Evaluation of Elacestrant and Olaparib in Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer with gBRCA1/2 Mutations
- Trial ID
- 2023-504925-38-00
- Protocol
- GBG 114
- Sponsor
- GBG Forschungs GmbH
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase II study is to evaluate the impact on **progression-free survival (PFS)** of combining elacestrant, an oral selective estrogen receptor degrader (SERD), with olaparib, compared to olaparib alone in patients with hormone receptor (HR)-positive, HER2-negative locally advanced or metastatic breast cancer with gBRCA1/2 mutations. This is clinically relevant as improving PFS can potentially lead to better management of the disease and delay in progression, which is crucial for patient outcomes.
Secondary objectives include:
- Comparing time to treatment failure (TTF) between treatment arms (elacestrant + olaparib vs. olaparib).
- Comparing overall survival (OS) between treatment arms.
- Assessing and comparing patient-reported outcomes (PRO) and quality of life (QoL) between treatment arms.
- Comparing PFS, TTF, and OS in minimization subgroups based on pre-treatment chemotherapy in the metastatic setting (yes vs. no).
- Comparing PFS, TTF, and OS in exploratory subgroups, including prior fulvestrant therapy and ESR1 wild type vs. mutant.
- Comparing objective response rate (ORR) between treatment arms.
- Comparing clinical benefit rate (CBR) between treatment arms.
- Assessing and comparing safety between treatment arms.
- Assessing and comparing compliance between treatment arms.
Participants
The clinical trial involves **patients with hormone receptor (HR)-positive, HER2-negative locally advanced or metastatic breast cancer** with gBRCA1/2 mutations. The study population includes both female and male participants, aged 18 years and older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. Participants are required to have a life expectancy of more than six months and must have centrally confirmed locally advanced or metastatic breast cancer that is HR-positive and HER2-negative. The trial population was selected based on the presence of deleterious or suspected deleterious gBRCA1/2 mutations detected through local testing. Participants must be willing and able to provide archived formalin-fixed paraffin-embedded tissue from a tumor or metastasis. The trial does not specify the total number of participants, as the sponsor has not provided this information. Both genders are included, and the study considers vulnerable populations. Participants' lifestyle considerations, such as diet and physical activity, are not detailed in the available data.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the efficacy of adding **elacestrant**, a selective estrogen receptor degrader (SERD), to standard-of-care **olaparib** in patients with hormone receptor (HR)-positive, HER2-negative locally advanced or metastatic breast cancer with gBRCA1/2 mutations. The primary objective is to assess progression-free survival (PFS) when elacestrant is combined with olaparib compared to olaparib alone. The trial is expected to commence recruitment on December 15, 2024, and conclude by December 15, 2028, with a maximum treatment period of 48 weeks for participants.
Participants will undergo a sequence of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, cancer status, and genetic mutations. Following randomization, participants will attend regular follow-up visits to monitor treatment efficacy and safety, including assessments of PFS, time to treatment failure (TTF), overall survival (OS), and quality of life (QoL) using the FACT-ES scale. The end-of-study visit will occur upon completion of the treatment period or earlier if specific conditions arise.
The expected length of participant involvement is up to 48 weeks, with conditions for early termination including disease progression, treatment toxicity, patient preference, or death. Participants lost to follow-up or progression-free at the study's end will be censored at the last contact date. The trial will adhere to ethical standards, requiring informed consent and compliance with local regulatory requirements. The study will ensure the resolution of acute toxic effects from prior therapies to NCI CTCAE version 5.0 grade ≤ 1 before enrollment, except for alopecia or other non-safety risk toxicities.
Treatment
The clinical trial involves the administration of **Lynparza** (olaparib), a **PARP** (poly [adenosine diphosphate-ribose] polymerase) inhibitor, in the form of 150 mg film-coated tablets. The pharmaceutical form is designed for **oral** administration. The maximum daily dose of Lynparza is 600 mg, and the treatment period extends up to 48 weeks. Lynparza is manufactured by AstraZeneca AB and is authorized for use in the European Union under the marketing authorization number EU/1/14/959/005. The active substance, olaparib, is of chemical origin and is classified under the ATC code L01XX46.
In addition to Lynparza, the trial includes the administration of **Elacestrant**, a selective estrogen receptor degrader (**SERD**), also in the form of film-coated tablets. Elacestrant is administered orally, with a maximum daily dose of 400 mg, and the treatment period is similarly set at 48 weeks. The active substance in Elacestrant is elacestrant dihydrochloride, which is of chemical origin. This medication is produced by Stemline Therapeutics, Inc. and is identified by the product number PRD10200789. Elacestrant is not a pediatric formulation and is not classified as an orphan drug.
Both medications are administered orally, and participant compliance is monitored throughout the trial to ensure adherence to the dosing schedule. The trial aims to evaluate the impact on progression-free survival (PFS) of combining elacestrant with olaparib compared to olaparib alone in patients with hormone receptor (HR)-positive, HER2-negative locally advanced or metastatic breast cancer with gBRCA1/2 mutations.
Efficacy
Efficacy in this clinical trial will be assessed primarily through **Progression-Free Survival (PFS)**, which is defined as the time from randomization to the first progression of the disease as assessed by the investigator, or death, whichever occurs first. Patients who are lost to follow-up or remain progression-free at the end of the study will be censored at the date of last contact. Secondary endpoints include **Time to Treatment Failure (TTF)**, **Overall Survival (OS)**, patient-reported breast cancer-specific quality of life as measured by the FACT-ES scale, **Objective Response Rate (ORR)**, and **Clinical Benefit Rate (CBR)**. TTF is defined as the time from randomization to discontinuation of treatment due to disease progression, treatment toxicity, patient's preference, or death. OS is defined as the time from randomization to death due to any reason. ORR is the percentage of patients who achieve either a confirmed complete response or partial response, while CBR includes patients who achieve a confirmed complete response, partial response, or stable disease for at least 24 weeks from randomization.
The frequency and severity of adverse events will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. Additionally, dose reductions, dose delays, treatment interruptions, and treatment discontinuation rates will be monitored. These efficacy parameters will be collected and analyzed at various time points throughout the study, with specific schedules for measurement and data collection as per the trial protocol. The trial aims to evaluate the impact of adding elacestrant to standard-of-care olaparib in patients with hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer with gBRCA1/2 mutations.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Written informed consent prior to beginning specific protocol procedures, including expected cooperation of the patients for scheduled visit, the treatment and follow-up, must be obtained and documented according to the local regulatory requirements.
- Female or male patients.
- Age at study entry of at least 18 years.
- Centrally confirmed locally advanced or metastatic breast cancer that is HR-positive (ER and/or PgR ≥ 10% of stained cells at IHC) and HER2-negative (IHC 0 or 1+, or 2+ and ISH negative according to ASCO/CAP guidelines).
- Patients with deleterious or suspected deleterious gBRCA1/2 detected upon local testing.
- Willingness and ability to provide archived formalin fixed paraffin embedded tissue (FFPE) block or a partial block from archived tumor or metastasis.
- Indication for standard-of-care PARP inhibitor therapy and planned treatment with olaparib.
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2.
- Resolution of all acute toxic effects of prior anti-cancer therapy including endocrine therapy or surgical procedures to NCI CTCAE version 5.0 grade ≤ 1 (except alopecia or other toxicities not considered a safety risk for the patient at investigator’s discretion).
- Life-expectancy > 6 months.
- For female patients: patients of childbearing potential (defined as not post-menopausal and not permanently sterile [latter defined as having undergone hysterectomy, bilateral salpingectomy, or bilateral oophorectomy]) require a negative serum or urinary pregnancy test within 72 hours before starting treatment in this study (in this case, patients need to use highly effective non-hormonal contraceptive methods as specified in the protocol). For male patients: during the intervention period and for at least 120 days after the last dose of elacestrant, patients should refrain from heterosexual intercourse or use a condom (and should also be advised of the benefit for a female partner to use a highly effective method of contraception as a condom may break or leak), and they should refrain from donating sperm.
Exclusion Criteria
- Known hypersensitivity reaction to one of the compounds, excipients, or substances used in this protocol.
- Active or newly diagnosed CNS metastases, including leptomeningeal carcinomatosis, carcinomatous meningitis, or radiographic signs of CNS hemorrhage. Note: Patients with stable brain metastases are allowed. Radiotherapeutic treatment must be completed 1 week before planned day 1 of study therapy.
- Presence of symptomatic metastatic visceral disease that are at risk of life-threatening complications in the short term, including but not confined to massive uncontrolled effusions (peritoneal, pleural, pericardial), pulmonary lymphangitis, or fulminant liver involvement.
- Inadequate organ function prior to enrolment including: o Hemoglobin < 9 g/dL (< 5.6 mmol/L) o Absolute neutrophil count (ANC) < 1500/mm³ (< 1.5 x 10^9/L) o Platelets < 100,000/mm³ (< 100 x 10^9/L) o Alanine aminotransferase (ALT/SGPT) and/or aspartate aminotransferase (AST/SGOT) > 3 x upper normal limits (ULN). If the patient has liver metastases, ALT and AST should not be ≥ 5 x ULN. o Alkaline phosphatase (ALP) > 2.5 x ULN o Total serum bilirubin > 1.5 x ULN (exception: patients with Gilbert’s syndrome permitted up to ≤ 3 x ULN) o Serum creatinine > 1.5 x ULN or estimated creatinine clearance < 50 mL/min as calculated using the standard method for the institution.
- Existing contraindication against the use of the elacestrant or olaparib.
- Prior treatment with PARP inhibitors.
- Female patients: pregnancy or lactation at the time of randomization or intention to become pregnant during the study and for a predefined period after the end of treatment (as described in protocol). Male patients: intention to get a child during the study and for a predefined period after the end of treatment (as described in protocol). According to the treatment received during the study, required contraception timelines for female and male patient after the end of therapy differ (refer to the study protocol).
- Any of the following within 6 months prior to enrolment: myocardial infarction, severe/unstable angina, ongoing grade ≥ 2 cardiac dysrhythmias, prolonged QT corrected by Fridericia’s formula (QTcF) grade ≥ 2, uncontrolled atrial fibrillation of any grade, coronary/peripheral artery bypass graft, heart failure of New York Heart Association (NYHA) Class II or greater, or cerebrovascular accident including transient ischemic attack.
- Uncontrolled hypertension at the time of screening (systolic BP > 140 mmHg or diastolic BP > 90 mmHg that has not been adequately treated or controlled).
- Active and current anticoagulation for treatment purposes of thrombotic events occurring < 6 months before enrolment is not allowed (prophylactic anticoagulation, however, is acceptable). Treatment with an anticoagulant for a thrombotic event occurring > 6 months before enrolment, or for an otherwise stable and allowed medical condition (e.g., well controlled atrial fibrillation) is acceptable, provided dose and coagulation parameters (as defined by local standard of care) are stable for at least 28 days prior to the first dose of study drug.
- Known difficulty in tolerating oral medications or conditions which would impair absorption of oral medications such as: uncontrolled nausea or vomiting (i.e., CTCAE ≥ grade 3 despite antiemetic therapy), ongoing gastrointestinal obstruction/motility disorder, malabsorption syndrome, or prior gastric bypass.
- History of endometrial intraepithelial neoplasia in patients who have not undergone a hysterectomy.
- Malignant disease other than breast cancer, active or being disease-free for less than 5 years (except carcinoma in situ of the cervix, DCIS, and non-melanomatous skin cancer adequately treated).
- Uncontrolled significant active infections including HBV, HCV, and/or HIV. Patients with a positive hepatitis B surface antigen result or a positive hepatitis C antibody test result at screening or within 3 months before first dose of study treatment are excluded, except for the following: Participants with positive anti-HBs antibody titer and confirmatory negative hepatitis B DNA polymerase chain reaction. Participants with positive hepatitis C antibody due to prior resolved disease can be enrolled only if they have both completed curative therapy and have a hepatitis C viral load < quantifiable limit.
- Any severe, acute, uncontrolled, or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational or non-investigational products administration, or may interfere with the interpretation of study results, and, in the judgment of the investigator, would make the patient inappropriate for entry into this study. Moreover, patients who, by virtue of an order issued by judicial or administrative authorities, are committed to an institution or those who cannot take part in clinical trials are excluded from this study.
- History of significant neurological or psychiatric disorders including psychotic disorders, dementia, or seizures that would prohibit the understanding and giving of informed consent.
- Unable or unwilling to avoid medications, supplements (e.g., St. John’s wort), or foods (e.g., grapefruit, pomegranate, pomelos, star fruit, Seville oranges and their juices) that are moderate/strong inhibitors or inducers of CYP3A4 activity. Participation will be allowed if the medication, supplements, or foods are discontinued for at least 14 days prior to study entry and for the duration of the study.
- Concurrent treatment with other experimental drugs. Participation in another clinical trial with any investigational not marketed drug within 30 days prior to study entry.
- Receipt of live attenuated vaccination within 30 days prior to study entry. COVID-19 vaccines that do not contain live viruses are allowed (at least one week prior to study entry).
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Recruiting | 15 Dec 2024 | 176 |
Sites & Investigators
Research sites
Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Elacestrant | Test | FILM-COATED TABLET | ORAL USE | 400 | 48 | PRD10200788 |
Elacestrant | Test | FILM-COATED TABLET | ORAL USE | 400 | 48 | PRD10200789 |
Lynparza 150 mg film-coated tablets | Other | FILM-COATED TABLETS | ORAL | 600 | 48 | PRD6152234 |