After multiple high-profile clinical trial terminations for selective estrogen receptor degraders (SERDs) in breast cancer, Olema Oncology is taking a stab at the notoriously hard-to-treat disease with a new dual-mechanism approach.

Olema plans to run two Phase III trials of its lead candidate OP-1250 in ER-positive, HER2-negative breast cancer, CEO Sean Bohen tells Clinical Trials Arena. OP-1250 is both a SERD and a complete estrogen receptor antagonist (CERAN), which Bohen says could more effectively block the estrogen receptor than the single mechanism of a SERD.

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Olema Oncology CEO Sean Bohen

In the past year, most trials pursuing the SERD mechanism in breast cancer have been ill-fated. Sanofi terminated a Phase III trial of amcenestrant last month, shortly after Roche’s SERD giredestrant failed a Phase II study. And last October, Novartis terminated a Phase I trial of the SERD LSZ102. However, Radius Health’s elacestrant had the first Phase III success for oral SERDs, leading to a Prescription Drug User Fee Act (PDUFA) date of February 17.

Meanwhile, Olema is eyeing two different Phase III strategies for OP-1250 in the same indication. The first trial, slated for mid-2023, will test OP-1250 as a second- and third-line monotherapy for patients who have previously used a CDK4/6 inhibitor, Bohen says. The second trial will combine OP-1250 with a CDK4/6 inhibitor and could start as early as 2024, he adds.

Looking ahead, Bohen says these planned Phase III trials could position OP-1250 as a long-term treatment option in breast cancer: “Our vision for OP-1250, as it moves into earlier lines of therapy, is that women will be taking this drug daily for years.”

Early data sets stage for upcoming trials

In Q4, Olema will release data from the dose expansion phase of an ongoing Phase I/IIa trial (NCT04505826), Bohen says. As part of the release, Olema will announce the recommended Phase II dose is 120mg orally once-a-day, he adds. In preliminary data from the Phase Ia portion, OP-1250 demonstrated orally availability with an effective half-life of 2–3 days.

Meanwhile, Olema is also testing OP-1250 in combination with Pfizer’s CDK4/6 inhibitor Ibrance (palbociclib) in a 30-subject Phase I trial (NCT05266105). The study has an estimated primary completion date of January 2023, according to

Though Olema has not yet finalized plans for the forthcoming Phase III trials, Bohen says the first Phase III study of OP-1250 as a monotherapy could enroll in the range of 300–450 patients, as is standard in the field. Olema has around $250 million cash on hand, which the biotech will use to fund this Phase III study, he adds.

As for the first-line Phase III trial of OP-1250, Olema will likely seek a partner to provide capital, Bohen says. Olema’s ideal partner will also have global marketing and commercialization capabilities and potentially provide a CDK4/6 inhibitor, he adds. Though Olema has not finalised a trial initiation date, the study could begin as early as 2024, he notes.

Estrogen receptor target in breast cancer

Olema’s two potential Phase III trials come amid growing interest in estrogen receptor antagonist trials. The percentage of breast cancer drug trials targeting HER2- breast cancer with estrogen receptor agonists reached an all-time high in 2022, according to GlobalData’s Clinical Trials Database. Meanwhile, Phase III trials more than doubled from 1% of trials in 2013 to 2.3% in 2022. Phase GlobalData is the parent company of Clinical Trials Arena.

Though the class of oral SERDs has faced some trial setbacks, experts say optimism remains high. Meanwhile, the need for new treatments in ER+, HER2- breast cancer looms large.