Abstract 4693: A Phase 1b study of BYL719 (Alpelisib) in combination with androgen receptor inhibitor (enzalutamide) in patients with androgen receptor (AR)-positive and PTEN-positive metastatic breast cancer
Authors: Karuturi Meghan , Fuji Takeo , Ueno Naoto 
Published: March 2024

Abstract
Background: Novel combination therapies treatment of Hormone Receptor (HR)+/HER2- metastatic breast cancer, with a high incidence of AR expression, remains to be a priority in modern-day clinical trials. The PI3K pathway, a crucial regulator of cell processes, has been closely linked to AR signaling, with the interplays between the AR and PI3K pathways leading to emerging interest in exploring combination that target both pathways. Several studies have hinted at concordance between AR expression and PI3K pathway aberrations in breast cancer. therapies.
Methods: We conducted a phase 1b clinical trial of BYL719 in combination with enzalutamide for patients with AR-positive (defined as ≥ 1% of nuclear staining) , PTEN-positive (defined as &gt;0% of nuclear staining), HER2-negative metastatic breast cancer (MBC). The primary objective was to determine the recommended dose of the 2 drugs for a phase II study (RP2D), in addition to the toxicity/safety profile of the combination. A conventional 3+3 dose escalation design was applied.
Results: A total of 18 patients were enrolled, with 17 ultimately treated (12 in dose-finding and 5 in dose-expansion). The median age was 57 (28-77 y/o). Two of the 17 were classified as having metastatic TNBC, and the remainder ER and/or PR+ MBC. Patients received a median of 2 prior endocrine therapies (range 0-5) and a median of 2 prior chemotherapies (range 0-4). Dose-limiting toxicities (DLTs) established a dose of BYL719 of 200 mg in combination with enzalutamide 160 mg. 4 patients experienced DLTs at the higher dose of BYL719 of 250 mg PO daily (4 with a maculopapular rash ranging from grade 1-3, 1 additionally with allergic reaction and lung infection categorized as grade 3). Three patients experienced SAEs, 2 at a higher dose of BYL 719 (fever, maculopapular rash, infection, allergic reaction) and 1 at the 200 mg dose, thought to be unrelated. The most common AEs attributed to enzalutamide included anemia (6 total, 3 grade 3, 3 grade 2), headache (6 total, 4 grade 1, 2 grade 2), and nausea (6 total, 3 grade 1, 3 grade 2). The most common AEs attributed to alpelisib included diarrhea (8 total, 5 grade 1, 2 grade 2, 1 grade 3), hyperglycemia (14 total, 7 grade 1, 4 grade 2, 3 grade 3) and rash (7 total, 1 grade 2, 6 grade 3). Clinical benefit rate was observed at 16 weeks, 6.7% partial response, 26.7% stable disease, and 60% progressive disease. Overall survival in the total cohort was 19.4 month (95% CI 4.11-NA), with a median time to progression of 2.07 months (95% CI 1.81-NA).
Conclusions: The Phase 1b study of BYL719 in combination with enzalutamide provides valuable insights into the safety and tolerability of the combination in AR/PTEN-positive MBC, including RP2D. Further studies are needed to evaluate their treatment efficacy fully.
Citation Format: Meghan Karuturi, Takeo Fuji, Naoto Ueno. A Phase 1b study of BYL719 (Alpelisib) in combination with androgen receptor inhibitor (enzalutamide) in patients with androgen receptor (AR)-positive and PTEN-positive metastatic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4693.