The purpose of this study is to determine the safety and efficacy of PF-07220060 with letrozole compared to approved treatments (ie, palbociclib, ribociclib or abemaciclib with letrozole) in people with breast cancer:

• HR-positive (breast cancer cells that need estrogen or progesterone to grow)
• HER2-negative (cells that have a small amount or none of a protein called HER2 on their surface);
• locally advanced (that has spread from where it started to nearby tissue or lymph nodes) or metastatic disease (the spread of cancer to other places in the body)
• who have not received any prior systemic anti-cancer treatment for advanced/metastatic disease.

Approximately half of the participants will receive PF-07220060 plus letrozole while the other half of participants will receive the investigator's choice of treatment plus letrozole.

The study team will monitor how each participant is doing with the study treatment during regular visits at the study clinic.

Inclusion Criteria:

• Histological confirmation of breast cancer with evidence of locally advanced or metastatic disease, which is not amenable to surgical resection or radiation therapy with curative intent.
• Documented estrogen receptor (ER) and/or progesterone receptor (PR)-positive tumor
• Documented HER2-negative tumor
• Previously untreated with any systemic anticancer therapy for their locally advanced or metastatic disease.
• Measurable disease or non-measurable bone only disease as defined by RECIST version 1.1

Exclusion Criteria:

• In visceral crisis at risk of immediately life-threatening complications in the short term.
• Current or past history of central nervous system metastases.
• Have received prior (neo)adjuvant endocrine therapy (ET) and had recurrence during or within 12 months after the last dose of ET.
• Have received prior (neo)adjuvant CDK4/6i and had recurrence during or within 12 months after the last dose of CDK4/6i.
• Inadequate renal function, hepatic dysfunction, or hematologic abnormalities.

Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical\_trials/trial\_data\_and\_results/data\_requests.