A Study to Evaluate the Effect of GDC-4198 Alone and in Combination With Giredestrant Versus Abemaciclib and Giredestrant in Participants With Locally Advanced or Metastatic Estrogen Receptor-Positive (ER+), Human Epidermal Growth Factor Receptor-Negative (HER2-) Breast Cancer

• GDC-4198 (Drug), also known as RGT-419B, RO7840734: GDC-4198 will be administered orally.
• Giredestrant (Drug), also known as GDC-9545, RO7197597: Giredestrant will be administered orally.
• Abemaciclib (Drug): Abemaciclib will be administered orally.

Primary outcomes

• Phase Ib: Incidence and Severity of Adverse Events (AEs) [Up to 36 months]: Severity of AEs determined according to the CTCAE v5.0 grading scale
• Phase Ib: Number of Participants With Dose-Limiting Toxicity (DLTs) [From Day 1 to Day 28 of Cycle 1 (1 cycle=28 days)]
• Phase II: Progression-free Survival (PFS) [Up to 36 months]

Secondary outcomes

• Phase Ib: Objective Response Rate (ORR) [Up to 36 months]
• Phase Ib: Clinical Benefit Rate (CBR) [Up to 36 months]
• Phase II: ORR [Up to 36 months]
• Phase II: Duration of Response (DOR) [Up to 36 months]
• Phase II: CBR [Up to 36 months]
• Phase II: Overall Survival (OS) [Up to 36 months]
• Phase II: OS Rate at 6 Months and 12 Months [Month 6, Month 12]
• Phase II: PFS Rate at 6 Months and 12 Months [Month 6, Month 12]
• Phase II: Incidence and Severity of Adverse Events (AEs) [Up to 36 months]: Severity of AEs determined according to the CTCAE v5.0 grading scale
• Phase II: Plasma Concentration of GDC-4198 [Up to 36 months]
• Phase II: Recommended Dose of GDC-4198 [Up to 36 months]

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Histologically and/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 after treatment with an approved cyclin-dependent kinase 4/6 (CDK4/6) inhibitor and approved endocrine therapy (ET) in the locally advanced or metastatic setting.
* Measurable or non-measurable evaluable, disease per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1).
* Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
* Life expectancy >= 6 months.

Exclusion Criteria:

* 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.
* Have received more than one-line of therapy for locally advanced or metastatic disease.
* Have received prior chemotherapy for metastatic breast cancer.
* Treatment with an approved oral ET within 7 days prior to initiation of study drug; treatment with fulvestrant or an approved CDK4/6 inhibitor within 21 days prior to initiation of study drug.
* Malabsorption condition or other gastrointestinal (GI) conditions/surgeries that the investigator assesses may significantly interfere with enteral absorption
* History of malignancy within 3 years prior to screening, except for cancer under investigation in this study and malignancies with a negligible risk of metastasis or death.
* Known allergy or hypersensitivity to any component of the study treatments.

• Clinical Trials, Study director, Hoffmann-La Roche

NIH grants: 2025