Phase 3 Randomized Open-Label Study of OP-1250 Versus Standard of Care in ER+, HER2- Advanced or Metastatic Breast Cancer Post-Endocrine and CDK4/6 Inhibitor Therapy

The primary objective of this study is to evaluate the **safety** of OP-1250 at dose levels of 90 and 120 mg. Additionally, the study aims to compare progression-free survival (PFS), based on a blinded independent review committee (BIRC) assessment, between arms of OP-1250 at the selected dose and standard of care (SOC) treatment. These objectives are clinically relevant as they assess the potential of OP-1250 to provide a safer and more effective treatment option for patients with ER+, HER2- metastatic breast cancer following endocrine and CDK4/6 inhibitor therapy.

Secondary objectives include:

• Evaluating the objective response rate (ORR), duration of response (DoR), disease control rate (DCR), clinical benefit rate (CBR), and PFS based on local investigator assessment of palazestrant at dose levels of 90 and 120 mg.
• Evaluating the pharmacokinetics (PK) of palazestrant at these dose levels.
• Comparing overall survival (OS) between arms of palazestrant at the selected dose and SOC treatment.
• Evaluating PFS and ORR based on BIRC assessment.
• Assessing safety and tolerability, as well as changes from baseline in health-related patient-reported outcomes (PROs).

The clinical trial involves a total of **510 participants** diagnosed with **ER+, HER2- metastatic breast cancer** following endocrine and CDK 4/6 inhibitor therapy. The study population includes both adult female and male participants, with an age range corresponding to categories 3 and 4, indicating a broad adult age group. Participants were selected based on their diagnosis of locally advanced or metastatic breast cancer that is not amenable to curative therapy, and they must have previously received a CDK4/6 inhibitor in combination with endocrine therapy in the advanced setting. The trial includes individuals with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, ensuring they have adequate hematologic, hepatic, and renal functions. Female participants can be pre-, peri-, or postmenopausal, while male and pre- or peri-menopausal female participants are required to take a GnRH (LHRH) agonist. The trial population is characterized by a diverse range of health statuses, and the inclusion of both genders highlights the comprehensive nature of the study. The selection process ensures that participants have evaluable disease, either measurable or bone-only, and are capable of adhering to the study's requirements.

The clinical trial is a **Phase 3 randomized, open-label study** designed to evaluate the efficacy and safety of OP-1250 monotherapy compared to standard of care (SOC) treatments in patients with **ER+, HER2- metastatic breast cancer** following prior endocrine and CDK4/6 inhibitor therapy. The trial aims to assess progression-free survival (PFS) based on a blinded independent review committee (BIRC) assessment and to evaluate the safety profile of OP-1250 at dose levels of 90 mg and 120 mg. The study is expected to commence recruitment on March 31, 2024, and conclude by November 30, 2027.

Participants will be randomly assigned to receive either OP-1250 or SOC treatments, which include **exemestane**, **letrozole**, **anastrozole**, **fulvestrant**, and **goserelin acetate**. The trial will involve a series of study visits, beginning with a screening visit to confirm eligibility based on inclusion criteria such as having ER+, HER2- locally advanced or metastatic breast cancer, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate organ function. Participants must have previously received a CDK4/6 inhibitor in combination with endocrine therapy.

The trial will include regular follow-up visits to monitor safety and efficacy outcomes, including adverse events (AEs), serious adverse events (SAEs), dose modifications, and clinical laboratory parameters. Pharmacokinetic (PK) assessments will be conducted at predefined intervals to determine plasma levels of OP-1250 and establish PK parameters such as Cmax, Cmin, Tmax, and AUC. The end-of-study visit will occur after the completion of the treatment period, which is set at a maximum of 42 days for most treatments, with some extending to 43 days.

Participant involvement is expected to last for the duration of the treatment period, with additional time allocated for follow-up assessments. Conditions that may lead to early termination from the study include the occurrence of unacceptable toxicity, withdrawal of consent, or any other reason deemed necessary by the investigator. The primary endpoints of the study are safety and tolerability, as well as BIRC-assessed PFS. Secondary endpoints include overall survival, local investigator-assessed response rates, and patient-reported outcomes (PROs) using standardized questionnaires.

The clinical trial involves the administration of several **experimental medications** and comparator treatments. **Palazestrant**, also known by its sponsor product code OP-1250, is a film-coated tablet administered orally. It is provided at a maximum daily dose of 120 mg, with a total maximum dose of 141,120 mg over a treatment period of 42 to 43 days. This chemical substance is developed by Olema Pharmaceuticals, Inc. and serves as the test medication in the trial.

**Exemestane** is another film-coated tablet used in the study, administered orally at a maximum daily dose of 25 mg, with a total maximum dose of 31,500 mg over 42 days. It is a chemical substance used as a comparator in the trial.

**Letrozole** is also administered as a film-coated tablet, taken orally at a maximum daily dose of 2.5 mg, with a total maximum dose of 3,150 mg over 42 days. This chemical substance serves as a comparator treatment.

**Anastrozole** is provided in the form of film-coated tablets, administered orally at a maximum daily dose of 1 mg, with a total maximum dose of 1,260 mg over 42 days. It is used as a comparator in the study.

**Fulvestrant** is administered via intramuscular injection at a maximum daily dose of 500 mg, with a total maximum dose of 21,500 mg over 42 days. This chemical substance is used as a comparator treatment.

**Goserelin acetate** is administered as a subcutaneous injection at a maximum daily dose of 3.6 mg, with a total maximum dose of 151.2 mg over 42 days. It is a protein-based substance used as a comparator in the trial.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial aims to evaluate the safety and efficacy of the test medication, Palazestrant, in comparison to the standard-of-care treatments, including the aforementioned comparator medications.

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include safety and tolerability, which will be evaluated through adverse events (AEs), serious adverse events (SAEs), dose modifications, clinical laboratory parameters such as hematology, chemistry, and coagulation, electrocardiograms (ECGs), and vital signs measurements. Additionally, **Progression-Free Survival (PFS)** will be assessed by a Blinded Independent Review Committee (BIRC).

Secondary endpoints will include local investigator-assessed Overall Response Rate (ORR), Duration of Response (DoR), Disease Control Rate (DCR), Clinical Benefit Rate (CBR), and PFS. Plasma levels of OP-1250 will be measured at predefined intervals to establish pharmacokinetic (PK) parameters, including maximum concentration (Cmax), minimum concentration (Cmin), time to reach maximum concentration (Tmax), area under the curve (AUC), and trough concentration at steady state. Overall survival will also be evaluated, along with BIRC-assessed ORR, DoR, and CBR. Safety and tolerability will be further assessed through additional parameters such as performance status and vital sign measurements.

Patient-reported outcomes (PROs) will be assessed using the EORTC-QLQ-C30 and EQ-5D-5L questionnaires. The schedule for measuring these efficacy parameters will be aligned with the trial's protocol, ensuring systematic data collection and analysis throughout the study duration. The trial aims to provide comprehensive data on the efficacy of OP-1250 monotherapy compared to standard of care in treating ER+, HER2- advanced or metastatic breast cancer following endocrine and CDK4/6 inhibitor therapy.