Abstract PO4-19-11: A Multicenter, Phase Ib/II Study of Abemaciclib in Combination with Bicalutamide for Androgen Receptor-positive, HER2-negative Metastatic Breast Cancer
Authors: Casasanta Nicole , Landry Chrystal , Shao Theresa , Klein Paula , Fasano Julie , Bhardwaj Aarti , Berger Natalie , Moshier Erin , Joshi Gargi Atul , Vaccaro Rita , Sparano Joseph , Tiersten Amy 
Published: May 2024

Abstract
Background The androgen receptor (AR) is expressed in approximately 30% of breast cancers. Phase I and II trials of bicalutamide in HR-negative and enzalutamide in both triple negative breast cancer (TNBC) and hormone receptor (HR) positive populations have shown safety and favorable clinical benefit rates (CBR). Additionally, cell cycle (CC) inhibitors, such as abemaciclib, have demonstrated improved progression free survival (PFS) for patients with HR-positive metastatic breast cancer (MBC) in combination with ET in the first line and subsequent lines of therapy. A preclinical study showed that anti-androgen therapies enhanced CKD4/6 induced cytostatic effect in AR-positive TNBC cell lines. We performed a retrospective, institutional study evaluating metastatic HR+ tumor samples with immunohistochemistry (IHC) from patients treated with CDK4/6 inhibitor, palbociclib. We found a statistically significant increase in event free survival (EFS) for those that had any expression of AR (&gt;0%, median EFS 19 months vs 5 months, HR 0.26, p=0.01). Additionally, AR expression was associated with intact phosphorylated retinoblastoma (Rb) expression (100%, P=0.02), which may represent a mechanism by which CC inhibition is effective in AR+ MBC.
Trial Design NCT 05095207 is an ongoing, Phase Ib/II, open label, multi-center study. The primary objective for the phase I portion is to determine the recommended phase II dose (RP2D) of abemaciclib in combination with bicalutamide. The primary objective for the phase II portion is to determine the disease control rate (DCR) at 6-month treatment with abemaciclib and bicalutamide. Patients with HER2-negative MBC who are AR+ (IHC &gt;1%) are eligible. HR-positive participants must have had one prior line of ET in the metastatic setting and no more than 2 prior lines of cytotoxic chemotherapy. HR-negative participants may have had up to 4 prior lines of cytotoxic chemotherapy.
In the Phase I portion, up to 12 patients are given abemaciclib 100 mg oral, twice daily on days 1 to 28 and bicalutamide 150 mg oral, daily on days 1 to 28. If there is no toxicity after cycle 1 for the first 3 patients, the dose of abemaciclib will increase to 150 mg twice daily. However, if there is a dose limiting toxicity (DLT) within the first cycle (28 days) of therapy, the dose will decrease to 50 mg twice daily. In the Phase II portion, 51 patients will receive abemaciclib at the RP2D twice daily in addition to bicalutamide 150 mg daily on days 1 to 28. The estimated study duration is 36 months. The drugs will be administered until disease progression or unacceptable toxicity.
The primary end points include the DLT and the RP2D for abemaciclib administered with bicalutamide and the DCR at 6 months. The secondary end points include the frequency of adverse effects, the DCR stratified by HR status, and PFS. Exploratory endpoints are to determine whether Ki67, cyclin D1, p16, and phosphorylated Rb expression at baseline are predictors of response to abemaciclib and to determine potential mechanisms for resistance to treatment.
For Phase Ib, we will utilize the Bayesian optimal interval (BOIN) design, the RP2D will be selected as the dose closest to the target toxicity rate of 0.3. The observed DLT rate at the current dose is ≤ 0.236, the next cohort will be treated at the next higher dose level, if it is ≥ 0.359 the next cohort will be treated with the next lower dose level. For Phase II, we will assess the DCR using a Simon 2 stage optimal design. If among the 46 evaluable patients, 12 or fewer achieve disease control, the treatment will be rejected, however if 13 or more have disease control, the treatment will be considered worthy for further study. We define inactivity as DCR of 0.20 and activity as DCR of 0.35. To date, the study has recruited 21 participants, the goal accrual is 60 patients.
Citation Format: Nicole Casasanta, Chrystal Landry, Theresa Shao, Paula Klein, Julie Fasano, Aarti Bhardwaj, Natalie Berger, Erin Moshier, Gargi Atul Joshi, Rita Vaccaro, Joseph Sparano, Amy Tiersten. A Multicenter, Phase Ib/II Study of Abemaciclib in Combination with Bicalutamide for Androgen Receptor-positive, HER2-negative Metastatic Breast Cancer [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 PO4-19-11.