Olema Oncology Announces Data Highlighting Palazestrant’s Ability to Inhibit Wild-Type & Mutant ER+ Breast Cancer Both as Monotherapy & in Combination With CDK4/6 Inhibitors

Olema Pharmaceuticals, Inc. recently announced that Molecular Cancer Therapeutics, an American Association for Cancer Research journal, has selected as a featured article a data publication that describes the distinct properties of palazestrant (OP-1250). The paper, titled Palazestrant (OP-1250), a Complete Estrogen Receptor Antagonist, Inhibits Wild-type and Mutant ER-positive Breast Cancer Models as Monotherapy and in Combination, describes the scientific background underlying the design, discovery and optimization of palazestrant.

“The research described in this paper reviews the deliberate design and processes used in discovering and optimizing palazestrant as a molecule purpose-built to address a crucial unmet need in the treatment of women’s cancers, and we are delighted that Molecular Cancer Therapeutics has featured our work,” said David C. Myles, PhD, Olema’s Chief Discovery and Non-Clinical Development Officer. “What’s even more exciting is to see how faithfully the preclinical research predicted the behavior of palazestrant now that it is in late-stage clinical development. We saw the potential then, as told in the paper, and we believe that every day brings us closer to having a real impact transforming the treatment paradigm for women with cancer.”

As part of the discovery and optimization process, palazestrant was assessed across an extensive series of biochemical, cell culture, and in vivo assays comparing it with other antiestrogens and compounds that are either approved for use by the FDA or are currently in clinical development, including aromatase inhibitors, selective ER modulators (SERMs), traditional SERDs, and proteolysis-targeting chimeras (PROTACs). As a CERAN, palazestrant has a distinct mechanism of action (MOA), and though it actively degrades the ER, the paper shows that degradation alone is not a reliable mechanism to drive the efficacy of an endocrine agent. In mouse xenograft models, palazestrant demonstrated excellent pharmacokinetics, was well tolerated, showed synergy with CDK4/6 inhibitors, and was highly effective at reducing tumor growth in both wild-type and ESR1-mutant ER+ breast cancer. In addition, in an ESR1-mutant intercranial xenograft model, palazestrant inhibited tumor growth and improved survival of animals with CNS metastases, even after stopping drug treatment.

The paper can be accessed in the latest print edition of Molecular Cancer Therapeutics or online at https://aacrjournals.org/mct/article/doi/10.1158/1535-7163.MCT-23-0351/731746/Palazestrant-OP-1250-a-Complete-Estrogen-Receptor.

Palazestrant (OP-1250) is a novel, orally-available small molecule with dual activity as both a complete estrogen receptor (ER) antagonist (CERAN) and selective ER degrader (SERD). It is currently being investigated in patients with recurrent, locally advanced or metastatic ER-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer. In clinical studies, palazestrant completely blocks ER-driven transcriptional activity in both wild-type and mutant forms of metastatic ER+ breast cancer and has demonstrated anti-tumor efficacy along with attractive pharmacokinetics and exposure, favorable tolerability, CNS penetration, and combinability with CDK4/6 inhibitors. Palazestrant has been granted U.S. Food and Drug Administration (FDA) Fast Track designation for the treatment of ER+/HER2- metastatic breast cancer that has progressed following one or more lines of endocrine therapy with at least one line given in combination with a CDK4/6 inhibitor. It is currently being evaluated both as a single agent in an ongoing Phase 3 clinical trial, OPERA-01, and in Phase 2 combination studies with CDK4/6 inhibitors (palbociclib and ribociclib) and a PI3Ka inhibitor (alpelisib). For more information, visit www.opera01study.com.

Olema Oncology is a clinical-stage biopharmaceutical company committed to transforming the standard of care and improving outcomes for women living with cancer. Olema is advancing a pipeline of novel therapies by leveraging our deep understanding of endocrine-driven cancers, nuclear receptors, and mechanisms of acquired resistance. In addition to our lead product candidate, palazestrant (OP-1250), a proprietary, orally-available complete estrogen receptor (ER) antagonist (CERAN) and a selective ER degrader (SERD), Olema is developing a potent KAT6 inhibitor. Olema is headquartered in San Francisco and has operations in Cambridge, Massachusetts. For more information, visit www.olema.com.