Abstract PS4-06-15: Safety Run-In Phase of the ATRiBRAVE trial: a Phase II Study Evaluating Ceralasertib Priming Followed by Durvalumab/Nab-Paclitaxel to Restore Immunotherapy Sensitivity in Advanced Triple Negative Breast Cancer (TNBC)

Abstract Background: Preclinical studies have reported that Ataxia telangiectasia and Rad3-related (ATR) inhibition results in increased nuclear envelope fragility and promotion of cGAS-STING activation, thus potentially resulting in an enhanced immune response. The phase II investigator-initiated ATRiBRAVE trial evaluates the efficacy of the ATR inhibitor ceralasertib priming followed by durvalumab-nab-paclitaxel in patients with TNBC relapsing after immune checkpoint inhibitors (ICIs) and chemotherapy (CT) treatment in the curative setting.This report presents results from the safety run-in phase (SRP) of the trial, representing the first assessment of the safety and feasibility of the triple combination of ceralasertib, durvalumab and nab-paclitaxel in human. Methods: This single-arm trial enrolls patients with unresectable/metastatic TNBC (ER<10% HER2-), previously treated with ICIs and CT in the early setting (adjuvant, neoadjuvant or both) and not previously treated in the metastatic setting. Treatment consists of: Ceralasertib 240mg orally BID (DL 0) for 7 days before cycle 1, then days 22-28 of each cycle (with planned dose de-escalation if needed), Durvalumab 1500 mg IV, day 1 (q28), Nab-paclitaxel 100mg/m2 IV, days 1, 8, 15 (q28). Treatment continues until disease progression or unacceptable toxicity. Primary endpoint of the study: Progression-free survival (PFS). Study sample size: 37 patients (34 evaluable patients + 10% drop-out) SRP design: a SRP with a 3+3 de-escalation schema was preplanned in the study to assess safety. If fewer than 2 dose-limiting toxicities (DLTs) occur in the first 6 patients at DL 0, SRP is successfully completed. Otherwise, ceralasertib will be de-escalated to 160 mg BID (DL-1) and, if necessary, to 120 mg BID (DL-2). Results: Up to date, 18 patients have been enrolled in the study, 9 of which were treated in the SRP (3+6). Among the first 3 patients, 2 DLTs (prolonged neutropenia leading to significant dose omissions) were observed, prompting ceralasertib reduction to 160 mg BID (DL-1). No DLTs were observed in the first 6 (3+3) patients at DL-1 (ceralasertib 160 mg BID for 7 days), thus successfully completing SRP. Among patients treated in the SRP, no grade 5 AEs occurred. All grade 3-4 AEs observed were hematologic but did not qualify as DLTs. No patients discontinued treatment due to toxicity during SRP. Durvalumab safety profile was consistent with previous reports. Conclusions: Ceralasertib priming at a 160 mg BID for 7 days, followed by durvalumab and nab-paclitaxel, is feasible and well tolerated. Nine additional patients have already been enrolled in the phase II portion of the trial (total enrolment: 18 patients) and patient enrolment is currently ongoing. Updated safety data for patients who completed treatment in the study will be presented at the meeting. This study was funded by Fondazione AIRC under 5 per mille 2019 (ID. 22759 program—group leader VG and SM). This study was conducted with the unconditional support of AstraZeneca. Citation Format: V. Guarneri, G. Griguolo, C. Vernieri, M. Dieci, Y. Silvestri, F. Giovanardi, F. Ligorio, G. Fotia, S. Rapisarda, A. Chirco, A. Zambelli, M. De Laurentiis, A. Gennari, S. Marsoni, S. Piccolo, M. Foiani. Safety Run-In Phase of the ATRiBRAVE trial: a Phase II Study Evaluating Ceralasertib Priming Followed by Durvalumab/Nab-Paclitaxel to Restore Immunotherapy Sensitivity in Advanced Triple Negative Breast Cancer (TNBC) [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 PS4-06-15.