Efficacy%20of%20BSI-201,%20a%20PARP%20Inhibitor,%20in%20Combination%20with%20Gemcitabine/Carboplatin%20(GC)%20in%20Triple%20Negative%20Metastatic%20Breast%20Cancer%20(mTNBC):%20Results%20of%20a%20Phase%20II%20Study

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

• OShaughnessy 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 OShaughnessy 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 OShaughnessy 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 gt 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) lt0.0001
Median overall survival (n 59, 57) 5.7 mos 9.2 mos 0.348 (0.19-0.65) 0.0005
Source OShaughnessy J et al. ASCO 2009
Abstract 3.
5
Progression-Free Survival
100 80 60 40 20 0
BSI-201 Gem/Carbo (n 57) Median PFS 6.9 months Gem/Carbo (n 59) Median PFS 3.3 months
P lt 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 OShaughnessy J et al. ASCO 2009
Abstract 3.
6
Overall Survival
100 80 60 40 20 0
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
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 0.0002)
• ORR (48 vs 16, P 0.002)
• Median PFS (6.9 months vs 3.3 months, P lt 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 OShaughnessy 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
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.