This is a first-in-human, Phase Ia/Ib, dose-escalation and expansion study evaluating the safety, pharmacokinetics, and activity of GDC-0587 (cyclin-dependent kinase-4 [CDK4] inhibitor) as a monotherapy and in combination with giredestrant in participants with locally advanced or metastatic estrogen receptor-positive and human epidermal growth factor receptor 2-negative (ER+/HER2-) breast cancer who have previously progressed during or after CDK 4/6 inhibitor therapy.

Inclusion Criteria:

• Agreement to adhere to the contraception requirements
• For females of childbearing potential ≤60 years of age and males: treatment with luteinizing hormone-releasing hormone (LHRH) agonist therapy beginning at least 2 weeks prior to Cycle 1, Day 1 and agreement to continue LHRH agonist therapy for the duration of the study
• Histologically or cytologically confirmed adenocarcinoma of the breast that is locally advanced or metastatic
• Previously documented ER+ and HER2- tumor according to American Society of Clinical Oncology (ASCO)/ College of American Pathologists (CAP) or European Society of Medical Oncology (ESMO) guidelines or any national guidelines with criteria conforming to ASCO/CAP or ESMO guidelines
• Disease progression during or following treatment with an approved CDK 4/6 inhibitor, with or without endocrine therapy, in the locally advanced or metastatic setting
• Measurable, or non-measurable but evaluable, disease per RECIST v1.1
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
• Life expectancy ≥6 months
• Creatinine clearance ≥60 milliliter per minute (mL/min) (calculated through use of the Cockcroft-Gault formula)

Exclusion Criteria:

• Pregnant or breastfeeding, or intention of becoming pregnant during the study
• Advanced, symptomatic, visceral spread that is at risk of life-threatening complications in the short term appropriate for treatment with cytotoxic chemotherapy at time of entry into the study, as per national or local treatment guidelines
• Five or more prior lines of systemic therapy in the locally advanced or metastatic setting
• Treatment with anti-cancer therapies, including investigational therapies, within 28 days or 5 drug elimination half-lives, whichever is shorter, prior to initiation of study drug
• Treatment with an approved oral endocrine therapy within 7 days prior to initiation of study drug or treatment with fulvestrant or an approved/investigational CDK inhibitor within 21 days prior to initiation of study drug
• History of Grade ≥3 adverse event attributed to prior CDK inhibitor therapy that resulted in permanent discontinuation of prior CDK inhibitor therapy
• Poor peripheral venous access
• Malabsorption condition or other gastrointestinal (GI) conditions/surgeries that the investigator assesses may significantly interfere with enteral absorption
• Major surgical procedure within 28 days prior to initiation of study drug
• Untreated, active CNS metastases
• Infection requiring systemic (i.e., oral, IV, or intramuscular) antibiotics, chronic infection requiring treatment within 1 year prior to screening, or any evidence of current infection
• History of malignancy within 3 years prior to screening, except for cancer under investigation in this study
• Known history of a clinically significant abnormal ECG