Evexta pairs ex-Merck drug with Roche’s giredestrant

Why it matters: The all-oral combination is designed to block two mechanisms that allow estrogen receptor-positive tumors to escape endocrine therapy. It also gives rupitasertib a new clinical route after an earlier combination plan failed to begin on schedule.

Zoom in: The study will enroll at least 15 patients with ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer. Evexta expects to start it in the fourth quarter of 2026.

• Roche will supply giredestrant, while Evexta will sponsor and conduct the trial, assessing safety, tolerability and preliminary antitumor activity. Financial terms were not disclosed, and the agreement does not make Roche a co-developer of rupitasertib.

How it works: ESR1 mutations can keep the estrogen receptor active without estrogen, making tumors resistant to aromatase inhibitors, which are normally used to reduce estrogen production.

• Giredestrant is an oral selective estrogen receptor degrader, or SERD, designed to block and remove that receptor.
• Rupitasertib attacks the parallel PI3K/AKT/mTOR (PAM) pathway, which can help cancer cells survive endocrine treatment. The drug inhibits S6K and AKT1/3, aiming to prevent the compensatory AKT activation that can follow inhibition of a single point in the pathway.
• Evexta says sparing AKT2 could also limit hyperglycemia, a frequent problem with broader PAM-pathway inhibitors. That proposed safety advantage remains to be established in comparative trials.

Backstory: Rupitasertib began life at Merck KGaA as M2698. Merck tested it in 101 heavily pretreated patients between 2013 and 2018, as a monotherapy and alongside trastuzumab or tamoxifen. The drug showed a 27.4% stable disease rate as monotherapy without

objective responses recorded among 62 patients. One patient responded in each breast cancer combination cohort, with progression-free survival of 31 months and 2.7 months, respectively. Gastrointestinal problems, fatigue and abnormal dreams were among the most common treatment-related adverse events.

• Evexta’s predecessor, Diaccurate, acquired exclusive global rights in 2021 and renamed the drug DIACC3010. Merck became a shareholder in the Paris-based company, which was founded by Truffle Capital in 2013 and changed its name to Evexta in 2023. At the time of the acquisition Diaccurate planned to start exploratory Phase 2 programs in incurable solid tumors and lymphomas during the second half of 2022, but those trials seem to have never materialized.
• In April 2024, Evexta said it planned to start a Phase 2 trial combining rupitasertib with Menarini’s approved SERD elacestrant in the fourth quarter of that year. The new announcement does not explain if and why that plan was replaced by a smaller Phase 1b study using giredestrant instead. Evexta did not respond to a request for comment by the time of publication.

The bigger picture: Roche’s oral SERD programme has produced a mixture of late-stage wins and setbacks.

• Giredestrant plus everolimus succeeded in the Phase 3 evERA trial after prior CDK4/6 treatment. In patients with ESR1 mutations, it reduced the risk of progression or death by 62%, with median progression-free survival of 9.99 months versus 5.45 months. The FDA is reviewing the combination, with a decision expected Dec. 18.
• Giredestrant alone also succeeded in the adjuvant Phase 3 lidERA trial, reducing the risk of invasive recurrence or death by 30%. A separate FDA decision is due Nov. 30.
• However, giredestrant plus palbociclib missed the primary endpoint in the first-line Phase 3 persevERA trial. Roche is continuing the Phase 3 pionERA study with other CDK4/6 inhibitors and the heredERA trial combining giredestrant with Phesgo.

The competition: Evexta is entering an increasingly crowded market for drugs that overcome resistance to hormone therapy.

• Its closest benchmark may be Roche’s giredestrant combined with everolimus, an mTOR inhibitor originally developed by Novartis as Afinitor. The all-oral regimen already has positive Phase 3 evidence and, like Evexta’s combination, attacks both the estrogen receptor and the PI3K/AKT/mTOR survival pathway. Roche

Also notable: Several rival estrogen-receptor degraders have also reached the market:

• Menarini’s elacestrant, the oral SERD that Evexta previously planned to combine with rupitasertib, is approved in Europe and the U.S.
• Eli Lilly’s imlunestrant, another oral SERD, is approved in the U.S.
• Arvinas and Pfizer’s vepdegestrant is approved in the U.S. It is a PROTAC, which recruits the cell’s protein-disposal machinery to remove the estrogen receptor.
• AstraZeneca’s camizestrant, an oral SERD, was approved in the EU in July for patients whose tumors develop an ESR1 mutation during first-line treatment, before the cancer progresses on scans. AstraZeneca also announced this week a partnership with Pathos AI to develop AZD4241, an oral PROTAC that could offer another approach compared to camizestrant.

The bottom line: For Evexta, the test is therefore whether rupitasertib’s dual-node mechanism can turn an old Merck asset into a genuinely differentiated combination in a field where competitors are already reaching the market.