NEPTUNE

1. NEPTUNE Taxane Chemotherapy AnthracyclineChemotherapy Surgery Radio therapy A trial for women with ‘Triple negative’ breast cancer (TNBC) Localised to breast +/- lymph nodes Recommended standard treatment involves +/- 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. Microarray classification help us understand biological differences between cancers ER-ve ER+ve HER2+ve Arrays: Separate breast cancers by gene cluster ‘Basal-like’ subgroup Adapted from Sorlie PNAS 2001

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

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

7. Few normal tissue effects Homologous recombination (HR) repair HR repair DNA repair DNA repair Base excision DNA repair BRCA1/BRCA2 deficient Tumor cells Specific tumor cell killing HR repair The IKEA principle Normal tissue cells 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

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 Progression Free Survival Overall Survival-Exploratory 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 • 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 O’Shaughnessy et al. NEJM Jan 2011

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. NEPTUNE No window Start chemo Docetaxel 4 cycles Surgery Adjuvant chemotherapy Radio therapy Randomise between 4 treatment groups Iniparib 2wk window Docetaxel + Iniparib 4 cycles Gem/Carbo 4 cycles Iniparib 2wk window Iniparib 2wk window Gem/Carbo + Iniparib 4 cycles -4 weeks 0 2 weeks 14 weeks 26-30 weeks 2 Tumour biopsies & surgery specimen 6 Blood samples • 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. NEPTUNE No window Start chemo Docetaxel 4 cycles Surgery Adjuvant chemotherapy Radio therapy Randomise between 4 treatment groups Iniparib 2wk window Docetaxel + Iniparib 4 cycles Gem/Carbo 4 cycles Iniparib 2wk window Iniparib 2wk window Gem/Carbo + Iniparib 4 cycles -4 weeks 0 2 weeks 14 weeks 26-30 weeks 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 Iniparibmonotherapy 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. How you can help us 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?