Treatment of breast cancer with amsenestrant

Abstract

The present disclosure provides methods of treating breast cancer with amsenestrant.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority from U.S. Patent Application No. 63 / 319,373, filed March 13, 2022; U.S. Patent Application No. 63 / 375,108, filed September 9, 2022; and European Patent Application No. 22315323.0, filed December 9, 2022. The disclosures of the aforementioned priority applications are hereby incorporated by reference in their entireties. [Background technology]

[0002] Breast cancer is the most commonly diagnosed cancer in the United States and the second leading cause of death in women. Endogenous and exogenous steroid hormones, such as estrogen and progesterone, are involved in the pathogenesis of breast cancer. Clinical treatment decisions are determined in part by the expression status of hormone receptors (HR), more specifically the estrogen receptor (ER) and progesterone receptor (PgR), as well as human epidermal growth factor receptor 2 (HER2). There are three molecular subtypes of breast cancer: HER2+, HR+ / HER2-, and ER- / PgR- / HER2- (triple negative).

[0003] A key protein target in the treatment of breast cancer is estrogen receptor alpha (ERα), a hormone-regulated transcription factor encoded by the ESR1 gene and expressed at high levels in approximately 75% of breast cancers. ERα enables breast cancer to respond to the mitogenic effects of estrogen. ER-positive breast cancers respond well to therapies that target ER signaling, either by competitive binding of the ER with antagonists such as tamoxifen, or by blocking the production of estrogen with aromatase inhibitors (AIs).

[0004] Selective ER degradation inducers (SERDs) are competitive ER antagonists that also induce conformational changes, which lead to degradation of the ER via the ubiquitin-proteasome system. The unique dual function of SERDs (ER antagonism and depletion) may enable blocking ER signaling in cellular environments where other endocrine agents such as tamoxifen or AIs have failed.

[0005] Fulvestrant is the only approved SERD drug currently on the market, but this treatment is limited by its poor pharmaceutical properties, which require intramuscular administration and limit applicable dose, exposure, and receptor binding.

[0006] Amsenestrant is a potent, orally bioavailable, selective estrogen receptor (ER) inhibitor that also belongs to the SERD class of compounds. It antagonizes estradiol binding to the ER and promotes the transition of the ER to an inactive conformation, which results in up to 98% receptor degradation at nanomolar concentrations in cellular assays.

[0007] For ER+ / HER2- patients without rapidly progressing visceral or symptomatic metastases, sequential hormonal therapy (alone or in combination) is currently the standard of care in the metastatic breast cancer setting. Unfortunately, not all patients respond to first-line hormonal therapy, as patients exhibit primary or de novo resistance, and some initially responding patients subsequently progress with breast cancer (acquired resistance). Although resistance to endocrine therapy is frequent, recurrent tumors remain ER-dependent, as evidenced by the response of patients to second- and third-line endocrine therapy after failure of the first line of hormonal therapy. For patients with locally advanced / metastatic breast cancer who progress after one or more lines of hormonal therapy, three classes of compounds primarily represent additional single-agent treatment options: the selective estrogen receptor modulator (SERM) tamoxifen; AIs such as letrozole, anastrozole, and exemestane; and the SERD fulvestrant.

[0008] Overall, in patients with metastatic breast cancer who had progressed after one or two lines of hormone-based therapy and further received hormone monotherapy, efficacy results showed progression-free survival (PFS) ranging from 1.9 to 5.1 months across trials. Summary of the Invention [Problem to be solved by the invention]

[0009] Thus, there remains a need for effective, well-tolerated SERD therapies with improved routes of administration (oral and intramuscular), bioavailability, and maintenance of ER receptor blockade. [Means for solving the problem]

[0010] The present disclosure provides a method of treating breast cancer comprising orally administering to a patient in need thereof a 400 mg dose of amsenestrant or a pharma- ceutically acceptable salt thereof.

[0011] In one aspect, the disclosure provides a method for reducing disease progression or death, or the risk of disease progression or death, in a patient in need thereof, relative to treatment with a therapy selected from fulvestrant, an aromatase inhibitor, and a selective estrogen receptor modulator, wherein the patient has ER+ / HER2- advanced / metastatic breast cancer with a mutated estrogen receptor 1 (ESR1), the method comprising administering amsenestrant or a pharmaceutically acceptable salt thereof to the patient.

[0012] In one aspect, the disclosure provides a method of treating ER+ / HER2- advanced / metastatic breast cancer with mutated estrogen receptor 1 (ESR1) in a patient in need thereof, the method comprising administering amsenestrant or a pharmaceutically acceptable salt thereof to the patient.

[0013] In some embodiments, the treatment methods described herein result in a 10.0% reduction in the risk of disease progression or death compared to treatment with a therapy selected from fulvestrant, an aromatase inhibitor, and a selective estrogen receptor modulator.

[0014] In some embodiments, the aromatase inhibitor is exemestane, letrozole, or anastrozole.

[0015] In some embodiments, the selective estrogen receptor modulator is tamoxifen.

[0016] In some embodiments, the treatment method increases the progression-free survival (PFS) of a patient. In some embodiments, the method results in a median PFS of about 3.7 months.

[0017] In some embodiments, amsenestrant or its pharmaceutically acceptable salt is orally administered to the patient at a dose of 400 mg per day, optionally once a day. In some embodiments, amsenestrant or its pharmaceutically acceptable salt is provided as a capsule or tablet, optionally containing 100 mg of amsenestrant per capsule or tablet. In some embodiments, amsenestrant or its pharmaceutically acceptable salt is administered to the patient in the morning, regardless of food status.

[0018] In some embodiments, the breast cancer is advanced breast cancer. In some embodiments, the advanced breast cancer is locally advanced cancer that is not amenable to curative radiation therapy or surgery. In some embodiments, the breast cancer is metastatic.

[0019] In some embodiments, the patient is a pre- or post-menopausal woman or man, hi some embodiments, the patient is a post-menopausal woman.

[0020] In some embodiments, the patient is resistant to endocrine therapy.

[0021] In some embodiments, the patient has previously been treated with at least one line of endocrine therapy, optionally one or two lines of endocrine therapy for advanced breast cancer, and optionally the patient's breast cancer has progressed during or after the previous endocrine therapy. In some embodiments, the patient has previously been treated with adjuvant endocrine therapy and has relapsed after the first two years of adjuvant endocrine therapy or within 12 months of completing adjuvant endocrine therapy. In some embodiments, the previous adjuvant endocrine therapy is selected from treatment with tamoxifen, fulvestrant, or an aromatase inhibitor, and optionally the aromatase inhibitor is exemestane, letrozole, or anastrozole.

[0022] In some embodiments, the patient has previously been treated with chemotherapy or targeted therapy, hi some embodiments, the patient has previously been treated with no more than one chemotherapy or targeted therapy for advanced or metastatic disease.

[0023] In some embodiments, the patient has previously been treated with a CDK4 / 6 inhibitor, hi some embodiments, the patient has not previously been treated with an mTOR inhibitor and / or a SERD other than fulvestrant.

[0024] In some embodiments, the patient does not experience clinically significant bradycardia, QTc prolongation, or visual disturbances following treatment.

[0025] In another aspect, the disclosure provides an article of manufacture or kit comprising amsenestrant for use in treating ER+ / HER2- breast cancer in the subject therapeutic methods and instructions for use.

[0026] Also provided herein is amsenestrant, or a pharma- ceutically acceptable salt thereof, for use in the treatment of breast cancer in the present therapeutic methods, as well as the use of amsenestrant, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for treating breast cancer in the present therapeutic methods.

[0027] Other features, objects and advantages of the present invention will become apparent in the following detailed description. It should be understood, however, that the detailed description, while illustrating embodiments and aspects of the present invention, is given by way of illustration only and not by way of limitation. Various changes and modifications within the scope of the present invention will become apparent to those skilled in the art from the detailed description. [Brief description of the drawings]

[0028] [Figure 1] FIG. 1 is a graphical representation of the clinical trial design. C=cycle; D=day; IMP=investigational drug; OS=overall survival; PD=progressive disease; R=randomization. [Diagram 2] Kaplan-Meier graph of the primary endpoint of PFS assessed by ICR in the ITT population. [Diagram 3] Kaplan-Meier graph of the OS key secondary endpoint in the ITT population. [Figure 4] 1 is a forest plot showing subgroup analysis of PFS based on ICR assessment by baseline characteristics in the ITT population. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0029] Figures 2-4 display the results resulting from a study cutoff date of February 15, 2022 and patient database lock on March 8, 2022.

[0030] The present disclosure provides a method of treatment with amsenestrant for the treatment of breast cancer, including in patients with ESR1 mutations.

[0031] It was found that the SERD amsenestrant 400mg QD can achieve numerically similar progression-free survival compared to physician's choice of endocrine therapy in patients with ER+ / HER2- advanced / metastatic breast cancer.

[0032] This treatment regimen has been shown to achieve a median PFS of 3.6 months (95% confidence interval 2.0-3.9). Thus, the treatment regimen described herein provides a median time to progression of 3.6 months until patients show progressive disease or death from any cause, whichever occurs first.

[0033] It has also been found that amsenestrant, when used at 400mg QD, can provide numerically longer progression-free survival compared to physician-choice endocrine therapy in patients with ESR1-mutated ER+ / HER2- advanced / metastatic breast cancer. In said patients, the amsenestrant treatment regimen described herein has been shown to achieve a median PFS of 3.7 months (95%CI 1.9-7.2). Thus, the treatment regimen described herein provides a median time of 3.7 months until patients show progressive disease or death from any cause, whichever occurs first.

[0034] The safety profile of the treatment regimen described herein is further detailed below and is consistent with that observed in previous studies.

[0035] I. Amsenestrand Amsenestrant is a potent, orally bioavailable, selective ER inhibitor belonging to the SERD family of compounds. It has full estrogen receptor antagonist properties and promotes proteasomal degradation of the ER. Amsenestrant (test code: SAR439859) has the chemical name: 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid, or 8-(2,4-dichlorophenyl)-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (C 31 H 30Cl2FNO3), which is described in WO 2017 / 140669. Amsenestrant has the following structural formula (I): [ka] has.

[0036] Amsenestrant may be provided as a zwitterion (i.e., an overall neutral molecule having one acidic and one basic group) without any additional counterion. Amsenestrant may also be provided in the form of a salt having one or more additional acidic or basic molecules. Unless otherwise noted, the dose of amsenestrant administered to a patient refers to the dose of free zwitterionic (i.e., uncharged) amsenestrant administered and does not include the weight of any counterion.

[0037] As used herein, amsenestrant may be provided as a pharmaceutical composition comprising a therapeutically effective amount of amsenestrant or a pharma- ceutically acceptable salt thereof, with or without other active ingredients. The pharmaceutical composition may typically be in the form of, for example, a solution, dispersion, suspension, tablet, capsule, etc. The pharmaceutical composition may also include inactive ingredients that are pharma- ceutically acceptable excipients and / or carriers. Amsenestrant is usually administered orally (i.e., po, PO, or per os). The patient may receive the dose with or without food.

[0038] In some embodiments, amsenestrant is suitable for oral administration formulated as a tablet or capsule. In some embodiments, amsenestrant is suitable for oral administration formulated as a capsule containing 100 mg of amsenestrant.

[0039] In some embodiments, amsenestrant or a pharma- ceutically acceptable salt thereof is orally administered to a patient at a dose of 400 mg per day.In some embodiments, amsenestrant or a pharma- ceutically acceptable salt thereof is administered to a patient once per day.

[0040] In some embodiments, amsenestrant or a pharma- ceutically acceptable salt thereof is administered to a patient in need thereof.

[0041] II. Treatment regimens As used herein, the term "treating" or "treatment" means preventing, slowing, or reducing disease progression or death (including the risk thereof). In some embodiments, treating or treatment means reducing disease progression or death (including the risk thereof). In some embodiments, treating or treatment means reducing disease progression or death (including the risk thereof) in a patient in need thereof with ER+ / HER2- advanced / metastatic breast cancer with mutated estrogen receptor 1 (ESR1) compared to treatment with a therapy selected from fulvestrant, an aromatase inhibitor, and a selective estrogen receptor modulator.

[0042] A patient in need thereof may receive the therapeutic regimen of the present disclosure until the patient is no longer benefiting from the treatment, shows disease progression, or shows unacceptable toxicity.

[0043] As used herein, administration of amsenestrant includes self-administration by the patient (eg, oral ingestion by the patient).

[0044] In some embodiments, amsenestrant is administered in a total daily dose of 400 mg (e.g., provided as four capsules, each containing 100 mg of amsenestrant). Amsenestrant may be administered orally once a day (QD) (i.e., once every 24 hours). In some embodiments, amsenestrant is administered in the morning at approximately the same time each day (± 3 hours), regardless of food status. For purposes of treatment, one cycle is artificially defined as 4 weeks.

[0045] In some embodiments, treatment is continued until the patient is no longer benefiting from the treatment. In some embodiments, treatment is continued until the patient shows unacceptable toxicity. In some embodiments, treatment is continued until the patient shows disease progression.

[0046] During treatment, patients are periodically monitored for disease status and / or dosage adjustments.

[0047] During the treatment period, patients may also be advantageously monitored for possible side effects, such as toxicity and adverse events. In particular, potential side effects and risks anticipated in humans include: Gastrointestinal toxicity, including loss of appetite, nausea, vomiting, diarrhea (and, in severe cases, possibly dehydration and electrolyte abnormalities), and upper and / or lower abdominal pain. · Changes in liver function, including elevated liver enzymes and bilirubin. Hematological toxicity which may manifest as laboratory abnormalities (leukopenia, neutropenia, thrombocytopenia, anemia), infection, and neutropenic fever. Effects on the female reproductive system (ovaries, uterus, cervix, vagina, mammary glands). · Risk of male infertility. Risk of photosensitivity. Risk of severe rash. Theoretical risk of osteoporosis due to amsenestrant's mechanism of action in case of long-term exposure. Risk of drug-drug interactions.

[0048] During treatment, patients may be advised to avoid the concomitant use of the following treatments / medications: ·Drugs that are strong inducers of CYP3A; Botanicals and food supplements such as St. John's Wort and genistein; · Drugs that are sensitive substrates of OATP1B1 / 1B3, such as asunaprevir, atorvastatin, bosentan, danoprevir, fexofenadine, glyburide, nateglinide, pitavastatin, pravastatin, repaglinide, rosuvastatin, and simvastatin acid; ·Medications that may inhibit UGT and are contraindicated for use with UGT substrates (e.g., but not limited to, atazanavir, probenecid).

[0049] III. Patient Selection The present treatment method can be used to treat adult patients with breast cancer (e.g., patients ≥18 years of age). In some embodiments, the patient has ER+ / HER2- breast cancer that is locally advanced and not suitable for curative radiation therapy or surgery, and / or metastatic breast cancer (hereinafter also referred to as "locally advanced / metastatic" breast cancer or "advanced / metastatic" breast cancer). In some embodiments, the patient has locally advanced / metastatic breast cancer and has failed (i.e., shown disease progression) during or after treatment with one or more other hormonal therapies. In some embodiments, the patient is a late menopausal woman, a premenopausal woman, or a man. In some embodiments, the patient has ER+ / HER2- locally advanced or metastatic breast cancer and has previously received ≤2 prior line therapies of ET in the advanced / metastatic setting; and ≤1 prior chemotherapy or ≤1 targeted therapy. In some embodiments, the patient has no prior experience with mTOR inhibitors or SERDs other than fulvestrant. In yet another embodiment, the treatment method for such patients includes oral administration of amsenestrant at a dose of 400 mg daily.

[0050] In some embodiments, patients have a histologically or cytologically proven diagnosis of adenocarcinoma of the breast. Patients may have evidence of either locally advanced disease and / or metastatic disease that is unsuitable for curative-intent radiation therapy or surgery.

[0051] A primary tumor or metastatic site can be considered ER positive if ≥ 1% of tumor cells stain positive in a tumor cell staining immunohistochemistry (IHC) assay. Patients cannot have an ER positive primary tumor combined with a separate ER negative metastatic lesion.

[0052] Primary tumors or metastatic sites are determined to not overexpress HER2 based on analysis of tumor samples by IHC (0, 1+) ​​or are in situ hybridization negative based on a single-probe mean HER2 copy number <6.0 signal / cell or a dual-probe HER2 / centromeric probe for chromosome 17 (CEP17) ratio <2 and a mean HER2 copy number <6.0 signal / cell according to American Society of Clinical Oncology guidelines. Patients must not have a HER2-negative primary tumor in combination with a separate HER2-positive metastatic lesion.

[0053] In some embodiments, prior chemotherapy (including antibody drug conjugates) or targeted therapy is permitted. In some embodiments, the patient has received no more than one prior chemotherapy or no more than one targeted therapy regimen for advanced / metastatic disease. In some embodiments, the patient has previously been treated with a CDK4 / 6 inhibitor. In some embodiments, the patient has previously been treated with a CDK4 / 6 inhibitor in combination with fulvestrant or an AI.

[0054] In some embodiments, the patient has received at least 6 months of continuous prior endocrine therapy for advanced breast cancer and has progressed while receiving endocrine therapy (single agent or combination). In some embodiments, the number of prior advanced hormone-selective therapies is 2 or less. In yet another embodiment, the patient has experienced a recurrence while receiving adjuvant endocrine therapy and after the first 2 years, or has experienced a recurrence within 12 months of completing adjuvant endocrine therapy.

[0055] A postmenopausal woman is defined as: i) Females aged ≥ 60 years; or ii) Women aged <60 years with: -Subjects whose menses have naturally ceased >12 months prior to the initiation of amsenestrand treatment in the absence of chemotherapy, tamoxifen, or toremifene; - Cessation of menses for ≤12 months or cessation of menses since hysterectomy and follicle-stimulating hormone (FSH) levels within the institutional range for postmenopausal women (>34.4 IU / L if no institutional range exists) before initiating amsenestrand treatment; - those who have previously received hormone replacement therapy but have discontinued such therapy and have had FSH levels within the institutional range for postmenopausal status (>34.4 IU / L if no institutional range exists) prior to initiating amsenestrant treatment; Following bilateral oophorectomy; or · Condition after bilateral oophorectomy with pelvic radiotherapy.

[0056] As used herein, "initiation of amsenestrant treatment" refers to the day on which treatment with amsenestrant is initiated, or 1, 2, or 3 days prior thereto.

[0057] In some embodiments, the patient is a premenopausal female (i.e., not a postmenopausal female) or a male. In some embodiments, male patients and premenopausal / postmenopausal females who have not previously undergone bilateral orchiectomy begin treatment with a GnRH agonist at least 4 weeks prior to treatment.

[0058] In some embodiments, the patient does not have an Eastern Cooperative Oncology Group (ECOG) performance status of > 2. The criteria for ECOG status are defined in Table 1 below.

[0059] [Table 1]

[0060] In some embodiments, the patient has no significant co-morbidities, including psychiatric conditions, that may adversely affect the patient's adherence to the treatment methods described herein. In further embodiments, the patient has no history or ongoing gastrointestinal disorders that potentially affect the absorption of oral medications (e.g., amsenestrant), can swallow normally, and can take capsules. In some embodiments, the patient has not undergone major surgery within 4 weeks prior to the start of amsenestrant treatment.

[0061] In some embodiments, the patient is free of other cancers. The patient may have basal cell or squamous cell skin cancer, or epithelial cervical cancer, or any other cancer that has been appropriately treated and has been disease-free for >3 years thereafter.

[0062] In some embodiments, the patient has no history of abnormal coagulation profile or coagulation disorder, such as a history of deep vein thrombosis or pulmonary embolism, within 6 months prior to the first dose of amsenestrant. The patient may have (i) adequately treated catheter-related venous thrombosis that occurred more than 1 month prior to the first dose of IMP, or (ii) been treated with an anticoagulant (e.g., warfarin or heparin) for a thrombotic event that occurred 6 months or more prior to enrollment, or for an otherwise stable and tolerated medical condition (e.g., well-controlled atrial fibrillation), provided that the dose and coagulation parameters have been stable for at least 1 month prior to the first dose of amsenestrant.

[0063] In some embodiments, the patient does not have known brain metastases that are untreated, symptomatic, or require therapy to control symptoms. Patients with brain metastases can be treated with this treatment regimen if (i) they have completed treatment (whole brain radiation therapy, radiosurgery, or a combination) at least 4 weeks prior to the start of study treatment, (ii) they have recovered from the effects of this treatment, and (iii) they are neurologically stable. In some embodiments, the patient has discontinued the use of corticosteroids for brain metastases for ≥2 weeks without subsequent symptoms prior to the first dose of amsenestrant.

[0064] In some embodiments, patients have no prior treatment-related adverse reactions resolved to < Grade 2, except for alopecia per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0.

[0065] In some embodiments, the patient has not received prior treatment with a mammalian targeting rapamycin inhibitor or other SERD compound (unless fulvestrant has been discontinued for at least 3 months prior to initiating amsenestrant treatment).

[0066] In some embodiments, the patient has not been treated with drugs that may inhibit UGT, including but not limited to atazanavir and probenecid, for less than 2 weeks or 5 elimination half-lives, whichever is longer, prior to initiating treatment. In yet another embodiment, the patient has not been treated with a strong CYP3A inducer within 2 weeks or 5 elimination half-lives, whichever is longer, prior to initiating treatment. In yet another embodiment, the patient has not been treated with drugs that are sensitive substrates of OATP1B1 / B3 (e.g., asunaprevir, atorvastatin, bosentan, danoprevir, fexofenadine, glyburide, nateglinide, pitavastatin, pravastatin, repaglinide, rosuvastatin, and simvastatin acid).

[0067] In some embodiments, the patient has a neutrophil count <1.5×10 9 / L or platelet count <100×10 9 In yet another embodiment, the patient does not have a prothrombin time / international normalized ratio (INR) >1.5 times the upper limit of normal (ULN), or a prothrombin time / international normalized ratio (INR) outside the therapeutic range if receiving anticoagulant therapy that may affect the INR. In some embodiments, the patient does not have a serum creatinine ≥ 1.5 x ULN, or between 1.0 and 1.5 x ULN and a glomerular filtration rate < 60 mL / min / 1.73 m as estimated using the simplified Modification of Diet in Renal Disease formula shown below: 2 Do not have insufficient renal function: GFR (mL / min / 1.73m2) = 175 x (Scr) - 1.154 x (age) - 0.203 x (0.742 for women) x (1.212 for African Americans) (usual units) GFR = glomerular filtration rate; Scr = serum creatinine

[0068] In yet another embodiment, the patient does not have inadequate liver function as indicated by aspartate aminotransferase >3xULN, ALT >3xULN, or total bilirubin >1.5xULN. In the presence of liver metastases, AST and ALT less than 5xULN are permitted.

[0069] IV. Treatment results and tumor shrinkage evaluation The therapeutic methods of the present invention can result in complete response (CR), partial response (PR), or stable disease (SD) in patients, as well as prevent progressive disease (PD).

[0070] In some embodiments, the patient has measurable disease at baseline. Measurable disease is defined by the presence of at least one measurable lesion. A measurable lesion refers to a tumor lesion that is precisely measured in at least one dimension (within the measurement plane to be recorded) and has the following minimum longest dimension: (i) 10 mm by CT scan (CT scan slice thickness ≤ 5 mm); (ii) 10 mm caliper measurement by clinical examination (lesions that cannot be accurately measured with a caliper should be recorded as non-measurable). (iii) Chest X-ray 20 mm. A measurable malignant lymph node is a pathologically enlarged, measurable lymph node. Malignant lymph nodes must have a short axis of ≥15 mm when assessed by CT scan (a CT scan slice thickness of ≤5 mm is recommended).

[0071] In some embodiments, various levels of response can be assessed according to Tables 2 and 3 below.

[0072] [Table 2]

[0073] [Table 3]

[0074] Table 4 shows a summary of the calculated overall response status at each time point for patients with measurable disease at baseline. If a patient has only non-measurable (and therefore non-target) disease, Table 5 is used. The best overall response (Table 6) is determined when all patient data are known.

[0075] [Table 4]

[0076] [Table 5]

[0077] [Table 6]

[0078] If SD is considered the best response, a minimum time from baseline (defined as 42 days) must also be met. Alternatively, when SD is the best time point response, if the minimum time is not met, the patient's best response depends on the subsequent evaluation. For example, a patient with SD at the first evaluation and PD at the second evaluation, who does not meet the minimum duration of SD, will have a best response of PD. If the same patient is lost to follow-up after the first SD evaluation, he or she is considered unevaluable. A complete or partial response can only be claimed if the respective criteria are met at a subsequent time point (e.g., after 4 weeks).

[0079] Progression-free survival is defined as the time to objective PD (i.e., tumor progression) or death from any cause, whichever occurs first, as defined by RECIST 1.1 (Response Evaluation Criteria in Solid Tumors, version 1.1) (i.e., from the date of initiation of amsenestrant treatment).

[0080] The objective response rate is defined as the proportion of patients who achieved a confirmed complete response (CR) or partial response (PR) as the best overall response (BOR) derived from the overall response determined according to RECIST 1.1 from the start date of treatment with Amsenestrant to the end date of treatment. In clinical trials, such BOR determination is made by the ICR.

[0081] Overall survival is defined as the time to death from any cause (ie, from the date of initiation of amsenestrant treatment).

[0082] Disease control rate is defined as the proportion of patients who achieved CR, PR, stable disease (SD), or non-CR / non-PD as BOR according to RECIST 1.1 from the start date of amsenestrant treatment to the end date of treatment.

[0083] Clinical benefit rate is defined as the proportion of patients who achieved confirmed CR, PR, SD, or non-CR / non-PD (Non-CR / Non-PD) according to RECIST 1.1 for at least 24 weeks from the start date of Amsenestrant treatment to the end date of treatment.

[0084] In some embodiments, PFS is evaluated in patients based on baseline ESR1 status (mutated or wild type). ESR1 status can be determined, for example, using multiplex droplet digital polymerase chain reaction (ddPCR) after extraction of plasma circulating DNA.

[0085] In some embodiments, the method of treatment results in survival of the patient.

[0086] In some embodiments, the treatment method results in a median progression-free survival of 3.6 months (95% CI: 2.0-3.9).

[0087] In some embodiments, the treatment method results in a progression-free survival rate of 35.5% (95% CI: 27.2-43.9) at 6 months.

[0088] In some embodiments, the treatment method results in a progression-free survival rate of 20.4% (95% CI: 13.4-28.4) at 12 months.

[0089] In some embodiments, the treatment method results in a complete response (CR), partial response (PR), or stable disease (SD) in the patient.

[0090] In some embodiments, the treatment method results in an objective response rate of 11.9% (95% CI: 7.1-18.4).

[0091] In some embodiments, the treatment method results in a clinical benefit rate of 27.3% (95% CI: 20.2-35.3).

[0092] In some embodiments, the treatment method results in a disease control rate of 54.5% (95% CI: 46.0-62.9).

[0093] In yet another embodiment, the treatment achieves the above results in patients with ER+ / HER2- locally advanced / metastatic breast cancer who have previously been exposed to hormone therapy.

[0094] V. Manufactured Articles and Kits The disclosure also provides articles of manufacture, e.g., kits, that include one or more doses of amsenestrant or a pharma- ceutically acceptable salt thereof, and instructions for a patient, e.g., for treatment according to the methods described herein. Amsenestrant tablets or capsules may be blistered and then carded. In some embodiments, each amsenestrant capsule or tablet contains 100 mg of amsenestrant.

[0095] VI. ILLUSTRATIVE EMBODIMENTS Non-limiting exemplary embodiments of the present disclosure are further described below.

[0096] Embodiment 1: A method for reducing disease progression or death (including risk thereof) compared to treatment with a therapy selected from fulvestrant, an aromatase inhibitor, and a selective estrogen receptor modulator in a patient in need thereof, wherein the patient has ER+ / HER2- advanced / metastatic breast cancer with a mutated estrogen receptor 1 (ESR1), the method comprising administering to the patient amsenestrant or a pharmaceutically acceptable salt thereof.

[0097] Embodiment 2: The method of embodiment 1, resulting in a 10.0% reduction in the risk of disease progression or death.

[0098] Embodiment 3: The method of embodiment 1 or 2, wherein the aromatase inhibitor is exemestane, letrozole, or anastrozole.

[0099] Embodiment 4: The method of embodiment 1 or 2, wherein the selective estrogen receptor modulator is tamoxifen.

[0100] Embodiment 5: The method according to any one of embodiments 1 to 4, wherein said method increases the progression-free survival (PFS) of the patient.

[0101] Embodiment 6: The method according to any one of embodiments 1 to 5, wherein said method results in a median PFS of about 3.7 months.

[0102] Embodiment 7: The method of any one of embodiments 1-6, wherein amsenestrant or a pharma- ceutically acceptable salt thereof is orally administered to the patient at a dose of 400 mg per day, optionally once per day.

[0103] Embodiment 8: The method of any one of embodiments 1 to 7, wherein amsenestrant or a pharma- ceutically acceptable salt thereof is provided as a capsule or tablet, optionally containing 100 mg of amsenestrant per capsule.

[0104] Embodiment 9: The method of any one of embodiments 1 to 8, wherein amsenestrant or a pharma- ceutically acceptable salt thereof is administered to the patient in the morning, regardless of food status.

[0105] Embodiment 10: The method of any one of embodiments 1 to 9, wherein the breast cancer is advanced breast cancer.

[0106] Embodiment 11: The method of embodiment 10, wherein the advanced breast cancer is a locally advanced cancer that is not amenable to curative radiation therapy or surgery.

[0107] Embodiment 12: The method of any one of embodiments 1 to 9, wherein the breast cancer is metastatic.

[0108] Embodiment 13: The method of any one of embodiments 1 to 12, wherein the patient is a pre- or post-menopausal woman, or a man.

[0109] Embodiment 14: The method of embodiment 13, wherein the patient is a late menopausal woman.

[0110] Embodiment 15: The method of any one of embodiments 1 to 14, wherein the patient is resistant to endocrine therapy.

[0111] Embodiment 16: The method of any one of embodiments 1 to 15, wherein the patient has previously been treated with at least one line of endocrine therapy, optionally one or two lines of endocrine therapy for advanced breast cancer, and optionally the patient's breast cancer has progressed during or after treatment with the previous endocrine therapy.

[0112] Embodiment 17: The method of embodiment 16, wherein the patient has previously been treated with adjuvant endocrine therapy and has relapsed after the first 2 years of adjuvant endocrine therapy or within 12 months of completing adjuvant endocrine therapy.

[0113] Embodiment 18: The method of embodiment 17, wherein the prior adjuvant endocrine therapy is selected from treatment with tamoxifen, fulvestrant, or an aromatase inhibitor, optionally wherein the aromatase inhibitor is exemestane, letrozole, or anastrozole.

[0114] Embodiment 19: The method of any one of embodiments 1 to 18, wherein the patient has previously been treated with chemotherapy or targeted therapy.

[0115] Embodiment 20: The method of embodiment 19, wherein the patient has been previously treated with no more than one chemotherapy or targeted therapy for advanced or metastatic disease.

[0116] Embodiment 21: The method of any one of embodiments 1 to 20, wherein the patient has previously been treated with a CDK4 / 6 inhibitor.

[0117] Embodiment 22: The method of any one of embodiments 1 to 21, wherein the patient has not previously received treatment with a SERD other than an mTOR inhibitor and / or fulvestrant.

[0118] Embodiment 23: A method of treating ER+ / HER2- advanced / metastatic breast cancer with mutated estrogen receptor 1 (ESR1) in a patient in need thereof, said method comprising administering amsenestrant or a pharmaceutically acceptable salt thereof to said patient.

[0119] Embodiment 24: The method of embodiment 23, wherein treatment is a 10.0% reduction in the risk of disease progression or death compared to treatment with a therapy selected from fulvestrant, an aromatase inhibitor, and a selective estrogen receptor modulator.

[0120] Embodiment 25: The method of embodiment 24, wherein the aromatase inhibitor is exemestane, letrozole, or anastrozole.

[0121] Embodiment 26: The method of embodiment 24, wherein the selective estrogen receptor modulator is tamoxifen.

[0122] Embodiment 27: The method according to any one of embodiments 23 to 26, wherein said method increases the progression-free survival (PFS) of the patient.

[0123] Embodiment 28: The method according to any one of embodiments 23 to 27, wherein said method results in a median PFS of about 3.7 months.

[0124] Embodiment 29: The method of any one of embodiments 23 to 28, wherein amsenestrant or a pharma- ceutically acceptable salt thereof is orally administered to the patient, optionally once a day, at a dose of 400 mg per day.

[0125] Embodiment 30: The method of any one of embodiments 23 to 29, wherein amsenestrant or a pharma- ceutically acceptable salt thereof is provided as a capsule or tablet, optionally containing 100 mg of amsenestrant per capsule.

[0126] Embodiment 31: The method according to any one of embodiments 23 to 30, wherein amsenestrant or a pharma- ceutically acceptable salt thereof is administered to the patient in the morning, regardless of food status.

[0127] Embodiment 32: The method of any one of embodiments 23 to 31, wherein the breast cancer is advanced breast cancer.

[0128] Embodiment 33: The method of embodiment 32, wherein the advanced breast cancer is a locally advanced cancer that is not amenable to curative radiation therapy or surgery.

[0129] Embodiment 34: The method of any one of embodiments 23 to 31, wherein the breast cancer is metastatic.

[0130] Embodiment 35: The method of any one of embodiments 23 to 34, wherein the patient is a pre- or post-menopausal woman, or a man.

[0131] Embodiment 36: The method of embodiment 35, wherein the patient is a late menopausal woman.

[0132] Embodiment 37: The method of any one of embodiments 23 to 36, wherein the patient is resistant to endocrine therapy.

[0133] Embodiment 38: The method of any one of embodiments 23 to 37, wherein the patient has previously been treated with at least one line of endocrine therapy, optionally one or two lines of endocrine therapy for advanced breast cancer, and optionally the patient's breast cancer has progressed during or after treatment with the previous endocrine therapy.

[0134] Embodiment 39: The method of embodiment 38, wherein the patient has previously been treated with adjuvant endocrine therapy and has relapsed after the first 2 years of adjuvant endocrine therapy or within 12 months of completing adjuvant endocrine therapy.

[0135] Embodiment 40: The method of embodiment 39, wherein the prior adjuvant endocrine therapy is selected from treatment with tamoxifen, fulvestrant, or an aromatase inhibitor, optionally wherein the aromatase inhibitor is exemestane, letrozole, or anastrozole.

[0136] Embodiment 41: The method of any one of embodiments 23 to 40, wherein the patient has previously been treated with chemotherapy or targeted therapy.

[0137] Embodiment 42: The method of embodiment 41, wherein the patient has previously been treated with no more than one chemotherapy or targeted therapy for advanced or metastatic disease.

[0138] Embodiment 43: The method of any one of embodiments 23 to 42, wherein the patient has previously been treated with a CDK4 / 6 inhibitor.

[0139] Embodiment 44: The method of any one of embodiments 23 to 43, wherein the patient has not previously received treatment with a SERD other than an mTOR inhibitor and / or fulvestrant.

[0140] Embodiment 45: An article of manufacture or kit comprising amsenestrant and instructions for use in treating ER+ / HER2- breast cancer according to the method of any one of embodiments 1 to 44.

[0141] Embodiment 46: Amsenestrant or a pharma- ceutically acceptable salt thereof for use in the treatment of breast cancer in a method according to any one of embodiments 1 to 44.

[0142] Embodiment 47: Use of amsenestrant or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for treating breast cancer in a method according to any one of embodiments 1 to 44.

[0143] Embodiment 48: The method of any one of embodiments 1 to 44, wherein a patient in need thereof does not experience clinically significant bradycardia, QTc prolongation, or visual disturbances.

[0144] Unless otherwise defined herein, scientific and technical terms used in connection with this disclosure have the meanings commonly understood by those of ordinary skill in the art. Exemplary methods and materials are described below, although methods and materials similar or equivalent to those described herein may also be used in the practice or testing of this disclosure. In the event of a conflict, the present specification, including definitions, will control. In general, the nomenclature used in connection with oncology, medicine, pharmaceutical and medicinal chemistry, and cell biology described herein, and the techniques thereof, are those known and commonly used in the art. Furthermore, unless otherwise required by context, singular terms shall include the plural, and plural terms shall include the singular. Throughout this specification and embodiments, the words "having" and "including", or variations such as "having", "having", "including", or "including", are understood to mean the inclusion of a stated integer or group of integers, but not the exclusion of other integers or groups of integers. All publications and other references cited herein are incorporated by reference in their entirety. Although many documents are cited herein, the citation does not acknowledge that any of these documents form part of the general knowledge in the art. As used herein, the term "approximately" or "about" as applied to one or more values ​​of interest refers to a value similar to the stated reference value. In certain embodiments, the term refers to a range of values ​​that is within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater or less) of the stated reference value, unless otherwise stated or clear from the context.

[0145] According to the present disclosure, back references in dependent claims are intended as a shorthand for direct and clear disclosure of each and every combination of claims set forth by the back reference. Any compound disclosed herein may also be used in any of the methods of treatment described herein, where the individual to be treated is as defined elsewhere herein. Additionally, the headings herein are created for ease of organization and are not intended to limit the scope of the claimed invention in any way. List of Abbreviations AE: Adverse event AESI: Adverse events of particular interest AI: aromatase inhibitor ALT: Alanine aminotransferase ANC: absolute neutrophil count AST: Aspartate aminotransferase BOR: Best Overall Effectiveness CBR: Clinical usefulness rate cfDNA: cell-free deoxyribonucleic acid CI: Confidence interval COD: Cut-off date CR: complete response CT: Computed tomography CYP: Cytochrome P450 DCR: Disease control rate DNA: Deoxyribonucleic acid ECOG: Eastern Cooperative Oncology Group EOT: End of treatment ER: Estrogen receptor ESR1: Estrogen receptor 1 gene FSH: Follicle-stimulating hormone GnRH: gonadotropin releasing hormone HER2: Human epidermal growth factor receptor 2 HR: Hazard ratio IB: Investigational Drug Brochure ICH: International Council for Harmonisation ICR: independent central review IHC: Immunohistochemistry IM: Intramuscular injection IMP: Investigational Drug INR: International Normalized Ratio IRB: Institutional Review Board IRT: Interactive Response Technology ITT: intent-to-treat LFT: Liver function test MedDRA: Medical Dictionary for Regulatory Activities NCI-CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events ORR: Objective Response Rate OS: overall survival PCEM: Physician Choice Endocrine Monotherapy PD: Progress PFS: Progression-free survival PgR: Progesterone receptor PO: per os (oral administration) PR: partial response QD: Once a day RECIST: Response Evaluation Criteria in Solid Tumors RNA: Ribonucleic acid SAE: serious adverse event SD: Stable SERD: Selective estrogen receptor degraders SERM: Selective estrogen receptor modulators eTEAE: treatment-emergent adverse event UGT: Uridine 5'-diphospho-glucuronosyltransferase ULN: Upper limit of normal EXAMPLES

[0146] AMEERA-3: An open-label, randomized phase 2 study of amcenestrant versus endocrine monotherapy according to physician's choice in patients with estrogen receptor (ER)-positive, HER2-negative locally advanced or metastatic breast cancer who have received prior hormonal therapy. Example 1: Clinical Trial Protocol This example describes the clinical trial protocol used in the study described below. This study was an open-label randomized phase 2 study of amsenestrant monotherapy versus endocrine monotherapy according to physician's choice in patients with estrogen receptor (ER)-positive, HER2-negative locally advanced or metastatic breast cancer who had previously received hormonal therapy (Figure 1). For the purposes of this study, a cycle was defined as 4 weeks.

[0147] Purpose of the test The primary objective of this study is to determine whether oral amsenestrant 400 mg improves progression-free survival (PFS) compared with physician's choice of endocrine monotherapy in patients with metastatic or locally advanced breast cancer.

[0148] A key secondary objective was to compare overall survival between the treatment groups.

[0149] Other secondary objectives were to evaluate the following in the two treatment arms: i. objective response rate; ii.Disease control rate, iii.Clinical usefulness rate, iv. Progression-free survival (PFS) according to estrogen receptor 1 gene (ESR1) mutation status, and v. Overall Safety Profile.

[0150] Study Evaluation Items The primary endpoint of the study was measurement of PFS, defined as the time from the date of randomization to the first documented tumor progression according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) assessed by Independent Central Review (ICR), or death (from any cause), whichever occurred first.

[0151] Secondary endpoints are defined as follows: · Overall survival: the time from the date of randomization to the date of recorded death (from any cause); ·Objective response rate: the proportion of participants who achieved a confirmed complete response (CR) or partial response (PR) as best overall response (BOR) determined by ICR according to RECIST 1.1 from the date of randomization to the end of treatment; Disease control rate: the proportion of participants who achieved confirmed CR, PR, stable disease (SD), or non-CR / non-PD as BOR as determined by ICR according to RECIST 1.1 from the date of randomization to the end of treatment; · Clinical benefit rate: the proportion of participants with confirmed CR, PR, SD, or non-CR / non-PD for at least 24 weeks as determined by ICR according to RECIST 1.1 from the date of randomization to the date of end of treatment; Progression-free survival by ESR1 status: determined on day 1 of cycle 1; Overall safety profile: assessed by adverse events / serious adverse events and laboratory abnormalities.

[0152] Study design This is an international, prospective, open-label, randomized phase 2 trial in which men with locally advanced or metastatic breast cancer, late menopausal women, and premenopausal women receiving gonadotropin-releasing hormone analogues were randomly assigned (1:1) to one of two treatment arms: amsenestrand or physician's choice of endocrine monotherapy (Figure 1).

[0153] Randomization was stratified by the presence (yes or no) of visceral metastases (defined by at least one liver or lung metastasis), prior treatment with a CDK4 / 6 inhibitor (yes or no), and Eastern Cooperative Oncology Group status (0 or 1).

[0154] In total, 290 patients were randomized to study intervention in the global part of the study with a balanced randomization ratio. The number of CDK4 / 6 inhibitor-naïve patients was limited to 20% of the total sample size.

[0155] Patients were treated with either amsenestrant or the investigator's choice of monoendocrine therapy depending on randomization. Potential comparators were selected according to the Investigator's best clinical judgment before randomization.

[0156] Dosage regimen and formulation The amnestic arm was treated as follows: Formulation: 100mg capsule Route of administration: PO Dosage regimen: 400 mg (4 capsules) was administered once daily in the morning, regardless of food status. Capsules were taken at approximately the same time each day (± 3 hours). One cycle was artificially defined as 4 weeks.

[0157] Only one of the following single-agent control treatments was permitted per patient randomized to the control arm. Treatments were selected according to the investigator's best clinical judgment prior to randomization, and treatments were administered as follows, with one cycle defined as 4 weeks: Fulvestrant (Faslodex®): Formulation: 50mg / mL injection (for IM administration) Route of administration: IM Dosage regimen: 500 mg as two 250 mg (5 mL) injections, one in the buttock (gluteal area) on days 1 and 15 of a cycle and one on day 1 of each 28-day cycle thereafter. AI Formulation: According to approved labeling Route of administration: PO Dosage regimen: · Anastrozole: 1 mg QD, taken at approximately the same time each day, regardless of food status; Letrozole: 2.5 mg QD, taken at approximately the same time each day, regardless of food status; or Exemestane: 25 mg QD, taken after meals at approximately the same time each day. Selective estrogen receptor modulators: Tamoxifen: Formulation: According to approved labeling Route of administration: PO Dosage regimen: 20 mg once daily or 10 mg twice daily at approximately the same time each day, regardless of food intake.

[0158] Each individual patient's study period included the following: -An eligibility evaluation period (screening period) of up to 4 weeks (28 days) prior to randomization; A treatment duration of 28 days per cycle; and End of Treatment (EOT) visit at least 30 days after the last dose of amsenestrant (or until the patient receives another anti-cancer drug, whichever comes first).

[0159] Study treatment continued until unacceptable toxicity, disease progression, patient request to discontinue treatment, or investigator discretion, whichever occurred first. Patients continued treatment after the final cut-off date (COD). Patients who discontinued study treatment without documented PD were followed every 8 weeks until documented PD or the primary analysis COD, whichever occurred first.

[0160] Study population Patients were eligible to participate in the study only if they met all of the following criteria: I 01: Patients must be 18 years of age or older at the time of signing the informed consent, or the legal age of adulthood in their country if the legal age in their country is 19 years of age or older; I 02: Patients with histologically or cytologically diagnosed adenocarcinoma of the breast. I 03: Patients with evidence of either locally advanced and / or metastatic disease who are not amenable to radiation therapy or surgery with curative intent. I 04: Documentation of ER positivity (≥1% positively staining cells) based on recent tumor cell staining by immunohistochemistry (IHC) assay consistent with local criteria (note that patients cannot be selected for inclusion if the primary tumor is ER positive and another metastatic lesion is ER negative). I 05: Documentation of non-HER2 overexpression (0,1+) based on most recent tumor sample by IHC or negative in situ hybridization (based on single-probe mean HER2 copy number <6.0 signals / cell or dual-probe HER2 / centromeric chromosome 17 (CEP17) probe ratio <2 and mean HER2 copy number <6.0 signals / cell according to American Society of Clinical Oncology guidelines (28)) (note that patients cannot be selected for inclusion if the primary tumor is HER2-negative and another metastatic lesion is HER2-positive). I 06: Deleted. I 07: Prior chemotherapy (including antibody-drug conjugates) or targeted therapy was allowed: Patients must have received no more than one prior chemotherapy or targeted therapy for advanced / metastatic disease. For patients with CDK4 / 6 inhibitors available (i.e., locally approved and reimbursable), prior treatment with a CDK4 / 6 inhibitor in combination with fulvestrant or an AI was mandatory (Note: the number of CDK4 / 6 inhibitor-naive patients should be limited to 20% of the total sample size). I 08: Patients must have previously received at least 6 months of continuous endocrine therapy for advanced breast cancer and progressed while on endocrine therapy (monotherapy or combination therapy). The number of hormonal therapy options was limited to 2. Patients on adjuvant endocrine therapy who relapsed after the first 2 years or within 12 months of completing adjuvant endocrine therapy. I 09: Male or female A) Women in postmenopause as defined by one of the following: i) Females aged ≥ 60 years ii) Women aged <60 years: -Subjects had naturally stopped menstruating >12 months prior to randomization in the absence of chemotherapy, tamoxifen, or toremifene. OR, cessation of menses for ≤12 months or cessation of menses since hysterectomy and a follicle-stimulating hormone (FSH) level within the institutional postmenopausal range (or >34.4 IU / L if institutional range was not available) prior to randomization. OR, had previously received hormone replacement therapy but discontinued such therapy and had an FSH level within the institutional postmenopausal range (or >34.4 IU / L if institutional range was not available) prior to randomization. - Or those who have undergone bilateral oophorectomy. - Or those who have undergone bilateral oophorectomy with pelvic radiotherapy. B) Pre / perimenopausal women, i.e., women who do not meet the criteria for late menopause. C) A male patient. Note: Men and pre- / post-menopausal women who have not undergone bilateral orchiectomy must have been receiving GnRH agonist treatment for at least 4 weeks prior to randomization (and continued during study treatment). I 10: Ability to provide signed informed consent, including compliance with the requirements and limitations set forth in this protocol. I 11: Patients must be deemed clinically eligible by the investigator to receive monotherapy.

[0161] Patients were excluded from the study if they met any of the following criteria: E 01: Eastern Cooperative Oncology Group performance status ≥ 2. E 02: Significant comorbidities, such as psychiatric disorders, that, in the opinion of the investigator or sponsor, may adversely affect the patient's participation in the study. E 03: History or ongoing gastrointestinal disorder that may affect oral IMP absorption. Patients unable to swallow normally and take capsules. Predicted poor compliance with oral therapy. E 04: Includes patients who, in the opinion of the investigator, are unsuitable for participation for any reason, e.g., because of a medical or clinical condition, or because they are potentially at risk for non-compliance with study procedures (i.e., unwillingness and ability to comply with clinic visit schedules, drug regimens, laboratory tests, other study procedures, and study constraints). E 05: Subjects who underwent major surgery within 4 weeks prior to randomization. E 06: Patients with any other cancer. Patients with basal or squamous cell skin cancer, or epithelial cervical cancer, or any other cancer that has been adequately treated and in which the patient has been disease-free for >3 years are permitted. E 07: Any medical condition contraindicated to endocrine therapy selected by the physician (see approved labeling for details). E 08: Patients with a history of abnormal coagulation profile or coagulation disorder within 6 months prior to the first dose of IMP, such as a history of deep vein thrombosis or pulmonary embolism. However, patients with the following conditions are eligible to participate: -Patients with adequately treated catheter-related venous thrombosis that occurred >1 month prior to the first dose of IMP. Patients receiving anticoagulant therapy (e.g., warfarin or heparin) for a thrombotic event occurring >6 months prior to enrollment or for an otherwise stable, tolerated medical condition (e.g., well-controlled atrial fibrillation) with stable doses and coagulation parameters (as defined by local standard of care) for at least 1 month prior to the first dose of IMP. E 09: Patients with life expectancy <3 months. E 10: Deleted. E11: Patients with known brain metastases who are treatment-naïve, symptomatic, or requiring treatment to control symptoms. Patients with brain metastases are eligible if: Completed treatment (whole brain radiation therapy, radiosurgery, or a combination) at least 4 weeks prior to the start of study treatment, and - have recovered from the effects of this treatment, and · Neurologically stable. Corticosteroids for brain metastases must be discontinued and patients must be asymptomatic for ≥ 2 weeks prior to the first IMP administration. E12: Previous treatment-related adverse reactions have not resolved to < Grade 2, except for alopecia per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0. E 13: Previous treatment with mammalian targeting rapamycin inhibitors or other SERD compounds (unless fulvestrant was discontinued for at least 3 months prior to randomization). E14: Received treatment with drugs that may inhibit UGT, including but not limited to atazanavir and probenecid, for less than 2 weeks or 5 elimination half-lives prior to randomization, whichever is longer. E15: Received treatment with a strong CYP3A inducer within 2 weeks or 5 elimination half-lives prior to randomization, whichever is longer. E 16: Received treatment with drugs that are sensitive substrates of OATP1B1 / B3 (asunaprevir, atorvastatin, bosentan, danoprevir, fexofenadine, glyburide, nateglinide, pitavastatin, pravastatin, repaglinide, rosuvastatin, and simvastatin acid). E17: Received anticancer drug treatment (including investigational drugs) for less than 3 weeks prior to randomization. E 18: Neutrophil count < 1.5 × 10 9 / L; Platelet count <100×10 9 Inadequate hematological function such as / L. E 19: Prothrombin time / international normalized ratio (INR) > 1.5 times the upper limit of normal (ULN) or prothrombin time / INR outside the therapeutic range if receiving anticoagulant therapy that may affect the INR. E20: Serum creatinine ≥ 1.5 × ULN or 1.0–1.5 × ULN and glomerular filtration rate estimated using the simplified Modification of Diet in Renal Disease formula of 60 mL / min / 1.73 m 2 Less than 50%. Inadequate renal function. E 21: Liver function: Aspartate aminotransferase >3×ULN, ALT >3×ULN Total bilirubin >1.5×ULN. Note: If liver metastases are present, AST and ALT < 5 x ULN are acceptable. E 22: Patients held in an institution by regulation or legal order, prisoners or legally institutionalized patients. E 23: Patients dependent on the sponsor or investigator (in conjunction with article 1.61 of the International Council for Harmonisation-Good Clinical Practice Ordinance E6). E 24: Employees of a clinical trial site or other individuals directly involved in the conduct of the trial, or close relatives of such individuals. E 25: Hypersensitivity or other allergy to the investigational intervention or any of its components, or to any medication, which in the opinion of the investigator makes participation in the trial inadvisable.

[0162] Combination therapy Patients were asked to refrain from taking prescription or non-prescription medications (e.g., vitamins and dietary supplements or herbal supplements) for 7 days (or 14 days if the medication was a potential enzyme inducer) or 5 half-lives (whichever was longer) before starting treatment until the end of follow-up, unless in the opinion of the investigator and sponsor the medication would not interfere with the study.

[0163] Bisphosphonates and receptor activators of nuclear factor-κB ligand inhibitors were permitted.

[0164] Special attention was given to the treatment of: Other investigational or commercially available anticancer drugs, such as chemotherapy, immunotherapy, targeted therapy, biological response modifiers, or endocrine therapy other than amsenestrand or the selected comparator, were not permitted in the active treatment phase. In general, drugs with a statement on the product label that they are "intended to treat breast cancer" were not permitted during the study. Palliative radiotherapy was performed for palliative pain control. The irradiated area was kept as small as possible, never reaching more than 20% of the bone marrow during a 3-week period. In all such cases, physical and radiological evaluation of the tumor ruled out possible tumor progression. Patients were discontinued from study treatment if only evaluable lesions were to be irradiated. The irradiated area could not be used as a parameter for response evaluation. Drugs that are sensitive substrates of CYP3A, CYP2B6, CYP2C, and / or UGT should be closely monitored with amsenestrant as concurrent use may result in loss of efficacy of the above drugs due to the possible inductive effects of amsenestrant.

[0165] In the Amnestyndt treatment arm, the following therapies / medications were prohibited throughout the active treatment phase: ·Medicines that are strong inducers of CYP3A (which may reduce amsenestrant exposure). Botanicals and food supplements such as St. John's Wort and genistein during treatment (which may reduce amcenestrant exposure). · Drugs that are sensitive substrates of OATP1B1 / 1B3, such as asunaprevir, atorvastatin, bosentan, danoprevir, fexofenadine, glyburide, nateglinide, pitavastatin, pravastatin, repaglinide, rosuvastatin, and simvastatin acid (amsenestrant is a potential inhibitor and may reduce their clearance); -Medicines that may inhibit UGTs and are contraindicated for use with UGT substrates, including but not limited to atazanavir and probenecid (amsenestrant is a substrate for UGT1A1 and UGT1A4).

[0166] Test evaluation Day 1 of Cycle 1 refers to the day participants received their first dose of study treatment, which was a single dose of amsenestrant, or their physician's choice of comparator.

[0167] Day 15 of cycle 1 corresponds to the second fulvestrant injection for participants randomized to the control arm and treated with fulvestrant.

[0168] Cycle duration is 28 days. Day 1 of Cycle 1 refers to the day the participant received their first dose of study treatment. Day 1 of each subsequent cycle corresponds to the visit occurring on Day 29 ± 2 of the previous cycle.

[0169] Primary and secondary efficacy outcomes were assessed according to RECIST 1.1 criteria. Tumor assessments were centrally reviewed by the ICR and supported by investigator assessment.

[0170] With regard to adverse event monitoring, reference may be made to Adverse Events of Special Interest (AESIs) that are of scientific and medical concern (serious or non-serious) specific to the sponsor's product or program and require ongoing monitoring and immediate notification by the investigator to the sponsor. Further investigation may be required to characterize and understand such events. Examples include pregnancy of the participant or the female partner of a male participant in a study with IMP, symptomatic overdose of IMP, Grade 3 or greater ALT elevation, photosensitivity, etc.

[0171] Analysis population The analysis population was defined as follows: Enrollment population: All patients who signed an informed consent form. Intent-to-treat (ITT) population: all patients from the enrollment population whose successful allocation of a randomization number was confirmed by Interactive Response Technology (IRT). Patients were analyzed according to the treatment group they were assigned to at randomization. Safety population: all patients randomized to and who received at least one dose of the study intervention. Patients were analyzed according to the treatment arm they actually received.

[0172] Efficacy Analysis All efficacy analyses for the global part were performed on the intention-to-treat (ITT) population unless otherwise noted. All primary and secondary efficacy endpoints based on radiological assessment of tumor burden (i.e., PFS, BOR, ORR, disease control rate [DCR], and clinical benefit rate [CBR]) were derived using ICR tumor assessment. Analyses based on local radiologist / investigator assessment were considered supplemental analyses. A summary of the efficacy analyses performed is shown in Table 7.

[0173] [Table 7]

[0174] The primary efficacy analysis consisted of a comparison of PFS (based on ICR) between the amsenestrant arm and the control arm by a log-rank test procedure stratified by stratification factors. A one-sided type I error rate of 2.5% was used for statistical testing.

[0175] The primary analysis of PFS was based on the following censoring rules: If no progression or death was observed by the COD of final PFS, PFS was censored at the date of the last available disease assessment without evidence of disease progression prior to initiation of further anticancer treatment (if any). Patients without an event (death or disease progression) and without a valid post-baseline disease assessment were censored at the day of randomization (Day 1). Patients with a documented event after two or more non-evaluable tumor evaluations were censored at the date of the last evaluable tumor evaluation documenting no progression before initiation of further anticancer treatment.

[0176] The COD for the final PFS analysis was the date when approximately 201 PFS events assessed by ICR were observed or when all patients in the global cohort had been followed for at least 10 months (or discontinued treatment), whichever occurred first.

[0177] HR estimates and corresponding 95% two-sided CIs were provided using Cox proportional hazards models stratified by the same stratification factors used for the log-rank test described above. Progression-free survival in the two treatment arms was summarized and displayed graphically using the Kaplan-Meier method. In addition to median PFS, the 25th, 50th, and 75th percentiles of event time and associated 95% CIs were obtained, along with the probability of being progression-free at different time points.

[0178] For overall survival (OS), in the absence of observed deaths, survival was censored at the last date the patient was known to be alive. HR estimates and corresponding 95% two-sided CIs were obtained using a Cox proportional hazards model stratified by the same stratification factors used for the PFS analysis described above. Overall survival for the two treatment arms was summarized using the Kaplan-Meier method and displayed graphically. Median, 25th, 50th, and 75th percentiles of event times and associated 95% CIs were obtained. Survival probabilities and their 95% CIs were estimated using the Kaplan-Meier method and a log-ratio approach based on the normal approximation according to the Greenwood formula. A hierarchical testing strategy was defined to ensure robust control of the one-sided 2.5% overall type I error rate. In other words, comparisons between arms regarding OS were only performed if the primary analysis regarding PFS was statistically significant. If PFS was statistically significant, OS was to be compared between treatment arms by the log-rank test stratified by stratification factors entered into the IRT. Otherwise, descriptive statistics for OS were to be provided at the time of the final PFS analysis. The COD for the final OS analysis was set as the date when approximately 196 death events had been observed (approximately 70% of patients had died).

[0179] The objective response rate (ORR) for each randomized treatment arm was estimated by dividing the number of patients who had an objective response (CR or PR with confirmed BOR according to RECIST 1.1) by the number of patients from the analysis population in each treatment arm, and 95% two-sided CIs were calculated using the Clopper-Pearson method.

[0180] Disease control rates (DCR) for each randomized treatment arm were estimated by dividing the number of patients with disease control (CR or PR with confirmed BOR according to RECIST 1.1, SD, or non-CR / non-PD) by the number of patients from the analysis population in each treatment arm, and 95% two-sided CIs were calculated using the Clopper-Pearson method.

[0181] Clinical benefit rates (CBRs) in each randomized treatment arm were estimated by dividing the number of patients with clinical benefit (CR or PR confirmed as BOR, SD, or non-CR / non-PD lasting at least 24 weeks according to RECIST 1.1) by the number of patients from the analysis population in each treatment arm. Additionally, 95% two-sided CIs were calculated using the Clopper-Pearson method.

[0182] Example 2: Clinical Trial Results The results presented herein arise from the patient database cutoff date of February 15, 2022.

[0183] Patient population A total of 290 patients were randomized into the study, with 143 patients randomized to the amnestic arm and 147 patients randomized to the control arm.

[0184] Patients in the control arm were treated with the following endocrine therapies: · SERD (fulvestrant): 132 patients (89.8%); · Aromatase inhibitors: 10 patients (6.8%), including 4 (2.7%) receiving letrozole and 6 (4.1%) receiving exemestane; · SERM (tamoxifen): 5 patients (3.4%).

[0185] Thus, most patients in the control arm were treated with fulvestrant.

[0186] The main baseline characteristics of the patients were balanced between treatment arms and are listed in Table 8.

[0187] [Table 8]

[0188] All patients were ER positive, and 73.1% were progesterone receptor positive (PgR). All but one patient was HER2 negative.

[0189] Overall, this population is representative of the ER+, HER2- advanced / metastatic breast cancer patients refractory to endocrine therapy expected in this study: · 84.8% were in late menopausal status; ·63.8% had visceral involvement (by ICR); · 42.9% had ESR1 mutations; 79.6% of patients initiated second-line therapy. 79% had prior CDK4 / 6i treatment

[0190] exposure At the cutoff date, 20 patients remained as treatment continuers in each study arm; 123 patients discontinued treatment in the amnestic arm and 127 patients discontinued treatment in the control arm, mainly due to the development of PD.

[0191] Duration of IMP exposure was as follows: · Mean (standard deviation) duration: 26.3 (23.7) weeks in the amsenestrant arm and 25.4 (23.5) weeks in the PCEM arm. Median duration: 16.0 weeks in the amsenestrant arm and 15.9 weeks in the PCEM arm. Minimum to maximum exposure period: 0 to 116 weeks in the amsenestrant arm and 2 to 102 weeks in the PCEM arm.

[0192] The relative dose mean (standard deviation), defined as the ratio of the total cumulative dose to the total planned dose, was 97.7% (9.6) and 97.3% (8.4) in the PCEM arm and amsenestrant group, respectively.

[0193] Efficacy analysis-PFS Figure 2 shows the Kaplan-Meier graph of PFS assessed by ICR in the ITT population. The results of PFS assessed by ICR (the primary objective of this study) are shown in Table 9.

[0194] [Table 9]

[0195] With a median follow-up of 11.2 months, the risk of disease progression or death was numerically equivalent between the two treatment arms (HR=1.051 95% CI (0.789-1.4)). Median PFS (95% CI) was numerically similar between amsenestrant (3.6 months (2.0-3.9)) and PCEM (3.7 months (2.0-4.9)).

[0196] PFS findings indicate that treatment effects were generally consistent across key subgroups determined by baseline characteristics (Figure 4).

[0197] ESR1 wild type patient Among baseline ESR1-wild type participants, 54 (72.0%) and 50 (58.8%) had PFS events in the amsenestrant and PCEM arms, respectively, as assessed by ICR. The stratified HR was 1.305 (95% CI: 0.88-1.937). Median PFS was 3.5 months (95% CI: 2.0-3.7) in the amsenestrant arm and 3.9 months (95% CI: 3.6-9.2) in the PCEM arm.

[0198] Patients with ESR1 mutations In patients with ESR1 mutations at baseline, 44 (67.7%) and 38 (69.1%) participants were observed to have PFS events in the amsenestrant and PCEM arms, respectively, according to ICR assessment (Table 10). The stratified HR was 0.9 (95% CI: 0.565-1.435), which corresponds to a 10.0% reduction in the risk of disease progression or death with amsenestrant compared with the PCEM arm. The median PFS was 3.7 months (95% CI: 1.9-7.2) in the amsenestrant arm and 2.0 months (95% CI: 1.9-4.3) in the PCEM arm. Thus, participants with ESR-1 mutations at baseline performed better with amsenestrant therapy than with PCEM therapy overall.

[0199] [Table 10]

[0200] Patients with ESR1-Y537S mutation Mutational profiling of 12 pathogenic ESR1 mutations was performed by droplet digital polymerase chain reaction in plasma cell-free DNA at baseline (BL) and on treatment in cycle 3, day 1 (C3D1). At BL, ESR1 mutations were present in 65 / 140 patients (46.4%) and 55 / 140 patients (39.3%) in the amsenestrant and PCEM arms, respectively, with similar numbers and types of ESR1 mutations between both arms. In patients with ESR1-Y537S mutations (amsenestrant, N=27 / 140 [19.3%]; PCEM, N=26 / 141 [18.4%]), a numerically longer PFS was observed in amsenestrant versus PCEM (median PFS 3.8 vs. 1.9 months; stratified HR=0.431 [95% CI: 0.205, 0.909] Error! Reference source not found). In patients with ESR1 data in both BL and C3D1 (amsenestrant, N=90; PCEM, N=82), 20 / 44 patients with ESR1 mutations detected in BL were cured by treatment with amsenestrant compared with 2 / 29 in PCEM.

[0201] Efficacy Analysis-OS Figure 3 shows the Kaplan-Meier plot of OS in the ITT population. OS results are shown in Table 11.

[0202] [Table 11]

[0203] At a median follow-up of 16.2 months, OS assessment was incomplete, but a numerically similar survival trend was observed between the two treatment arms (HR=0.913 95% CI (0.595-1.403)). OS rates (95% CI) at 12 months were 77.4% (69.4-83.6) in the PCEM arm versus 80.4% (72.5-86.2) in the amsenestrant arm.

[0204] Efficacy – Antitumor activity Secondary efficacy endpoints based on tumor response are shown in Table 12.

[0205] [Table 12]

[0206] safety A summary of adverse events (TEAEs: study drug-emergent adverse events; SAEs: serious adverse events; AESIs: adverse events of special interest) is shown in Table 13.

[0207] [Table 13]

[0208] A higher frequency of gastrointestinal disorders was observed in the amsenestrant treatment arm (22.4% in the PCEM arm vs. 44.8% in the amsenestrant arm), most of which were grade 1 or 2. Also, a higher rate of skin and subcutaneous tissue disorders was observed (7.5% in the PCEM group vs. 18.9% in the amsenestrant group), again most of which were grade 1 or 2.

[0209] Although a numerically higher incidence of adverse events was observed in the amsenestrant arm compared to the PCEM arm, overall the adverse event profile in the amsenestrant treatment arm was consistent with earlier studies with the same product. Importantly, bradycardia / QTc prolongation, as seen with several other SERDs in clinical development, was not observed in the amsenestrant treatment arm.

[0210] conclusion The AMEERA-3 trial did not meet its primary objective regarding PFS by ICR, as amsenestrant did not prove statistically superior to PCEM. The observed risks of disease progression or death were numerically similar between treatment arms.

[0211] The AMEERA-3 study demonstrated that amsenestrant, when used at 400mg QD, can provide numerically longer progression-free survival compared with physician's choice of endocrine therapy in patients with ER+ / HER2- advanced / metastatic breast cancer harboring an ESR1 mutation.Treatment with amsenestrant was associated with numerically longer progression-free survival compared with physician's choice of endocrine therapy in patients with ER+ / HER2- advanced / metastatic breast cancer harboring an ESR1-Y537S mutation.

[0212] The safety profile of amsenestrant was consistent with previous studies with the product, with a numerically higher rate of TEAEs (all grades, grade ≥3 TEAEs, related TEAEs, and SAEs) observed with amsenestrant compared to PCEM, primarily attributable to gastrointestinal disorders.

Claims

1. A method for reducing disease progression or death compared to treatment with a therapy selected from fulvestrant, an aromatase inhibitor, and a selective estrogen receptor modulator in a patient in need thereof, wherein the patient has ER+ / HER2- advanced / metastatic breast cancer with a mutated estrogen receptor 1 (ESR1), the method comprising administering to the patient amsenestrant or a pharmaceutically acceptable salt thereof.

2. 1. A method of treating ER+ / HER2- advanced / metastatic breast cancer with mutated estrogen receptor 1 (ESR1) in a patient in need thereof, said method comprising administering amsenestrant or a pharmaceutically acceptable salt thereof to said patient.

3. 3. The method of claim 1 or 2, wherein the method results in a 10.0% reduction in the risk of disease progression or death compared to treatment with a therapy selected from fulvestrant, an aromatase inhibitor, and a selective estrogen receptor modulator.

4. 4. The method of claim 1 or 3, wherein the aromatase inhibitor is exemestane, letrozole, or anastrozole.

5. 4. The method of claim 1 or 3, wherein the selective estrogen receptor modulator is tamoxifen.

6. The method of any one of claims 1 to 5, wherein said method increases the progression free survival (PFS) of said patient.

7. The method of any one of claims 1 to 6, wherein the method results in a median PFS of about 3.7 months.

8. The method according to any one of claims 1 to 7, wherein amsenestrant or a pharma- ceutically acceptable salt thereof is orally administered to the patient at a dose of 400 mg per day, optionally once per day.

9. The method according to any one of claims 1 to 8, wherein amsenestrant or a pharma- ceutically acceptable salt thereof is provided as a capsule or tablet, optionally containing 100 mg of amsenestrant per capsule or tablet.

10. The method according to any one of claims 1 to 9, wherein amsenestrant or a pharma- ceutically acceptable salt thereof is administered to the patient in the morning, regardless of food status.

11. The method according to any one of claims 1 to 10, wherein the breast cancer is advanced breast cancer.

12. 12. The method of claim 11, wherein the advanced breast cancer is a locally advanced cancer that is not amenable to curative radiation therapy or surgery.

13. The method of any one of claims 1 to 10, wherein the breast cancer is metastatic.

14. The method of any one of claims 1 to 13, wherein the patient is a pre- or post-menopausal woman or a man.

15. 15. The method of claim 14, wherein the patient is a post-menopausal woman.

16. The method of any one of claims 1 to 15, wherein the patient is resistant to endocrine therapy.

17. 17. The method of any one of claims 1 to 16, wherein the patient has previously been treated with at least one line of endocrine therapy, optionally one or two line of endocrine therapy for advanced breast cancer, and optionally the patient's breast cancer has progressed during or after treatment with the previous endocrine therapy.

18. 18. The method of claim 17, wherein the patient has previously been treated with adjuvant endocrine therapy and relapsed after the first 2 years of adjuvant endocrine therapy or within 12 months of completing adjuvant endocrine therapy.

19. 20. The method of claim 18, wherein the prior adjuvant endocrine therapy is selected from treatment with tamoxifen, fulvestrant, or an aromatase inhibitor, optionally wherein the aromatase inhibitor is exemestane, letrozole, or anastrozole.

20. The method of any one of claims 1 to 19, wherein the patient has previously been treated with chemotherapy or targeted therapy.

21. 21. The method of claim 20, wherein the patient has been previously treated with no more than one chemotherapy or targeted therapy for advanced or metastatic disease.

22. The method of any one of claims 1 to 21, wherein the patient has previously been treated with a CDK4 / 6 inhibitor.

23. The method of any one of claims 1 to 22, wherein the patient has not previously received treatment with a SERD other than an mTOR inhibitor and / or fulvestrant.

24. 24. The method of any one of claims 1 to 23, wherein the patient does not experience clinically significant bradycardia, QTc prolongation, or visual disturbances.

25. An article of manufacture or kit comprising amsenestrant and instructions for use in treating ER+ / HER2- breast cancer in the method of any one of claims 1 to 24.

26. 25. Amsenestrant or a pharma- ceutically acceptable salt thereof for use in the treatment of breast cancer in the method according to any one of claims 1 to 24.

27. 25. Use of amsenestrant or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for treating breast cancer in the method according to any one of claims 1 to 24.

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