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‘Arimidex’, Tamoxifen, Alone or in Combination (ATAC) trial: Completed Treatment Analysis. Surgery radiotherapy chemotherapy. Tamoxifen n=3116. ‘Arimidex’ n=3125. Combination n=3125. ATAC trial design. 9366 Postmenopausal women with invasive breast cancer
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‘Arimidex’, Tamoxifen, Alone or in Combination (ATAC) trial: Completed Treatment Analysis
Surgery radiotherapy chemotherapy Tamoxifen n=3116 ‘Arimidex’ n=3125 Combination n=3125 ATAC trial design 9366 Postmenopausal women with invasive breast cancer mean age 64 years; 84% hormone receptor positive 61% node negative; 64% with tumour 2 cm in diameter â â Randomization 1:1:1 for 5 years å æ â Discontinued following initial analysis as no efficacy or tolerability benefit compared with tamoxifen arm â Regular follow-up â • Secondary trial endpoints: • Incidence of contralateral breast cancer • Time to distant recurrence • Overall survival • Time to breast cancer death • Primary trial endpoints: • Disease-free survival • Safety / tolerability
First analysis – Dec 2001 Median follow-up : 33 months1 Updated analysis – November 2002 Median follow-up : 47 months2 Treatment Completion analysis – November 2004 Median follow-up : 68 monthsWomen years’ follow up: 49,941Total events: 1867 1. The ATAC Trialists’ Group. Lancet 2002; 359: 2131–2139 2. The ATAC Trialists’ Group. Cancer 2003; 98: 1802 – 1810 3. The ATAC Trialists’ Group. Lancet 2005; 365: 60-62 ATAC trial analysis history
ATAC completed treatment analysis • Data cut off: 31st March 2004: • prospectively defined based on at least 704 deaths in the two monotherapy arms combined • Follow-up: • 68 months’ median follow-up – i.e. extends beyond completion of treatment • 59 months’ median treatment duration • Only 8% of patients remain on treatment – the great majority of these nearing completion
At risk: A 2618 2540 2448 2355 2268 2014 830 T 2598 2516 2398 2304 2189 1932 774 Disease-free survivalCurves shown for HR+ patients 17% RR HR# 0.83 0.87 95% CI (0.73–0.94) (0.78-0.97) p-value 0.005 0.01 25 HR+* 20 ITT** 15 Patients (%) ‘Arimidex’ (A) 10 Tamoxifen (T) 5 Absolute difference: 1.6% 2.6% 2.5% 3.3% 0 0 1 2 3 4 5 6 Follow-up time (years) *ITT = Intention-to-treat population; **HR+ = Hormone receptor-positive patients; #A vs T
HR 0.74 0.79 95% CI (0.64–0.87) (0.79-0.90) p-value 0.0002 0.0005 HR+ ITT A 2618 2540 2448 2355 2268 2014 830 Time to RecurrenceCurves shown for HR+ patients 26% RR 25 20 15 Patients (%) ‘Arimidex’ (A) 10 Tamoxifen (T) 5 Absolute difference: 1.7% 2.4% 2.8% 3.7% 0 0 1 2 3 4 5 6 Follow-up time (years) At risk: T 2598 2516 2398 2304 2189 1932 774
3.0 2.5 2.0 1.5 1.0 0.5 0 Smoothed hazard rates for recurrence (HR+ population) Annualhazardrates(%) ‘Arimidex’ (A) Tamoxifen (T) 0 1 2 3 4 5 6 Follow-up time (years)
‘Arimidex’ (A) Tamoxifen (T) A 2618 2550 2464 2386 2309 2051 845 Time to Distant RecurrenceCurves shown for HR+ patients 25 HR 0.84 0.87 95% CI (0.70–1.00) (0.74-0.99) p-value 0.06 0.04 HR+ 20 ITT 15 Patients (%) 10 5 0 0 1 2 3 4 5 6 At risk: T 2598 2533 2438 2361 2257 2005 816
T 2598 2549 2502 2430 2333 2080 855 Overall Survival* Curves shown for HR+ patients HR 0.97 0.97 95% CI (0.83–1.14) (0.85-1.12) p-value 0.7 0.7 25 HR+ 20 ITT 15 Patients (%) ‘Arimidex’ (A) 10 Tamoxifen (T) 5 0 0 1 2 3 4 5 6 Follow-up time (years) At risk: A 2618 2566 2505 2437 2377 2117 867 * Includes non breast cancer deaths
A 2618 2566 2505 2437 2377 2117 867 Time to Breast Cancer DeathCurves shown for HR+ patients HR 0.87 0.88 95% CI (0.70–1.09) (0.74-1.05) p-value 0.2 0.2 25 HR+ 20 ITT 15 Patients (%) ‘Arimidex’ (A) 10 Tamoxifen (T) 5 0 0 1 2 3 4 5 6 Follow-up time (years) At risk: T 2598 2549 2502 2430 2333 2080 855
Incidence of new (contralateral) breast primaries in HR+ population HR 95% CI p-value A vs T 0.47 (0.29–0.75) 0.001 Number of cases 60 54 50 40 30 26 20 10 0 ‘Arimidex’ (A) (n=2618) Tamoxifen (T) (n=2598)
Efficacy analysis – ITT and HR+ populations ITT population Disease-free survival HR+ population Time to recurrence Time to distant recurrence Overall survival Time to breast cancer death Contralateral breast cancer 0.2 0.4 0.6 0.8 1.0 1.2 2.0 1.5 Hazard Ratio (A:T) and 95% CI ‘Arimidex’ (A) better Tamoxifen (T) better *ITT= intent-to-treat *HR+=hormone receptor-positive
Nodal status +ve -ve unknown Tumour size ≤2 cm >2 cm unknown* Receptor status +ve -ve unknown Previous chemotherapy yes no 0.60 ‘Arimidex’ better Tamoxifen better Analysis of time to recurrence for subgroups of the ITT* population All patients 0.40 0.80 1.00 1.25 1.50 1.75 Hazard ratio (A:T) and 95% CI *Confidence limit extends beyond plot
Summary of efficacy endpoints • In the HR+ population, compared with tamoxifen, ‘Arimidex’ reduces the risk of : • all events: 17% (p=0.005) • recurrence: 26% (p=0.0002) • distant recurrence: 16% (p=0.06) • contralateral recurrence: 53% (p=0.001) • There is also a (non-significant trend for a reduction in breast cancer mortality: 13% (p=0.2)
‘Arimidex’ demonstrates superior efficacy to tamoxifen • ‘Arimidex’ is more effective than tamoxifen in reducing the risk of recurrence, distant recurrence and contralateral breast cancer • The absolute difference between ‘Arimidex’ and tamoxifen continues to increase over time, and extends beyond completion of treatment • As expected, overall survival is similar for both treatments, i.e. ‘Arimidex’ maintains the significant survival benefit already established for tamoxifen, with a trend in favour of ‘Arimidex’ for breast cancer death • There are no significant subgroup interactions
Added benefit versus tamoxifen ATACAdditional benefit of ‘Arimidex’ vs tamoxifen 26% 13% 53% EBCTCGBenefit for tamoxifen vs placebo 50% 28% 47%* HR+ve population Reduction in risk of recurrence Reduction in risk of breast cancer mortality Reduction in risk of contralateral breast cancer *hormone receptor-positive and -negative patients EBCTCG = Early Breast Cancer Trialists’ Collaborative Group
Added benefit versus tamoxifen 38% risk of recurrence with no adjuvant treatment 50% risk reduction with tamoxifen Further 26% risk reduction with ‘Arimidex’
When to treat? • Recurrence rates in early breast cancer are highest in the first 5 years after surgery, with a peak at 2 years, regardless of baseline prognostic factors • Tamoxifen is associated with higher rates of recurrence, AEs and withdrawals than ‘Arimidex’ • Substantial benefit with ‘Arimidex’ in the first 3 years justifies offering the most effective therapy at the earliest opportunity Best treatment first !
Annual hazard of recurrence peaks at 2 years regardless of baseline prognostic factors Need to give most effective treatment firstto reduce risk of recurrence Adapted from Saphner et al, 1996
Overview of adverse events* Adverse events leading to withdrawal Drug-related adverse events leading to withdrawal All serious adverse events Serious adverse events leading to withdrawal Serious adverse events leading to death Drug-related serious adverse events leading to death 'Arimidex' (%)(n=3092) 11.1 6.5 33.3 4.7 3.3 0.2 Tamoxifen (%)(n=3094) 14.3 8.9 36.0 5.9 3.6 0.3 p-value 0.0002 0.0005 0.03 0.04 0.6 0.5 *Adverse events on treatment or within 14 days of discontinuation
p-value <0.0001 <0.0001 <0.0001 0.02 0.03 0.0004 0.02 <0.0001 <0.0001 Pre-defined adverse events* Completion analysis A 35.7 5.4 3.5 0.2 2.0 2.8 1.6 35.6 11.0 T 40.9 10.2 13.2 0.8 2.8 4.5 2.4 29.4 7.7 Hot flushes Vaginal bleeding Vaginal discharge Endometrial cancer** Ischaemic cerebrovascular event Venous thromboembolic events Deep venous thromboembolic events Joint symptoms Total fractures*** *Adverse events on treatment or within 14 days of discontinuation; **Excludes patients with prior hysterectomy and includes on- and off-therapy AEs; ***Fractures occurring at anytime prior to recurrence (includes patients no longer receiving treatment)
Tolerability summary • Compared with tamoxifen, 'Arimidex' is associated with significantly fewer: • SAEs, treatment-related AEs and withdrawals • potentially life threatening AEs such as endometrial cancer, thromboembolic, and cerebrovasular events • No new safety concerns with long-term follow-up • Only 'Arimidex' has a tolerability profile this robust and mature, covering the full 5 year treatment period • 'Arimidex' now has a known, predictable and manageable safety profile Tolerability profile not only different but SUPERIOR
ATAC summary • ATAC Completed Treatment Analysis extends and strengthens the evidence that 5 years of 'Arimidex' is significantly more effective and better tolerated than 5 years of tamoxifen • Overall risk:benefit profile remains clearly in favour of 'Arimidex' • The absolute benefits for 'Arimidex' over and above those of tamoxifen continue to increase with time and extend beyond the completion of therapy
ATAC in context • 'Arimidex' is a more effective and better-tolerated adjuvant treatment than tamoxifen • These findings provide a basis for establishing 'Arimidex' as the standard of care for the initial 5 years’ adjuvant treatment of postmenopausal women with hormone receptor-sensitive early breast cancer Howell, SABCS 2004
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