Abstract PS5-07-15: A randomized phase II study to evaluate the efficacy and safety of Trastuzumab deruxtecan (T-DXd) versus CDK4/6 inhibitor-based endocrine therapy as first-line therapy of hormone receptor-positive (HR+) and HER2-low/ultralow advan

Abstract HR-positive and HER2-negative breast cancers exhibiting non-luminal subtypes by PAM50 gene expression profiling are associated with a more aggressive clinical behaviour and reduced sensitivity to endocrine-based therapies. Trastuzumab deruxtecan (T-DXd) is a HER2-directed antibody-drug conjugate that has demonstrated to improve clinical outcomes in endocrine-resistant patients (pts) with HR+ and HER2-low/ultralow ABC as shown in the DESTINY-Breast04 and DESTINY-Breast06 phase III trials. However, there are currently no available data supporting the use of this therapy in the frontline setting.The aim of the PONTIAC study is to evaluate the safety and efficacy profiles of T-DXd compared with endocrine therapy plus a CDK4/6 inhibitor as first-line therapy in pts with HR+ and HER2-low/ultralow ABC classified as non-luminal according to PAM50 gene expression profiling. PONTIAC (NCT06486883) is an international, multicenter, open label, randomized, phase II trial.Adult pts with HR+ and centrally confirmed HER2-low (IHC 1+ or 2+ with negative in situ hybridization test) or ultralow (IHC 0 with faint membrane staining in ≤ 10% of tumor cells) ABC, classified as non-luminal by central PAM50 analysis and previously untreated for advanced disease, are eligible. Moreover, pts treated with a CDK4/6 inhibitor in the adjuvant setting with a treatment-free interval ≥ 12 months following CDK4/6 inhibitor treatment completion are allowed.Pre-screening central PAM50 analysis will be conducted in endocrine-resistant pts and in endocrine-sensitive pts who meet at least one of the following criteria: estrogen receptor expression ≤ 50% or presence of liver metastases, or high histological grade or Ki67 > 50% in the primary tumor or known non-luminal subtype as per local PAM50 analysis.Pts will be randomized 1:1 to either T-DXd (5.4 mg/kg intravenously once every 3 weeks) or endocrine therapy (fulvestrant or an aromatase inhibitor ± GnRH analogs for men and pre-/perimenopausal women) plus investigator’s choice of CDK4/6 inhibitor (palbociclib, abemaciclib, or ribociclib). Stratification factors are visceral disease (yes vs. no), PAM50 intrinsic subtype (basal-like vs. others), and HER2 protein expression (HER2-low vs. HER2-ultralow). Pts will receive study treatment until disease progression, death, unacceptable toxicity, or consent withdrawal.Primary endpoints are to assess progression-free survival (PFS) in HER2-low pts and in both HER2-low and ultralow pts (all population). Key secondary endpoints include overall survival, objective response rate, clinical benefit rate, duration of response, time to response, health-related quality-of-life, and safety and toxicity.PFS will be estimated using the Kaplan-Meier method. Stratified log-rank tests at an overall two-side significance level of 0.05 will be used to assess treatment-group differences. An interim PFS analysis with the possibility of stopping the trial for futility will be carried out when 36% of the information is available. The primary PFS endpoints will be assessed by two-sided log-rank tests in HER2-low and all pts, with 80% power to detect hazard ratios (HR) of 0.526 and 0.608, respectively. Two hundred pts (100 per arm) are needed to test the hypotheses with 80% power. Secondary endpoints including ORR, CBR, DoR, and OS will be analyzed using stratified methods with appropriate confidence intervals. Pts-reported outcomes and safety will be analyzed descriptively. Target enrollment is 200 pts, and initial patient enrollment is anticipated to begin in Q3 2025. Citation Format: J. Cortes, Á. Guerrero-Zotano, M. Gion, M. Campolier, M. Verbeni, S. Iacobucci, A. del Pino, S. Santasusagna, K. Jhaveri, A. Bardia, C. Barrios, S. Franco Millan, G. Antonarelli, S. Kümmel, P. Cottu, J. Pérez-García, A. Llombart-Cussac. A randomized phase II study to evaluate the efficacy and safety of Trastuzumab deruxtecan (T-DXd) versus CDK4/6 inhibitor-based endocrine therapy as first-line therapy of hormone receptor-positive (HR+) and HER2-low/ultralow advanced breast cancer (ABC) patients classified as non-luminal subtype according to gene expression profiling: the PONTIAC study [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 PS5-07-15.