HIGHLIGHT 1

Participant is eligible for participation in the study if all of the following apply:

Age

1. Participant is at least 18 years of age at the time of signing the ICF.

Type of Participant and Disease Characteristics

2. Participant has a personal history of stage 0-3 HR+, either HER-2+ or HER-2- breast cancer; appropriate documentation includes a written or electronic report.

3. Participant must be receiving stable maintenance adjuvant endocrine therapy (tamoxifen 20 mg daily or aromatase inhibitors, such as anastrozole, letrozole and exemestane) with or without GnRH agonists/antagonists for a minimum of 4 months and be planning to continue on adjuvant endocrine therapy for the duration of the trial without change to therapy, brand or dose. Add-on therapies for breast cancer adjuvant treatment (e.g., CDK4 inhibitors) are allowed at the investigator’s judgement.

4. Participant has a minimum average of 7 moderate to severe HFs (VMS) per day as recorded in the electronic daily diary (data must be available for at least 7 of the last 10 days prior to randomization).

5. Has an ECOG score 0 or 1.

6. Has at least 12-month life expectation in the opinion of the investigator.

Sex and Contraceptive Requirements

7. Participant is born female.

8. Female participant:

● Is not pregnant (see [Section 10.2]) and at least 1 of the following conditions apply:

a. Not a WOCBP (see [Section 10.2]).

b. WOCBP who has a negative urine or serum pregnancy test at screening and day 1 and agrees to follow the contraceptive guidance (see [Section 10.2]) from the time of informed consent through at least 30 days after final study intervention administration.

● Must not be breastfeeding or lactating starting at screening and throughout the investigational period and for 30 days after final study intervention administration.

● Must not donate ova starting at first administration of study intervention and throughout the investigational period and for 30 days after final study intervention administration.

Informed Consent

9. The participant has provided informed consent as described in [Section 10.1.3] which includes compliance with the requirements and restrictions listed in the ICF and protocol.

Other Inclusion Criteria

10. Participant agrees not to participate in another interventional study while participating in the present study.

11. Participant has a BMI range of 18 kg/m2 to 38 kg/m2 inclusive at screening.

12. Participant’s condition is stable as determined on the basis of medical history and general physical examination (including a bimanual clinical pelvic examination devoid of relevant clinical findings performed at the screening visit), haematology and biochemistry parameters, pulse rate and/or blood pressure and ECG (or showing no clinically relevant deviations obtained within the last 3 months or at screening), as judged by the investigator.

13. Participant has no new clinically significant findings on breast examination or from imaging (mammogram or breast ultrasound). Results indicate, in the opinion of the investigator, that the participant is a good candidate for the study. Appropriate

documentation includes a written or electronic report. In case of double mastectomy, imaging is not needed.

14. Participant has no clinically significant findings on a TVU result obtained within the last 3 months or at screening. Results indicate that, in the opinion of the investigator, the participant is a good candidate for the study. This is not required for participants who have had a partial (supra-cervical) or total hysterectomy.

15. Participant has a negative serology panel (including HBsAg, HCV antibody and HIV antibody screens). 

Participant will be excluded from participation in the study if any of the following apply:

Medical Conditions

1. Participant has diagnosis of metastatic breast cancer (stage 4).

2. Participant has current or history (except complete remission for 5 years or more prior to signing informed consent) of any malignancy except for HR+ breast cancer (stage 0 to 3) or basal cell carcinoma.

3. Participant has had surgery or non-surgical (chemotherapy or radiotherapy) treatment for breast cancer within the last 3 months prior to signing informed consent.

4. Participant has active liver disease, jaundice, or elevated liver aminotransferases (ALT or AST), elevated TBL or DBL, elevated INR or elevated ALP at screening. A participant with mildly elevated ALT or AST up to < 2 × ULN can be enrolled if TBL and DBL are normal. Participant with mildly elevated ALP (up to < 1.5 × ULN) can be enrolled if cholestatic liver disease is excluded and no cause other than fatty liver is diagnosed. Participant with Gilbert’s syndrome with elevated TBL may be enrolled as long as DBL,

hemoglobin and reticulocytes are normal.

5. Participant has creatinine > 1.5 x ULN; or eGFR using the Modification of Diet in Renal Disease formula < 30 mL/min/1.73 m2

at the screening visit.

6. Participant has a history of endometrial hyperplasia or uterine/endometrial cancer.

7. Participant has a medical condition or chronic disease (including history of neurological [including cognitive], hepatic, renal, cardiovascular, gastrointestinal, pulmonary [e.g., moderate asthma], endocrine, or gynaecological disease) or malignancy that could confound interpretation of the study outcome in the opinion of the investigator.

Prior/Concomitant Therapy

8. Participant uses a prohibited therapy (MHT, estradiol-containing hormonal contraceptive progestin and progesterone-only medicines, any treatment for VMS [prescription medications, over-the-counter, or herbal] or CYP1A2 inhibitors) or is not willing to wash out such drugs; in addition, investigators should consider medications that are contraindicated due to underlying breast cancer diagnosis and the adjuvant endocrine therapy. For more details on prohibited concomitant medications, see [Section 6.8] and [Section 10.5].

9. Participant has a known substance abuse or alcohol addiction within 6 months of screening, as assessed by investigator.

Prior/Concurrent Clinical Study Experience

10. Participant has received any investigational therapy within 90 days or 5 half-lives, whichever is longer, prior to screening.

Other Exclusion Criteria

11. Participant has any condition, which, in the investigator’s opinion, makes the participant unsuitable for study participation.

12. Participant has a known or suspected hypersensitivity to fezolinetant, the adjuvant endocrine therapy being used, or any components of the formulations used. 

Research Nurse: Deborah Weavers (x8475) Deborah.Weavers@lthtr.nhs.uk

Administrator: Bethany Webster (x8475)