Darolutamide alone or with standard pre-surgery therapy for stage II–IIIA AR‑positive triple‑negative breast cancer.

A Phase II Neoadjuvant Clinical Trial of the Androgen Receptor Inhibitor Darolutamide in Early-Stage Androgen Receptor Positive (AR+) Triple-Negative Breast Cancer

This trial will test whether adding darolutamide to standard pre-surgery chemo‑immunotherapy helps people with stage II–IIIA androgen receptor–positive triple‑negative breast cancer.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 51 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Vanderbilt-Ingram Cancer Center (Academic / other)
• Drugs / interventions: pembrolizumab, cyclophosphamide, doxorubicin, chemotherapy, immunotherapy
• Locations: 1 site (Nashville, Tennessee)
• Trial ID: NCT07016399 on ClinicalTrials.gov

What this trial studies

This randomized phase II study compares neoadjuvant darolutamide plus standard chemotherapy and immunotherapy versus standard chemotherapy and immunotherapy alone in patients with stage II–IIIA androgen receptor–positive triple‑negative breast cancer. Patients undergo baseline and week‑2 tumor biopsies, serial blood draws for circulating tumor DNA (ctDNA), and standard imaging before surgery, with the primary endpoint the mean change in Ki‑67 proliferation index. Secondary endpoints include pathologic complete response (pCR), overall response rate (ORR), event‑free survival (EFS), and correlations of AR IHC, ctDNA, and molecular sequencing with treatment response. Exploratory analyses use whole exome sequencing, bulk RNAseq, and single‑cell RNAseq on tumor samples to study AR alterations, splice variants, and transcriptional activity.

Who should consider this trial

Good fit: Adults (≥18 years) with newly diagnosed stage II–IIIA triple‑negative breast cancer whose tumors are strongly AR‑positive (≥80% nuclear staining), with ECOG 0–1 and adequate blood counts and organ function are eligible.

Not a fit: Patients whose tumors lack high AR expression, are HER2‑positive or ER/PR‑positive (>10%), have disease outside stage II–IIIA, poor performance status, or cannot tolerate chemo/immunotherapy are unlikely to benefit.

Why it matters

Potential benefit: If effective, adding darolutamide could increase tumor shrinkage and raise the chance of a complete response before surgery, potentially improving long‑term outcomes.

How similar studies have performed: Targeting the androgen receptor in AR‑positive TNBC has produced mixed but encouraging signals in small studies, and using darolutamide in the neoadjuvant setting is a relatively new approach under active investigation.

Eligibility criteria

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

Where this trial is running

Nashville, Tennessee

• Vanderbilt University/Ingram Cancer Center — Nashville, Tennessee, United States (Recruiting)

Study contacts

• Principal investigator: Vandana G Abramson — Vanderbilt University/Ingram Cancer Center

Conditions Anatomic Stage II Breast Cancer AJCC v8; Anatomic Stage IIIA Breast Cancer AJCC v8; Triple-Negative Breast Carcinoma; Androgen Receptor-Positive; Luminal Androgen Receptor