Home › Trials › NCT06982521

RLY-2608 plus fulvestrant versus capivasertib plus fulvestrant for PIK3CA‑mutant HR+/HER2‑ advanced breast cancer

A Phase 3 Open-Label Randomized Study Assessing the Efficacy and Safety of RLY-2608 + Fulvestrant Versus Capivasertib + Fulvestrant as Treatment for PIK3CA-mutant Hormone Receptor Positive, Human Epidermal Growth Factor Receptor 2 Negative (HR+/HER2-) Locally Advanced or Metastatic Breast Cancer Following Recurrence or Progression On or After Treatment With a CDK4/6 Inhibitor

Phase 3 Interventional Relay Therapeutics, Inc. · NCT06982521

This trial tests whether RLY-2608 combined with fulvestrant works better than capivasertib combined with fulvestrant for adults with HR+/HER2‑ advanced breast cancer that has a PIK3CA mutation and progressed after a CDK4/6 inhibitor.

Quick facts

PhasePhase 3
Study typeInterventional
Enrollment540 (estimated)
Ages18 Years and up
SexAll
SponsorRelay Therapeutics, Inc. Industry-sponsored
Drugs / interventionsImmunotherapy, radiation
Locations158 sites (Gilbert, Arizona and 157 other locations)
Trial IDNCT06982521 on ClinicalTrials.gov

What this trial studies

This is a global, multicenter, open‑label, randomized Phase 3 trial comparing RLY-2608 plus fulvestrant against capivasertib plus fulvestrant in patients with HR+/HER2‑ locally advanced or metastatic breast cancer harboring PIK3CA mutations who have progressed after CDK4/6 inhibitor therapy. Eligible participants must have measurable disease or evaluable bone‑only disease and an ECOG performance status of 0–1, and premenopausal women must receive a GnRH agonist. Patients are randomized to one of the two combination regimens and undergo regular radiologic assessments per RECIST v1.1 with ongoing safety monitoring. The study is open‑label, so treating physicians and patients know the assigned therapy while outcomes are compared across the randomized arms.

Who should consider this trial

Good fit: Adults (men and women) with histologically confirmed HR+/HER2‑ locally advanced or metastatic breast cancer, a documented PIK3CA mutation, ECOG 0–1, measurable or bone‑only disease, and disease progression on or after prior CDK4/6 inhibitor therapy are the intended participants.

Not a fit: Patients without a PIK3CA mutation, those with HER2‑positive disease, poor performance status (ECOG >1), or those who have not progressed after CDK4/6 inhibitor therapy are unlikely to qualify or benefit from this comparison.

Why it matters

Potential benefit: If successful, the RLY-2608 combination could provide a more effective targeted treatment option that delays disease progression for patients with PIK3CA‑mutant HR+/HER2‑ advanced breast cancer.

How similar studies have performed: Prior studies have shown activity for capivasertib combined with endocrine therapy in HR+ breast cancer, while a head‑to‑head Phase 3 comparison with RLY-2608 represents a novel direct comparison.

Eligibility criteria

Show full inclusion / exclusion criteria 
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:

  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:

     1. CDK4/6 inhibitor + ET in the ABC setting
     2. 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
     3. 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:

  1. CDK2 or selective CDK4 inhibitors or any investigational therapies targeting cyclin dependent kinases
  2. PIK3, AKT, or mTOR inhibitors or any agent whose mechanism of action is the inhibit the PIK3/AKT/mTOR pathway
  3. Immunotherapy
  4. 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

Where this trial is running

Gilbert, Arizona and 157 other locations

+108 more sites — see ClinicalTrials.gov for the full list.

Study contacts

How to participate

  1. Review the eligibility criteria above with your treating physician.
  2. Visit the official trial page on ClinicalTrials.gov for the most current contact information and recruitment status.
  3. Contact the listed study coordinator or principal investigator to request pre-screening. Pre-screening is free and never obligates you to enroll.
View on ClinicalTrials.gov → Find more trials like this →
Conditions PIK3CA MutationHER2- Negative Breast CancerHormone Receptor Positive TumorBreast CancerMetastatic Breast CancerAdvanced Breast Cancer
Last reviewed 2026-06-13 by the Find a Trial editorial team. Information on this page is for educational purposes and is not medical advice. Always consult qualified healthcare professionals about clinical trial participation.