Abstract OT2-01-15: PARTNER - Randomised, phase II/III trial to evaluate the safety and efficacy of the addition of olaparib to platinum-based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients
Authors: Abraham JE , Vallier A-L , Qian W , Grybowicz L , Thomas S , Mahmud S , Harvey C , McAdam K , Hughes-Davies L , Roylance R , Copson E , Brown J , Provenzano E , Tischkowitz M , Earl HM 
Published: March 2017

Background: Triple Negative Breast Cancers (TNBC) are a biologically diverse and aggressive sub-group. Early effective treatment can lead to cure. Current standard treatment is systemic chemotherapy either pre-/post-definitive surgery. No specific targeted therapies are available for TNBC. There are phenotypic and molecular similarities between germline BRCA (gBRCA) breast cancer and TNBC. In TNBC 10%-20% harbour gBRCA mutations. In gBRCA patients, and potentially other homologous recombination deficiencies, these already compromised pathways allow drugs called PARP inhibitors (olaparib) to work particularly effectively.

Aims: To establish if the addition of olaparib to neoadjuvant platinum-based chemotherapy for TNBC and/or gBRCA breast cancer is safe and improves efficacy.

Trial design: 3-stage open label randomised phase II/III trial of neoadjuvant olaparib +/- platinum containing chemotherapy followed by clinicians' choice of anthracycline regimen. Stage 1 and 2, patients are randomised (1:1:1) to either control (3 weekly carboplatin AUC5/weekly paclitaxel 80mg/m2 chemotherapy - 4 cycles) or one of two research arms which uses the same chemotherapy regimen but with two different schedules of olaparib 150mg BD). Stage 3: patients are randomised (1:1) to either control arm or to the research arm selected in stage 2.

Primary outcome measures:

Stage 1: safety of the addition of olaparib to chemotherapy. Prophylactic G-CSF is mandatory.

Stage 2: pathological complete response (pCR) in each of the two research arms. At the end of stage 2, one of the research arms will be dropped.

Stage 3: pCR at surgery after neoadjuvant treatment. pCR - defined as no residual invasive carcinoma within the breast (ductal carcinoma in situ permitted) AND no evidence of metastatic disease within the lymph nodes.

Eligibility:

•Aged 16 to 70.

•Written informed consent.

•Histologically confirmed invasive breast cancer.

•Clinical stage T1-4 N0-2 (tumour or metastatic node diameter&gt;10mm)

•Confirmed ER-negative and HER2-negative or gBRCA mutation positive, irrespective of hormone status.

•Performance Status 0-1

Statistical Methods: Stage 1, Safety: both research arms combined. Stage 2, Schedule selection criteria: pCR rate and completion rate of olaparib protocol treatment. It is a “pick-the winner” design with 53 patients in each research arm. This allows a 90% power, 5% one-sided significance level to test null hypothesis of pCR ≤35% versus an alternative hypothesis of pCR ≥55% in each of the research arms.

Stage 3, Efficacy: anticipated pCR ∼45-55% for all trial patients and ∼50-60% for gBRCA patients. The trial is powered to detect an absolute improvement of 15% (all patients) and 20% (gBRCA patients) by adding olaparib to chemotherapy (enriched design). TNBC patient recruitment will be capped, to ensure the required number of gBRCA patients are enrolled. Enrichment design is applied with the overall significance level 0.05(α)=0.025(αall)+ 0.025(αgBRCA) and 80% power.

Present accrual: 1 [Trial opened: 23rd May 2016]

Target accrual: 527 (TNBC 307; gBRCA 220)

Contact information: Dr. Jean Abraham; Email: ja344@medschl.cam.ac.uk.

Citation Format: Abraham JE, Vallier A-L, Qian W, Grybowicz L, Thomas S, Mahmud S, Harvey C, McAdam K, Hughes-Davies L, Roylance R, Copson E, Brown J, Provenzano E, Tischkowitz M, Earl HM. PARTNER - Randomised, phase II/III trial to evaluate the safety and efficacy of the addition of olaparib to platinum-based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT2-01-15.