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

PRIMARY OBJECTIVE:

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

SECONDARY OBJECTIVES:

I. 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.

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

EXPLORATORY OBJECTIVES:

I. 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.

V. 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.

Inclusion criteria

• Signed and dated written informed consent as well as the ability to understand and the willingness to sign written consent prior to study registration
• Male or female ≥ 18 years of age on the day of signing informed consent
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Histologically confirmed newly diagnosed breast cancer with the following requirements:

• <10% staining for estrogen receptor (ER) and progesterone receptor (PR) by immunohistochemistry (IHC)
• HER2 negative by fluorescence in situ hybridization (FISH)
• AR positive: defined as ≥ 80% staining for AR by IHC
• Primary tumor clinically or radiographically ≥ 1cm in size or stage II-IIIA and eligible for neoadjuvant treatment
• Absolute neutrophil count (ANC) ≥ 1500/µL (≤ 28 days prior to first dose of protocol-indicated treatment)
• Platelets ≥ 100,000/µL (≤ 28 days prior to first dose of protocol-indicated treatment)
• Hemoglobin ≥ 9.0 g/dL or ≥ 5.6 mmol/L (≤ 28 days prior to first dose of protocol-indicated treatment)
• Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min (as calculated by the Cockcroft-Gault Formula or calculated/measured by an alternative established institutional standard consistently applied across participants at the site) (≤ 28 days prior to first dose of protocol-indicated treatment)
• Total bilirubin ≤ 1.5 times institutional upper limit of normal (ULN), or direct bilirubin ≤ ULN for participants with total bilirubin > 1.5 x ULN (≤ 28 days prior to first dose of protocol-indicated treatment)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) ≤ 2.5 times institutional upper limit of normal (ULN) (≤ 28 days prior to first dose of protocol-indicated treatment)
• Calcium ≤ 11.5 mg/dL or ≤ 2.9 mmol/L; in patients with albumin outside the normal range, calcium (corrected for albumin) must be ≤ 11.5 mg/dL or ≤ 2.9 mmol/L (≤ 28 days prior to first dose of protocol-indicated treatment)
• Women must not be breastfeeding and further agree to not breastfeed during study treatment and for at least 120 days after completion of treatment
• A woman of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test during screening within 21 days prior to receiving first dose of protocol-indicated treatment, and must agree to follow instructions for using acceptable contraception from the time of signing consent, and until at least 120 days after completion of treatment
• Men must refrain from donating sperm for at least 120 days after completion of treatment
• A man able to father children who is sexually active with a WOCBP must agree to follow instructions for using acceptable contraception, from the time of signing consent, and until at least 120 days after completion of treatment

Exclusion criteria

• Non-resectable breast cancer as assessed by the primary treating surgeon or evidence of metastatic disease
• Malignancies other than TNBC within 5 years prior to randomization, with the exception of those with a negligible risk of metastases or death and treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix or basal or squamous cell skin cancer)
• Patient is pregnant or breastfeeding
• Patients with moderate hepatic impairment (Child-Pugh Class B cirrhosis or higher)
• Is currently participating in or within four weeks prior to receiving first dose of study treatment in a study of an investigational agent or investigational device

• Participants who have entered the follow-up phase of an investigational study may participate as long as it has been four weeks after the last dose or last exposure to the previous investigational agent or investigational device
• Recipient of previous allogeneic tissue/solid organ transplant
• Known severe hypersensitivity (≥ Grade 3) to study drug, pembrolizumab, carboplatin, doxorubicin/epirubicin, paclitaxel, or cyclophosphamide and/or any of the excipients of these drugs
• History of myocarditis or pericarditis or other known underlying heart disease that is clinically significant by investigator judgment (for example, cardiomyopathy, congestive heart failure with New York Heart Association [NYHA] functional classification III or IV, symptomatic arrhythmia not controlled by medication, unstable angina, history of acute myocardial infarction). History of cerebrovascular accident (including transient ischemic attack [TIA]) within the past six months (24 weeks) prior to starting study treatment
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection/sepsis, or psychiatric illness/social situations that would limit compliance with study requirements
• Known conditions that would preclude the use of checkpoint inhibitors