1. A trial for women with –‘Triple negative’ breast cancer (TNBC) –Localised to breast +/- lymph nodes –Recommended standard treatment involves NEPTUNE Taxane Chemotherapy SurgeryRadio therapy +/- Anthracycline Chemotherapy Goal is cure

2. We need to improve outcomes for women with Triple Negative breast cancer Currently no targeted treatment for this type of breast cancer which is particularly aggressive. We need to find pathways to target

3. PARP inhibitors Some tumours are less able to repair genetic damage –This seems to be an ‘Achilles heel’ for these cancers –Can be exploited by a group of drugs called PARP inhibitors. –PARP inhibitors further impair DNA repair in a way which is lethal to tumours but not to normal tissues

4. Adapted from Sorlie PNAS 2001 ER+veER-ve HER2+ve Microarray classification help us understand biological differences between cancers ‘Basal-like’ subgroup Arrays: Separate breast cancers by gene cluster

5. Sorlie PNAS 2003 BRCA1 and Basal-like/TNBC phenotypes overlap Basal-like Sub-Type BRCA1 mutated Basal Cancers

6. Key role in DNA damage Repair Implications for targeted agents- PARP BRCA 1 Normal tissue cells DNA repair DNA repair Base excision DNA repair Homologous recombinatio n (HR) repair BRCA1/BRCA2 deficient Tumor cells HR repair

7. Specific tumor cell killing HR repair Few normal tissue effects Normal tissue cells DNA repair DNA repair Base excision DNA repair Homologous recombination (HR) repair BRCA1/BRCA2 deficient Tumor cells HR repair PARP inhibitor Base excision DNA repair PARP inhibitor Base excision DNA repair HR repair Tutt and Ashworth Cold Spring Harb Symp Quant Biol 2005;70:139–148; McCabe N et al. Cancer Res 2006;66:8109–8115 The IKEA principle

8. Why PARPi for TNBC Many TNBC cancers appear to have a similarly impaired DNA damage repair to the genetic breast cancers →They may benefit from similar approaches Current and pending trials –Test strategies which exploit DNA damage –Incorporate translational research to define sensitive subsets

9. Gemcitabine/ Carboplatin ± Iniparib in metastatic TNBC O’Shaughnessy et al. NEJM Jan 2011 OS + 4.6 months HR 0.57; 95% CI 0.36-0.90 PFS + 2.3 months HR 0.59; 95% CI 0.39-0.9 Progression Free SurvivalOverall Survival-Exploratory Safety Summary No significant differences in toxicity G3/4 toxicity between GC and GCI arms Grade 3 or 4 adverse events (81% vs 86%)—mainly haematologic toxicity 14% in iniparib group and 27% in chemo-alone group discontinued treatment because of adverse events

10. NEPTUNE Investigates a PARP inhibitor called ‘iniparib’ We know iniparib works in combination with chemotherapy in metastatic TNBC –Stops damage from chemotherapy being repaired in cancer cells. –Data especially with platinum in TNBC –Safety and efficacy testing needed in early breast cancer Iniparib may also work on its own in TNBC –If this is the case could provide a ‘maintenance’ therapy

11. 2 weeks14 weeks26-30 weeks-4 weeks0 2 Tumour biopsies & surgery specimen 6 Blood samples Surgery Docetaxel + Iniparib 4 cycles Gem/Carbo 4 cycles Gem/Carbo + Iniparib 4 cycles Adjuvant chemotherapy Radio therapy Randomise between 4 treatment groups NEPTUNE Docetaxel 4 cycles No window Start chemo Iniparib 2wk window Iniparib 2wk window Iniparib 2wk window Tests the addition of iniparib to chemotherapy against standard docetaxel Iniparib 2 week ‘window’ tests for monotherapy activity Primary endpoint is pathological complete response

12. 2 weeks14 weeks26-30 weeks-4 weeks0 Surgery Docetaxel + Iniparib 4 cycles Gem/Carbo 4 cycles Gem/Carbo + Iniparib 4 cycles Adjuvant chemotherapy Radio therapy Randomise between 4 treatment groups NEPTUNE Docetaxel 4 cycles No window Start chemo Iniparib 2wk window Iniparib 2wk window Iniparib 2wk window Optional Functional Imaging Substudies PET MRI Participants would be asked to have a biopsy after these 3 scans

13. Why all these extra research assessments? Does iniparib work on its own? –To seek evidence of Iniparib monotherapy activity: ?potential maintenance role –To further understanding of how it works –Does it only work in certain patients and can we identify them early on in treatment Iniparib with chemotherapy –To further understanding of how they work together –Does it only work in certain patients and can we identify them early on in treatment Why imaging substudies? - Advantageous to future patients to have non-invasive means of showing how well treatment is working early on. But we have to prove it with matching biopsy at this stage.

14. NEPTUNE trial Your initial thoughts? Our concerns Complicated to explain very close to time of diagnosis lots of hospital visits –(up 6 visits every 3 weeks for 14 weeks, some visits will be full days) Number of research biopsies –not optional… may involve a visit to hospital specifically for a biopsy… –PET scans or MRI scans, is this too much to ask of patients? Will women sign up to an optional substudy which includes 3 or 4 of these and biopsy? How you can help us