1. 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)

2. 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.

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.

4. 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 ( )
<0.0001
Median overall survival (n = 59, 57)
5.7 mos
9.2 mos
0.348
( )
0.0005
Source: O’Shaughnessy J et al. ASCO 2009; Abstract 3.

5. Progression-Free Survival
100 80 60 40 20
BSI Gem/Carbo (n = 57)
Median PFS = 6.9 months
Gem/Carbo (n = 59)
Median PFS = 3.3 months
P <
HR = (95% CI, )
PFS (%)
PFS Months
Source: O’Shaughnessy J et al. ASCO 2009; Abstract 3.

6. Survival Probability (%)
Overall Survival
100 80 60 40 20
BSI Gem/Carbo (n = 57)
Median OS = 9.2 months
Gem/Carbo (n = 59)
Median OS = 5.7 months
Survival Probability (%)
P =
HR = (95% CI, )
OS Months

7. 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 = )
ORR (48% vs 16%, P = 0.002)
Median PFS (6.9 months vs 3.3 months, P < )
Median OS (9.2 months vs 5.7 months, P = )
Planned phase III study of GC + BSI-201 in mTNBC
Source: O’Shaughnessy J et al. ASCO 2009; Abstract 3.

8. 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)

9. 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.

10. 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.