351TiP - EORTC BCG 1984 – NOBLE: Noeoadjuvant olaparib and durvalumab for patients with BRCA-associated triple-negative breast cancer

Background

The standard of care for patients with early triple-negative breast cancer (TNBC) is neoadjuvant chemotherapy followed by surgery. Recently, immune checkpoints inhibitors (ICI) added to neoadjuvant chemotherapy have shown efficacy. Among TNBC, BRCA mutations and other homologous recombination deficiency (HRD) signals are relatively frequent. As opposed to other types of breast cancer, HRD TNBC show a high neoantigen load, a large number of tumour infiltrating lymphocytes (TILs), and a high PD-L1 expression. In BRCA/HRD breast cancer, PARP inhibitors (PARPi) exhibit a distinct anticancer activity. In addition, they show immunomodulatory effects by promoting PD-L1 expression and DNA damage, increasing neoantigen load. Chemotherapy-free regimens combining PARPi and ICI result in promising synergistic activity as shown in the metastatic setting, supporting investigation in the neoadjuvant setting.

Trial design

NOBLE is an EORTC phase 2, randomized, multicentre, open label, clinical trial. It includes a minimax Simon's two-stage design with an early feasibility step. Eligible patients must have early TNBC harbouring a tumoral (t)BRCA1/2 mutation, or another HRD signal based on methylation. Following central screening for tumoral BRCA/HRD (Institute Curie, 455 patients), 152 patients will be randomized between olaparib vs olaparib and durvalumab for 4 cycles of neoadjuvant treatment. Thereafter, patients will undergo surgery. All patients will be followed-up to 2 years (y) after surgery. The trial will be conducted in 3 steps (screening/randomization): Step 1 – Feasibility (60/20): to assess the central testing failure rate, the turn-around time for central testing and the prevalence of tBRCA/HRD; Step 2 (193/64) – Futility; and Step 3 (202/152) – Expansion of recruitment. The primary endpoint is the rate of pathologic complete response at the time of surgery, defined as ypT0/is ypN0. Secondary endpoints are response based on RECIST v1.1, surgery rate, 2-y event-free-survival, 2-y overall survival, safety, and quality of life. The study is expected to be activated in early autumn 2023 and the primary endpoint will be available approximately 5 years after the screening of the first patient.

Clinical trial identification

EudraCT 2022-003594-33. NCT05209529.

Editorial acknowledgement

Legal entity responsible for the study

EORTC.

Funding

EORTC is the legal sponsor of the study. AstraZeneca provided an educational grant.

Disclosure

C. Callens: Financial Interests, Institutional, Advisory Board: AstraZeneca. E.G.C. Brain: Financial Interests, Personal, Invited Speaker, Webinars, optimized endocrine therapy for older breast cancer patients: Eli Lilly; Financial Interests, Personal, Advisory Board, Palbociclib and older breast cancer patients: Pfizer; Financial Interests, Personal, Invited Speaker, Symposium HER2+ MAO conference 03/21: SEAGEN; Financial Interests, Personal, Invited Speaker, ELEVATE 10/2021 and ABC 11/2021 meeetings: Pfizer; Financial Interests, Personal, Other, IDMC DESTINY 05: DAIICHI; Financial Interests, Personal, Advisory Board, GCSF and FN in older patients: SANDOZ; Financial Interests, Personal, Advisory Board, Underserved Patients Populations with breast cancer, advisory board: Pfizer; Financial Interests, Personal, Invited Speaker, Management of older patients with cancer, series of seminars in Canada for HCP: Pfizer; Financial Interests, Institutional, Coordinating PI, APPALACHES study EORTC 1745: Pfizer; Financial Interests, Institutional, Coordinating PI, TOUCH study (IBCSG 55/GERICO study): Pfizer; Financial Interests, Institutional, Local PI, DEESTINY 09: DAIICHI; Financial Interests, Institutional, Local PI, DESTINY 06: Daiichi; Financial Interests, Institutional, Local PI, SERENA 06: AstraZeneca; Financial Interests, Institutional, Coordinating PI, AMEERA 6: Sanofi. All other authors have declared no conflicts of interest.