Focusing on a superior scientific approach targeting ER+ breast cancer.

Many forms and stages of cancer continue to elude control. Malignant cells adapt and exploit mutations and redundancies, so partial targeting leaves vulnerabilities. Despite availability of endocrine therapies for advanced or metastatic breast cancer, there remains a critical unmet need for more effective and convenient treatment options that improve both the patient experience and health outcomes.

At Olema, we are committed to improving outcomes for people with metastatic breast cancer. Palazestrant (OP-1250) is a novel investigational agent with combined activity as both a next-generation complete estrogen receptor antagonist (CERAN) and a selective estrogen receptor degrader (SERD), which we believe will drive deeper, more durable responses than currently available therapies.

Understanding estrogen receptors

The estrogen receptor (ER) resides in the nucleus of the cell and functions as a ligand-regulated transcription factor that includes two transcriptional activation domains – AF1 and AF2. When bound to estrogen, the ER directs the expression of genes that are essential for breast cancer cells’ survival and proliferation. The normal biology of estrogen receptor signaling is vital for normal reproductive and bone health.

The estrogen receptor (ER) is a nuclear receptor that functions as a ligand-regulated transcription factor and includes two transcriptional activation domains – AF1 and AF2. When bound to estrogen, the ER directs the expression of genes that are essential for breast cancer cells’ survival and proliferation. Usually, the process works smoothly to keep women healthy, from puberty and childbearing to bone health.

For the approximately 80% of breast cancers categorized as estrogen receptor-positive (ER+), the treatment of choice is endocrine therapy that directly or indirectly targets ER activation.

Currently available FDA-approved endocrine treatments for ER+ breast cancer seek to stop estrogen from fueling cancer growth by either preventing the body from producing estrogen or by attempting to block the estrogen receptor. Partial agonists of the ER, like tamoxifen, prevent activation of the AF2 function but do not block AF1 activity, leaving the ER vulnerable to transcriptional activation which could lead to cancer cell growth and proliferation.

Olema’s palazestrant (OP-1250) takes a complete antagonist approach

Our team at Olema has spent the past decade characterizing the structure and function of the estrogen receptor to develop more potent therapies that completely inactivate this signaling pathway. Our lead investigational asset, palazestrant, is a novel oral compound with combined activity as both an advanced complete estrogen receptor antagonist, or a CERAN, that completely blocks the estrogen receptor and the signaling pathway, and a selective estrogen receptor degrader, or SERD, which we believe could lead to more durable and deeper anti-tumor activity.

Our team at Olema has spent the past decade characterizing the structure and function of the estrogen receptor to develop more potent therapies that completely inactivate this signaling pathway. Our lead investigational asset, palazestrant, is a novel oral compound with combined activity as both an advanced complete estrogen receptor antagonist, or a CERAN, that completely blocks the estrogen receptor and the signaling pathway, and a selective estrogen receptor degrader, or SERD, which we believe could lead to more durable and deeper anti-tumor activity.

Accelerating clinical advances

Through our investigative work, our team at Olema is focused on addressing the challenges of existing therapies for ER+ breast cancer and generating data to guide the development of next generation therapies. We have presented data at numerous medical and scientific congresses from our ongoing clinical studies of palazestrant in patients with advanced breast cancer, both as a single agent and in combination with CDK4/6 inhibitors. In preclinical models, we have demonstrated that palazestrant is an active drug and achieves sufficient exposure levels to completely antagonize the ER and block the ER-mediated cancer cell growth and proliferation signal.

The clinical trial data to date support palazestrant’s potential as a once-daily oral monotherapy in people with recurrent, locally advanced or metastatic ER+/HER2- breast cancer, with favorable pharmacokinetics and tolerability, and anti-tumor activity in a heavily pretreated patient population.

Based on these encouraging data, we initiated our first pivotal Phase 3 trial, OPERA-01, which tests palazestrant as a monotherapy in the second- and third-line metastatic setting. In parallel, we are continuing to study palazestrant in combination with CDK4/6 inhibitors, palbociclib and ribociclib.

Recent research

View our publications to learn more about our recent research.