This neoadjuvant trial for patients with TNBC and/or gBRCA breast cancer, aims to investigate the safety and efficacy (improvement in pathological Complete Response at surgery) of concurrent platinum-based chemotherapy with olaparib an inhibitor of the PARP enzyme (PARPi).
Aged between 16 and 70.
Written informed consent, willing and able to comply with the Protocol for the duration of the trial including undergoing treatment and scheduled visits and examinations.
Histologically confirmed invasive breast cancer.
ER-negative*, and HER2-negative** breast cancer (TNBC). Patients will be eligible with any PR status but PR expression must be scored.
T0 tumour in absence of axillary node >10mm.
TNBC with a non-basal phenotype which strongly expresses Androgen Receptor.
Previous or concomitant chemotherapy or biological agents used for the treatment of cancer in the last 5 years.
Malignancy within the last 5 years except: adequately treated non-melanoma skin cancer; curatively treated in situ cancer of the cervix; ductal carcinoma in situ (DCIS); Stage 1, grade 1 endometrial carcinoma; or other solid tumours including lymphomas (without bone marrow involvement) curatively treated with no evidence of disease for ≥5 years.
Parallel
Olaparib
DrugPatients will self-administer Olaparib by mouth. Olaparib tablets should be taken twice daily at the same time each day approximately 12 hours apart.
Paclitaxel and Carboplatin
DrugPaclitaxel I.V. 80mg/m2 in 0.9% sodium chloride 500ml or according to local practice, will be given over 60 minutes on days 1, 8 \& 15, every 3 weeks for 4 cycles. Carboplatin I.V. AUC5 in 5% dextrose 500ml or according to local practice, over 30-60minutes on day 1 every 3 weeks for 4 cycles.
Stage 1 - Number of participants with treatment-related adverse events as assessed by NCI CTCAE v4.03.
Primary outcome measure - safety of the addition of olaparib to three weekly carboplatin/weekly paclitaxel chemotherapy.
Stage 2 - pCR rate and completion rate of Olaparib treatment as per protocol.
Primary outcome measure - pCR in each of the two research arms. At the end of stage 2, one of the research treatments will be dropped using the 'pick the winner' method.
Stage 3 - Efficacy analysis based on pCR at surgery. To be assessed by central review of pathology reports.
Primary outcome measure - pCR at surgery after neoadjuvant treatment. pCR rates after neoadjuvant chemotherapy +/- olaparib, defined as no residual invasive carcinoma within the breast (Ductal Carcinoma in situ permitted) AND no evidence of metastatic disease within the lymph nodes.
pCR at surgery - assessed by review of histopathology slides
pCR at surgery assessed by central pathology review of the diagnosis and surgery slides.
PARTNERing Pathway
For those patients who still have residual disease after receiving neoadjuvant chemotherapy there is the opportunity to receive a further two cycles of Duralumab and AZD6738. Durvalumab I.V will be administered on cycle 1, day 1 and cycle 2, day 1. AZD6738 will be self administered by patients by mouth twice a day for 7 days beginning on cycle 1, day 22 and cycle 2, day 22.
Relapse-Free Survival (RFS)
Relapse Free Survival (RFS), calculated from date of randomisation to date of first relapse or date of death from all causes, whichever occurs first.
Breast cancer specific survival (BCSS)
Breast cancer specific survival (BCSS), calculated from date of randomisation to date of death from breast cancer.
Discovery and validation of markers that can be correlated with outcomes (pCR and RFS).
Discovery and validation of prognostic, pharmacogenetic and pharmacogenomic markers that can be correlated with outcomes (pCR and RFS) in patients randomised to received olaparib compared with those who are not.
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Cambridge University Hospitals NHS Foundation Trust
Lead sponsor
University of Cambridge
Sponsor institution
AstraZeneca
Collaborator
Cancer Research UK
Collaborator
