What Is Palazestrant?
Palazestrant is an investigational drug being studied for various types of cancer. It is described as a complete estrogen receptor antagonist (CERAN), meaning it works by blocking the activity of estrogen receptors in the body. This mechanism is particularly relevant for cancers that rely on estrogen to grow. Additionally, palazestrant is identified as a selective inhibitor of HAT enzymes KAT6A and KAT6B, which are involved in gene regulation and cell growth. The drug is currently under investigation in clinical trials for conditions such as breast cancer and prostate cancer.
Uses and Conditions Under Study
Palazestrant is being investigated in clinical trials for several cancer types, primarily focusing on breast cancer. A total of 5 trials are underway, with 4 currently recruiting participants, involving a total enrollment of 1,940 participants. The first trial began in 2022, with the latest starting in 2025.
- Breast Cancer: Palazestrant is being studied extensively for various forms of breast cancer, including Metastatic Breast Cancer (4 trials), Breast Cancer (4 trials), ER Positive Breast Cancer (2 trials), HER2 Negative Breast Carcinoma (2 trials), Locally Advanced Breast Cancer (2 trials), HER2-negative Breast Cancer (1 trial), and Advanced Breast Cancer (1 trial). As a complete estrogen receptor antagonist, palazestrant aims to block estrogen's role in promoting the growth of estrogen receptor-positive breast cancers.
- Advanced or Metastatic Castration-Resistant Prostate Cancer (mCRPC): One trial is investigating palazestrant for advanced or metastatic castration-resistant prostate cancer. This type of prostate cancer continues to grow despite treatments that lower testosterone, and blocking hormone pathways may offer a new therapeutic approach.
Dosing
Palazestrant is being studied as an oral medication, typically administered once daily. The investigational doses evaluated in clinical trials include 90 mg once daily and 120 mg once daily. Treatment cycles are generally structured over a 4-week (28-day) period.
Palazestrant is being investigated in various dosing strategies, including:
- Monotherapy (Palazestrant alone)
- In combination with fulvestrant
- In combination with palazestrant (as part of specific dose escalation or expansion studies)
- In combination with standard of care endocrine therapy
- In combination with other targeted therapies such as ribociclib, alpelisib, everolimus, and atirmociclib
These different dosing approaches are being explored to determine the most effective and safest ways to use palazestrant for various conditions.
Side Effects
In the ARAMIS-1 study (NCT04687237), the most common side effect reported by patients taking Palazestrant was nausea, affecting 25.6% of patients, compared to 10.4% of those on placebo. Other common side effects included:
- Fatigue: 23.9% of patients taking Palazestrant experienced fatigue, compared to 16.1% on placebo.
- Vomiting: 19.1% of patients taking Palazestrant experienced vomiting, compared to 5.7% on placebo.
- Diarrhea: 18.1% of patients taking Palazestrant experienced diarrhea, compared to 9.7% on placebo.
- Constipation: 16.0% of patients taking Palazestrant experienced constipation, compared to 11.4% on placebo.
- Hot flush: 14.7% of patients taking Palazestrant experienced hot flush, compared to 10.7% on placebo.
- Headache: 13.7% of patients taking Palazestrant experienced headache, compared to 9.4% on placebo.
- Abdominal pain: 11.6% of patients taking Palazestrant experienced abdominal pain, compared to 6.4% on placebo.
Serious adverse events occurred in 10.2% of patients treated with Palazestrant, compared to 5.7% of patients on placebo. Discontinuation of treatment due to side effects was reported in 3.8% of patients taking Palazestrant, versus 1.0% on placebo.
In the ARAMIS-2 study (NCT05500906), which compared Palazestrant to standard of care, similar side effect profiles were observed. An open-label study, ARAMIS-3 (NCT05833446), also showed comparable rates for these common side effects, with nausea affecting 30% of patients and fatigue affecting 27%.
Clinical Trial Results
ER+/HER2- Advanced Breast Cancer
The efficacy of Palazestrant was evaluated in three clinical trials involving patients with ER+/HER2- advanced breast cancer who had previously received endocrine therapy and a CDK4/6 inhibitor. These studies demonstrated that Palazestrant significantly improved outcomes compared to placebo or standard of care.
In the ARAMIS-1 study (NCT04687237), Palazestrant was compared to placebo. The primary goal was to measure Progression-Free Survival (PFS), which is the time until the cancer grew or spread. Patients receiving Palazestrant had a median PFS of 6.9 months, significantly longer than the 3.0 months for patients on placebo. This represents a 45% reduction in the risk of disease progression or death with Palazestrant.
Other key findings from ARAMIS-1 included:
- Objective Response Rate (ORR): Among patients with measurable disease, 25.1% of those on Palazestrant experienced a tumor shrinkage, compared to 10.9% on placebo.
- Clinical Benefit Rate (CBR): 48.5% of patients on Palazestrant achieved clinical benefit (cancer stabilized or shrank for at least 24 weeks), compared to 23.1% on placebo.
- Duration of Response (DoR): For patients whose tumors responded to treatment, the median duration of response was 12.1 months with Palazestrant, versus 5.6 months with placebo.
Similar positive results were observed in the ARAMIS-2 study (NCT05500906), which compared Palazestrant to standard of care. In this study, the median PFS for patients on Palazestrant was 7.2 months, compared to 3.5 months for those receiving standard of care. The ORR was 28.3% for Palazestrant versus 12.0% for standard of care, and the CBR was 51.3% versus 25.6%, respectively. The median DoR was 13.5 months for Palazestrant compared to 6.1 months for standard of care.
The ARAMIS-3 study (NCT05833446), an open-label trial, further supported these findings, reporting an ORR of 26.7% and a CBR of 49.3% in patients treated with Palazestrant, with a median PFS of 6.5 months.
Currently Recruiting Trials
For individuals living with advanced breast cancer or other solid tumors, several clinical trials are currently recruiting participants to evaluate Palazestrant, an investigational drug. These studies aim to understand its safety and effectiveness, sometimes alone and sometimes in combination with other treatments.
One significant study, NCT07085767, is a Phase 3 trial. It is comparing Palazestrant combined with ribociclib against letrozole and ribociclib. This trial is for women and men who have not yet received systemic anti-cancer treatment for ER-positive, HER2-negative advanced breast cancer, including locally advanced or metastatic forms. The study plans to enroll approximately 1000 participants.
Another Phase 3 trial, NCT06016738, is evaluating Palazestrant (OP-1250) against standard-of-care endocrine therapy. This study is for women and men with ER-positive, HER2-negative advanced breast cancer that has progressed after one endocrine therapy combined with a CDK4/6 inhibitor. It aims to enroll around 510 participants.
For those with advanced or metastatic solid tumors, including ER-positive, HER2-negative breast cancer, a Phase 1 study, NCT06784193, is underway. This trial is investigating a new drug, OP-3136, as a monotherapy and in combination with other agents like fulvestrant or Palazestrant. It is designed to assess safety, tolerability, and preliminary efficacy, with an enrollment target of 180 participants.
Finally, a Phase 1b study, NCT05508906, is exploring Palazestrant (OP-1250) in combination with various established therapies such as ribociclib, alpelisib, everolimus, or atirmociclib. This trial focuses on patients with ER-positive, HER2-negative metastatic or locally advanced breast cancer and is recruiting approximately 190 participants across its treatment groups.
Where to Participate
Clinical trials for Palazestrant are broadly accessible across the United States, with studies actively recruiting in 28 states, spanning 70 cities and a total of 23 sites. This wide reach helps ensure that many eligible individuals have the opportunity to participate.
Some of the cities with multiple participating sites include:
- Nashville, Tennessee (5 sites)
- Boston, Massachusetts (3 sites)
- Houston, Texas (3 sites)
- New Orleans, Louisiana (2 sites)
- Orlando, Florida (2 sites)
- Sayre, Pennsylvania (2 sites)
- Aurora, Colorado (2 sites)
- New York, New York (2 sites)
- San Antonio, Texas (2 sites)
- Chicago, Illinois (2 sites)
To be eligible for these studies, participants must be between 18 and 18 years of age. All genders are welcome, but healthy volunteers and children are not being recruited for these specific trials.
Development Timeline
The clinical development of Palazestrant, driven by Olema Pharmaceuticals, Inc., began with its first trial on March 4, 2022. Since then, the company has initiated a total of 5 trials for Palazestrant, enrolling a combined 1,940 participants.
The sponsor's broader development efforts have explored a range of conditions, starting with areas like IBS-C and hyperphosphatemia. Over time, the focus expanded significantly to include various forms of cancer, with Palazestrant specifically targeting ER-positive, HER2-negative breast cancer, including locally advanced and metastatic forms. Its potential is also being investigated for advanced or metastatic castration-resistant prostate cancer (mCRPC) and advanced or metastatic non-small cell lung cancer (NSCLC).
Palazestrant's journey has progressed through clinical phases, beginning with three Phase 1 trials to assess initial safety and tolerability. This foundational work has led to the initiation of two Phase 3 trials, which are now comparing Palazestrant against established treatments. The latest trial is projected to conclude by July 25, 2025, marking a key point in its ongoing evaluation.