• Participants must have histologically or cytologically confirmed invasive breast cancer with unresectable locally advanced or metastatic disease. Participants without pathologic or cytologic confirmation of metastatic disease should have unequivocal evidence of metastasis from physical examination or radiologic evaluation.

• Estrogen-receptor and progesterone-receptor expression both ≤ 5% by immunohistochemistry (IHC), and HER2-negative status as determined by the current ASCO/CAP guidelines. If a patient has more than one histological result, the most recent sample will be considered for inclusion.

• Participants must have PD-L1-negative metastatic breast cancer defined as less than 1% expression of PD-L1 on tumor-infiltrating immune cells (IC) by the PD-L1 IHC SP142 assay or a Combined Positive Score (CPS) less than 10 by the PD-L1 IHC 22C3 assay measured with standard of care testing.

• Participants must be treatment-naïve in the metastatic setting.

• Participants must have evaluable or measurable disease per RECIST 1.1. Patients with bone only disease will be allowed to participate.

• Participants must agree to undergo a research biopsy, if tumor is safely accessible, at baseline. Previously collected archival tissue will also be obtained on all participants. Tissue needs to be located and availability confirmed at time of registration (see Section 9 for more details). Participants must agree to a mandatory repeat biopsy 3-6 weeks after starting treatment, if tumor is safely accessible.

• Prior chemotherapy: Participants must have received no prior chemotherapy for metastatic breast cancer and must have discontinued all chemotherapy at least 28 days prior to study treatment initiation. No prior irinotecan or topoisomerase I-containing antibody drug conjugates in the metastatic or neo/adjuvant setting are allowed. All toxicities related to prior chemotherapy must have resolved to CTCAE v5.0 grade 1 or lower, unless otherwise specified per protocol, except alopecia can be any grade and neuropathy can be grade 2 or lower.

• Prior biologic therapy: Patients must have received no prior biologic therapy for metastatic breast cancer and discontinued all biologic therapy at least 28 days prior to study treatment initiation. All toxicities related to prior biologic therapy must have resolved to CTCAE v5.0 grade 1 or lower, unless otherwise specified per protocol.

• Prior radiation therapy: Patients may have received prior radiation therapy. Radiation therapy must be completed at least 7 days prior to study treatment initiation, and all toxicities related to prior radiation therapy must have resolved to CTCAE v5.0 grade 1 or lower, unless otherwise specified per protocol. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.

• Previously treated brain metastases are permitted, with the following provisions:

‣ Prior SRS should complete ≥ 7 days before study treatment initiation

⁃ Prior WBRT should complete ≥ 7 days before study treatment initiation.

⁃ Any corticosteroid use for brain metastases must have been discontinued for ≥ 7 days prior to study treatment initiation.

• The subject is ≥ 18 years old.

• ECOG performance status 0-1 (Karnofsky \> 60%, see Appendix A).

• Participants must have normal organ and marrow function as defined below:

‣ Absolute neutrophil count ≥1,000/mcL

⁃ Platelets ≥100,000/mcL

⁃ Hemoglobin ≥ 9.0 g/dl

⁃ INR/PT/aPTT ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is in therapeutic range of anticoagulant

⁃ Total bilirubin ≤1.5 × institutional upper limit of normal (ULN)(or ≤2.0 x ULN in patients with documented Gilbert's Syndrome)

⁃ AST(SGOT)/ALT(SGPT) ≤2.5 × institutional ULN or ≤5 × institutional ULN for participants with documented liver metastases

⁃ Serum creatinine ≤1.5 × institutional ULN OR creatinine clearance ≥ 30 mL/min/ 1.73m2 for participants with creatinine levels above institutional ULN.

• Female subjects of childbearing potential must have a negative serum or urine pregnancy test within 2 weeks prior to study treatment initiation. Childbearing potential is defined as participants who have not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause) and have not undergone surgical sterilization (removal of ovaries and/or uterus).

• Women of childbearing potential (WOCBP) must agree to use an adequate method of contraception. Contraception is required starting with the first dose of study medication through 180 days (6 months) after the last dose of study medication. Examples of contraceptive methods with a failure rate of \< 1% per year include bilateral tubal ligation, male sterilization, established and proper use of hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.

• Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of study treatment with pembrolizumab and 3 months after the last dose of study treatment

• Participants on bisphosphonates or RANK ligand inhibitors may continue receiving therapy during study treatment and also may initiate therapy with these agents on study if clinically indicated.

• The participant must be capable of understanding and complying with the protocol and willing to sign a written informed consent document.