra James
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1 ATAC Trial 10 year median follow-up data Approval Code: AZT-ARIM-10005

2 Background FDA post-approval commitment analysis to update DFS, TTR, OS and Safety Prof. Jack Cuzick on behalf of ATAC/LATTE Trialists Group conducted 10 year analysis independently of AZ Analysis presented as poster 12 th Milan Breast Cancer Conference th June, 2010

3 Introduction The primary aim of treatment in early breast cancer (EBC )is preventing recurrence The benefit of tamoxifen on tumour recurrence and mortality is well-established Nevertheless, recurrence rates are >2% per year long term, and >30% of women develop recurrent disease within 15 years 1 Clinical trials have confirmed that AIs reduce recurrence rates further and offer tolerability advantages compared with tamoxifen during adjuvant treatment 2 4 For AIs, several questions remain unanswered including the extent to which treatment benefits continue after completion of therapy AIs, aromatase inhibitors 1 EBCTCG overview. Lancet 2005; 365: ATAC Trialists Group. Lancet 2005; 365: Coates et al. J Clin Oncol 2007; 25: Coombes et al. Lancet 2007; 369:

4 ATAC trial design Postmenopausal women with invasive breast cancer (n = 9366) Surgery radiotherapy chemotherapy Randomisation 1:1:1 for 5 years Anastrozole (n = 3125) Tamoxifen (n = 3116) Combination n=3125 ITT population n = 3125 Safety population n = 3092 HR+ subpopulation n = 2618 ITT population n = 3116 Safety population n = 3094 HR+ subpopulation n = 2598 Discontinued following initial analysis as no efficacy or tolerability benefit compared with tamoxifen arm ITT, intent-to-treat; HR+, hormone receptor-positive

5 ATAC 10 year : Efficacy Update

6 Efficacy endpoints for HR+ve patients Favors (A) Favors (T) HR P-value Disease-free survival Time to recurrence Contralateral breast cancer Time to distant recurrence Death after recurrence Death all causes Hazard ratio (A / T) and 95% CI J. Cuzick on behalf of ATAC/LATTE Trialists Group. Poster presented at 12 th Milan Breast Cancer Conference 2010

7 Patients (%) DISEASE FREE SURVIVAL (DFS) HR+VE PATIENTS Tamoxifen (T) Anastrozole (A) 16.5% 13.9% 33.7% 30.2% Follow-up time (years) At risk: A 2618 T Disease recurrence was defined as the earliest of loco-regional or distant recurrence, death or new primary (contralateral) breast cancer. J. Cuzick on behalf of ATAC/LATTE Trialists Group. Poster presented at 12 th Milan Breast Cancer Conference 2010

8 Disease Free Survival (DFS) The 10 Year follow-up data on DFS confirms the early and long-term superior efficacy of anastrozole over tamoxifen: for the HR+ population, the absolute benefit of 2.6% at 5 years increasing to 3.5% at 10 years These results confirm the significant carryover effect that was seen in earlier analyses of this study, is maintained at 10 years.

9 Efficacy Conclusion for DFS Significant advantage for anastrozole compared to tamoxifen is maintained over 10 years, confirming the early and long-term efficacy of anastrozole Significant benefit for the anastrozole group was maintained after treatment completion (HR=0.86 [ ], p=0.003) 5. J. Cuzick on behalf of ATAC/LATTE Trialists Group. Poster presented at 12 th Milan Breast Cancer Conference 2010, th June.

10 Patients (%) TIME TO RECURRENCE (TTR) in HR+ patients Disease recurrence was defined as the earliest of loco-regional or distant recurrence, death or new primary (contralateral) breast cancer Tamoxifen (T) Anastrozole (A) 24.0% 15 Absolute difference 2.7% 12.5% 19.7% % Absolute difference 4.3% Follow-up time (years) J. Cuzick on behalf of ATAC/LATTE Trialists Group. Poster presented at 12 th Milan Breast Cancer Conference 2010

11 Efficacy Conclusion for TTR The carry-over effect for anastrozole compared with tamoxifen was statistically significant after treatment completion Reduces the risk of recurrence by 21% (HR=0.79 [ ] p<0.0002) The absolute difference remained over time (TTR 2.7% at year 5, 4.3% at year 10) J. Cuzick on behalf of ATAC/LATTE Trialists Group. Poster presented at 12 th Milan Breast Cancer Conference 2010

12 Patients (%) TIME TO DISTANT RECURRENCE (TTDR) in HR+ patients 30 Disease recurrence was defined as the earliest of loco-regional or distant recurrence, death or new primary (contralateral) breast cancer Tamoxifen (T) Anastrozole (A) 17.7% Absolute difference 1.3% 9.2% 15.1% 5 7.9% Absolute difference 2.6% Follow-up time (years) At risk: A T J. Cuzick on behalf of ATAC/LATTE Trialists Group. Poster presented at 12 th Milan Breast Cancer Conference 2010

13 Efficacy conclusions for TTDR* and CLBC + A significant 15% reduction in TTDR was seen for anastrozole when compared with tamoxifen in HR+ve patients (HR=0.85 ( ), P=0.02) A significant 38% reduction was seen with anastrozole compared with tamoxifen for contralateral tumours (HR=0.62 ( ), P=0.003) The absolute difference for Contralateral Breast Cancer (CLBC) increased from 0.8% at year 5 to 1.7% at year 10 *TTDR and CLBC were additionally analysed independently by Prof Cuzick on behalf of ATAC/LATTE Trialist s Group. This is calculation is not reflected in AstraZeneca s Clinical Summary Report +CLBC=Contralateral Breast Cancer J. Cuzick on behalf of ATAC/LATTE Trialists Group. Poster presented at 12 th Milan Breast Cancer Conference 2010

14 Death after recurrence The endpoint of death after recurrence* also includes those patients who recurred and then died of other causes. Therefore there is some dilution in assessing the true mortality from breast cancer Results were non-significantly lower in the anastrozole group compared with tamoxifen (HR=0.87 ( ), P=0.09) *Previously labelled Breast cancer deaths in previous ATAC reports and elsewhere. This endpoint was additionally analysed independently by J. Cuzick on behalf of ATAC/LATTE Trialist s Group. Death after recurrence was not calculated in AstraZeneca s Clinical Summary Report J. Cuzick on behalf of ATAC/LATTE Trialists Group. Poster presented at 12 th Milan Breast Cancer Conference 2010

15 Overall survival There was no difference in overall survival (HR 0.95 [ ]; p=0.35 Deaths from other causes formed a component of overall survival Overall survival data indicate that the established survival benefit of tamoxifen is maintained with anastrozole 1 mg J. Cuzick on behalf of ATAC/LATTE Trialists Group. Poster presented at 12 th Milan Breast Cancer Conference 2010

16 Summary of efficacy endpoints (A v T) (HR+ve patients) 2004 results (5-year analysis) results 2009 results (100 month FU analysis) 6 (Median 10-year analysis) 5 ENDPOINT HAZARD RATIO (95% CI) P-VALUE HAZARD RATIO (95% CI) P-VALUE HAZARD RATIO (95% CI) P-VALUE DFS 0.83 ( ) (0.76, 0.94) ( ) TTR 0.74 ( ) (0.67, 0.87) ( ) OS 0.97 ( ) (0.86, 1.11) ( ) CLBC * ( ) ( ) ( ) TTDR * ( ) ( ) ( ) Death after recurrence 0.87 ( ) ( ) ( ) 0.09* *Data analysed by J.Cuzick independently of AZ on behalf of the ATAC/LATTE Trialists Group 2. ATAC Trialist s Group Lancet 2005;365: J. Cuzick on behalf of ATAC/LATTE Trialists Group. Poster presented at 12 th Milan Breast Cancer Conference 2010, th June. 6. ATAC Trialists Group Lancet Oncol 2008;9:45-53

17 Summary of efficacy endpoints (HR+ve patients) Previous table illustrates the maintenance of the carry-over effect for anastrozole the statistically significant benefits in DFS,TTR, TTDR and CLBC seen for anastrozole compared with tamoxifen in previous analyses have been maintained at 10 years J. Cuzick on behalf of ATAC/LATTE Trialists Group. Poster presented at 12 th Milan Breast Cancer Conference 2010

18 Competing causes of mortality in HR+ve patients A recent study investigated non-breast cancer deaths in women aged 50 with node-negative, oestrogen receptor-positive primary breast cancer treated with adjuvant tamoxifen For at least 10 years after diagnosis, the large majority of deaths were unrelated to breast cancer 7.Hanrahan et al. J Clin Oncol 2007; 25:

19 Competing causes of mortality in HR+ve patients Age 50 years and ER+ Probability 0.4 Breast-cancer deaths Other deaths Time from diagnosis (years) ER+, oestrogen receptor-positive 7. Hanrahan et al. J Clin Oncol 2007; 25:

20 ATAC 10 year: Safety and Tolerability

21 SAFETY Safety results consistent with previous analyses. Serious adverse events according to treatment group in the safety population J. Cuzick on behalf of ATAC/LATTE Trialists Group. Poster presented at 12 th Milan Breast Cancer Conference 2010

22 Fracture Risk Following end of treatment fracture rates were similar in both groups (RR=0.98 ( ), p=0.5 J. Cuzick on behalf of ATAC/LATTE Trialists Group. Poster presented at 12 th Milan Breast Cancer Conference 2010

23 Conclusions ATAC10 year median follow-up demonstrated that anastrozole is: - significantly superior to tamoxifen at preventing recurrence on treatment and beyond the completion of treatment - significantly superior to tamoxifen at preventing both distant recurrence and contralateral breast cancer J. Cuzick on behalf of ATAC/LATTE Trialists Group. Poster presented at 12 th Milan Breast Cancer Conference 2010, th June.

24 Conclusions The absolute difference in DFS for anastrozole for the HR+ population increased from 2.6% at 5 years to 3.5% at 10 years The absolute difference in TTR for anastrozole for the HR+ population increased from 2.7% at 5 years to 4.3% at 10 years J. Cuzick on behalf of ATAC/LATTE Trialists Group. Poster presented at 12 th Milan Breast Cancer Conference 2010

25 Conclusions Anastrozole is generally well-tolerated long term: - No excess fracture rate seen after treatment completion - No new safety concerns were identified Statistically significant evidence for a larger carryover effect with anastrozole compared with tamoxifen confirms efficacy benefits of anastrozole in early and long term treatment beyond 5 years initial therapy anastrozole as initial adjuvant therapy J. Cuzick on behalf of ATAC/LATTE Trialists Group. Poster presented at 12 th Milan Breast Cancer Conference 2010

26 Thank You!

Choosing between different hormonal therapies. Rudy Van den Broecke UZ Ghent

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