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Anastrozole (‘Arimidex’): a new standard of care? Professor Gershon Y. Locker Northwestern University Feinberg School of Medicine, Evanston, IL, USA ASCO technology assessment 2004 Recommended a fundamental change in standard clinical practice Five years’ tamoxifen should no longer be the standard treatment choice for patients with EBC “Adjuvant hormonal therapy for postmenopausal women with HR+ve breast cancer should include an AI in order to lower the risk of tumour recurrence” – “Neither MA.17 or IES trials addressed the use of an AI as initial therapy” nor the option of planning at the time of initial diagnosis to switch to, or sequence, an AI after tamoxifen ASCO = American Society of Clinical Oncology; EBC = early breast cancer; HR = hormone receptor; AI = aromatase inhibitor Winer EP et al. J Clin Oncol 2005; 23, in press Data covered in the ASCO technology assessment 2004 ATAC – 47 month update, 2002 analysis ITA IES MA.17 ASCO = American Society of Clinical Oncology Winer EP et al. J Clin Oncol 2005; 23, in press New data not addressed in the ASCO technology assessment 2004 ATAC completed treatment analysis (68 month, 2004 analysis) BIG 1-98 ABCSG 8/ARNO 95 ASCO = American Society of Clinical Oncology Winer EP et al. J Clin Oncol 2005; 23, in press ATAC Trialists’ Group. Lancet 2005; 365: 60–62 Key unresolved questions from the ASCO technology assessment 2004 Include: – are the AIs most effective: if used as initial therapy? or after exposure to tamoxifen? – what are the long-term toxicities and risks associated with AIs? ASCO = American Society of Clinical Oncology Winer EP et al. J Clin Oncol 2005; 23, in press What have we learned from the ATAC completed treatment analysis? Anastrozole demonstrates significant and consistent long-term efficacy benefits over tamoxifen in the adjuvant treatment of postmenopausal women with EBC – significantly reduced risk of local and distant recurrence Anastrozole has a significantly better and consistent long-term tolerability profile than tamoxifen Anastrozole is the most effective adjuvant treatment for EBC – anastrozole has a known risk-benefit profile over the full 5 years’ treatment EBC = early breast cancer The ATAC Trialists’ Group. Lancet 2005; 365: 60–62 Efficacy analysis: ITT and HR+ populations Disease-free survival Time to recurrence ITT population HR+ population 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 1.5 2.0 Hazard ratio (A:T) and 95% CI Anastrozole (A) better ITT = intent-to-treat HR+ = hormone receptor-positive Tamoxifen (T) better ATAC Trialists’ Group. Lancet 2005; 365: 60–62; Howell A. Breast Cancer Res Treat 2004; 88 (Suppl 1): S7, abs 1 Analysis of time to recurrence for subgroups Nodal status +ve -ve Tumour size ≤ 2 cm >2 cm Receptor status +ve -ve unknown Previous chemotherapy yes no All patients 0.40 Hazard ratio (A:T) and 95% CI *HR+=hormone receptor positive 0.60 0.80 1.00 Anastrozole better 1.25 1.501.75 Tamoxifen better Howell A. Breast Cancer Res Treat 2004; 88 (Suppl 1): S7, abs 1 ATAC: summary of efficacy endpoints In the overall ITT population, compared with tamoxifen, anastrozole significantly reduced risk of: – all events: 13% (p=0.01) – recurrence: 21% (p=0.0005) – distant recurrence: 14% (p=0.04) – contralateral recurrence: 42% (p=0.01) 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 for this population, overall survival is similar for both treatments, with a trend in favour of anastrozole for breast cancer death There are no significant subgroup interactions ATAC Trialists’ Group. Lancet 2005; 365: 60–62; Howell A. Breast Cancer Res Treat 2004; 88 (Suppl 1): S7, abs 1 Added benefit versus tamoxifen EBCTCG ATAC Benefit for tamoxifen vs placebo Additional benefit of anastrozole vs tamoxifen Reduction in risk of recurrence 50% 26% Reduction in risk of breast cancer mortality 28% 13% Reduction in risk of contralateral breast cancer 47%* 53% Hormone receptor-positive population *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 anastrozole Overview of adverse events* Anastrozole (%) Tamoxifen (%) (n=3092) (n=3094) p-value All adverse events 93.9 94.6 0.2 Adverse events leading to withdrawal 11.1 14.3 0.0002 6.5 8.9 0.0005 33.3 36.0 0.03 Serious adverse events leading to withdrawal 4.7 5.9 0.04 Serious adverse events leading to death 3.3 3.6 0.6 Drug-related serious adverse events leading to death 0.2 0.3 0.5 Drug-related adverse events leading to withdrawal All serious adverse events *Adverse events on treatment or within 14 days of discontinuation Pre-defined adverse events* Hot flushes Joint disorders Vaginal bleeding Vaginal discharge Endometrial cancer** Fractures*** Ischaemic cerebrovascular event Venous thromboembolic events Deep venous thromboembolic events 0.2 0.4 0.6 In favour of anastrozole 0.8 1.0 1.5 2.0 In favour of tamoxifen Odds ratio (anastrozole / tamoxifen) *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) ATAC Trialists’ Group. Lancet 2005; 365: 60–62 ATAC: tolerability and safety 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 cerebrovascular events No new safety concerns have emerged with long-term followup Anastrozole now has a known, predictable and manageable safety profile Only anastrozole has a tolerability profile of this robustness and maturity, as it covers more than 5-years’ follow-up from 3 analyses AEs = adverse events; SAEs = serious AEs The ATAC Trialists’ Group. Lancet 2005; 365: 60–62; Howell A. Breast Cancer Res Treat 2004; 88 (Suppl 1): S7, abs 1 ABCSG 8/ARNO 95: summary of efficacy endpoints Switching from tamoxifen to anastrozole at 2 years is superior to continuing on tamoxifen in terms of: – EFS (HR=0.60; p=0.0009) – DRFS (HR=0.61; p=0.0067) – Data are not yet sufficiently mature to show a significant difference in OS The benefits of switching to anastrozole are seen regardless of baseline prognostic factors EFS = event free survival DRFS = distant recurrence free survival When to treat? Recurrence rates in EBC 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 EBC = early breast cancer; AEs = adverse events Annual hazard of recurrence Hazard of 25 recurrence by yearly 20 interval 15 10 5 0 0.5 1.5 2.5 3.5 4.5 5.5 6.5 7.5 8.5 9.5 10.5 Year Saphner et al. J Clin Oncol 1996; 14: 2738–2746 Smoothed hazard rates for recurrence (ITT population) Annual hazard rates (%) 3.0 2.5 2.0 1.5 1.0 Anastrozole Tamoxifen 0.5 0 0 ITT = intent-to-treat 1 2 3 4 Follow-up time (years) 5 6 ATAC Trialists’ Group. Lancet 2005; 365: 60–62; Howell A. Breast Cancer Res Treat 2004; 88 (Suppl 1): S7, abs 1 Use the best drug first Estimated 100 proportion of receptor-positive patients without 90 recurrence (%) ATAC ATAC switching from tamoxifen 80 EBCTCG after 5 years’ tamoxifen Control (EBCTCG) Tamoxifen (EBCTCG) 70 EBCTCG Anastrozole (ATAC) Tamoxifen (ATAC) 0 0 1 2 3 4 5 Years Comparison with Early Breast Cancer Trialists’ Collaborative Group (EBCTCG): receptor-positive patients >50 years ATAC Trialists’ Group. Lancet 2005; 365: 60–62; EBCTCG. Lancet 1998; 351: 1451–1467 Summary 5 years of tamoxifen alone is no longer the optimum treatment choice for EBC1 ATAC completed treatment analysis confirms the benefits of anastrozole as initial adjuvant therapy2 For patients already receiving initial adjuvant tamoxifen switching studies3,4 and extended adjuvant studies5 suggest it is reasonable to switch these patient to an AI after 2–3 or 5 years 1. Winer EP et al. J Clin Oncol 2005; 23, in press; 2. ATAC Trialists’ Group. Lancet 2005; 365: 60–62; 3. Boccardo et al. Breast Cancer Res Treat 2003; 82 (Suppl 1): S6; 4. Coombes et al. NEJM 2004; 350: 1081–1092; 5. Goss et al. NEJM 2003; 349: 1793–1802 Conclusion Higher rates of recurrence, increased AEs and treatment withdrawals with tamoxifen support the use of the best treatment first 5 years of anastrozole should now be considered as the preferred initial adjuvant endocrine treatment for postmenopausal women with hormone receptor-sensitive EBC