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A Study Comparing RLY-2608 and Fulvestrant with Capivasertib and Fulvestrant for Patients with PIK3CA-Mutant Hormone Receptor Positive, HER2-Negative Advanced Breast Cancer

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What is this trial about?

A plain-language summary of the goals, design and what participants do

This study is looking at a type of breast cancer that is hormone receptor positive and HER2-negative and has a specific change in a gene called PIK3CA. This cancer has spread to other parts of the body or has grown in a way that cannot be removed with surgery. The people in this study will have already received treatment with a type of medicine called a CDK4/6 inhibitor but their cancer has continued to grow or come back. The study will compare two different treatment combinations. One group will receive a medicine called RLY-2608 together with fulvestrant, and the other group will receive capivasertib together with fulvestrant. RLY-2608 is taken by mouth as a capsule, capivasertib is taken by mouth as a tablet, and fulvestrant is given as an injection into the muscle.

The purpose of the study is to compare how well RLY-2608 combined with fulvestrant works compared to capivasertib combined with fulvestrant in controlling the cancer and preventing it from getting worse. During the study, patients will be randomly assigned to one of the two treatment groups. They will continue receiving their assigned treatment for as long as it is helping them and they are not experiencing unacceptable side effects. Regular check-ups will be done to see how the cancer is responding to treatment using imaging scans, and to monitor for any side effects. Blood samples will be taken to measure the amount of medicine in the body.

The study will also look at how long people live, how many people respond to treatment, how long the response lasts, and whether the cancer remains stable for a certain period. Information will be collected about any unwanted effects that occur, including their severity and how they relate to the study medicines. The study will also assess how the treatment affects quality of life by using questionnaires that ask about symptoms and daily activities. The study is expected to start enrolling people in December 2025 and is planned to continue until July 2028.

The research process

The trial runs in 6 steps – from screening to follow-up. Each step says what happens and what the team monitors.

  1. Step 1

    Treatment assignment

    Your treatment will be randomly assigned to one of two groups. This means that neither you nor your doctor will choose which treatment you receive.

    One group will receive RLY-2608 combined with fulvestrant. The other group will receive capivasertib combined with fulvestrant.

    If you are a woman who has not yet gone through menopause, you must have started treatment with a hormone medication called a GnRH agonist at least 4 weeks before being assigned to a treatment group. You will need to continue taking this medication throughout the study.

  2. Step 2

    Treatment with RLY-2608 and fulvestrant (if assigned to this group)

    You will take RLY-2608 by mouth in capsule form. The specific dosage and schedule will be determined by your doctor.

    You will receive fulvestrant as an injection into your muscle. The dose is 250 mg per injection.

    The treatment will continue until your disease progresses or until side effects become too severe to continue.

  3. Step 3

    Treatment with capivasertib and fulvestrant (if assigned to this group)

    You will take capivasertib by mouth in tablet form. Two tablet strengths are available: 200 mg and 160 mg. Your doctor will determine the appropriate dose for you.

    You will receive fulvestrant as an injection into your muscle. The dose is 250 mg per injection.

    The treatment will continue until your disease progresses or until side effects become too severe to continue.

  4. Step 4

    Regular monitoring and assessments

    Your disease will be monitored regularly using imaging scans to check whether the cancer is responding to treatment, staying stable, or progressing.

    Your doctor will assess your health using a performance status scale called ECOG, which measures how well you can carry out daily activities.

    Blood samples will be taken to measure the levels of study medication in your blood and to check for safety.

    You will have regular safety checks including vital signs, heart rhythm recordings (ECGs), and laboratory tests.

    Any side effects you experience will be recorded and graded according to their severity.

  5. Step 5

    Quality of life assessments

    You will be asked to complete questionnaires about your quality of life and any symptoms you are experiencing. These include the EORTC QLQ-C30 (a general cancer questionnaire) and EORTC QLQ-BR23 (a breast cancer-specific questionnaire).

    You will also complete a health questionnaire called EQ-5D-5L which asks about your mobility, self-care, usual activities, pain or discomfort, and anxiety or depression.

  6. Step 6

    Ongoing treatment and follow-up

    The study is expected to continue until approximately July 2028.

    Your treatment will continue as long as it is providing benefit and you are not experiencing unacceptable side effects.

    Your doctor will monitor the amount of medication you are taking and may adjust your dose if needed based on how you are tolerating the treatment.

Who can join the trial?

8 criteria

  • You must have an ECOG performance status of 0-1, which is a score that measures how the disease affects your daily living abilities, where 0 means you are fully active and 1 means you have some restrictions but can still do light work
  • You must be an adult female or adult male with a diagnosis of breast cancer
  • If you are a woman who has not gone through menopause yet, you must be willing to receive treatment with a GnRH agonist, which is a medication that stops your ovaries from making certain hormones. You need to start this treatment at least 4 weeks before joining the study and continue it throughout the study
  • You must have a confirmed diagnosis through tissue or cell samples showing HR positive and HER2 negative breast cancer that has spread to other parts of the body or has grown in your breast area in an advanced way. HR positive means your cancer grows in response to hormones, and HER2 negative means your cancer does not have too much of a certain protein called HER2. The cancer must have grown or come back and cannot be removed completely with surgery
  • You must have disease that can be measured on scans according to specific guidelines called RECIST v1.1, or you must have cancer that has spread only to the bones that can be evaluated
  • Your cancer must have one or more specific changes in a gene called PIK3CA mutation, which is an abnormal change in your genetic material that helps cancer cells grow
  • Your cancer must have gotten worse during or after previous treatment, and you must have received at least 1 but no more than 2 courses of endocrine therapy, which is hormone-based treatment, either before or after surgery with cancer returning within 12 months, or for advanced cancer
  • You must have received exactly 1 prior treatment with a CDK4/6 inhibitor, which is a type of medication that blocks proteins that help cancer cells divide. This treatment could have been given for advanced cancer, or after surgery if your cancer came back during treatment or within 12 months after finishing it. You cannot participate if you have received more than 1 course of CDK4/6 inhibitor treatment

Who cannot join the trial?

3 criteria

  • The specific exclusion criteria (reasons why patients cannot participate) have not been provided in the available study information
  • Generally, clinical trials have exclusion criteria to ensure patient safety and study accuracy, but these details are not included in the current documentation
  • Patients interested in this study should discuss with their doctor whether they meet the requirements to participate
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Investigated drugs

  • RLY-2608

    is an investigational medication being studied in combination with fulvestrant for the treatment of a specific type of breast cancer. This medicine is designed to target cancer cells that have a particular genetic mutation called PIK3CA. It works by blocking signals that help cancer cells grow and survive.

  • Fulvestrant

    is a hormone therapy medication used to treat hormone receptor positive breast cancer. It works by blocking and breaking down estrogen receptors on cancer cells, which helps stop the cancer from growing. This medication is already approved and used in clinical practice.

  • Capivasertib

    is a targeted therapy medication that blocks a protein called AKT, which helps cancer cells grow and survive. When combined with fulvestrant, it is used to treat hormone receptor positive breast cancer in patients whose cancer has continued to grow despite previous treatments.

What is already known about the treatment

  • RLY-2608

    RLY-2608 is an investigational medication currently being studied in clinical trials for the treatment of a specific type of advanced breast cancer that has a PIK3CA gene mutation and is hormone receptor positive but HER2 negative. This drug is being tested in combination with fulvestrant and is administered to patients whose cancer has progressed after treatment with CDK4/6 inhibitor medications. RLY-2608 works by targeting and blocking abnormal proteins produced by the PIK3CA mutation, which helps cancer cells grow and survive, and belongs to a class of drugs known as PI3K inhibitors that interfere with cancer cell growth pathways at the molecular level.

  • Fulvestrant

    Fulvestrant is an approved hormonal therapy medication used in the treatment of hormone receptor positive breast cancer, typically administered as an injection into the muscle. This drug works by blocking and breaking down estrogen receptors on cancer cells, preventing the hormone estrogen from attaching to these receptors and stimulating cancer cell growth. Fulvestrant belongs to a class of medications called selective estrogen receptor degraders and is often used in postmenopausal women with advanced breast cancer that has progressed after other hormone treatments.

  • Capivasertib

    Capivasertib is a targeted therapy medication being studied and used for treating advanced breast cancer with PIK3CA mutations, taken orally in tablet form. This drug works by blocking a protein called AKT, which is part of the same cellular pathway affected by PIK3CA mutations and helps cancer cells grow, divide, and survive. Capivasertib belongs to a class of drugs known as AKT inhibitors and is being compared with other similar treatments to determine the most effective approach for patients whose cancer has continued to grow after previous therapies.

Investigated diseases

Breast Cancer – Breast cancer is a disease where abnormal cells in the breast tissue grow uncontrollably and form a tumor. In this study, the focus is on a specific type called hormone receptor positive and human epidermal growth factor receptor 2 negative breast cancer, which means the cancer cells grow in response to certain hormones but do not have excess amounts of a particular protein. The disease has progressed to a locally advanced stage, meaning it has spread to nearby tissues, or a metastatic stage, meaning it has spread to distant parts of the body. This particular form of breast cancer also has a mutation in a gene called PIK3CA, which affects how cells grow and divide. As the disease progresses, tumors can grow larger and spread to other organs through the bloodstream or lymphatic system. The cancer cells continue to multiply and can interfere with normal body functions in affected areas.
Trial detailsLast updated 7 Oct 2026
Age18+ yearsPhasePhase IIITrial ID2025-523083-21-00Protocol codeRLY-2608-102Estimated enrolment568 patientsSponsorRelay Therapeutics Inc.

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