Background: HR+/HER2− advanced breast cancer that progresses on endocrine therapy is treated with chemotherapy (chemo). The phase 1b KEYNOTE-028 trial showed durable activity with pembrolizumab (pembro) monotherapy in previously treated HR+/HER2−, PD-L1–positive (combined positive score [CPS] ≥1) advanced breast cancer. KEYNOTE-B49 (NCT04895358) is a phase 3, randomized, double-blind study of pembro + chemo vs placebo (pbo) + chemo in centrally assessed PD-L1–positive, HR+/HER2− locally recurrent inoperable or metastatic breast cancer (mBC) after progression on prior endocrine therapy. Methods:∼800 patients (pts) with HR+/HER2− locally recurrent inoperable or mBC who are candidates for chemo (no prior chemo for metastatic disease) with PD-L1 CPS ≥1 and documented progression on prior endocrine therapy will be enrolled. Prior endocrine therapy comprises ≥2 lines (≥1 in combination with a CDK4/6 inhibitor) in the metastatic setting or 1 line with CDK4/6 inhibitor treatment for mBC in pts who had a relapse within 24 mo of primary surgery. Pts without prior CDK4/6 inhibitor treatment may enroll if they had progressed within 6 mo of starting endocrine therapy for metastatic disease and had previously relapsed within 24 mo of primary tumor surgery while on adjuvant endocrine therapy. Pts are randomized 1:1 to receive pembro 200 mg IV or pbo Q3W, each in combination with investigator’s choice of chemo: paclitaxel 90 mg/m² IV on days 1, 8, and 15 Q4W; nab-paclitaxel 100 mg/m² IV on days 1, 8, and 15 Q4W; liposomal doxorubicin 50 mg/m² IV on day 1 Q4W; or capecitabine 1000 mg/m² PO BID on days 1–14 Q3W. Randomization is stratified by tumor PD-L1 (CPS 1–9 vs ≥10), presence of visceral metastases (yes vs no), and chemo on-study (taxanes vs liposomal doxorubicin vs capecitabine). Treatment is continued until disease progression, unacceptable toxicity, withdrawal, or, for pembro/pbo, completion of 35 cycles (̃2 years); chemo can be continued per investigator discretion. Tumor PD-L1 status is determined centrally using the PD-L1 IHC 22C3 pharmDx assay (Agilent Technologies; Carpinteria, CA, USA). Radiologic assessments are performed Q9W for 54 wk and then Q12W thereafter. AEs occurring from randomization until 30 d after treatment discontinuation (90 d for serious AEs) are graded per NCI-CTCAE v 5.0. Primary endpoints are PFS per RECIST v1.1 by BICR and OS in pts with PD-L1 CPS ≥10 and ≥1 tumors, separately. Enrollment is ongoing at 204 international sites. Clinical trial information: NCT04895358.