Onapristone Extended-Release, Letrozole, and Palbociclib for the Treatment of Unresectable or Metastatic Estrogen Receptor Positive, Progesterone Receptor Positive, HER2 Negative Breast Cancer

Inclusion Criteria

• Histologically confirmed ER+, PR+, HER2- metastatic or unresectable breast cancer * PR positivity is defined as >= 1% expression by immunohistochemistry (IHC) on fresh or archival tumor tissue * Tissue samples obtained, stained, and interpreted outside of Memorial Sloan Kettering Cancer Center (MSKCC) will be accepted * Those patients who do not have adequate/accessible archival tissue available and for whom biopsy is not a significant risk procedure may be required to consent to pretreatment biopsy
• Completed at least 6 months (+/- 4 weeks) of first-line letrozole/palbociclib without radiological progression or unresolved toxicity * Patients who underwent dose reduction of palbociclib to 100 mg daily or 75 mg daily will be eligible if: ** The dose reduction was implemented >= 4 weeks prior to enrollment ** Patients have demonstrated resolution of all acute toxic effects of prior therapy to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) (Version 5.0) grade =< 1
• ctDNA-positive, defined as: * Presence of a tumor-derived somatic mutation in the peripheral blood using the Memorial Sloan Kettering (MSK)-Analysis of Circulating cfDNA to Evaluate Somatic Status (ACCESS) assay after 6 months of letrozole/palbociclib (+/- 4 weeks); at least one mutation should have a variant allele fraction of >= 0.5%
• Completed MSK Integrated Mutation Profiling of Actionable Cancer Targets (IMPACT) testing from primary or metastatic tissue
• Radiologically evaluable or measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
• Age >= 18 years
• Pre-menopausal patients are eligible as long as they are on gonadotrophin releasing hormone (LHRH) agonist for at least four weeks prior to starting trial therapy and commit to continue LHRH agonist for as long as patient is receiving trial therapy or medical contraindications arise
• Eastern Cooperative Oncology Group performance status (ECOG) of 1 or Karnofsky performance status (KPS) of >= 70%
• Women of child-bearing potential: * Must have a negative pregnancy test within 14 days prior to commencement of study treatment * Agreement to remain abstinent (refrain from heterosexual intercourse) or use nonhormonal contraceptive methods with a failure rate of < 1% per year during the treatment period and for 120 days after the last dose and agreement to refrain from donating eggs during this same period * Note: for women with therapy-induced amenorrhea, baseline measurements of follicle stimulating hormone (FSH) and/or estradiol are needed to ensure menopausal status
• Absolute neutrophil count >= 1.2K/uL (within 14 days prior to initiation of study treatment)
• Hemoglobin >= 9 g/dL (within 14 days prior to initiation of study treatment)
• Platelet count >= 100,000/uL (within 14 days prior to initiation of study treatment)
• Total bilirubin >= 1.5 x upper limit of normal (ULN)
• Serum albumin >= 2.5 g/dL
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) >= 2.5 x ULN
• Serum creatinine >= 1.5 x ULN or creatinine clearance >= 50 mL/min on the basis of the Cockcroft-Gault glomerular filtration rate estimation
• International normalized ratio (INR) >= 1.5 x ULN and activated partial thromboplastin time (aPTT) >= 1.5 x ULN * For patients requiring anticoagulation therapy with warfarin, a stable INR between 2-3 is required. If anticoagulation is required for a prosthetic heart valve, then stable INR between 2.5-3.5 is permitted
• At least 4 weeks post-op from any major surgical procedure
• Patients with asymptomatic brain metastases which have been treated with surgery or radiation and demonstrate stability for >= 3 months will be allowed
• Able to swallow tablets whole, without crushing

Exclusion Criteria

• Radiologic disease progression while on treatment with letrozole and palbociclib in the first line prior to enrollment
• History of another invasive malignancy (other than non-melanoma skin cancer or curatively treated in situ carcinoma) with evidence of disease within the past 3 years
• Any psychological, familial, sociological or geographic condition that would potentially hinder compliance with the study protocol
• Known untreated or symptomatic brain metastasis
• Uncontrolled hypertension (systolic blood pressure [BP] >= 160 mmHg or diastolic BP >= 95 mmHg) despite medical treatment. Patients with a history of hypertension are allowed provided blood pressure is controlled by anti-hypertensive treatment
• Clinically significant heart disease as evidenced by myocardial infarction or arterial thrombotic event within the past 6 months, severe or unstable angina, or New York Heart Association (NYHA) class II-IV heart disease or cardiac ejection fraction measurement of < 50% at baseline
• Screening electrocardiogram (ECG) with rate-corrected (using Friderica’s correction) QT interval (QTcF) of > 480 msec or a history of cardiac arrhythmias
• Refractory nausea and vomiting, requirement for parenteral hydration and/or nutrition, drainage gastrostomy tube, malabsorption, external biliary shunt, or significant small bowel resection that would preclude adequate study drug absorption
• Is pregnant or breastfeeding, and/or expecting to conceive within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment
• Current use of estrogen or progesterone products including intrauterine and implantable contraceptive devices
• Anticipated or ongoing administration of anti-cancer therapies other than those administered in this study
• Active hepatitis B (hepatitis B surface antigen [HBsAg] positive or hepatitis B virus deoxyribonucleic acid [DNA] >= 1 x 10^3 copy/ml) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)
• Use of any prescription medication within 28 days prior to onapristone dosing that the investigator judges is likely to interfere with onapristone activity; specifically, strong inhibitors or inducers, or sensitive substrates of cytochrome P450 CYP3A4. Examples include phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital, and St. John’s wort