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Inclusion Criteria:

1. Age ≥ 18 years and \< 72
2. Patients with histologically confirmed locally advanced unresectable or metastatic, PD-L1 negative (CPS \<10), gBRCA-negative TNBC who received first-line ADC treatment and experienced disease progression and have sent 200mg (approximately) of tumor tissue (fresh tissue immersed in AllProtect then frozen) to BreakBio for analysis.
3. Must have measurable disease per RECIST v1.1 (at least one non-nodal lesion ≥10 mm in longest diameter and/or pathologic lymph node(s) ≥15 mm in short axis on CT/MRI) on imaging obtained within 21 days of first dose of treatment combination.
4. Must not have experienced progression during the induction chemotherapy cycles.
5. Eastern Cooperative Oncology Group (ECOG) performance status = 0 or 1 on day of first dose
6. Patient has adequate organ function on day one of the trial as defined by:

   * Neutrophil to Lymphocyte Ratio (NLR)1 at a healthy adult's normal level: ≤ 3.5
   * Absolute Neutrophil Count (ANC) at the normal level: ≤ 7,000/mm3
   * Absolute Lymphocyte Count in normal level: ≥ 1,000/mm3
   * Monocytes at normal level: \< 700/mm3
   * Platelet count: ≥ 100 x 109/L (without transfusion support in the last two weeks)
   * Hemoglobin: \> 10.0 g/dL (without transfusion support in the last two weeks)
   * AST and ALT: ≤ 3 X institutional upper limit of normal (ULN) in the absence of liver mets; AST and/or ALT may be ≤ 5 x ULN in the setting of liver metastases
   * Total Bilirubin: ≤ 1.2mg/dL
   * Serum creatinine: ≤ 1.5 x institution's ULN
   * Albumin: ≥ 3.4 g/dL
   * Serum Magnesium: ≥ 1.7 mg/dL
   * Pulse oximetry ≥ 95% on room air
7. Provision of consent for on-treatment biopsy (compulsory) and post-treatment biopsy (optional).
8. Both male and female patients enrolled in this trial must agree to use effective contraception during the course of the trial and for at least 3 months after discontinuing study treatment. Patients and/or partners who are surgically sterile or postmenopausal are exempt from this requirement.
9. Negative pregnancy test ≤ 7 days prior to day one of cycle 1, for women of childbearing potential only.
10. Life expectancy \> 6 months
11. Willing and able to provide informed consent

Exclusion Criteria:

1. Prior exposure to anti PD- 1/PD-L1 agents.
2. Prior exposure to immunosuppressive therapy within the last 12 months prior to enrollment
3. Receiving or previously receiving oral or IV steroids within 6 weeks of starting study treatment. Currently using or previously used topical steroids within 6 weeks of starting study treatment. Expected to require steroid-containing pre-meds before chemotherapy doses.
4. Patients with deficient mismatch repair (dMMR) or microsatellite instability (MSI-H) phenotype.
5. Any liver metastasis greater than 2 cm or greater than 5 liver metastases. Patients who have liver metastasis removed by surgery, and therefore meet this criterion at first dose, may enroll.
6. Patients not recovered from all clinically significant toxic effects of previous therapies to ≤Grade 1 or baseline with the exception of peripheral neuropathy and alopecia.
7. Patients not recovered adequately from the toxicity and/or complications from any major surgery prior to starting study treatment.
8. Known or suspected hypersensitivity to any of the study drugs
9. Received an investigational agent within 28 days prior to the first dose of study drug.
10. History of myocarditis or congestive heart failure (as defined by New York Heart Association Functional Classification III or IV), as well as unstable angina, serious uncontrolled cardiac arrhythmia, uncontrolled infection, or myocardial infarction within the past 6 months. Note: Prior to trial entry, any ECG abnormality at screening must be documented by the investigator as not medically relevant.
11. LVEF \<50%
12. Active interstitial lung disease (ILD)/pneumonitis or a history of ILD/pneumonitis requiring treatment with systemic steroids.
13. Untreated, symptomatic, or progressing brain/CNS metastases; leptomeningeal disease; or prior whole-brain radiation. CNS metastases are allowed only if treated and stable on MRI for ≥8 weeks, the patient has recovered from CNS therapy, and has been off steroids for ≥12 weeks.
14. Known history of Hepatitis B (defined as Hepatitis B surface antigen \[HBsAg\] reactive) or known active Hepatitis C virus (defined as HCV RNA \[qualitative\] is detected) infection. Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority. (Individuals who are hepatitis C antibody positive may be enrolled if negative viral load confirmed).
15. History of autoimmune disease including: inflammatory bowel disease (including ulcerative colitis and Crohn's Disease), rheumatoid arthritis, systemic progressive sclerosis (scleroderma), systemic lupus erythematosus, autoimmune vasculitis (e.g. Wegener's granulomatosis); central nervous system or motor neuropathy considered of autoimmune origin (e.g. Guillain-Barré syndrome, myasthenia gravis, multiple sclerosis). Individuals with vitiligo, Sjogren's Syndrome, interstitial cystitis, Graves' or Hashimoto's Disease, celiac disease, DM1, hypothyroidism stable on hormone replacement, or any autoimmune disease without symptoms and not requiring active therapy for at least 2 years will be allowed with Study Medical Monitor's approval.
16. A serious local infection (e.g. cellulitis, abscess) or systemic infection (e.g. pneumonia, septicemia) which requires systemic antibiotic treatment within 4 weeks prior to the first dose of study medication.
17. Receiving coumarin-derived anticoagulants.
18. Unable or unwilling to withhold or discontinue any prohibited or restricted medications/ procedures for the specified windows during the study.
19. Inability or refusal to comply with the protocol or with the clinical trial procedures
20. If female, pregnant or breastfeeding. All female patients with reproductive potential must have a negative pregnancy test prior to starting treatment.
21. Chronic intake of drugs that lead to known interference with metabolism through strong Cytochrome P450 3A4 (CYP3A4) interaction: e.g. Rifampicin, Rifabutin, Clarithromycin, Telithromycin, Ketoconazole, Itraconazole, Fluconazole, Hypericum perforatum (St. John's Wort /Johanniskraut) or any strong CYP3A4 inducing or inhibiting drug (Note: participants in this study should avoid consuming grapefruit or grapefruit-containing products during the duration of the study, including the screening phase, treatment period, and follow-up period.)
22. Uncontrolled hypertension defined as persistent systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg despite current therapy.
23. Arterial thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks) within 6 months before the start of study medication. Active pulmonary emboli or deep vein thrombosis that are significant or not adequately controlled on anticoagulation regimen
24. Any hemorrhage or bleeding event ≥ National Cancer Institute - Common terminology criteria for adverse events (NCI-CTCAE) Grade 3 within 28 days prior to the start of study medication
25. History of other invasive cancer within 2 years prior to enrollment, except for treated non-melanoma skin cancer
26. Known DNA Polymerase Epsilon (POLE) mutations

• Miami, Florida, United States