Neoadjuvant Darolutamide Alone or in Combination With Standard Therapy for Stage II-IIIA, AR+, TNBC

PRIMARY OBJECTIVE:

1. To compare the mean ΔKi-67 level between the darolutamide therapy arm and the control arm.

SECONDARY OBJECTIVES:

1. To determine the pathologic complete response rate (pCR) and overall response rate (ORR) in patients on the darolutamide and control arms.

II. To determine event-free survival (EFS) in patients with androgen receptor positive (AR+) breast cancer in both arms.

III. To correlate the change in Ki-67 at 2 weeks and 6 months with pCR rates and EFS in patients with AR+ breast cancer in both arms.

IV. To monitor circulating tumor deoxyribonucleic acid (ctDNA) throughout treatment and correlate with response in both arms.

1. To correlate percent of nuclear AR positivity with pCR and EFS in both arms.

EXPLORATORY OBJECTIVES:

1. To determine if patients with triple-negative breast cancer (TNBC) experience changes in ctDNA levels while undergoing neoadjuvant therapy.

II. To assess if changes in ctDNA levels correlate with response to neoadjuvant therapy observed in breast cancer tissue biopsies/surgical specimens.

III. To identify AR amplification and ligand binding mutations by whole exome sequencing and evaluate AR transcription targets and AR splice variants by ribonucleic acid sequencing (RNAseq) in baseline, week 2 and residual disease of patients on the darolutamide arm.

IV. To evaluate cell populations and AR transcriptional activity by single-cell RNAseq (scRNAseq) using baseline, week-2 biopsies and residual disease from patients on the darolutamide arm.

1. To assess tumor microenvironment changes in hormone receptors and immune cell populations by multiple immunofluorescences using the CO-Detection by indEXing (CODEX) platform.

VI. To evaluate AR-independent mechanisms of resistance to AR inhibitors using in vitro models for the discovery phase and human tissue for validation studies.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1 of each cycle, paclitaxel IV on days 1, 8, and 15 of each cycle, and carboplatin IV on days 1, 8, and 15 of each cycle. Cycles repeat every 21 days for up to 4 cycles (cycles 1-4) in the absence of disease progression or unacceptable toxicity. Then, patients receive pembrolizumab IV over 30 minutes, cyclophosphamide IV, and doxorubicin IV or epirubicin IV on day 1 of subsequent cycles. Cycles repeat every 21 days for up to an additional 4 cycles (cycles 5-8) in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo surgery on study, as well as ultrasound (US) or magnetic resonance imaging (MRI), blood sample collection, and breast biopsies throughout the study.

ARM B: Patients receive darolutamide orally (PO) twice daily (BID) for 14 days in the absence of disease progression or unacceptable toxicity. Patients then receive darolutamide PO BID, pembrolizumab IV over 30 minutes on day 1 of each cycle, and paclitaxel IV on days 1, 8, and 15 of each cycle, and carboplatin IV on days 1, 8, and 15 of each cycle. Cycles repeat every 21 days for up to 4 cycles (cycles 1-4) in the absence of disease progression or unacceptable toxicity. Then, patients receive pembrolizumab IV over 30 minutes, cyclophosphamide IV, and doxorubicin IV or epirubicin IV on day 1 of subsequent cycles. Cycles repeat every 21 days for up to an additional 4 cycles (cycles 5-8) in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo surgery on study, as well as US or MRI, blood sample collection, and breast biopsies throughout the study.

After completion of study treatment, patients are followed up after 30-37 days, at 6 months, 12 months, then yearly for up to 5 years.