Efficacy and Safety of RLY-2608 Plus Fulvestrant Versus Capivasertib Plus Fulvestrant in PIK3CA-Mutant HR+/HER2- Advanced Breast Cancer
- Trial ID
- 2025-523083-21-00
- Protocol
- RLY-2608-102
- Sponsor
- Relay Therapeutics Inc.
Trial statistics
Objectives
The primary objective is to evaluate the efficacy of RLY-2608 plus fulvestrant compared to capivasertib plus fulvestrant by assessing progression-free survival (PFS) via blinded independent central review (BICR) in both the overall and kinase populations. This assessment is clinically significant for patients with PIK3CA-mutant, hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) locally advanced or metastatic breast cancer following progression on or after CDK4/6 inhibitor therapy. 5
Secondary objectives include:
- Comparison of overall survival (OS) in the overall and kinase populations.
- Assessment of objective response rate (ORR) by BICR and investigator, duration of response (DOR), and clinical benefit rate (CBR).
- Evaluation of safety and tolerability. 4
- Assessment of pharmacokinetics (PK) of RLY-2608 and its metabolites. 6
- Analysis of impact on disease-related symptoms, physical function, health-related quality of life (HRQoL), and health state utility.
Participants
This study involves 268 participants diagnosed with PIK3CA-mutant hormone receptor-positive, human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer. The study population includes adult males and adult females, including both pre-menopausal and post-menopausal individuals. Eligible participants must possess an ECOG performance status of 0-1 and exhibit measurable disease according to RECIST v1.1. Specific requirements include the presence of one or more known primary oncogenic PIK3CA mutations and documented progression following specific prior treatments, including endocrine therapy and CDK4/6 inhibitor therapy. Pre-menopausal women are required to be treated with a gonadotropin-releasing hormone agonist for a minimum of four weeks prior to randomization.
Plans and Procedures
This Phase 3, open-label, randomized study is designed to evaluate the efficacy and safety of RLY-2608 combined with fulvestrant compared to capivasertib combined with fulvestrant in patients with PIK3CA-mutant, hormone receptor positive, human epidermal growth factor receptor 2 negative (HR+/HER2-) locally advanced or metastatic breast cancer. The primary efficacy endpoint is progression-free survival (PFS), assessed by blinded independent central review (BICR). The methodology involves the administration of RLY-2608 or capivasertib alongside fulvestrant following recurrence or progression on or after treatment with a CDK4/6 inhibitor. The study includes a screening visit to confirm eligibility based on histological or cytological diagnosis, PIK3CA mutation status, and ECOG performance status. Subsequent follow-up visits will monitor overall survival (OS), objective response rate (ORR), duration of response (DOR), and clinical benefit rate (CBR), as well as adverse events (AEs) and patient-reported outcomes. The total trial duration is estimated to extend through July 2028. Early termination from the study may occur based on clinical requirements or safety monitoring.
Treatment
The experimental treatment regimen consists of RLY-2608 administered as an oral capsule at a dosage of 800 mg. This is used in combination with fulvestrant, which is provided as a solution for injection. The fulvestrant is administered via intramuscular injection at a dose of 500 mg.
The comparator treatment regimen consists of capivasertib administered as film-coated tablets via the oral route at a dosage of 800 mg. This is used in combination with fulvestrant administered as a 500 mg intramuscular injection.
Efficacy
The primary efficacy endpoint is progression-free survival (PFS), which is defined as the time from randomization until radiographic progression as assessed by Blinded Independent Central Review (BICR) using RECIST v1.1, or death from any cause. This assessment will be conducted within the overall and kinase populations.
Secondary efficacy parameters include:
- Overall survival (OS), defined as the time from randomization to death from any cause.
- Objective response rate (ORR), representing the percentage of participants achieving complete response (CR) or partial response (PR) per RECIST v1.1.
- Duration of response (DOR), defined as the interval from the first documented response per RECIST v1.1 to the date of documented progression or death in the absence of disease progression.
- Clinical benefit rate (CBR), defined as the percentage of participants achieving CR, PR, or stable disease (SD) maintained for $\ge$24 weeks per RECIST v1.1 without subsequent therapy.
- Changes in EORTC QLQ-C30 and EORTC QLQ-BR23 scale or item scores, including change from baseline and time to deterioration.
- Health state utility data derived using the EQ-5D-5L index for economic evaluation.
- Plasma concentrations of RLY-2608 and its metabolites.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patient has ECOG performance status of 0-1
- 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.
- One or more known primary oncogenic PIK3CA mutation(s)
- Must have radiological evidence of progression on or after previous treatment for HR+/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 or in the ABC setting 2. 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
- History of hypersensitivity to fulvestrant or drugs in a similar class as fulvestrant, RLY-2608, or capivasertib, including their excipients
- 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
- Known activating AKT mutations, loss-of-function PTEN mutations, or loss of PTEN expression resulting in oncogenic pathway activation downstream of PI3K
- Type 1 diabetes, or Type 2 diabetes requiring antihyperglycemic medication, or fasting plasma glucose ≥ 140 mg/dL (7.8 mmol/L), or glycosylated hemoglobin (HbA1c) ≥7.0% (≥ 53 mmol/mol).
- 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
- Any factors that increase the risk of QTc prolongation or risk of arrhythmic events
- Clinically significant, uncontrolled cardiovascular disease
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Recruiting | 15 Dec 2025 | 10 |
 Belgium | Recruiting | 15 Dec 2025 | 20 |
 Bulgaria | Recruiting | 15 Dec 2025 | 21 |
 Czechia | Recruiting | 15 Dec 2025 | 11 |
 Denmark | Recruiting | 15 Dec 2025 | 9 |
 France | Recruiting | 15 Dec 2025 | 32 |
 Germany | Recruiting | 15 Dec 2025 | 23 |
 Greece | Recruiting | 15 Dec 2025 | 10 |
 Hungary | Not Yet Recruiting | 15 Dec 2025 | 13 |
 Ireland | Not Yet Recruiting | 15 Dec 2025 | 10 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Fulvestrant EVER Pharma 250 mg solution for injection in pre-filled syringe | Test | SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE | INTRAMUSCULAR INJECTION | 500 | 99999 | PRD6646866 |
RLY-2608 | Test | CAPSULE | ORAL | 800 | 99999 | PRD10323172 |
TRUQAP 160 mg film-coated tablets | Comparator | FILM-COATED TABLET | ORAL | 800 | 99999 | PRD11429951 |
Fulvestrant Dr. Reddy’s 250 mg Solution For Injection in Pre-Filled Syringe | Test | SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE | INTRAMUSCULAR INJECTION | 500 | 99999 | PRD5235872 |
TRUQAP 200 mg film-coated tablets | Comparator | FILM-COATED TABLET | ORAL | 800 | 99999 | PRD11429980 |
Fulvestrant Dr. Reddys 250 mg solución inyectable en jeringa precargada EFG | Test | SOLUCIÓN INYECTABLE EN JERINGA PRECARGADA | INTRAMUSCULAR INJECTION | 500 | 99999 | PRD7003633 |