Phase 3 Study of RLY-2608 + Fulvestrant vs Capivasertib + Fulvestrant as Treatment for Locally Advanced or Metastatic PIK3CA-mutant HR+/HER2- Breast Cancer

Inclusion Criteria:

• Patient has ECOG performance status of 0-1

• One or more known primary oncogenic PIK3CA mutation(s)

• Adult females, pre- and/or post-menopausal, and adult males. Pre-menopausal (andperi-menopausal) women can be enrolled if amenable to treatment with agonadotropin-releasing hormone (GnRH) agonist. Patients are to have commencedtreatment with a GnRH agonist at least 4 weeks prior to randomization and must bewilling to continue on it for the duration of the study.

• Histologically or cytologically confirmed diagnosis of HR+/HER2- locally advanced ormetastatic breast cancer (ABC) with radiological or objective evidence of recurrenceor progression; locally advanced disease must not be amenable to resection withcurative intent

• Measurable disease per RECIST v1.1 or evaluable bone-only disease.

• Must have radiological evidence of progression on or after previous treatment forHR+/HER2- ABC with:

1. At least 1 and no more than 2 lines of endocrine therapy (ET) in the (neo)adjuvant setting with recurrence on or within 12 months of completion orin the ABC setting

2. 1 prior line of CDK4/6 inhibitor therapy in one of the following settings:

3. CDK4/6 inhibitor + ET in the ABC setting

4. CDK4/6 inhibitor therapy in the adjuvant setting if progression occurredduring or within 12 months of completion of adjuvant CDK4/6 inhibitor withET

5. Patients who progressed during or within 12 months of completion ofadjuvant CDK4/6 inhibitor and after receiving CDK4/6 inhibitor therapy inthe advanced setting are considered to have had >1 prior line of CDK4/6inhibitor and are not eligible

Exclusion Criteria:

• Prior treatment with any of the following:

1. CDK2 or selective CDK4 inhibitors or any investigational therapies targetingcyclin dependent kinases

2. PIK3, AKT, or mTOR inhibitors or any agent whose mechanism of action is theinhibit the PIK3/AKT/mTOR pathway

3. Immunotherapy

4. Antibody drug conjugates

• Type 1 diabetes, or Type 2 diabetes requiring antihyperglycemic medication, orfasting plasma glucose ≥ 140 mg/dL, or glycosylated hemoglobin (HbA1c) ≥7.0% (≥ 53mmol/mol).

• Clinically significant, uncontrolled cardiovascular disease

• Any factors that increase the risk of QTc prolongation or risk of arrhythmic events

• Known active uncontrolled or symptomatic CNS metastases associated with progressiveneurological symptoms or requiring ongoing corticosteroids or anticonvulsants forsymptomatic control

• Past medical history of interstitial lung disease, drug-induced interstitial lungdisease, radiation pneumonitis which required steroid treatment, or any evidence ofclinically active interstitial lung disease

• History of hypersensitivity to fulvestrant or drugs in a similar class asfulvestrant, RLY-2608, or capivasertib, including their excipients

• Known activating AKT mutations, loss-of-function PTEN mutations, or loss of PTENexpression resulting in oncogenic pathway activation downstream of PI3K