1. www.OncologyEducation.ca Efficacy of BSI-201, a PARP-Inhibitor in combination with Gemcitabine/Carboplatin in Triple Negative Breast Cancer: Randomized Phase II trial Presented by Dr. Joyce OShaughnessey Authors: Dr. Sunil Verma Date posted: June 22 nd, 2009

2. www.OncologyEducation.ca Background Triple Negative (TN) disease represents the next frontier in Breast Cancer TN disease shares key features with Basal-like and BRCA associated cancer –BRCA dysfunction –Susceptibility to DNA damaging agents In the setting of BRCA dysfunction, the cancer cell increasingly relies on PARP for DNA repair process –This may represent an important therapeutic target

3. www.OncologyEducation.ca R Treatment A: Gemcitabine +Carboplatin Treatment B: Gemcitabine + Carboplatin + BSI-201 (a PARP – inhibitor) Triple Negative MBC

4. www.OncologyEducation.ca RESULTS Treatment A Treatment B p-value Response Rate (%) 16%48%0.002 PFS/TTP (median, mos) 3.3 m6.9 m<0.0001 OS (median, mos) 5.7 m9.2 m0.0005

5. www.OncologyEducation.ca STUDY COMMENTARY This is an important study as it shows that the addition of PARP- inhibitors to chemotherapy improves the outcome for TN MBC This is the first Phase II trial evaluating this class of drugs in MBC There is a planned Phase III trial designed to evaluate BSI-201 in combination with carboplatin+gemcitabine There are some unanswered questions related to this class of drugs: - Do PARP-Inhibitors need DNA damaging stimulus? -Will they be effective in a broader subgroup of patients? TN Non-TN - What are the long-term toxicities associated with these agents? ? Increase risk of tumorogenesis - Oral vs. IV

6. www.OncologyEducation.ca BOTTOM LINE FOR CANADIAN MEDICAL ONCOLOGISTS Triple Negative Breast Cancer is associated with poor prognosis and represents an aggressive phenotype of breast cancer. Majority of TN disease is associated with basal-like profile. Furthermore, basal-like breast cancer shares a number of features associated with BRCA related cancers TN breast cancer may particularly be sensitive to DNA damaging agents including Cisplatin and PARP inhibitors This study suggests that PARP inhibitors are efficacious for TN MBC While the results from this Phase II trial are impressive, there are still a number of unanswered questions and future trials evaluating PARP- inhibitors will help establish the magnitude of benefit and their role for early stage and advanced TN breast cancer