ReDiscover-2 (NCT06982521)

Failed CDK4/6 inhibition drug? Looking at trials?

In this trial, you may qualify for RLY-2608 + Fulvestrant or you may qualify for Capivasertib + Fulvestrant.

Treatment is chosen by randomisation (like a medical ‘coin toss’), so there is a chance of receiving either the new drug or the comparison treatment.

If someone is allocated to the Capivasertib and doesn’t feel comfortable, they can choose to withdraw before starting any trial medication

Trial details

• Name: ReDiscover-2

• NCT number: NCT06982521

• URL: clinicaltrials.gov/study/NCT06982521

• Drug: RLY-2608 + fulvestrant

• Email: ClinicalTrials@relaytx.com

Study title

International: Phase 3 study of RLY-2608 + fulvestrant for locally advanced or metastatic PIK3CA-mutant HR+/HER2- breast cancer

Criteria

• HR+/HER2‑ locally advanced or metastatic breast cancer

• Presence of one or more oncogenic PIK3CA mutations, without AKT or PTEN alterations

• Prior CDK4/6 inhibitor (within the allowed lines/settings)

What is the new drug?

An oral, pan-mutant-selective PI3K-alpha inhibitor for PIK3CA-mutant breast cancer.

RLY-2608 is essentially trying to keep the “good” of PI3Kα targeting, for clearly PIK3CA-driven disease, while minimizing the systemic metabolic punishment patients have seen with earlier PI3K inhibitors, by exploiting mutant-specific allostery and isoform selectivity.

Designed to hit PIK3CA-mutant PI3Kα precisely, aiming for strong tumor control with fewer glucose, rash and gut side effects than older PI3K drugs.

PubMed reference

What RLY-2608 is targeting - more details

RLY-2608 (zovegalisib) is a mutant-selective, allosteric inhibitor of PI3K-alpha (PI3Kα), encoded by PIK3CA. PI3Kα is a lipid kinase in the PI3K/AKT/mTOR pathway and is one of the most frequently mutated kinases across solid tumors, including around 40% of HR+/HER2- breast cancers.

Unlike earlier PI3Kα inhibitors, for example alpelisib, RLY-2608 is designed to be isoform-selective and pan-mutant. That means it preferentially inhibits multiple activating PIK3CA mutations, helical and kinase domain, while sparing wild-type PI3Kα as much as possible.

It binds an allosteric “cryptic” pocket adjacent to the ATP-binding site, identified using molecular dynamics and cryo-EM, rather than competing directly at the ATP pocket. This allosteric, mutant-biased binding is what underpins the goal of decoupling antitumor activity from the classic PI3K-inhibitor toxicities, hyperglycemia, rash and diarrhea, driven by wild-type PI3Kα inhibition.

Mechanistically, preclinical work shows that RLY-2608 reduces downstream p-AKT and inhibits proliferation in PIK3CA-mutant cancer cell lines and xenografts, with much smaller effects on insulin and glucose homeostasis compared with non-selective or wild-type-biased PI3Kα inhibition.

What early-phase data tell us

First-in-human / early proof-of-concept

A first-in-human Phase 1 program, ReDiscover (NCT05216432 and related trials), is evaluating RLY-2608 as:

• Monotherapy in advanced solid tumors with PIK3CA mutations

• Combination with endocrine therapy, fulvestrant ± CDK4/6 or CDK4 inhibitors, in advanced HR+/HER2- breast cancer

In the initial proof-of-concept report, objective tumor responses were observed in at least two patients with advanced HR+/HER2- breast cancer harboring helical or kinase domain PIK3CA mutations, with no wild-type PI3Kα-related toxicities detected.

Key early clinical signals

Interim data for RLY-2608 + fulvestrant at the recommended 600 mg BID dose in HR+/HER2- PIK3CA-mutant metastatic breast cancer showed:

• Median progression-free survival, PFS, about 10–11 months overall, with up to about 18 months median PFS in 2L patients with kinase-domain mutations

• Clinical benefit rate around two-thirds of evaluable patients, and partial responses in roughly one-third to two-thirds of measurable-disease subsets depending on mutation class

• About 80% of patients with measurable disease had tumor shrinkage, suggesting robust pathway dependence when PIK3CA is driving the disease

Pre-screening - Are you a good match?

ReDiscover-2 definitely requires PIK3CA testing, but it does not publicly commit to using or offering FoundationOne Liquid CDx as the universal prescreening tool.

A specific patient would need to ask the individual site whether a FoundationOne liquid biopsy is offered for free as part of their screening workflow or whether they should arrange PIK3CA testing separately.

• PubMed

• Relay Therapeutics updated data

Monitoring via scans CT/MRI discussion consideration if pre-screening leads to selection

To get a definitive answer on how much structured choice participants have, for example “this trial allows MRI instead of CT for routine restaging if local radiology can do it”, a patient would need to contact a trial site or Relay’s clinical team and ask for the imaging specifications or patient-facing consent language.

Those internal documents will spell out things like “CT or MRI, with contrast, unless contraindicated” and any radiation-sparing or gadolinium-sparing options.

Given that the trial scans may be as frequent as every 8 weeks, it's important to know if there are choices that can be made up front.

The moment the trial is underway, the scan type chosen is the one that sticks.

URL: clinicaltrials.gov/study/NCT06982521