Olema Pharmaceuticals (NASDAQ:OLMA) CEO Sean Bohen outlined the company’s focus on advancing endocrine therapies for ER-positive, HER2-negative breast cancer during a discussion at Citi’s Virtual Oncology Summit, highlighting two ongoing phase III trials for its lead drug palazestrant and providing updates on a separate early-stage KAT6 inhibitor program.
Company focus and late-stage palazestrant program
Bohen said Olema is focused on “improving the standard of care and improving the lives” of patients with ER-positive, HER2-negative breast cancer. The company’s lead asset, palazestrant, is described as a “complete estrogen receptor antagonist” administered as a once-daily oral pill.
- OPERA-01: A monotherapy trial expected to read out in the fall. It compares palazestrant to physician’s choice of fulvestrant or exemestane in the second- or third-line setting after progression on a CDK4/6 inhibitor plus endocrine therapy.
- OPERA-02: A first-line trial currently enrolling, comparing ribociclib (KISQALI) plus an aromatase inhibitor versus ribociclib plus palazestrant. Bohen estimated the earliest readout could be around 2028, “maybe more likely 2029,” noting that assumptions about control-arm performance could influence timelines.
How Olema describes palazestrant’s differentiation
Bohen emphasized that the key to maximizing inhibition of the estrogen receptor is complete antagonism—keeping receptor signaling “off all the time.” He contrasted complete antagonists with other endocrine approaches, noting that aromatase inhibitors reduce peripheral estrogen rather than directly inhibiting receptor signaling, and that some agents have partial agonist/antagonist activity depending on context.
He said pharmacokinetics and tolerability are also critical to maintaining continuous blockade, particularly in ESR1-mutant disease where the receptor can become constitutively active. Bohen highlighted palazestrant’s “eight-day half-life” and “very high exposure” at trough as advantages, arguing that the ability to sustain exposure depends on a clean tolerability profile.
He also pointed to combination flexibility as a distinguishing characteristic, stating Olema has not had to reduce doses when combining palazestrant with multiple agents, including ribociclib, palbociclib, alpelisib, and everolimus, and noted additional combinations under evaluation.
Competitive context: lidERA and implications for first-line trials
Asked about Roche’s giredestrant data and the evolving oral SERD landscape, Bohen said a key challenge in the field has been limited randomized controlled trial evidence in the ESR1 wild-type setting among endocrine-resistant patients post-CDK4/6 therapy. He said Olema’s phase II results support its ongoing phase III strategy, citing activity in both ESR1 wild-type and mutant disease as monotherapy and in combination with ribociclib.
Discussing Roche’s lidERA trial, Bohen called the results “excellent” and “a compelling demonstration” that giredestrant at its 30 mg dose improved patient benefit versus an aromatase inhibitor in the adjuvant setting. He framed lidERA as answering a question about whether next-generation agents can outperform aromatase inhibitors, saying the data suggest they can.
However, he cautioned that translating adjuvant results to metastatic first-line outcomes is complex due to differences in disease burden and prior treatment exposure. He noted that first-line metastatic populations are often endocrine-sensitive but not necessarily endocrine-naïve, with many patients having received prior adjuvant endocrine therapy, while a smaller subset is de novo metastatic and endocrine-naïve. Still, he said there is “some positive read-through” from lidERA to first-line metastatic trials, though the magnitude is difficult to gauge.
Bohen added that even a “decent trend toward positivity” in a competing first-line study could be encouraging for palazestrant, arguing Olema has shown strong comparative activity in combination settings and attributing this to the drug’s molecular and pharmacokinetic properties.
OPERA-01: Market opportunity, endpoints, and analysis approach
Bohen described the second-/third-line setting as a substantial market and unmet need, driven by the clinical goal of delaying chemotherapy as long as possible. He said endocrine monotherapy is commonly used after progression on first-line CDK4/6 plus endocrine therapy, which is the setting OPERA-01 is testing.
He cited prior Olema data in a second-/third-line population, including patients who could have received chemotherapy, reporting progression-free survival of 7.3 months in an ESR1-mutant subset and 5.5 months in an ESR1 wild-type subset. He estimated the broader market opportunity at about $5 billion annually, with the ESR1-mutant segment around $2 billion and representing roughly 40% of patients. He characterized the ESR1 wild-type segment as “completely unaddressed” and “wide open.”
For OPERA-01, Bohen said the bar is approximately a two-month improvement in median progression-free survival versus standard of care. He estimated fulvestrant or exemestane post-CDK4/6 would be about two to three months, implying four to five months could support approval and adoption. He also noted OPERA-01 excludes prior chemotherapy and requires patients to have been on their prior endocrine therapy for at least six months, which he said could support the trial’s likelihood of success.
On analysis, Bohen said Olema has not disclosed the full statistical plan but confirmed the trial will test ESR1-mutant and ESR1 wild-type populations separately rather than as a combined intent-to-treat analysis. He argued prior mixed-population approaches have tended to yield benefit driven primarily by the ESR1-mutant subset, influencing labels that do not reflect wild-type efficacy.
Commercial plans and pipeline: KAT6 inhibitor OP-3136 and future research
If OPERA-01 is positive, Bohen said the company plans to file on its own in the U.S. and EU and is building commercial infrastructure for a potential U.S. launch next year. He said Olema would seek a collaborator for markets outside the U.S. to enable broader global access, noting potential deal structures could include profit sharing or co-promotion terms.
Bohen also discussed OP-3136, an oral KAT6 inhibitor in phase I dose escalation moving toward phase II. He contrasted Olema’s approach with Pfizer’s KAT6 molecule, which he said has shown encouraging efficacy but faced tolerability challenges including cytopenias and dysgeusia, leading to a high level of dose reductions at Pfizer’s phase III dose. Olema’s strategy, he said, is to target KAT6A/B and KAT7 while “dialing out” other targets in an effort to improve tolerability and combinability.
He said upcoming OP-3136 updates are expected around late Q2, primarily from monotherapy cohorts. He also noted the monotherapy trial includes not only ER-positive, HER2-negative breast cancer but also castration-resistant prostate cancer and non-small cell lung cancer, reflecting preclinical activity seen in other tumor types.
Finally, Bohen said Olema continues to run a research program focused on ER-positive, HER2-negative breast cancer and plans to announce additional pipeline assets once they reach development candidate or IND-enabling stages. On the question of an adjuvant palazestrant trial, he said it is not something the company can dismiss but emphasized the scale and cost of such a study—particularly if combination with a CDK4/6 inhibitor is required—would be challenging for Olema at present and could depend on future collaboration opportunities and additional readouts in the field.
About Olema Pharmaceuticals (NASDAQ:OLMA)
Olema Pharmaceuticals, Inc, a clinical-stage biopharmaceutical company, focuses on the discovery, development, and commercialization of therapies for women’s cancers. Its lead product candidate is OP-1250, an estrogen receptor (ER) antagonist and a selective ER degrader, which is in Phase 3 clinical trial for the treatment of recurrent, locally advanced, or metastatic estrogen receptor-positive, human epidermal growth factor receptor 2-negative breast cancer; and OP-1250 combine with CDK4/6 inhibitors palbociclib, ribociclib, and alpelisib in Phase 1/2 clinical trial for the treatment of recurrent, locally advanced, or metastatic estrogen receptor-positive human epidermal growth factor receptor 2-negative breast cancer, as well as develops OPERA-01 for the of ER+/HER2- advanced or metastatic breast cancer.
