Abstract PS5-02-26: A phase I/II, single arm, non-randomized study of ribociclib, a CDK 4/6 inhibitor, in combination with bicalutamide, an androgen receptor inhibitor, in advanced AR-positive triple-negative breast cancer: A Big Ten Cancer Research

Abstract Background: Triple-negative breast cancer (TNBC) is a heterogenous disease encompassing different intrinsic molecular subtypes. Outcomes remain poor for those with advanced disease despite recent advancements in immunotherapy and antibody-drug conjugates. The androgen receptor (AR) is a luminal nuclear hormone steroid receptor in the same family as the estrogen receptor and progesterone receptor. Although dependent on assay and cutoff used, about 25-35% of TNBC have AR protein expression detectable by immunohistochemistry (IHC). Preclinical data suggest the luminal androgen receptor (LAR) molecular subtype of TNBC is dependent on AR signaling and is particularly susceptible to CDK 4/6 inhibition. Thus, AR has emerged as a therapeutic target via androgen blockade in AR+ TNBC. We hypothesized that the combination of ribociclib, a CDK 4/6 inhibitor, and bicalutamide, an androgen receptor inhibitor, will demonstrate clinical benefit for patients with advanced AR+ TNBC. Methods: In this single arm, non-randomized phase I/II study, patients with AR+ TNBC were treated with combination ribociclib and bicalutamide. AR+ was defined as >0% in phase I and ≥10% in phase II. Up to 3 prior lines of systemic therapy for metastatic disease were allowed. Dose escalation was by 3+3 design with fixed bicalutamide at 150 mg daily and ribociclib (1) 400 mg QD on days 1-21, (2) 400 mg on days 1-28, and (3) 600 mg on days 1-21. A Simon two stage design was utilized with a planned total of 25 patients, including phase I patients treated at the recommended phase II dose (RP2D). The primary efficacy endpoint was clinical benefit rate (CBR) at 16 weeks. Secondary objectives were progression free survival (PFS), objective response rate (ORR), overall survival (OS), duration of response (DOR), and safety/tolerability. Additionally, a circulating tumor cell (CTC) AR gene signature was explored. The study was concluded early due to low enrollment. Results: 21 patients were enrolled. Median age was 56 (range 37-75 yrs) and all patients were female. 76% of patients were non-Hispanic white, 19% Black, and 5% unknown. AR positivity was between 2-95%. In the phase I dose escalation, the RP2D was determined to be the standard doses of each agent: ribociclib 600 mg daily on days 1-21 of the 28-day cycle and bicalutamide 150 mg daily. Of the 19 patients with available adverse event data, the most common treatment-emergent adverse events included: leukopenia 79% (47% grade 3), neutropenia 74% (47% G3, 16% G4), lymphopenia 47% (11% G3), fatigue 47%, thrombocytopenia 37% (11% G3), anemia 37% (5% G3), nausea 37%, AST elevation 26% (5% G3), ALT elevation 21%, constipation 21%, hot flashes 21%, creatinine elevation 16%. Two patients experienced a grade 3 infection: one with urinary tract infection and one with skin infection. 18/21 patients were evaluable for efficacy, which included both the phase I and phase II cohorts. The CBR at 16 weeks was 27% (5/18 patients, 95% CI [0.097, 0.535]; p-value 0.0481). There was a PR in 1 patient. OS, PFS, ORR, and DOR will be presented, as well as efficacy in patients treated at RP2D. AR-V7 was detected in baseline CTC samples in 2 out of the first 11 patients in the cohort, neither of whom achieved disease control at 16 weeks. CTC analysis for the remaining patients is ongoing and will be reported. Conclusions: Although the study did not complete accrual, there were 5 patients with AR+ TNBC treated with ribociclib and bicalutamide combination therapy who achieved disease control at 16 weeks. Further, the AR V7 CTC gene signature may be an emerging biomarker of treatment response to AR and CDK 4/6 inhibition. Future investigation of biomarkers beyond tissue AR IHC staining could be investigated to improve patient selection. Citation Format: J. Knight-Shefner, R. M. O'Regan, E. Sampene, O. Danciu, K. Hoskins, M. E. Burkard, M. T. West, V. Carreno, I. Fernandez, K. B. Wisinski, M. N. Sharifi. A phase I/II, single arm, non-randomized study of ribociclib, a CDK 4/6 inhibitor, in combination with bicalutamide, an androgen receptor inhibitor, in advanced AR-positive triple-negative breast cancer: A Big Ten Cancer Research Consortium 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 PS5-02-26.