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‘Arimidex’, Tamoxifen, Alone or in Combination (ATAC) trial: Completed Treatment Analysis. Introduction. Which problems does ATAC address?. Is tamoxifen still the best adjuvant therapy for early breast cancer (EBC)?. How do we reduce recurrences in the first few years of treatment?.
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‘Arimidex’, Tamoxifen, Alone or in Combination (ATAC) trial: Completed Treatment Analysis
Which problems does ATAC address? • Is tamoxifen still the best adjuvant therapy for early breast cancer (EBC)? • How do we reduce recurrences in the firstfew years of treatment? • Can we improve upon the tolerability problems associated with adjuvant tamoxifen? • Is anastrozole superior to tamoxifenin the adjuvant setting?
If tamoxifen is not the best adjuvant treatment: • Should anastrozole be considered the preferred initial endocrine therapy? • When should anastrozole be given? • Is there robust and mature data to support the use of anastrozole in this setting?
Surgery radiotherapy chemotherapy Tamoxifen n=3116 Anastrozole 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 Randomisation 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
ATAC completed treatment analysis • Follow-up: • Data cut-off 31st March 2004, based on at least 704 deaths in the two monotherapy arms combined • 68 months’ median follow-up – beyond completion of treatment • 59 months’ median treatment duration • Only 8% of patients remain on treatment – the great majority of these nearing completion • Results: • Anastrozole demonstrates superior efficacy to tamoxifen • Anastrozole demonstrates superior tolerability to tamoxifen • The results of this analysis are mature and the overall risk:benefit profile of anastrozole can be considered final
3.0 2.5 2.0 1.5 1.0 0.5 0 Smoothed hazard rates for recurrence (HR*-positive population) Annualhazardrates(%) Anastrozole Tamoxifen 0 1 2 3 4 5 6 Follow-up time (years) *HR=hormone receptor
p-value 0.005 HR 0.83 95% CI (0.73–0.94) 25 A vs T 20 15 Patients (%) 10 Anastrozole (A) 5 Tamoxifen (T) 0 Disease-free survival (HR*-positive population) 1.6% 2.6% 2.5% 3.3% Absolute difference: 0 1 2 3 4 5 6 Follow-up time (years) At risk: A 2618 2540 2448 2355 2268 2014 830 T 2598 2516 2398 2304 2189 1932 774 *HR=hormone receptor
p-value 0.0002 HR 0.74 95% CI (0.64–0.87) 25 A vs T 20 15 Patients (%) 10 Anastrozole (A) 5 Tamoxifen (T) 0 Recurrence (HR*-positive population) 1.7% 2.4% 2.8% 3.7% Absolute difference: 0 1 2 3 4 5 6 Follow-up time (years) At risk: A 2618 2540 2448 2355 2268 2014 830 T 2598 2516 2398 2304 2189 1932 774 *HR=hormone receptor
Analysis of time to recurrence for subgroups of the HR*-positive population Nodal status +ve -ve unknown** Tumour size 2 cm 2–5 cm >5 cm* Previouschemotherapy Yes No All patients *HR=hormone receptor Hazard ratio (A:T) and 95% CI 0.40 0.60 0.80 1.00 1.25 1.50 1.75 Anastrozole better Tamoxifen better **Confidence limit extends beyond plot
p-value 0.06 HR 0.84 95% CI (0.70–1.00) 25 A vs T 20 15 Patients (%) 10 Anastrozole (A) 5 Tamoxifen (T) 0 Time to distant recurrence (HR*-positive population) 0 1 2 3 4 5 6 Follow-up time (years) At risk: A 2618 2549 2463 2385 2308 2051 845 T 2598 2533 2437 2359 2255 2005 816 *HR=hormone receptor
p-value 0.7 HR 0.97 95% CI (0.83–1.14) 25 A vs T 20 15 Patients (%) 10 Anastrozole (A) 5 Tamoxifen (T) 0 Overall survival (HR*-positive population) 0 1 2 3 4 5 6 Follow-up time (years) At risk: A 2618 2566 2505 2437 2377 2117 867 T 2598 2549 2502 2430 2333 2080 855 *HR=hormone receptor
Incidence of new (contralateral) breast primaries in HR*-population HR 95% CI p-value AN vs TAM 0.47 0.29–0.75 0.001 Number of cases 53 5 DCIS 26 48 Invasive* 5 DCIS 21 Invasive* Anastrozole (AN) (n=3125) Tamoxifen (TAM) (n=3116) *p=0.001 for invasive cancers. *HR=hormone receptor
Most recurrences occur within the first 5 years of primary therapy Recurrence rate/year(%) Need to give most effective treatment firstto reduce risk of recurrence Year Saphner et al JCO 1996; 14: 2738-2746
p-value 0.005 HR 0.83 95% CI (0.73–0.94) 25 A vs T 20 15 Patients (%) 10 Anastrozole (A) 5 Tamoxifen (T) 0 Disease-free survival (HR*-positive population) 1.6% 2.6% 2.5% 3.3% Absolute difference: 0 1 2 3 4 5 6 Follow-up time (years) At risk: A 2618 2540 2448 2355 2268 2014 830 T 2598 2516 2398 2304 2189 1932 774 *HR=hormone receptor
Anastrozole demonstrates superior efficacy to tamoxifen • Anastrozole is more effective than tamoxifen in reducing the risk of recurrence, distant recurrence and contralateral breast cancer • The absolute difference between anastrozole and tamoxifen continues to increase over time, and extends beyond completion of treatment • As expected, overall survival is similar for both treatments, with a trend in favour of anastrozole for breast cancer death • There are no significant subgroup interactions
Added benefit versus tamoxifen ATACAdditional benefit of anastrozole vs tamoxifen 26% 13% 52% EBCTCGBenefit for tamoxifen vs placebo 50% 28% 47%* Hormone receptor-positive 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 patientsEBCTCG = Early Breast Cancer Trialists’ Collaborative Group
Added benefit versus tamoxifen 38% risk of recurrence with no adjuvant treatment 50% reduction in risk with tamoxifen Further 26% risk reduction with anastrozole
When to treat? • Recurrence rates I 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 anastrozole • Substantial benefit with anastrozole in the first 3 years justifies offering the most effective therapy at the earliest opportunity
Overview of adverse events* All 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 Anastrozole (%)(n=3092) 93.9 11.1 6.5 33.3 4.7 3.3 0.2 Tamoxifen (%)(n=3094) 94.6 14.3 8.9 36.0 5.9 3.6 0.3 p-value 0.2 0.0002 0.0005 0.03 0.04 0.6 0.5 *Adverse events on treatment or within 14 days of discontinuation
Completion analysis p-value 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 <0.0001 <0.0001 <0.0001 0.01 0.03 0.0004 0.02 <0.0001 <0.0001 Pre-defined adverse events Hot flushes Vaginal bleeding Vaginal discharge Endometrial cancer* Ischaemic cerebrovascular event Venous thromboembolic events Deep venous thromboembolic events Joint symptoms Total fractures *Excludes patients with prior hysterectomy and includes on- and off-therapy AEs
Hot flushes Joint symptoms Vaginal bleeding Vaginal discharge Fractures Endometrial cancer Ischaemic cerebrovascular events Venous thromboembolic events Pre-defined adverse events 0.2 0.4 0.6 0.8 1.0 1.5 2.0 In favour of anastrozole In favour of tamoxifen Relative risk (anastrozole / tamoxifen)
Tolerability summary • Compared with tamoxifen, anastrozole is associated with significantly fewer: • SAEs, treatment-related AEs and withdrawals due to SAEs or AEs • potentially life threatening AEs such as endometrial cancer, thromboembolic, and cerebrovasular events • No new safety concerns have emerged with long-term follow-up • Only anastrozole has a tolerability profile of this robustness and maturity, as it covers the full 5 year treatment period • Anastrozole now has a known, predictable and manageable safety profile
ATAC summary • ATAC Completed Treatment Analysis extends and strengthens the evidence that 5 years of anastrozole is significantly more effective and better tolerated than 5 years of tamoxifen • Overall risk:benefit profile remains clearly in favour of anastrozole • The absolute benefits for anastrozole over and above those of tamoxifen continue to increase with time and extend beyond the completion of therapy
ATAC in context • Anastrozole is a more effective and better-tolerated adjuvant treatment than tamoxifen • These findings provide a basis for establishing anastrozole 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
Definition of endpoints (1) • Disease-free survival (DFS) • loco-regional recurrence (inc. ipsilateral new breast cancer) or new contralateral breast cancer • distant recurrence or death (for any reason) • Distant disease-free survival (DDFS) • distant recurrence • death (for any reason) • Time to recurrence (TTR) • loco-regional recurrence (inc. ipsilateral new breast cancer) or new contralateral breast cancer • distant recurrence or death due to breast cancer
Definition of endpoints (2) • Overall survival (OS) • death (for any reason) • Time to distant recurrence (TTDR) • distant recurrence or any death following a loco-regional recurrence (inc. ipsilateral new breast cancer) • breast cancer death • Time to breast cancer death (TTBCD) • any death following a loco-regional (inc. ipsilateral new breast cancer) or distant recurrence • breast cancer death
ATAC: patient characteristics Anastrozole (n=3125) Tamoxifen (n=3116) Mean age (years) Mean weight (kg) Receptor status (%) positive negative unknown Primary treatment (%) mastectomy axillary surgery radiotherapy chemotherapy prior tamoxifen 64.1 70.8 83.7 8.3 8.0 47.8 95.5 63.3 22.3 1.6 64.1 71.1 83.4 8.7 7.9 47.3 95.7 62.5 20.8 1.6
ATAC: baseline disease characteristics Anastrozole (n=3125) Tamoxifen (n=3116) Primary tumour size (%) T1 (2 cm) T2 (2 cm to 5 cm) T3 (5 cm) Nodal status (%) node-positive Grading (%) well differentiated moderately differentiated poorly / undifferentiated not assessed / recorded 63.9 32.6 2.7 34.9 20.8 46.8 23.7 8.5 62.9 34.2 2.2 33.6 20.5 47.8 23.3 8.3
First analysis – June 2002 Median follow-up : 33 months1 Updated analysis – November 2003 Median follow-up : 47 months2 Completion analysis – November 2004 Median follow-up : 68 monthsWomen years’ follow up: 49,941Total events: 1867 ATAC trial analysis history 1.The ATAC Trialists’ Group. Lancet 2002; 359: 2131–2139 2.The ATAC Trialists’ Group. Cancer 2003; 98: 1802 – 1810
Anastrozole Tamoxifen Smoothed hazard rates for recurrence (ITT* population) 3.0 Annualhazardrates(%) 2.5 2.0 1.5 1.0 0.5 0 0 1 2 3 4 5 6 Follow-up time (years) *ITT=intent-to-treat
p-value 0.013 HR 0.87 95% CI (0.78–0.97) A vs T Anastrozole (A) Tamoxifen (T) Disease-free survival (ITT* population) 25 20 15 Patients (%) 10 5 1.5% 2.0% 2.4% 2.9% Absolute difference: 0 0 1 2 3 4 5 6 Follow-up time (years) At risk: A 3125 3004 2874 2757 2645 2350 984 T 3116 2992 2835 2709 2575 2273 933 Includes non breast cancer deaths*ITT=intent-to-treat
p-value 0.0005 HR 0.79 95% CI (0.70–0.90) A vs T Anastrozole (A) Tamoxifen (T) Recurrence (ITT* population) 25 20 15 Patients (%) 10 5 1.6% 2.1% 2.8% 3.4% Absolute difference: 0 0 1 2 3 4 5 6 Follow-up time (years) At risk: A 3125 3004 2874 2757 2645 2350 984 T 3116 2992 2835 2709 2575 2273 933 *ITT=intent-to-treat
Nodal status +ve -ve unknown Tumour size ≤2 cm >2 cm unknown** Receptor status +ve -ve unknown Previous chemotherapy yes no 0.60 Anastrozole 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 *ITT=intent-to-treat Hazard ratio (A:T) and 95% CI **Confidence limit extends beyond plot
p-value 0.043 HR 0.86 95% CI (0.74–0.99) A vs T Anastrozole (A) Tamoxifen (T) Time to distant recurrence(ITT* population) 25 20 15 Patients (%) 10 5 0 0 1 2 3 4 5 6 Follow-up time (years) At risk: A 3125 3022 2899 2802 2703 2406 1009 T 3116 3020 2890 2783 2656 2364 985 *ITT=intent-to-treat
p-value 0.7 HR 0.97 95% CI (0.85–1.12) A vs T Anastrozole (A) Tamoxifen (T) Overall survival (ITT* population) 25 20 15 Patients (%) 10 5 0 0 1 2 3 4 5 6 Follow-up time (years) At risk: A 3125 2956 2865 2784 2479 1037 3051 T 3116 2972 2872 2747 2461 1037 3048 Includes non breast cancer deaths*ITT=intent-to-treat
p-value 0.2 HR 0.88 95% CI (0.74–1.05) A vs T Anastrozole (A) Tamoxifen (T) Time to breast cancer death (ITT* population) 25 20 15 Patients (%) 10 5 0 0 1 2 3 4 5 6 Follow-up time (years) At risk: A 3125 3051 2956 2865 2784 2479 1037 T 3116 3048 2972 2872 2747 2461 1037 *ITT=intent-to-treat
Incidence of new (contralateral) breast primaries in ITT* population HR 95% CI p-value AN vs TAM 0.58 0.38–0.88 0.01 58 Number of cases 6 DCIS 35 8 DCIS 52 Invasive* 27 Invasive* Anastrozole (AN) (n=3125) Tamoxifen (TAM) (n=3116) *p=0.004 for invasive cancers. *ITT=intent-to-treat
Summary of efficacy endpoints • In the overall ITT population, compared with tamoxifen, anastrozole provides significantly reduced risk of : • all events: 13% (p=0.013) • recurrence: 21% (p=0.0005) • distant recurrence: 14% (p=0.043) • contralateral recurrence: 42% (p=0.01)