HR+/HER2-breast Cancer

The goal of this clinical trial is to learn if alisertib in addition to usual care works to treat HR+/HER2+ breast cancer. The main questions it aims to answer are: * Does alisertib stop the communication between HR and HER2? * Are there genetic markers that predict how well someone's cancer will respond to alisertib? Participants will receive alisertib in addition to their usual care.

This phase II, multicenter, open-label, randomized controlled trial (FACET study) evaluates the efficacy and safety of fulvestaciclib, a novel oral CDK4/6 inhibitor, combined with anti-HER2 dual blockade (trastuzumab and pertuzumab, HP) and endocrine therapy (ET) in hormone receptor-positive (HR+) and HER2-positive advanced breast cancer (ABC). Patients with HR+/HER2+ ABC without prior systemic therapy for advanced disease are randomized in a 1:1:1 ratio into three arms, stratified by visceral metastasis status (yes vs. no) and metastatic type (de novo vs. recurrent). Arm A: After 4-8 cycles of induction chemotherapy (taxane) plus HP, patients receive fulvestaciclib + HP + ET as maintenance therapy. Arm B: After 4-8 cycles of induction chemotherapy (taxane) plus HP, patients receive HP + ET alone (without fulvestaciclib) as maintenance therapy. Arm C (exploratory): Patients receive upfront fulvestaciclib + HP + ET as first-line therapy without induction chemotherapy (chemo-free). For premenopausal/perimenopausal patients, ovarian function suppression (OFS) is added in all arms. Treatment continues until disease progression, unacceptable toxicity, withdrawal of consent, or death. The primary endpoint is investigator-assessed progression-free survival (PFS) comparing Arm A versus Arm B. Secondary endpoints include PFS (Arm A vs. Arm C), overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR), duration of response (DoR), cumulative incidence of central nervous system (CNS) metastases, safety, and patient-reported outcomes (PROs).