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Anastrozole (‘Arimidex’): a new standard of care?

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

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Anastrozole (‘Arimidex’): a new standard of care?

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  1. Anastrozole (‘Arimidex’): a new standard of care? Professor Gershon Y. Locker Northwestern University Feinberg School of Medicine, Evanston, IL, USA

  2. 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

  3. Data covered in the ASCOtechnology 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

  4. 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 Winer EP et al. J Clin Oncol 2005; 23, in press ATAC Trialists’ Group. Lancet 2005; 365: 60–62 ASCO = American Society of Clinical Oncology

  5. 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

  6. 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 The ATAC Trialists’ Group. Lancet 2005; 365: 60–62 EBC = early breast cancer

  7. 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 2.0 1.5 Hazard ratio (A:T) and 95% CI Anastrozole (A) better Tamoxifen (T) better ATAC Trialists’ Group. Lancet 2005; 365: 60–62; Howell A. Breast Cancer Res Treat 2004; 88 (Suppl 1): S7, abs 1 ITT = intent-to-treat HR+ = hormone receptor-positive

  8. Analysis of time torecurrence for subgroups Nodal status +ve -ve Tumour size ≤2 cm >2 cm Receptorstatus +ve -ve unknown Previous chemotherapy yes no All patients 0.40 0.60 0.80 1.00 1.25 1.50 1.75 Tamoxifen better Anastrozole better Hazard ratio (A:T) and 95% CI *HR+=hormone receptor positive Howell A. Breast Cancer Res Treat 2004; 88 (Suppl 1): S7, abs 1

  9. 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)

  10. 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

  11. Added benefit versus tamoxifen ATACAdditional benefit of anastrozole vs tamoxifen 26% 13% 53% 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

  12. Added benefit versus tamoxifen 38% risk of recurrence with no adjuvant treatment 50% risk reduction with tamoxifen Further 26% risk reduction with anastrozole

  13. 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

  14. Hot flushes Vaginal bleeding Vaginal discharge Endometrial cancer** Ischaemic cerebrovascular event Venous thromboembolic events Deep venous thromboembolic events Pre-defined adverse events* Joint disorders Fractures*** 0.2 0.4 0.6 0.8 1.0 1.5 2.0 In favour of anastrozole 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

  15. 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 follow-up • 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

  16. 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

  17. 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

  18. Annual hazard of recurrence Hazard of recurrence by yearly interval Year Saphner et al. J Clin Oncol 1996; 14: 2738–2746

  19. 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) ATAC Trialists’ Group. Lancet 2005; 365: 60–62; Howell A. Breast Cancer Res Treat 2004; 88 (Suppl 1): S7, abs 1 ITT = intent-to-treat

  20. switching from tamoxifen after 5 years’ tamoxifen Use the best drug first Estimated proportion of receptor-positivepatients withoutrecurrence (%) 100 ATAC 90 ATAC EBCTCG 80 Control (EBCTCG) Tamoxifen (EBCTCG) 70 EBCTCG Anastrozole (ATAC) Tamoxifen (ATAC) 0 0 1 2 3 4 5 Years Comparison with Early BreastCancer Trialists’ CollaborativeGroup (EBCTCG): receptor-positivepatients >50 years ATAC Trialists’ Group. Lancet 2005; 365: 60–62; EBCTCG. Lancet 1998; 351: 1451–1467

  21. 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

  22. 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

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