OP-1250 for Advanced Breast Cancer

(OPERA-01 Trial)

Recruiting at 191 trial locations

Overseen By Olema Pharmaceuticals, Inc.

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Olema Pharmaceuticals, Inc.

Must be taking: GnRH agonist

Must not be taking: Chemotherapy, Elacestrant

Disqualifiers: Visceral disease, CNS metastases, Cardiac, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 4 years

510 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called palazestrant (OP-1250) for individuals with advanced breast cancer. It aims to determine if this treatment is safer and more effective than standard treatments like fulvestrant (a hormone therapy) or aromatase inhibitors (such as anastrozole, exemestane, or letrozole). Participants should have breast cancer that has worsened despite previous treatments, including a CDK4/6 inhibitor. This trial targets those whose cancer cannot be cured by surgery or other local treatments and who have hormone receptor-positive (ER+) breast cancer without excessive HER2 protein. As a Phase 3 trial, it represents the final step before FDA approval, offering participants access to a potentially groundbreaking treatment.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, it mentions that participants must have previously received a CDK4/6 inhibitor with endocrine therapy, so you might need to continue certain treatments. It's best to discuss your current medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that Palazestrant (OP-1250) generally has a manageable safety profile, based on previous studies. The side effects are considered acceptable, particularly since patients had already tried several other cancer treatments. While some side effects were reported, they were usually not severe. The treatment also demonstrated potential in fighting tumors, offering hope for those with advanced breast cancer.

This trial is in a later stage, indicating that a substantial amount of safety information is already available. In earlier studies, Palazestrant was tested with other drugs and continued to exhibit a manageable safety profile.

Overall, while every treatment can have side effects, existing data on Palazestrant suggests it is generally well-tolerated. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Palazestrant (OP-1250) is unique because it introduces a novel approach to treating advanced breast cancer by acting as a selective estrogen receptor degrader (SERD). Unlike standard endocrine therapies like anastrozole, exemestane, fulvestrant, and letrozole, which mainly block estrogen production or its effects, Palazestrant targets and degrades estrogen receptors directly. This mechanism may overcome resistance seen in current therapies, potentially offering a more effective option for patients whose cancers have progressed on standard treatments. Researchers are excited about Palazestrant's potential to improve outcomes by providing a new pathway to combat this challenging condition.

What evidence suggests that this trial's treatments could be effective for advanced breast cancer?

Research has shown that palazestrant (OP-1250), which participants in this trial may receive, may help treat advanced breast cancer. In earlier studies, more than half of the tumors shrank significantly with OP-1250 treatment. This drug blocks signals from estrogen receptors, slowing tumor growth, especially in cases with changes in the ESR1 gene. Patients in these studies experienced a period where their cancer did not worsen, known as good progression-free survival. Overall, these findings suggest that OP-1250 could be a helpful option for those whose cancer has progressed after other treatments. ^{3 6 7 8 9}

Who Is on the Research Team?

Medical Director, MD

Principal Investigator

Olema Pharmaceuticals, Inc.

Are You a Good Fit for This Trial?

This trial is for adults with ER+/HER2- advanced breast cancer that's progressed after endocrine therapy and a CDK4/6 inhibitor. Participants need to be in good physical condition (ECOG 0 or 1), have proper organ function, and if male or pre-menopausal female, agree to take hormone-blocking injections.

Inclusion Criteria

I am an adult.

My cancer can be measured or is only in my bones.

I've been treated with a CDK4/6 inhibitor and hormone therapy for advanced cancer.

Exclusion Criteria

My cancer is causing symptoms or organ failure, making me ineligible for hormone therapy.

I need urgent treatment for cancer spread to my brain or spinal cord.

I have no major health issues that could affect my treatment.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose-Selection

Participants are randomized to one of the two doses of palazestrant or to the standard-of-care endocrine therapy to evaluate adverse events, drug discontinuation, and dose reduction

16 weeks

Treatment

Participants receive either palazestrant or standard-of-care endocrine therapy to compare overall survival and progression-free survival

Up to 4 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

What Are the Treatments Tested in This Trial?

Interventions

• Anastrozole
• Exemestane
• Fulvestrant
• Letrozole
• OP-1250 (Palazestrant)

Trial Overview The study compares OP-1250, a new treatment option, against standard treatments like fulvestrant or aromatase inhibitors (Anastrozole, Letrozole, Exemestane) in patients whose breast cancer has worsened despite previous therapies.

How Is the Trial Designed?

Group I: Palazestrant (OP-1250) Experimental Treatment 1 Intervention

Participants will receive Palazestrant

Group II: Standard of Care Endocrine Therapy Active Control 4 Interventions

Participants will receive Investigator's choice of one of the Standard of Care drugs (fulvestrant, anastrozole, letrozole, or exemestane)

Anastrozole is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Arimidex for:

• Breast cancer
• Early breast cancer in postmenopausal women

Approved in United States as Arimidex for:

• Adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer
• First-line treatment of postmenopausal women with hormone receptor-positive or hormone receptor unknown locally advanced or metastatic breast cancer

Approved in Canada as Arimidex for:

• Adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer
• Treatment of postmenopausal women with hormone receptor-positive advanced breast cancer

Approved in Japan as Arimidex for:

• Breast cancer

Who Is Running the Clinical Trial?

Olema Pharmaceuticals, Inc.

Lead Sponsor

Trials

5

Recruited

970+

Published Research Related to This Trial

Letrozole is a new non-steroidal aromatase inhibitor approved in Japan for treating postmenopausal women with breast cancer, particularly effective for those with steroid receptor positive or receptor-unknown locally advanced or metastatic cases.

The drug is generally well-tolerated, with mostly mild side effects such as hot flashes and fatigue, and has shown beneficial results in large international studies for post-surgical endocrine therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Introduction of new drug: letrozole, a new non-steroidal aromatase inhibitor for the treatment of postmenopausal women with breast cancer]. Tsukagoshi, S.[2018]

In a study involving 3697 postmenopausal women with hormone receptor-positive early breast cancer, the upfront treatment with aromatase inhibitors for 5 years did not show superior disease-free survival compared to a switch strategy of 2 years of tamoxifen followed by 3 years of aromatase inhibitors, with 5-year disease-free survival rates of 89.8% and 88.5%, respectively.

No significant differences in efficacy were found among the three aromatase inhibitors (anastrozole, exemestane, and letrozole), suggesting that factors like patient preference and tolerability should guide treatment decisions rather than efficacy alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjuvant anastrozole versus exemestane versus letrozole, upfront or after 2 years of tamoxifen, in endocrine-sensitive breast cancer (FATA-GIM3): a randomised, phase 3 trial. De Placido, S., Gallo, C., De Laurentiis, M., et al.[2019]

The FACE trial is a large-scale study involving 4000 postmenopausal women with hormone receptor-positive, node-positive breast cancer, comparing the efficacy and safety of letrozole and anastrozole over a treatment period of up to 5 years.

The primary goal of the trial is to assess disease-free survival (DFS), while secondary objectives include evaluating overall survival (OS) and the time to distant metastases, which will provide comprehensive insights into the effectiveness of both treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The FACE trial: letrozole or anastrozole as initial adjuvant therapy? Jonat, W., Mundhenke, C.[2018]

Anastrozole and letrozole are effective oral treatments for advanced breast cancer in postmenopausal women, especially when other therapies like tamoxifen have not worked.

Both drugs are claimed to be more effective and less toxic than the standard treatment, megestrol acetate, although the review assesses the validity of these claims.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New aromatase inhibitors for breast cancer. [2019]

Third-generation aromatase inhibitors (AIs) like anastrozole, letrozole, and exemestane have emerged as effective alternatives to tamoxifen for treating postmenopausal breast cancer, particularly in hormone receptor-positive cases, as shown in the ATAC trial with over five years of follow-up.

Fulvestrant, a new type of estrogen receptor antagonist with no partial agonist activity, represents a promising option in breast cancer treatment, and the review discusses future sequencing strategies for using AIs earlier in treatment regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New developments in the treatment of postmenopausal breast cancer. Howell, A.[2018]

Letrozole is an effective treatment for postmenopausal women with early-stage or advanced hormone-sensitive breast cancer, showing a 43% reduction in disease recurrences when used as extended adjuvant therapy beyond standard tamoxifen treatment.

In advanced breast cancer, letrozole outperformed tamoxifen in terms of time to disease progression (9.4 months vs. 6.0 months) and has a similar tolerability profile, making it a recommended first-line therapy according to treatment guidelines.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Letrozole: a review of its use in postmenopausal women with breast cancer. Simpson, D., Curran, MP., Perry, CM.[2018]

In a study involving 713 postmenopausal women with advanced breast cancer, letrozole (2.5 mg/day) demonstrated a significantly higher overall response rate (19.1%) compared to anastrozole (1 mg/day) (12.3%), indicating that letrozole may be more effective as a second-line endocrine therapy.

Despite the improved response rate with letrozole, both treatments showed no difference in time to progression, overall survival, or safety profiles, suggesting that while letrozole is more effective in eliciting responses, both drugs are well tolerated and have similar safety outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An open randomised trial of second-line endocrine therapy in advanced breast cancer. comparison of the aromatase inhibitors letrozole and anastrozole. Rose, C., Vtoraya, O., Pluzanska, A., et al.[2022]

Aromatase inhibitors like anastrozole, letrozole, and exemestane are now the preferred hormonal treatments for estrogen-receptor-positive, postmenopausal metastatic breast cancer, replacing older therapies such as tamoxifen.

Recent studies have confirmed the effectiveness of these aromatase inhibitors in managing breast cancer, highlighting their critical role in targeting the hormonal pathways involved in the disease's progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nonsteroidal and steroidal aromatase inhibitors in breast cancer. Hamilton, A., Volm, M.[2018]

Letrozole, at both 2.5 mg and 10 mg doses, was effective as a neoadjuvant therapy for locally advanced breast cancer, with significant reductions in tumor volume observed in all patients, allowing for breast-conserving surgery.

There were no significant differences in efficacy between the two doses, and both were well-tolerated with no recordable side effects, indicating a favorable safety profile for letrozole in this treatment setting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Letrozole as primary medical therapy for locally advanced and large operable breast cancer. Dixon, JM., Love, CD., Bellamy, CO., et al.[2022]

Citations

1. ir.olema.com ir.olema.com/news-releases/news-release-details/olema-oncology-announces-new-data-phase-1b2-trial-palazestrant

Olema Oncology Announces New Data from the Phase 1b/ ... “We are very pleased with these latest data showing compelling progression-free survival and favorable tolerability of palazestrant plus ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10911704/

Palazestrant (OP-1250), A Complete Estrogen Receptor ... At the highest tested OP-1250 dose, all tumors displayed >50% reduction in tumor volume. OP-1250 blocks ER signaling and proliferation in ESR1-mutant breast ...

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.TPS1131

OPERA-01: A randomized, open-label, phase 3 study of ... A multicenter, randomized, open-label, phase 3 clinical trial comparing the efficacy and safety of palazestrant as a single agent to SOC ET.

4. annalsofoncology.org annalsofoncology.org/article/S0923-7534(23)01395-9/fulltext

382MO Updated results from the phase I/II study of OP ... By March 17, 2023, of 86 pts on OP-1250 (120 mg), 66% had ≥2 prior lines of ET, 30% prior chemotherapy, 67% prior fulvestrant, and 98% prior cyclin-dependent ...

5. breast-cancer-research.biomedcentral.com breast-cancer-research.biomedcentral.com/articles/10.1186/s13058-025-02049-y

Palazestrant, a novel oral Complete Estrogen Receptor ... Here we present the results of a first-in-human, phase 1/2 study investigating palazestrant for the treatment of advanced or metastatic ER+/HER2 ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12210654/

advanced or metastatic breast cancer: phase 1/2 study results Conclusions. Palazestrant demonstrated a manageable safety profile, with antitumor activity observed in patients with heavily pretreated cancers ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT05508906

NCT05508906 | Phase 1b Study of OP-1250 (Palazestrant) ... This is a Phase 1b open-label, 2-part study in 3 treatment groups. The 3 treatment groups are as follows: Treatment Group 1: Palazestrant (OP-1250) in ...

8. esmoopen.com esmoopen.com/article/S2059-7029(24)01002-0/fulltext

212P A phase Ib/II study of palazestrant (OP-1250) in ... This study evaluates the safety, PK, and antitumor activity of palazestrant plus ribociclib in pts with ER+, HER2– MBC (NCT05508906).

9. aacrjournals.org aacrjournals.org/mct/article/23/3/285/734962/Palazestrant-OP-1250-A-Complete-Estrogen-Receptor

Palazestrant (OP-1250), A Complete Estrogen Receptor ... OP-1250 blocks ER signaling and proliferation in ESR1-mutant breast cancer models. A and B, AP mean and SD of indicated homozygous ESR1-mutant Ishikawa ...