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 (and peri-menopausal) women can be enrolled if amenable to treatment with a gonadotropin-releasing hormone (GnRH) agonist. Patients are to have commenced treatment with a GnRH agonist at least 4 weeks prior to randomization and must be willing to continue on it for the duration of the study.
• Histologically or cytologically confirmed diagnosis of HR+/HER2- locally advanced or metastatic breast cancer (ABC) with radiological or objective evidence of recurrence or progression; locally advanced disease must not be amenable to resection with curative intent
• Measurable disease per RECIST v1.1 or evaluable bone-only disease.
• Must have radiological evidence of progression on or after previous treatment for HR+/HER2- ABC with:

• 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 or in the ABC setting
• 1 prior line of CDK4/6 inhibitor therapy in one of the following settings:

• CDK4/6 inhibitor + ET in the ABC setting
• CDK4/6 inhibitor therapy in the adjuvant setting if progression occurred during or within 12 months of completion of adjuvant CDK4/6 inhibitor with ET
• Patients who progressed during or within 12 months of completion of adjuvant CDK4/6 inhibitor and after receiving CDK4/6 inhibitor therapy in the advanced setting are considered to have had >1 prior line of CDK4/6 inhibitor and are not eligible

Exclusion criteria

• Prior treatment with any of the following:

• CDK2 or selective CDK4 inhibitors or any investigational therapies targeting cyclin dependent kinases
• PIK3, AKT, or mTOR inhibitors or any agent whose mechanism of action is the inhibit the PIK3/AKT/mTOR pathway
• Immunotherapy
• Antibody drug conjugates
• Type 1 diabetes, or Type 2 diabetes requiring antihyperglycemic medication, or fasting plasma glucose ≥ 140 mg/dL, or glycosylated hemoglobin (HbA1c) ≥7.0% (≥ 53 mmol/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 progressive neurological symptoms or requiring ongoing corticosteroids or anticonvulsants for symptomatic control
• Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease
• History of hypersensitivity to fulvestrant or drugs in a similar class as fulvestrant, RLY-2608, or capivasertib, including their excipients
• Known activating AKT mutations, loss-of-function PTEN mutations, or loss of PTEN expression resulting in oncogenic pathway activation downstream of PI3K