Alisertib Plus Endocrine Therapy Is Under Evaluation in HR+/HER2-Negative Metastatic Breast Cancer

The ongoing phase 2 ALISCA-Breast1 study (NCT06369285) is evaluating the efficacy, safety, and optimal dose of alisertib (MLN8237) in combination with endocrine therapy in patients with hormone receptor (HR)–positive, HER2-negative recurrent or metastatic breast cancer previously treated with at least 2 lines of endocrine therapy.1

Alisertib is a second-generation, oral, small molecule designed to selectively inhibit the Aurora A kinase (AURKA) with potential antineoplastic activity.2 AURKA inhibition can lead to abnormal spindle formation, mitotic defects, and cell death.1

“AURKA is a key regulator of mitosis, and increased AURKA expression has been associated with poor prognosis in multiple tumor types,” lead study author Pooja P. Advani, MBBS, MD, of Mayo Clinic in Jacksonville, Florida, and colleagues wrote in a trial-in-progress poster presentation given at the 42nd Annual Miami Breast Cancer Conference.

Previously reported data from the phase 2 TBCRC041 trial (NCT02860000), which evaluated alisertib alone and in combination with fulvestrant (Faslodex) in patients with endocrine-resistant metastatic breast cancer, the overall response rates (ORRs) were 19.6% for alisertib monotherapy and 20% for alisertib plus fulvestrant. The median progression-free survival (PFS) was 5.4 months and 5.6 months, respectively.

Regarding safety, the most common grade 3 or higher adverse effects (AEs) reported during TBCRC041 included neutropenia, anemia, and leukopenia.

ALISCA-Breast1 Enrollment Criteria and Design

Eligible patients must be at least 18 years of age with HR-positive/HER2-negative recurrent or metastatic breast cancer not amenable to curative therapy. Participants must have experienced disease progression on or after at least 2 prior lines of endocrine therapy in the recurrent or metastatic setting, including 1 that included a CDK4/6 inhibitor. Notably, metastatic recurrence within 6 months of completing adjuvant endocrine therapy counted as 1 line of prior therapy. Metastatic recurrence on or within 6 months of discontinuing adjuvant CDK4/6 inhibitor plus endocrine therapy also meets eligibility requirements.

Other key inclusion criteria included measurable disease per RECIST 1.1 criteria, an ECOG performance status of 0 or 1, and adequate hematologic, renal, and hepatic function. Patients need to be naive to the investigator-selected endocrine therapy for the recurrent or metastatic setting, and they must be willing to provide tumor tissue for retrospective biomarker analysis.

Key exclusion criteria include prior chemotherapy for recurrent or metastatic disease; bone-only disease that does not meet RECIST 1.1 criteria; major surgery within 28 days before randomization; and prior treatment with an AURKA-specific or pan-Aurora–targeted agent, including alisertib. Patients with symptomatic or untreated central nervous system (CNS) metastases, active infections requiring systemic treatment, uncontrolled symptomatic visceral disease, significant chronic gastrointestinal disorders affecting oral drug absorption, or uncontrolled cardiac disease are also excluded.

Patients enrolled in ALISCA-Breast1 are being randomly assigned 1:1:1 to receive oral alisertib at 50 mg twice per day (n = 50), 40 mg twice per day (n = 50), or 30 mg twice per day (n = 50). In each arm, the experimental drugs is being administered on days 1 to 3, 8 to 10, and 15 to 17 of each 28-day cycle. In each arm, alisertib is being combined with an investigator-selected endocrine therapy, including anastrozole, exemestane, fulvestrant, letrozole, or tamoxifen. Treatment is continuing until disease progression, unacceptable toxicity, or patient withdrawal.

The primary end point is to determine the optimal dose of alisertib in combination with endocrine therapy, based on the incidence of AEs and serious as graded per NCI CTCAE v5.0.

Secondary end points include ORR, duration of response (DOR), disease control rate (DCR), PFS, and overall survival (OS). The study will also evaluate biomarker correlations with efficacy outcomes and update the pharmacokinetic profile of alisertib.

Recruitment is ongoing at an estimated 50 sites across the United States and Europe with a planned sample size of 150 patients. An interim analysis for safety and efficacy will be conducted after approximately 75 patients have completed at least 2 tumor assessments or experienced documented disease progression. The estimated study duration is approximately 56 months.

References

1. Advani P, Braga S, Brufsky A, et al. ALISertib in combination with endocrine therapy in patients with hormone receptor-positive, HER2-negative recurrent or metastatic breast cancer: the phase 2 ALISCA-Breast1 study. Presented at: 42nd Annual Miami Breast Cancer Conference. March 6-9, 2025; Miami Beach, FL. Poster 105.
2. Alisertib. National Cancer Institute. 2025. Accessed March 10, 2025. https://www.cancer.gov/publications/dictionaries/cancer-drug/def/alisertib