A Study of GDC-9545 Alone or in Combination With Palbociclib and/or Luteinizing Hormone-Releasing Hormone (LHRH) Agonist in Locally Advanced or Metastatic Estrogen Receptor-Positive Breast Cancer

Inclusion Criteria for Dose Escalation:

- Histologically or cytologically proven diagnosis of adenocarcinoma of the breast with
evidence of either locally recurrent disease not amenable to resection or radiation
therapy with curative intent or with metastatic disease

- ER-positive tumor

- HER2-negative breast cancer as per local laboratory testing

- Measurable disease, or evaluable bone disease; that is, bone lesions that are lytic or
mixed (lytic + sclerotic) in the absence of measurable lesion

- Required paired pre- and on-treatment tumor biopsies for participants with metastases
that are safely accessible as determined by the investigator

- Advanced or metastatic ER-positive/HER2-negative breast cancer that has recurred or
progressed while being treated with adjuvant endocrine therapy for a duration of at
least 24 months and/or endocrine therapy in the incurable, locally advanced, or
metastatic setting and derived a clinical benefit from therapy (i.e., tumor response
or stable disease for at least 6 months)

- No more than 2 prior lines of treatment for advanced or metastatic breast cancer

- ≥ 2 weeks must have elapsed from the use of any other endocrine, targeted therapy or
chemotherapy

- Single-Agent Cohorts (only applies to Dose Escalation): Advanced or metastatic disease
that is either refractory to or intolerant of existing standard therapy or for which
no effective standard therapy that confers clinical benefit is available

- Cohort B0: No prior treatment with Cyclin-Dependent Kinase (CDK) 4/6 inhibitor

- For participants undergoing 18F-fluoroestradiol-positron emission tomography (FES-PET)
imaging additional restrictions on prior therapy include: ≥2 months must have elapsed
from the use of tamoxifen; ≥6 months must have elapsed from the use of fulvestrant

- Postmenopausal status

- Eastern Cooperative Oncology Group (ECOG) Performance Status ≤1

- Resolution of all acute toxic effects of prior therapy or surgical procedures to
baseline or Grade ≤1 (except alopecia or other toxicities not considered to be a
safety risk for the patient)

- Life expectancy of ≥12 weeks

- Adequate organ function

Inclusion Criteria for Dose Expansion:

Same as above, except:

- In South Korea: Must have received exactly 2 prior lines of treatment for advanced or
metastatic breast cancer

- In the rest of the world: No more than one prior line of treatment for advanced or
metastatic breast cancer

And plus:

- Cohort B1−2: No prior treatment with CDK4/6 inhibitor

- Cohorts A1, A3, and B1 only: Postmenopausal status

- Cohorts A2, A4, and B2 only: Participants not defined as post-menopausal

- No prior treatment with an oral selective estrogen receptor degrader (SERD)

- For women of childbearing potential: agreement to remain abstinent (refrain from
heterosexual intercourse) or use non-hormonal contraceptive methods with a failure
rate of < 1% per year during the treatment period and for 40 days after the last dose
of GDC-9545, and agreement to refrain from donating eggs

Exclusion Criteria for Dose Escalation:

- Known brain metastases that are untreated, symptomatic, or require therapy to control
symptoms

- Current treatment with any systemic anti-cancer therapies for advanced disease

- Concurrent treatment with warfarin or phenytoin

- Diagnosis of any secondary malignancy within 3 years prior to enrollment, except for
appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or
Stage I uterine cancer

- Active inflammatory bowel disease, chronic diarrhea, short bowel syndrome, or major
upper GI surgery including gastric resection

- Known Human Immunodeficiency Virus (HIV) infection

- Known clinically significant history of liver disease consistent with Child-Pugh Class
B or C, including active viral or other hepatitis (e.g., hepatitis B or hepatitis C
virus), current alcohol abuse, or cirrhosis

- Major surgery within 4 weeks prior to enrollment

- Radiation therapy within 2 weeks prior to enrollment

Exclusion Criteria for Dose Expansion:

Same as above, plus:

- Pregnant, lactating, or breastfeeding

- Additional exclusion criteria for participants in Cohort B: History of venous
thromboembolic event requiring therapeutic anticoagulation