Abstract PO4-19-01: The SURVIVE-HERoes trial – a secondary adjuvant treatment intervention study with trastuzumab-deruxtecan in patients with HER2 positive/HER2 low early breast cancer and a molecular relapse, based on a positive ctDNA result

Abstract Background: Despite current adjuvant treatment strategies, ≥ 20% of patients with early breast cancer (EBC) experience a metastatic relapse. In the new era of highly effective antibody drug conjugates (ADCs), secondary adjuvant treatment options for EBC patients at a high risk of relapse arise. The ADC trastuzumab-deruxtecan (T-DXd) has so far shown promising efficacy in patients with HER2-positive and HER2-low metastatic breast cancer (DESTINY Breast 03 and -04 trial) and is currently tested in the post-neoadjuvant setting in patients with non-pCR (DESTINY Breast 05 (TRUDY) trial). However, to successfully apply ADCs as a secondary adjuvant treatment, identification of patients who would benefit the most is required. The detection of minimal residual disease (MRD) using liquid biopsy, e.g. ctDNA, may offer a promising approach for patient selection. The efficacy of such a secondary adjuvant treatment in terms of delaying or even preventing distant metastases has yet to be evaluated in a randomized clinical trial. Trial design: The SURVIVE-HERoes trial is a prospective, randomized, open label comparative Phase III superiority trial in patients with intermediate to high-risk HER2-positive or HER2-low EBC, who participate in the large breast cancer surveillance trial SURVIVE (NCT05658172) and experience a molecular relapse as determined by a positive ctDNA result, but show no evidence of relapse or metastatic disease based on imaging by CT-scan and SPECT. In total, 180 patients will be enrolled and randomized with 2:1 allocation to treatment with T-DXd + (only endocrine therapy, if HR positive) versus standard of care (including endocrine treatment +/- CDK4/6-inhibitors or Neratinib). The treatment period lasts 12 months during which ctDNA levels will be repeatedly measured every 3 months (additional ctDNA testing will be performed at month 24 and 36). Stratification factors are HER2-, hormonal- and nodal status. Recruitment start is planned for Q1 2024. Eligibility criteria: Eligible patients are adult females/males, with HER2-positive or HER2-low EBC, as defined in the ASCO-CAP guidelines, and a positive ctDNA result (obtained in the SURVIVE study) that has to be confirmed ≤ 8 weeks before randomization. Primary anti-tumor therapy (surgery, adjuvant chemo- or radiotherapy) has to be completed ≥14 months, (postneo)-adjuvant treatment with anti-HER2-antibodies, T-DM1, Capecitabine, Pembrolizumab and Olaparib ≥ 4 weeks before randomization. Adequate bone marrow and cardiac function and no signs of ILD are mandatory. Statistics: The primary objective of SURVIVE-HERoes is the comparison of ctDNA clearance rates 6 months after randomization between the two study arms, which will be analysed using the chi square test for two independent proportions. Secondary objectives include the comparison of overall survival (OS), invasive disease-free survival (IDFS), distant disease-free survival (DDFS), distant recurrence-free survival (DRFS), breast cancer specific survival (BCSS), invasive breast cancer free survival (IBCFS) and quality of life (QoL) between the study arms as well as the safety and tolerability of T-DXd. Secondary survival endpoints will be estimated by the Kaplan Meier method and compared between the randomization arms using log-rank tests and cox regression models. Special aims: This trial is a proof of principle study with the aim to establish the efficacy of secondary adjuvant treatment with the ADC T-DXd in patients with HER2-positive/HER2-low early breast cancer, who are at high risk of relapse, as evidenced by detection of ctDNA in the blood. Conclusion: If SURVIVE-HERoes is successful, it could lead to a treatment shift towards early intervention with secondary adjuvant targeted therapies following liquid-biopsy based MRD detection. Contact: University Hospital Ulm, Dpt. Obstetrics & Gynecology, Germany, mail: studienzentrale.ufk@uniklinik-ulm.de Citation Format: Sophia Huesmann, Franziska Mergel, Kerstin Pfister, Angelina Fink, Forca Mehmeti, Peter Möller, Tanja Fehm, Volkmar Müller, Klaus Pantel, Thomas Friedl, Andreas Hartkopf, Brigitte Rack, Wolfgang Janni. The SURVIVE-HERoes trial – a secondary adjuvant treatment intervention study with trastuzumab-deruxtecan in patients with HER2 positive/HER2 low early breast cancer and a molecular relapse, based on a positive ctDNA result [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-19-01.