Efficacy of BSI-201, a PARP Inhibitor, in Combination with Gemcitabine/Carboplatin (GC) in Triple Negative Metastatic Breast Cancer (mTNBC): Results of a Phase II Study O’Shaughnessy J et al. American Society of Clinical Oncology 2009; Abstract 3. (Plenary Presentation)

Introduction BRCA1/2-deficient cells: highly sensitive to PARP inhibition Triple-negative breast cancer (TNBC) share clinical and pathologic features with hereditary BRCA1-related BC P53 mutations, lack of ER, PR, HER2 Basal gene expression patterns Sensitivity to DNA damaging agents Gemcitabine/carboplatin (GC) Preclinical evidence of synergy Cause inter-strand DNA cross-links and double-strand DNA breaks Response rates: 21 to 53% in mBC PARP inhibitors augment cytotoxicity of platinums Inhibit base excision repair that removes platinum adducts BSI-201: oral small molecule PARP1 inhibitor Source: O’Shaughnessy J et al. ASCO 2009; Abstract 3.

Phase II Randomized Trial Gemcitabine (1000 mg/ m2 IV d1,8) + Carboplatin (AUC 2 IV d 1, 8) q21 days Eligibility mTNBC with measurable disease 0-2 prior chemotherapy regimens for mBC R BSI-201 (5.6 mg/kg IV D1, 4, 8, 11) Gemcitabine (1000 mg/ m2 IV d1,8) + Carboplatin (AUC 2 IV d 1, 8) q21 days Source: O’Shaughnessy J et al. ASCO 2009; Abstract 3.

Results: Efficacy (N = 116) GC GC + BS-201 HR (95% CI) P value Objective response rate (n = 44, 42) 16% 48% — 0.002 Clinical benefit rate (CR + PR + SD > 6 mos) (n = 44, 42) 21% 62% 0.0002 Median progression-free survival (n = 59, 57) 3.3 mos 6.9 mos 0.342 (0.20-0.58) <0.0001 Median overall survival (n = 59, 57) 5.7 mos 9.2 mos 0.348 (0.19-0.65) 0.0005 Source: O’Shaughnessy J et al. ASCO 2009; Abstract 3.

Progression-Free Survival 100 80 60 40 20 BSI-201 + Gem/Carbo (n = 57) Median PFS = 6.9 months Gem/Carbo (n = 59) Median PFS = 3.3 months P < 0.0001 HR = 0.342 (95% CI, 0.200-0.584) PFS (%) 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 PFS Months Source: O’Shaughnessy J et al. ASCO 2009; Abstract 3.

Survival Probability (%) Overall Survival 100 80 60 40 20 BSI-201 + Gem/Carbo (n = 57) Median OS = 9.2 months Gem/Carbo (n = 59) Median OS = 5.7 months Survival Probability (%) P = 0.0005 HR = 0.348 (95% CI, 0.189-0.649) 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 OS Months

Summary and Conclusions PARP1 was upregulated in most TNBC evaluated (N = 50) No differences in hematologic or non-hematologic toxicities or GC dose reductions between study arms Addition of BSI-201 improved clinical outcomes Clinical benefit rate (62% vs 21%, P = 0.0002) ORR (48% vs 16%, P = 0.002) Median PFS (6.9 months vs 3.3 months, P < 0.0001) Median OS (9.2 months vs 5.7 months, P = 0.0005) Planned phase III study of GC + BSI-201 in mTNBC Source: O’Shaughnessy J et al. ASCO 2009; Abstract 3.

Phase II Trial of the Oral PARP Inhibitor Olaparib in BRCA-Deficient Advanced Breast Cancer Tutt A et al. American Society of Clinical Oncology 2009; Abstract CRA501. (Clinical Science Symposium Presentation)

Trial Design Confirmed BRCA1 or 2 mutation Eligibility Confirmed BRCA1 or 2 mutation Stage IIIB/C or IV BC after failure ≥ 1 prior chemo for advanced disease (Non-randomized sequential cohorts) Cohort 2* Olaparib 100 mg po bid 28-day cycles Cohort 1 Olaparib 400 mg po bid (MTD) 28-day cycles * Following an interim review, patients in the 100 mg bid cohort were permitted to crossover to receive 400 mg bid Source: Tutt A et al. ASCO 2009; CRA501.

Summary and Conclusions First report of targeted therapy trial for patients with BC and BRCA1/2 mutations Single-agent oral olaparib 400 mg bid has substantial activity in heavily pretreated BRCA1/2 carriers with advanced BC Objective response rate ITT (RECIST): 41% Median PFS: 5.7 months Well tolerated Clinical proof-of-concept for targeting breast cancers in patients with BRCA1/2 mutations Source: Tutt A et al. ASCO 2009; CRA501.