Title: 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
1Efficacy 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)
2Introduction
- 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.
3Phase 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.
4Results 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.
5Progression-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.
6Overall 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
7Summary 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.
8Phase 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)
9Trial 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.
10Summary 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.