Abstract OT2-18-02: OlympiaN: a phase 2, multicenter, open-label study to assess the efficacy and safety of neoadjuvant olaparib monotherapy and olaparib plus durvalumab in patients with BRCA mutations and early-stage HER2-negative breast cancer

Abstract

Abstract Background: In early breast cancer (BC), neoadjuvant therapy can promote de-escalation of surgery or treat micrometastases. Pathological complete response (pCR) is a standard primary endpoint in neoadjuvant BC studies, and correlates with long-term outcomes such as event-free survival (EFS). The poly(ADP-ribose) polymerase (PARP) inhibitors olaparib and talazoparib are approved in the metastatic setting for patients with BC and a germline BRCA1 and/or BRCA2 pathogenic/likely pathogenic mutation (gBRCAm). Following the phase 3 OlympiA trial primary analysis (data cut-off [DCO] Mar 2020), the PARP inhibitor olaparib was FDA approved for the adjuvant treatment of patients with gBRCAm and HER2-negative, high-risk early BC who have been treated with neoadjuvant/adjuvant chemotherapy. At the second pre-specified OlympiA analysis (DCO Jul 2021), olaparib treatment sustained improvements in invasive disease-free survival (IDFS HR 0.63, 95% CI 0.50–0.78) and distant disease-free survival (DDFS HR 0.61, 95% CI 0.48–0.77), and also significantly reduced the risk of death (overall survival [OS] HR 0.68, 98.5% CI 0.47–0.97) vs placebo. PARP inhibitors have also shown efficacy in the neoadjuvant setting in smaller studies. Durvalumab, a programmed death-ligand 1 inhibitor, has been studied as neoadjuvant therapy in triple negative BC and showed improved IDFS, DDFS and OS vs placebo (GeparNuevo). For BRCAm carriers at low risk of recurrence, olaparib monotherapy may provide adequate neoadjuvant treatment, allowing de-escalation or omission of chemotherapy. For those at high risk of recurrence, it is hypothesized that addition of the immune checkpoint inhibitor durvalumab will enhance immunogenicity provided through cell death following PARP inhibition. Feasibility for a larger study will be assessed. Methods: OlympiaN is a phase 2, international, multicenter, open-label trial examining the efficacy and safety of neoadjuvant olaparib monotherapy and olaparib plus durvalumab in adults with deleterious/suspected deleterious BRCAm and operable, early-stage, HER2-negative, ER-negative or ER-low BC (immunohistochemistry nuclear staining < 10%). Patients will be enrolled in two cohorts: (A) patients at lower risk of recurrence: tumor size >5 to < 20 mm and nodal status N0 will receive olaparib 300 mg orally twice daily continuously in 28-day cycles; (B) patients at higher risk of recurrence: tumor size >20 to ≤50 mm and N0, or T1 and N1 will receive olaparib 300 mg orally twice daily continuously in 28-day cycles plus durvalumab 1500 mg IV infusion every four weeks. After four to six cycles, patients will undergo definitive surgery, then systemic and radiation therapy in accordance with local standard of care. Patients who achieve pCR at surgery will be able to receive adjuvant olaparib monotherapy in lieu of standard adjuvant systemic therapy for a total of twelve 28-day cycles of neoadjuvant and adjuvant olaparib therapy. The primary endpoint is the pCR rate after completion of neoadjuvant systemic therapy, assessed by central pathology review. Secondary endpoints include the pCR rate assessed by local pathology review, residual cancer burden, tumor volumetric analysis, EFS, safety and tolerability. Tumor tissue will be collected pre-treatment and at surgery to evaluate the mechanism of action of therapy. Baseline and longitudinal assessment of ctDNA and its association with clinical outcomes will also be performed. The primary pCR analysis will occur ~6 months after last participant enrollment; the final DCO will be 3 years after last participant dosed or once all participants have had an EFS event. No formal statistical analyses are planned, data will be summarized descriptively. Enrollment is planned to commence by late 2022, across ~65 sites in 10 countries; the target accrual is ~25 patients per cohort to ensure adequate precision in the estimated pCR rate. Funding: This study is funded by AstraZeneca UK Plc. Citation Format: Judith Balmaña, Mike Dymond, Elizabeth S. Lowe, Natalia Lukashchuk, Maria Winter, Nadine Tung. OlympiaN: a phase 2, multicenter, open-label study to assess the efficacy and safety of neoadjuvant olaparib monotherapy and olaparib plus durvalumab in patients with BRCA mutations and early-stage HER2-negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-18-02.