Clinical-stage biopharma Olema Oncology’s (Nasdaq:OLMA) lead product candidate is OP-1250, an orally-available small molecule that recently won FDA Fast Track Designation for the treatment of ER+/HER2– metastatic breast cancer.
OP-1250 is a complete estrogen receptor antagonist with combined activity as a complete estrogen receptor (ER) antagonist (CERAN) and a selective ER degrader (SERD).
The drug candidate competes with estrogen for binding to the estrogen receptor to ensure it remains in an inactive state. It thus differs from drugs such as tamoxifen that do not completely inactivate the receptor.
The Fast Track Designation specifically covers human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer that has progressed after patients receive at least one line of endocrine therapy. In addition, patients should receive at least one line of therapy with a cyclin-dependent kinase (CDK) 4/6 inhibitor.
Tens of thousands of U.S. patients meet that criteria every year, said Cyrus Harmon, co-founder and chief technology officer of Olema Oncology.
Potential broad opportunity for breast cancer in the long-run
For decades, scientists have known that the estrogen receptor is an important protein in the progression of estrogen-receptor-positive breast cancer.
OP-1250 could thus eventually find use in a larger number of breast cancer patients. “The broad opportunity is for all estrogen-receptor-positive breast cancers,” Harmon said in a recent interview. “OP-1250 has broad potential to be used throughout the spectrum of ER-positive breast cancer.”
Assuming the drug candidate ultimately wins FDA approval as a second-line therapy for ER+/HER2– breast cancer patients, Olema Oncology plans on continuing OP-1250 in clinical trials, comparing it to other standard-of-care treatments.
“There’s certainly potential for the drug to move into earlier settings down the road as well,” Harmon said.
There is historical precedent for endocrine agents for ER-positive breast cancer winning approval and then finding wider use over time. For instance, tamoxifen and FDA-approved aromatase inhibitors have eventually won authorization for adjuvant use in early breast cancer.
OP-1250 is now in a Phase 1/2 study and a Phase 1b study that is testing the drug candidate with Ibrance (palbociclib), which selectively inhibits CDK4 and CDK6.
In June, San Francisco–headquartered Olema announced a clinical trial update for OP-1250. The study found that it offered favorable tolerability and worked well with CDK4/6 inhibitor palbociclib across initial dose escalation cohorts. In addition, there were no dose-limiting toxicities and no induced metabolism of palbociclib.
The company is planning on launching a pivotal monotherapy study in 2023.
Where OP-1250 fits into the breast cancer treatment landscape
While current breast cancer drugs such as tamoxifen, fulvestrant and aromatase inhibitors have their place, they have limitations. “We think OP-1250 may improve on each of those drugs in material ways,” Harmon said.
The emergence of activating mutations in the estrogen receptor is one of the primary mechanisms of resistance to aromatase inhibitors and the estrogen-receptor antagonist fulvestrant. “When that happens, the aromatase inhibitors don’t work as well because the receptor is active without estrogen, and fulvestrant doesn’t work as well because you need more drug to counter the action of the mutant receptor.”
The emergence of CDK 4/6 inhibitors such as abemaciclib (Verzenio), palbociclib (Ibrance) and ribociclib (Kisqali), when combined with endocrine therapy, has led to benefits in terms of progression-free survival and overall survival in hormone receptor-positive, HER2-negative metastatic breast cancers.
“OP-1250 has great potential both as monotherapy and as the preferred combination partner with other targeted therapies for ER-positive breast cancer,” Harmon said.