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Published on: August 13, 2019
Palazestrant (OP-1250), A Complete Estrogen Receptor Antagonist, Inhibits Wild-type and Mutant ER-positive Breast
Alison D Parisian1, Susanna A Barratt1, Leslie Hodges-Gallagher1
1Olema Pharmaceuticals, San Francisco, California.
Abstract:
The estrogen receptor (ER) is a well-established target for the treatment of breast cancer, with the majority of patients presenting as ER-positive (ER+). Endocrine therapy is a mainstay of breast cancer treatment but the development of resistance mutations in response to aromatase inhibitors, poor pharmacokinetic properties of fulvestrant, agonist activity of tamoxifen, and limited benefit for elacestrant leave unmet needs for patients with or without resistance mutations in ESR1, the gene that encodes the ER protein. Here we describe palazestrant (OP-1250), a novel, orally bioavailable complete ER antagonist and selective ER degrader. OP-1250, like fulvestrant, has no agonist activity on the ER and completely blocks estrogen-induced transcriptional activity. In addition, OP-1250 demonstrates favorable biochemical binding affinity, ER degradation, and antiproliferative activity in ER+ breast cancer models that is comparable or superior to other agents of interest. OP-1250 has superior pharmacokinetic properties relative to fulvestrant, including oral bioavailability and brain penetrance, as well as superior performance in wild-type and ESR1-mutant breast cancer xenograft studies. OP-1250 combines well with cyclin-dependent kinase 4 and 6 inhibitors in xenograft studies of ER+ breast cancer models and effectively shrinks intracranially implanted tumors, resulting in prolonged animal survival. With demonstrated preclinical efficacy exceeding fulvestrant in wild-type models, elacestrant in ESR1-mutant models, and tamoxifen in intracranial xenografts, OP-1250 has the potential to benefit patients with ER+ breast cancer.
Insights
Palazestrant (OP-1250) is a new oral medication that acts as a complete estrogen receptor (ER) antagonist and degrader. It shows promise for treating ER-positive breast cancer, including resistant forms, with superior efficacy and pharmacokinetics compared to existing therapies.
Area of Science:
- Oncology
- Endocrinology
- Pharmacology
Background:
- Estrogen receptor (ER)-positive breast cancer remains a significant health concern, with current endocrine therapies facing challenges like resistance and suboptimal drug properties.
- Existing treatments such as aromatase inhibitors, fulvestrant, tamoxifen, and elacestrant have limitations, including resistance mutations in ESR1, poor pharmacokinetics, and agonist activity, highlighting the need for novel therapeutic strategies.
- The ESR1 gene encodes the ER protein, and mutations within it are implicated in treatment resistance.
Purpose of the Study:
- To introduce and characterize palazestrant (OP-1250), a novel oral complete ER antagonist and selective ER degrader.
- To evaluate the preclinical efficacy, pharmacokinetic profile, and potential therapeutic benefits of palazestrant in ER-positive breast cancer models, including those with ESR1 mutations.
Main Methods:
- Palazestrant's biochemical binding affinity, ER degradation capabilities, and antiproliferative activity were assessed in ER-positive breast cancer models.
- Pharmacokinetic properties, including oral bioavailability and brain penetrance, were compared to fulvestrant.
- Efficacy was evaluated in xenograft studies using both wild-type and ESR1-mutant ER-positive breast cancer models, including intracranial tumor models.
- Combination therapy with cyclin-dependent kinase 4 and 6 inhibitors was investigated.
Main Results:
- Palazestrant demonstrated comparable or superior ER degradation and antiproliferative activity versus other agents in preclinical models.
- OP-1250 exhibited favorable oral bioavailability and brain penetrance, outperforming fulvestrant in pharmacokinetic studies.
- Palazestrant showed superior efficacy in both wild-type and ESR1-mutant breast cancer xenograft models compared to relevant benchmarks.
- Combination therapy with CDK4/6 inhibitors proved effective, and palazestrant significantly reduced intracranial tumor burden, prolonging survival.
Conclusions:
- Palazestrant (OP-1250) is a promising novel oral agent with complete ER antagonism and degradation properties.
- Its superior preclinical efficacy, pharmacokinetic profile, and effectiveness against resistant mutations position it as a potential new treatment for ER-positive breast cancer.
- Palazestrant warrants further clinical investigation for its potential to address unmet needs in ER-positive breast cancer treatment.
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