1. Adult participation is greater than or equal to 18 years (or older if required by regulations).
2. Participant is willing and able to participate and comply with all study requirements and to provide signed and dated informed consent prior to initiation of any study procedures.
3. Participant has histologically or cytologically confirmed breast cancer with evidence of locally advanced or metastatic breast cancer that is not amenable to curative therapy and fulfills one of the following criteria:
a. Participant with de novo advanced breast cancer (including recurrent breast cancer in participants who did not receive adjuvant endocrine therapy).
b. Participant with disease recurrence occurring after 12 months of completing adjuvant endocrine therapy (with or without CDK4/6 inhibitors).
4. Participant must have ER+, HER2 breast cancer confirmed by local laboratory testing (results from the most recent tumor tissue sample are preferred). ER and HER2 testing must be performed and documented according to the American Society of Clinical Oncology (ASCO) - College of American Pathologists (CAP) guidelines in the following
manner:
a. -CAP guidelines for ER testing 30, with or without progesterone receptor positivity, AND b. HER2 negative tumor with an immunohistochemistry result of 0 or 1+ for cellular membrane protein expression or an in-situ hybridization negative result as defined in the ASCO-CAP recommendations for HER2 testing 23.
5. Participant must have evaluable disease with one of the following:
a. Measurable disease, ie, at least one measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Aa lesion at a previously irradiated site may only be considered as a measurable lesion, for eligibility purposes, if there is a clear sign of progression since the irradiation. OR
b. If no measurable disease is present, then bone disease with at least one lytic or mixed lytic/blastic bone lesion that can be evaluated by computed tomography (CT) / magnetic resonance imaging (MRI). Participants who have had prior radiation to bone must have at least 1 evaluable lesion in a nonirradiated area.

1. Participant whose disease recurs during adjuvant endocrine therapy received for at least 24 months.
2. Participant with prior treatment with fulvestrant, elacestrant or any other investigational endocrine therapy (e.g. CERAN, SERD, proteolysis targeting chimera [PROTAC], selective estrogen receptor covalent antagonist (SERCA) in any setting.
3. Participant currently receiving or has received prior systemic anti-cancer therapy (including endocrine therapy, targeted therapy, chemotherapy or antibody drug conjugates [ADC]) for ER+, HER2- advanced breast cancer.
4. Participant with any contraindication to ribociclib and letrozole based on the local prescribing information.
5. Participant with known history of allergic reactions to any of the following agents or components of these formulations: ribociclib (or to any of its excipients), palazestrant, or letrozole, or their matching placebos.

• Oncology (Adult)

• Olema Pharmaceuticals, Inc.