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Start or Switch?: Latest data from ABCSG/ARNO

Start or Switch?: Latest data from ABCSG/ARNO. Adjuvant endocrine therapy for early breast cancer. Recent trial data has challenged tamoxifen’s position as the gold standard adjuvant therapy 1

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Start or Switch?: Latest data from ABCSG/ARNO

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  1. Start or Switch?:Latest data from ABCSG/ARNO

  2. Adjuvant endocrine therapy for early breast cancer • Recent trial data has challenged tamoxifen’s position as the gold standard adjuvant therapy1 • The ATAC trial has shown that anastrozole provides a new standard of care for newly-diagnosed postmenopausal women • Anastrozole significantly decreases the risk of recurrence, distant recurrence and contralateral breast cancer and has a significantly better tolerability profile 1ATAC Trialists’ Group Lancet 2005; 365: 60–62

  3. Unanswered questions in adjuvant therapy for early breast cancer • Would postmenopausal patients already receiving tamoxifen benefit from switching to AI therapy? • Are AIs more effective if used as initial treatment or sequential to tamoxifen? • Could premenopausal women with breast cancer also benefit from AI therapy?

  4. Switching trials: evidence from 8,414 postmenopausal women Italian Tamoxifen Anastrozole (ITA) trial International Exemestane Study (IES) ABCSG 8/ARNO 95 combined analysis

  5. ITA: study design • All women were: • postmenopausal • hormone receptor positive • node positive Tamoxifen (n=225) • Women were regularly followed until they reached a major trial endpoint that included any of the following: • disease recurrence • second primary tumour (including a second breast tumour) • death (from any cause) Surgery ± RT ± Chemo Tamoxifen (n=448) Therapy blinded at randomization to A or T Anastrozole (n=223) 2–3 years 3–2 years Boccardo F et al. Breast Cancer Res Treat 2003; 82 (Suppl 1): S6–S7 (abs 3)

  6. 1.0 0.8 0.6 0.4 0.2 0.0 0 1 2 3 4 5 6 ITA: disease-free survival Proportion disease-free Anastrozole Tamoxifen No. of pts 223 225 Obs 17 45 p-value 0.0002 Years Boccardo F et al. Breast Cancer Res Treat 2003; 82 (Suppl 1): S6–S7 (abs 3)

  7. IES: trial design Diagnosis of breast cancer and treatment for primary disease Years from start of tamoxifen 2–3 years’ tamoxifen 0 2 RANDOMISED Years from randomisation n =4742 3 0 2–3 years’ tamoxifen n=2380 2–3 years’ exemestane n=2362 Patients followed-up 5 2-3 Coombes RC et al. N Engl J Med. 2004; 350: 1081–1092

  8. IES: disease-free survival 100 Proportion disease-free (%) 75 Hazard ratio = 0.68 (95% CI: 0.56–0.82)Log rank test: p-value < 0.001 50 25 Exemestane Tamoxifen 0 0 1 2 3 4 Years from randomisation No. of events/at risk: Exemestane 0/2362 52/2168 60/1696 44/757 20+6†/201 Tamoxifen 18+4†/185 0/2380 78/2173 90/1682 76/730 †events occurring more than 4 years after randomisation Coombes RC et al. N Engl J Med. 2004; 350: 1081–1092

  9. ABCSG 8/ARNO 95 combined analysis • Aim: to prospectively assess whether switching from tamoxifen to anastrozole after 2 years is more effective than continuing on tamoxifen • Pre-planned combined analysis of ABCSG 8 (Austria) and ARNO 95 (Germany) • Patients: postmenopausal women with hormone receptor-positive EBC • Median 28 months’ follow-up

  10. ABCSG 8/ARNO 95:Combined analysis trial structure Total patients n=3224 ABCSG 8 n=2262 + ARNO 95 n=962 TAM 3 years n=1606 Primary surgery +/- RTx + TAM 2 years ANA 3 years n=1618

  11. Patient demographics TAMn=1606% ANAn=1618% T1 Node negative Breast conservation G1,2,x Age < 60 yrs ER+/PgR+ ER+/PgR- ER-/PgR+ 69.7 74.0 77.3 93.7 39.9 81.1 18.3 0.6 70.2 74.2 76.4 95.2 38.6 81.3 18.1 0.6 Gx = lobular carcinoma

  12. Event-free survival Event-free survival (%) 100 ANA 95 90 TAM 85 80 ANA vs TAM p=0.0009 HR 0.60 [95% CI 0.44–0.81] 75 0 0 1 2 3 4 5 EFS time in years* At risk: 858 1606 1217 343 176 TAM 593 874 1618 1243 375 178 ANA 623 Zero point = 2 years after surgery

  13. Localisation of events Events Locoregional Contralateral BC Distant recurrences Total n=3224 177 44 28 121 TAM n=1606 110 24 16 75 ANA n=1618 67 20 12 46 Events occuring simultaneously are included twice

  14. TAM 1224 869 600 ANA 1247 879 631 Distant recurrence-free survival 100 Distant recurrence-free survival (%) ANA 96 92 TAM 88 ANA ANA vs vs TAM TAM 84 HR 0.60 [95% CI 0.42–0.88] p=0.0067 0 0 1 2 3 4 5 DRFS time in years At risk: 1606 351 181 1618 382 181 Zero point = 2 years after surgery

  15. Subgroup analysis of EFS* n 3224 2389 833 3044 167 1265 1959 2519 564 All patients Nodal status -ve +ve Grading G1, G2, Gx G3 Age <60 years >60 years Receptor (ER / PR) +ve / +ve +ve / -ve 0.25 0.50 0.80 1.00 1.25 1.50 2.00 3.00 *Events: locoregional, metastatic and contralateral recurrences ANA better TAM better Hazard ratio (ANA vs TAM)

  16. Tolerability data from ABCSG 8 • Both treatments were well tolerated • The incidence of prespecified side effects was low in both groups • As expected, there were significantly more fractures in patients switching to anastrozole: 27 (2.4%) vs 14 (1.2%) for tamoxifen • No significant difference between treatments was seen in gynaecological side effects because – as seen in ATAC – these generally occur soon after starting tamoxifen

  17. ABCSG 8/ARNO 95: Summary • These data confirm results from ITA and IES • Switching from TAM to ANA at 2 years is superior to continuing on TAM in terms of: • EFS (HR=0.60) • DRFS (HR=0.61) • Data are not yet sufficiently mature to show a significant difference in OS • The benefits of switching to ANA are seen regardless of baseline prognostic factors • Both treatments are well tolerated

  18. Conclusions • ATAC: initial adjuvant therapy with anastrozole is superior to tamoxifen • ABCSG/ARNO: switching to anastrozole after 2 years is superior to remaining on tamoxifen Which of these treatment strategies is more effective?

  19. Can these benefits of anastrozole in postmenopausal women be translated into the premenopausal setting?

  20. What do we know to date? • Premenopausal women: • Benefit from adjuvant tamoxifen alone or in combination with goserelin • Combining an LHRHa and tamoxifen confers better efficacy than LHRHa alone in advanced disease If a patient is rendered postmenopausal, could she also be eligible from the added benefit of anastrozole? Jakesz et al JCO 2002;20:4621-4627 Klijn et al. JCO 2001; 343–353 Klijn et al. JNCI 2000; 92: 903–911 Bonneterre et al. Cancer 2001; 92: 2247–2258 ATAC Trialists Group. Lancet 2005; 365: 60–62

  21. p<0.0001 250 200 Mean serum oestradiol (pmol/L) 150 100 p<0.0001 50 0 Baseline Goserelin + Goserelin + Tamoxifen Anastrozole Goserelin plus anastrozole in 2nd line ABC • Patients deriving clinical benefit from goserelin plus tamoxifen received goserelin plus anastrozole on progression Forward DP et al. Br J Cancer 2004; 90: 590–594

  22. Clinical benefit Partial response [PR] Stable disease [SD] 6 months Biochemical response [BR]* Clinical benefit (CB; PR + SD 6 months + BR) rate n (%) 1 (6) 9 (56) 2 (13) 75% N=16 *no evidence of progression beyond 6 months with decreasing blood tumour markers • Median duration of clinical benefit 17 months (range 6-47) Forward DP et al. Br J Cancer 2004; 90: 590–594

  23. Patients (%) Objective response 28 Complete response 6 Partial response 22 Stable disease 6 months 44 Clinical benefit 72 Goserelin plus anastrozole in 1st line ABC • Phase II trial of 22 patients whose E2 was decreased to postmenopausal levels with goserelin and then received anastrozole • To date median TTP = ~10 months Carlson R et al. Breast Cancer Res Treat 2004; 88 (Suppl 1):S237–238, abs 6052

  24. ABCSG 12: trial structure • 3 years adjuvant endocrine treatment +/- bisphosphonate therapy • premenopausal HR-positive patients Anastrozole 1 mg/d Anastrozole 1 mg/d Zoledronic acid 4 mg/d q 6 Mo Random 1 : 1 : 1 : 1 OP Goserelin 3.6 mg q 4W Tamoxifen 20 mg/d Tamoxifen 20 mg/d Zoledronic acid 4 mg/d q 6 Mo Accruals Target: 1800 (450/arm) Status: 1372 (Jan. 11, 2005)

  25. Conclusions • 4 trials have reported data suggesting that postmenopausal women receiving adjuvant tamoxifen should switch to an AI after 2–5 years • Postmenopausal women currently receiving tamoxifen are 40% less likely to relapse if switched to anastrozole after 2 years compared with continuing on tamoxifen • For premenopausal women with hormone-sensitive EBC, the combination of goserelin and anastrozole is a promising treatment and warrants further research

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