Evaluating the Addition of Elacestrant (Oral SERD) to Olaparib (PARP-inhibitor) in Patients With Advanced/Metastatic HR+/HER2- Breast Cancer

Inclusion Criteria:

Patients will be eligible for study participation only if they comply with the following criteria:

1. Written informed consent prior to beginning specific protocol procedures, includingexpected cooperation of the patients for scheduled visit, the treatment andfollow-up, must be obtained and documented according to the local regulatoryrequirements.

2. Female or male patients.

3. Age at study entry of at least 18 years.

4. 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 negativeaccording to ASCO/CAP guidelines).

5. Patients with deleterious or suspected deleterious gBRCA1/2 mutation detected uponlocal testing.

6. Willingness and ability to provide archived formalin fixed paraffin embedded tissue (FFPE) block or a partial block from archived tumor or metastasis.

7. Indication for standard-of-care PARP inhibitor therapy and planned treatment witholaparib.

8. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2.

9. Resolution of all acute toxic effects of prior anti-cancer therapy includingendocrine therapy or surgical procedures to NCI CTCAE version 5.0 grade ≤ 1 (exceptalopecia or other toxicities not considered a safety risk for the patient atinvestigator's discretion).

10. Life-expectancy > 6 months.

11. For female patients: patients of childbearing potential (defined as notpost-menopausal and not permanently sterile [latter defined as having undergonehysterectomy, bilateral salpingectomy, or bilateral oophorectomy]) require anegative serum or urinary pregnancy test within 72 hours before starting treatmentin this study (in this case, patients need to use highly effective non-hormonalcontraceptive 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:

Patients will be ineligible for study participation if they fulfill any of the following criteria:

1. Known hypersensitivity reaction to one of the compounds, excipients, or substancesused in this protocol.

2. Active or newly diagnosed CNS metastases, including leptomeningeal carcinomatosis,carcinomatous meningitis, or radiographic signs of CNS hemorrhage. Note: Patientswith stable brain metastases are allowed. Radiotherapeutic treatment must becompleted 1 week before planned day 1 of study therapy.

3. Presence of symptomatic metastatic visceral disease that are at risk oflife-threatening complications in the short term, including but not confined tomassive uncontrolled effusions (peritoneal, pleural, pericardial), pulmonarylymphangitis, or fulminant liver involvement.

4. Inadequate organ function prior to enrolment including:

• Hemoglobin < 9 g/dL (< 5.6 mmol/L)

• Absolute neutrophil count (ANC) < 1500/mm³ (< 1.5 x 109/L)

• Platelets < 100,000/mm³ (< 100 x 109/L)

• Alanine aminotransferase (ALT/SGPT) and/or aspartate aminotransferase (AST/SGOT) > 3 x upper normal limits (ULN). If the patient has livermetastases, ALT and AST should not be ≥ 5 x ULN.

• Alkaline phosphatase (ALP) > 2.5 x ULN

• Total serum bilirubin > 1.5 x ULN (exception: patients with Gilbert's syndromepermitted up to ≤ 3 x ULN)

• Serum creatinine > 1.5 x ULN or estimated creatinine clearance < 50 mL/min ascalculated using the standard method for the institution.

5. Existing contraindication against the use of the elacestrant or olaparib.

6. Prior treatment with PARP inhibitors.

7. Female patients: pregnancy or lactation at the time of randomization or intention tobecome pregnant during the study and for a predefined period after the end oftreatment (as described in protocol). Male patients: intention to get a child during the study and for a predefined periodafter the end of treatment (as described in protocol). According to the treatment received during the study, required contraceptiontimelines for female and male patients are described in the study protocol.

8. Any of the following within 6 months prior to enrolment: myocardial infarction,severe/unstable angina, ongoing grade ≥ 2 cardiac dysrhythmias, prolonged QTcorrected by Fridericia's formula (QTcF) grade ≥ 2, uncontrolled atrial fibrillationof any grade, coronary/peripheral artery bypass graft, heart failure of New YorkHeart Association (NYHA) Class II or greater, or cerebrovascular accident includingtransient ischemic attack.

9. Uncontrolled hypertension at the time of screening (systolic BP > 140 mmHg ordiastolic BP > 90 mmHg that has not been adequately treated or controlled).

10. Active and current anticoagulation for treatment purposes of thrombotic eventsoccurring < 6 months before enrolment is not allowed (prophylactic anticoagulation,however, is acceptable). Treatment with an anticoagulant for a thrombotic eventoccurring > 6 months before enrolment, or for an otherwise stable and allowedmedical condition (e.g., well controlled atrial fibrillation) is acceptable,provided dose and coagulation parameters (as defined by local standard of care) arestable for at least 28 days prior to the first dose of study drug.

11. Known difficulty in tolerating oral medications or conditions which would impairabsorption of oral medications such as: uncontrolled nausea or vomiting (i.e., CTCAE ≥ grade 3 despite antiemetic therapy), ongoing gastrointestinal obstruction/motilitydisorder, malabsorption syndrome, or prior gastric bypass.

12. History of endometrial intraepithelial neoplasia in patients who have not undergonea hysterectomy.

13. Malignant disease other than breast cancer, active or being disease-free for lessthan 5 years (except carcinoma in situ of the cervix, DCIS, and non-melanomatousskin cancer adequately treated).

14. Uncontrolled significant active infections including HBV, HCV, and/or HIV. Patientswith a positive hepatitis B surface antigen result or a positive hepatitis Cantibody test result at screening or within 3 months before first dose of studytreatment are excluded, except for the following:

• Participants with positive anti-HBs antibody titer and confirmatory negativehepatitis B DNA polymerase chain reaction.

• Participants with positive hepatitis C antibody due to prior resolved diseasecan be enrolled only if they have both completed curative therapy and have ahepatitis C viral load < quantifiable limit.

15. Any severe, acute, uncontrolled, or chronic medical or psychiatric condition orlaboratory abnormality that may increase the risk associated with studyparticipation or investigational or non-investigational products administration, ormay interfere with the interpretation of study results, and, in the judgment of theinvestigator, would make the patient inappropriate for entry into this study.Moreover, patients who, by virtue of an order issued by judicial or administrativeauthorities, are committed to an institution or those who cannot take part inclinical trials are excluded from this study.

16. History of significant neurological or psychiatric disorders including psychoticdisorders, dementia, or seizures that would prohibit the understanding and giving ofinformed consent.

17. Unable or unwilling to avoid medications, supplements (e.g., St. John's wort), orfoods (e.g., grapefruit, pomegranate, pomelos, star fruit, Seville oranges and theirjuices) that are moderate/strong inhibitors or inducers of CYP3A4 activity.Participation will be allowed if the medication, supplements, or foods arediscontinued for at least 14 days prior to study entry and for the duration of thestudy.

18. Concurrent treatment with other experimental drugs. Participation in anotherclinical trial with any investigational not marketed drug within 30 days prior tostudy entry.

19. Receipt of live attenuated vaccination within 30 days prior to study entry. COVID-19vaccines that do not contain live viruses are allowed (at least one week prior tostudy entry).