Abstract RF5-03: 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 Background: PARP inhibitors (PARPi) are approved for the treatment of patients with early or advanced breast cancer harboring a germline pathogenic/likely pathogenic variant in BRCA1 and/or BRCA2 (gBRCAm). PARPi, including olaparib, have shown promising activity in the neoadjuvant setting, and the addition of the anti-PD-L1 antibody, durvalumab, may enhance the antitumor immune responses promoted by PARPi. The OlympiaN trial (NCT05498155) was designed to assess the efficacy and safety of neoadjuvant olaparib and olaparib plus durvalumab in stage I and stage II BRCAm HER2-negative breast cancer. Methods: Patients with early-stage BRCAm, estrogen receptor (ER)-negative or -low (≤10%) HER2-negative breast cancer received neoadjuvant olaparib 300 mg BID monotherapy (Cohort A: stage T1b-c/N0) or olaparib 300 mg BID plus durvalumab 1500 mg IV Q4W (Cohort B: stage T2/N0 or T1/N1) for 4-6 cycles, followed by surgery. The primary endpoint was pathological complete response (pCR), defined as ypT0/Tis ypN0, by independent central pathology review (ICPR). Secondary endpoints included residual cancer burden (RCB), tumor volume assessed by magnetic resonance imaging and local radiology review, safety, and tolerability. Patients with pCR by local assessment could continue olaparib post-surgery for a total of 12 cycles of treatment. Patients without pCR received radiation therapy and adjuvant treatment in accordance with local standard of care. Results: At the data cutoff of November 20, 2024, 25 patients had enrolled into Cohort A (5 T1b/N0, 20 T1c/N0; median age 46 years) and 25 had enrolled into Cohort B (all T2/N0; median age 44 years). One patient in Cohort A had a somatic BRCA1 mutation per local testing; all other patients in both cohorts had gBRCAm. In Cohort A, 23 (92%) patients completed 4-6 cycles of neoadjuvant olaparib, 1 (4%) discontinued treatment due to an adverse event (AE; grade 2 neutropenia), and 1 (4%) progressed on treatment; 24 (96%) patients underwent definitive surgery. pCR rate by ICPR was 68% (n=17/25; 95% CI, 47-85%) and 72% (n=18/25; 95% CI, 51-88%) had RCB class 0/I by ICPR. Grade ≥3 AEs occurred in 5 (20%) patients; olaparib-related grade ≥3 anemia occurred in 3 (12%) patients. No deaths occurred during the study period. In Cohort B, 21 (84%) patients completed 4-6 cycles of neoadjuvant olaparib plus durvalumab, 2 (8%) discontinued treatment due to an AE, and 2 (8%) progressed on treatment; 22 (88%) patients underwent definitive surgery with central pathological assessment. pCR rate by ICPR was 80% (n=20/25; 95% CI, 59-93%) and 84% (n=21/25; 95% CI, 64-95%) had RCB class 0/I by ICPR. Grade ≥3 AEs occurred in 6 (24%) patients; olaparib-related grade ≥3 AEs occurred in 3 (12%) patients (1 with anemia, 1 with diarrhea, and 1 with hypersensitivity leading to discontinuation in Cycle 1); 1 patient discontinued olaparib in Cycle 4 following grade 2 nausea and grade 2 dizziness; 1 (4%) had durvalumab-related grade ≥3 diabetes. No deaths occurred during the study period. Conclusions: Neoadjuvant olaparib, alone or in combination with durvalumab, demonstrated high pCR rates (68% and 80%, respectively) in patients with early-stage BRCAm, HER2-negative, ER-negative/-low breast cancer. Safety data were consistent with the known safety profiles of olaparib monotherapy and olaparib plus durvalumab combination therapy. These results encourage future research and development of PARPi therapy in the neoadjuvant setting. Citation Format: N. Tung, A. Stradella, A. Brufsky, P. A. Fasching, J. A. García-Sáenz, S. Paluch-Shimon, F. M. Henao Carrasco, A. Marquez Aragones, T.-W. Park-Simon, S. Antolin Novoa, N. Ditsch, R. Greil, M.-P. Graas, N. Harbeck, I. Pimentel, A. Schneeweiss, K.-A. Phillips, K. S. Saini, M. Dymond, X. Liu, G. Rychlik, J. Balmaña. 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 San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr RF5-03.