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 The American Society of Clinical Oncology (ASCO) Technology Assessment Panel recently recommended a fundamental change in standard clinical practice for the treatment of postmenopausal women with hormone receptor-positive (HR+ve) early stage breast cancer (EBC) (Winer et al, In press). Five years of tamoxifen treatment has historically been the standard initial adjuvant endocrine treatment for EBC (Early Breast Cancer Trialists' Collaborative Group 1998); however, many patients develop recurrent disease and tamoxifen treatment is associated with serious safety issues, including an increased incidence of thromboembolic events, cerebrovascular events and endometrial cancer. For the first time, the ASCO Technology Assessment Panel recommended that 5 years’ tamoxifen alone should no longer be the optimum treatment choice for EBC and stated that “adjuvant therapy for postmenopausal women with HR+ve breast cancer should include an aromatase inhibitor (AI) in order to lower the risk of tumour recurrence” (Winer et al, In press). 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 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 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

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? AIs have been evaluated in the initial adjuvant setting versus tamoxifen, after switching from 2–3 years of adjuvant tamoxifen, and in the post- or extended adjuvant setting versus no further therapy. However, the most appropriate time to begin treatment with an AI has not been established and it remains unknown whether or not the AIs are interchangeable in clinical practice. 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 The ‘Arimidex’, Tamoxifen, Alone or in Combination (ATAC) trial compared the efficacy and safety of the third-generation AI anastrozole (‘Arimidex’) with tamoxifen, or a combination, as initial adjuvant treatment in postmenopausal women with EBC (The ATAC Trialists' Group 2002; The ATAC Trialists' Group 2003; ATAC Trialists' Group 2005). To date, the ATAC trial is the only study to compare an AI with tamoxifen over the standard 5-year treatment period. 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 The completed treatment analysis, after a median follow-up of 68 months (only 8% of patients still on therapy), demonstrated the superior efficacy of anastrozole over tamoxifen, which extended beyond completion of trial therapy and continued to increase over time (ATAC Trialists' Group 2005). Anastrozole significantly prolonged disease-free survival, time to recurrence and time to distant recurrence, showed a non-significant reduction in breast cancer mortality and significantly reduced the incidence of contralateral breast cancer compared with tamoxifen (ATAC Trialists' Group 2005). Overall survival was similar between treatment groups demonstrating that anastrozole maintains the established survival benefit seen with tamoxifen, with a non-significant 12% reduction in breast cancer deaths in the anastrozole group (ATAC Trialists' Group 2005). However, the significant reductions in recurrence and distant recurrence demonstrated by anastrozole strongly suggest that an eventual benefit in breast cancer survival will be observed (ATAC Trialists' Group 2005). 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 Tamoxifen (T) better ITT = intent-to-treat HR+ = hormone receptor-positive 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 Anastrozole was superior to tamoxifen with respect to time to recurrence for all subgroups examined in the ITT population. There was no significant interaction at the 1% level for any predefined baseline prognostic factor. All patients 0.40 0.60 0.80 1.00 1.25 1.50 1.75 Anastrozole better Tamoxifen 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

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 The absence of a statistically significant survival benefit at this point in the study is not unexpected and could be predicted from previous experience in a similar population. For example, it took at least 7 years to demonstrate a significant survival advantage for tamoxifen versus placebo in the NSABP B-14 trial (Fisher et al. 2001). 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 Benefit for tamoxifen vs placebo 50% 28% 47%* ATAC Additional benefit of anastrozole vs tamoxifen 26% 13% 53%   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 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 The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) found significant benefits for adjuvant tamoxifen versus placebo. The efficacy benefits shown in the ATAC trial for anastrozole are additional to the benefits seen with tamoxifen. Early Breast Cancer Trialists' Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 1998;351:1451-67.

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 To date, the ATAC trial is also the only study to provide robust long-term safety and tolerability data for an AI. The favourable tolerability profile compared with tamoxifen was maintained at the completed treatment analysis and no new safety concerns emerged during the 5-year treatment period (ATAC Trialists' Group 2005). Significantly fewer patients withdrew from anastrozole treatment compared with tamoxifen. *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 Similar to previous analyses (The ATAC Trialists' Group 2002; The ATAC Trialists' Group 2003), endometrial cancer, thromboembolic events, ischaemic cerebrovascular events, hot flushes, vaginal discharge and bleeding were significantly less common in the anastrozole group compared with tamoxifen, although fractures and joint symptoms continued to be more frequent (ATAC Trialists' Group 2005). However, risk ratios were similar to previous analyses, suggesting that the safety profile of anastrozole remains unchanged with long-term follow-up. 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

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

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 recurrence by yearly interval 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 Five years of initial adjuvant tamoxifen has previously demonstrated a 47% risk reduction in breast cancer recurrence versus placebo in HR+ve patients (Early Breast Cancer Trialists' Collaborative Group 1998). However, anastrozole showed a 26% reduction in risk over and above that seen with tamoxifen in this clinically relevant population (ATAC Trialists' Group 2005). In addition, although tamoxifen treatment is characterised by a peak hazard of recurrence in Years 1–3 of treatment (Saphner et al 1996; Howell 2004; ATAC Trialists' Group 2005), this was suppressed by anastrozole and the benefits over tamoxifen were seen throughout the entire 5-year treatment period and beyond (ATAC Trialists' Group 2005). 0.5 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

Use the best drug first Estimated proportion of receptor-positive patients without recurrence (%) 100 switching from tamoxifen ATAC 90 ATAC EBCTCG after 5 years’ tamoxifen 80 Control (EBCTCG) Tamoxifen (EBCTCG) 70 EBCTCG Anastrozole (ATAC) Tamoxifen (ATAC) 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 Switching studies have evaluated changing adjuvant therapy with tamoxifen to anastrozole (Boccardo et al 2003) or exemestane (Coombes et al 2004) after 2–3 years of adjuvant treatment compared with continuing tamoxifen. In addition, letrozole (Goss et al 2003) has been evaluated in the postadjuvant setting after completion of 5 years of initial adjuvant tamoxifen compared with placebo. These studies all randomised patients after an initial period of tamoxifen, a period when ATAC has shown that more women would recur and have significant toxicity than if they were started on anastrozole. Although the results from these studies do not address the use of AIs as initial adjuvant therapy (Winer et al, In press), they suggest it is reasonable to switch patients to an AI after 2–3 or 5 years of initial adjuvant tamoxifen treatment. The results from the ATAC trial, however, suggest that a better outcome for the newly diagnosed patient may be achieved with initial treatment with anastrozole rather than initiating adjuvant treatment with tamoxifen with the intention of switching to an AI. The higher rates of recurrence, particularly within the first 3 years, together with the higher proportion of adverse events and treatment withdrawals on tamoxifen versus anastrozole support offering the most effective and well-tolerated therapy at the earliest opportunity. 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 The completed treatment analysis of the ATAC trial extends and strengthens the evidence from initial analyses (The ATAC Trialists' Group 2002; The ATAC Trialists' Group 2003) that anastrozole is significantly more effective and better tolerated than tamoxifen. This analysis provides a basis for establishing 5 years of anastrozole as the new standard of care for the initial adjuvant treatment of postmenopausal women with hormone-sensitive EBC.