This is a Phase 1b open-label, 2-part study in 3 treatment groups. The 3 treatment groups are as follows:

Treatment Group 1: Palazestrant (OP-1250) in combination with ribociclib (KISQALI®, Novartis Pharmaceuticals Corporation).

Treatment Group 2: Palazestrant (OP-1250) in combination with alpelisib (PIQRAY®, Novartis Pharmaceuticals Corporation).

Treatment Group 3: Palazestrant (OP-1250) in combination with everolimus.

Treatment Group 4: Palazestrant (OP-1250) in combination with atirmociclib.

Part 1 (Dose Escalation): This part will evaluate the safety and pharmacokinetics of a range of doses of palazestrant administered orally (PO) daily to subjects in combination with 600 mg of ribociclib administered PO daily for 21 consecutive days followed by 7 days off treatment (Treatment Group 1) or with 300 mg or 250 mg of alpelisib administered PO daily (Treatment Group 2) or with everolimus 10 mg administered PO daily (Treatment Group 3) and determine the RP2D (Recommended Phase 2 Dose) for each treatment group. Part 1, for Treatment Group 4, will evaluate the safety and pharmacokinetics of OP-1250 at 60 mg or 90 mg doses administered orally (PO) QD in combination with atirmociclib 300 mg PO twice a day (BID).

Part 2 (Dose Expansion): This part of the study will further evaluate the safety and PK of palazestrant at the RP2D in combination with ribociclib (Treatment Group 1), alpelisib (Treatment Group 2), or everolimus (Treatment Group 3) and provide an exploratory estimate of anti-tumor activity of the combinations. An additional group of palazestrant at an alternate dose level in combination with ribociclib (Treatment Group 1b) will be explored to optimize the RP2D of palazestrant. Part 2, for Treatment Group 4, will further evaluate the safety and pharmacokinetics of atirmociclib and OP-1250 at the recommended dose for expansion.

Inclusion Criteria:

• Female or male aged >18 years.
• Willing and able to participate and comply with all study requirements.
• Histologically- or cytologically-confirmed advanced or metastatic Breast Cancer (mBC).
• ER+/HER2- disease, as determined in the most recently obtained archival tumor tissue sample from a metastatic site, using locally accepted criteria by the local pathology report.
• Evaluable disease with one of the following: Measurable disease, ie, at least 1 measurable lesion as per RECIST 1.1 (a lesion at a previously irradiated site may only be counted as a target lesion if there is clear sign of progression since the irradiation) OR patients with predominantly bone disease (with or without other non-measurable lesions) are allowed if it is possible to evaluate on radiological examinations (eg. bone scan, PET/CT, CT, MRI) even if lesions are non-measurable according to RECIST 1.1.
• Life expectancy ≥6 months, as judged by the investigator.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.
• Has received no more than 1 prior hormonal regimen (Treatment Group 1). Has received no more than 2 prior hormonal regimens (Treatment Group 2 and Treatment Group 3) . Has received no more than 2 prior hormonal regimens for metastatic disease in Part 1 (Dose Escalation) and no more than 1 prior hormonal regimes in Part 2 (Dose Expansion) for metastatic disease, regardless of type of endocrine agent (Treatment Group 4) for advanced or metastatic disease. Prior hormonal regimens in combination with CDK4/6 inhibitors are allowed in all treatment groups. For subjects in Treatment Group 4, no prior chemotherapy for metastatic breast cancer is allowed.
• Has received no more than 1 prior chemotherapy (which includes antibody drug conjugates) for locally advanced or metastatic breast cancer.

Exclusion Criteria:

• Prior or concurrent malignancy whose natural history or treatment may interfere with the safety or efficacy assessment of the investigational regimen.
• Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality.
• History of cerebral vascular disease within 6 months prior to the first administration of study drug dose.
• History of a pulmonary embolism, or deep venous thrombosis within the last 6 months, or subject has an increased risk of thrombosis as determined by the investigator.
• History of pneumonitis or interstitial lung disease.
• Leptomeningeal disease or spinal cord compression.
• Medical history or ongoing gastrointestinal disorders that could affect absorption of oral therapeutics.
• Known human immunodeficiency virus infection.
• Known clinically significant history of liver disease consistent with Child-Pugh Class B or C, including active viral or other hepatitis (eg, hepatitis B or hepatitis C virus), current alcohol abuse, or cirrhosis.
• History of severe cutaneous reaction, such as Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, or drug reaction with eosinophilia and systemic symptoms.
• Active infection or at a high risk of developing a serious infection (e.g. participants with immunodeficiencies, uncontrolled diabetes mellitus, uncontrolled heart disease, poor general health, poor nutritional status).
• Has clinically significant co-morbidities, such as, psychiatric disease, or any other condition that could impact the ability of the subject to participate in this study or otherwise has the potential to confound the study results.
• Have received prior treatment with OP-1250.
• Have received prior treatment with approved or investigational PI3K inhibitor (Treatment Group 2) or mTOR inhibitor (Treatment Group 3).