OI PARP ΑΝΑΣΤΟΛΕΙΣ ΣΤΟΝ ΚΑΡΚΙΝΟ ΤΟΥ ΜΑΣΤΟΥ ΝΙΚΟΛΑΙΔΗ ΑΔΑΜΑΝΤΙΑ ΠΑΘΟΛΟΓΟΣ-ΟΓΚΟΛΟΓΟΣ Β ΟΓΚΟΛΟΓΙΚΗ ΚΛΙΝΙΚΗ ΝΟΣ. ΜΗΤΕΡΑ

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1 OI PARP ΑΝΑΣΤΟΛΕΙΣ ΣΤΟΝ ΚΑΡΚΙΝΟ ΤΟΥ ΜΑΣΤΟΥ ΝΙΚΟΛΑΙΔΗ ΑΔΑΜΑΝΤΙΑ ΠΑΘΟΛΟΓΟΣ-ΟΓΚΟΛΟΓΟΣ Β ΟΓΚΟΛΟΓΙΚΗ ΚΛΙΝΙΚΗ ΝΟΣ. ΜΗΤΕΡΑ

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8 Study Overview Inhibition of poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP), a key enzyme for the repair of breaks in DNA, can lead to the accumulation of breaks in double-stranded DNA The BRCA1 and BRCA2 proteins help to repair such breaks In this phase 1 trial, the PARP inhibitor olaparib was shown to lack the severe toxic effects of conventional chemotherapy and to result in objective responses in tumors with a BRCA mutation

9 Baseline Characteristics of the 60 Study Patients Fong PC et al. N Engl J Med 2009;361:

10 Fong PC et al. N Engl J Med 2009;361: Doses of Olaparib at Baseline in the Study Patients

11 Olaparib-Related Adverse Events Found in at Least 5% of the Safety Population, According to Olaparib Dose Fong PC et al. N Engl J Med 2009;361:

12 Results of Pharmacokinetic and Pharmacodynamic Studies of Olaparib Fong PC et al. N Engl J Med 2009;361:

13 Clinical Responses in Study Patients for Whom the Response Could Be Evaluated Fong PC et al. N Engl J Med 2009;361:

14 Radiologic Evidence of Tumor Response to Olaparib Fong PC et al. N Engl J Med 2009;361:

15 Conclusion Olaparib has few of the adverse effects of conventional chemotherapy, inhibits PARP, and has antitumor activity in cancer associated with the BRCA1 or BRCA2 mutation

16 Study Overview In this phase 2 study, the use of gemcitabine and carboplatin plus iniparib, as compared with gemcitabine and carboplatin alone, resulted in a significantly higher rate of response and increased the progression-free survival.

17 Enrollment, Randomization, and Follow-up of the Study Patients. O'Shaughnessy J et al. N Engl J Med 2011;364:

18 Kaplan Meier Estimates of Progression-free and Overall Survival Rates, According to Treatment Group. O'Shaughnessy J et al. N Engl J Med 2011;364:

19 Baseline Characteristics of the Study Patients, According to Treatment Group. O'Shaughnessy J et al. N Engl J Med 2011;364:

20 Summary of Efficacy Measures in the Intention-to-Treat Population. O'Shaughnessy J et al. N Engl J Med 2011;364:

21 Common Adverse Events in the Safety Population. O'Shaughnessy J et al. N Engl J Med 2011;364:

22 Conclusions The addition of iniparib to chemotherapy improved the clinical benefit and survival of patients with metastatic triple-negative breast cancer without significantly increased toxic effects. On the basis of these results, a phase 3 trial adequately powered to evaluate overall survival and progression-free survival is being conducted.

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33 Olaparib breast cancer Phase III programme

34 OlympiA: Adjuvant olaparib in breast cancer patients with gbrca mutations at high risk of recurrence Post-neoadjuvant BRCA TNBC, Non-PathCR patients Assumptions: - Control arm 3-year EFS ~ 60% Post-adjuvant gbrca TNBC, Patients with node positive disease (any tumour size) or node negative, primary tumour >2 cm Assumptions: - Estimated control arm 3-year EFS ~ 77% Randomise 1:1 Double-blind N=1,320 Olaparib 300 mg bid 12-month duration Placebo 12-month duration IDFS Distant DFS; OS Study to start recruiting patients with TNBC; plan to add ER/PR+ patients once data available from PK/PD interactions (expected Mid 2014) All patients will have chemotherapy and surgery prior to randomisation For patients with unknown gbrca status, Myriad gbrca testing will be covered by AstraZeneca (patients selected for gbrca testing on basis of local guidelines) Patients with platins in neoadjuvant or adjuvant setting allowed Primary endpoint: IDFS (invasive disease-free survival; STEEP approach) HR=0.7 (CV=0.81), 90% power, 5% significance level, approx 330 events required Assumes consistent treatment effect (HR=0.7) across patient groups N=1320 (25% maturity), assuming 4 years recruitment, IDFS analysis estimated approx years from FSI Study being managed by BIG & NRG/Alliance TNBC, triple negative breast cancer; PathCR, pathologic complete response; EFS, event-free survival; DFS, disease-free survival; ER, estrogen receptor; PR, progesterone receptor; CV, coefficient of variation; BIG, Breast International Group

35 OlympiAD: Metastatic gbrcam breast cancer - Evidence of metastatic disease - gbrcam - 1st, 2nd or 3rd line - Must have received treatment with an anthracycline and a taxane in either the adjuvant or metastatic setting - Not eligible for anti-her2 therapy - Hormone-receptor-positive patients who are considered to be inappropriate for further endocrine therapy Randomise 2:1 open-label N=310 pts Olaparib 300 mg po bid daily, continuous to progression Physician s choice: Capecitabine 2500 mg/m 2 x 14 q 21 Vinorelbine 30 mg/m 2 d 1, 8 q 21 Eribulin 1.4 mg/m 2 d 1, 8 q 21 PFS PFS2 OS Primary endpoint: PFS 90% power, HR=0.64 translates to a 2.3-month improvement against a 4-month control Critical value HR=0.76 translates to a 1.3-month improvement against 4-month control PFS by RECIST (real-time central review) Supportive secondary endpoints PFS2, OS; ORR, tolerability, QoL, tumour tissue sampling on entry, optional on treatment & progression

36 Neo-Olympia: Neoadjuvant BRCAm breast cancer Arm A; 12 weeks paclitaxel 80 mg/m 2 x + olaparib 100 mg po bid Olaparib 300 mg bid (1 year) Randomisation to 3 arms gbrca TNBC following 4 cycles anthracycline + carboplatin Randomise 1:1:1 N=300 pts Arm B; 12 weeks of weekly paclitaxel 80 mg/m 2 + matched placebo Surgery PathCR rate Matched placebo (1 year) Arm C; 12 weeks olaparib 300 mg bid 12 weeks paclitaxel 80 mg/m 2 optional Arms A & B are blinded Primary endpoint: PathCR rate Supportive secondary endpoints: EFS, tolerability, QoL, mandatory tissue sampling on entry, sensitivity analysis for LOH Olaparib 300 mg bid (1 year) all