Use of CDK4 and 6 inhibitor in combination with fulvestrant for treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer in patients previously treated with CDK4 and 6 inhibitor

Abstract

To provide methods, uses, and combinations for treating hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer in patients previously treated with a CDK4 and 6 inhibitor.SOLUTION: The methods, uses and combinations include administration of a CDK4 and 6 inhibitor in combination with fulvestrant. The methods, uses and combinations may include a CDK4 and 6 inhibitor such as palbociclib, ribociclib or abemaciclib with fulvestrant.SELECTED DRAWING: None

Description

Technical Field

[0001] The present disclosure relates to the field of treatment of hormone receptor positive (HR+) and human epidermal growth factor receptor 2 negative (HER2-) advanced or metastatic breast cancer in patients previously treated with CDK4 and 6 inhibitors.

Background Art

[0002] The combination therapy of CDK4 and 6 inhibitors and endocrine therapy (ET) as primary treatment for locally advanced or metastatic hormone receptor positive (HR+) and human epidermal growth factor receptor 2 negative (HER2-) breast cancer has dramatically improved the outcome (Finn et al. 2016, Tripathy et al. 2018; Johnston et al. 2019). Nevertheless, these therapies are not curative, and most patients with metastatic breast cancer will experience disease progression. More recently, abemaciclib has shown significant improvement in invasive disease-free survival (IDFS) and distant recurrence-free survival (DRFS) in the adjuvant setting (Johnston et al. 2020) for patients with early breast cancer at high risk of recurrence. As the use of CDK4 and 6 inhibitors increases as an initial therapy, additional methods are needed to treat patients who experience disease progression or recurrence during or after CDK4 and 6-based therapy.

Summary of the Invention

[0003] In one embodiment, the present disclosure provides a method for treating a patient having hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer who has been previously treated with a therapy comprising CDK4 and 6 inhibitors, the method comprising administering the CDK4 and 6 inhibitors to the patient in combination with fulvestrant. In some further embodiments of this embodiment, the method comprises administering the patient a CDK4 and 6 inhibitor comprising abemaciclib, palbociclib, or ribociclib in combination with fulvestrant. In some preferred embodiments, the method comprises administering the patient abemaciclib in combination with fulvestrant. In another embodiment, the method comprises administering the patient palbociclib in combination with fulvestrant. In yet another embodiment, the method comprises administering the patient ribociclib in combination with fulvestrant.

[0004] In some embodiments of this model, the patient may have previously received a therapy containing CDK4 and CDK6 inhibitors as monotherapy. In some other embodiments, the patient may have previously received a therapy containing CDK4 and CDK6 inhibitors in combination with additional therapy. In some further embodiments, the therapy containing the prior CDK4 and CDK6 inhibitors includes abemaciclib, palbociclib, or ribociclib. In some further embodiments, the therapy containing the prior CDK4 and CDK6 inhibitors includes abemaciclib. In some further embodiments, the therapy containing the prior CDK4 and CDK6 inhibitors includes palbociclib. In some even further embodiments, the therapy containing the prior CDK4 and CDK6 inhibitors includes ribociclib.

[0005] In this embodiment, the patient may have previously received a therapy containing CDK4 and CDK6 inhibitors in combination with endocrine therapy. In some embodiments, the prior endocrine therapy includes tamoxifen. In some embodiments, the prior endocrine therapy includes an aromatase inhibitor. In some further embodiments, the aromatase inhibitor includes letrozole, anastrozole, or exemestane.

[0006] In the embodiments described above and in further embodiments of the embodiments, a patient may have received a combination of CDK4 and 6 inhibitors and endocrine therapy for first-line (or early-stage) treatment of HR+, HER2- advanced or metastatic breast cancer. In some embodiments, the first-line treatment includes endocrine therapy selected from tamoxifen and aromatase inhibitors. In some embodiments, the first-line treatment includes ribociclib as the CDK4 and 6 inhibitor. In some embodiments, the first-line treatment includes palbociclib as the CDK4 and 6 inhibitor. In some embodiments, the first-line treatment includes abemaciclib as the CDK4 and 6 inhibitor.

[0007] In the embodiments described above and in further embodiments of the embodiments, the patient may have previously received a therapy comprising CDK4 and CDK6 inhibitors as monotherapy. In some other embodiments, the patient may have received a therapy comprising the prior CDK4 and CDK6 inhibitors in combination with additional treatment. In some further embodiments, the therapy comprising the prior CDK4 and CDK6 inhibitors comprises abemaciclib, palbociclib, or ribociclib.

[0008] In further embodiments, the therapy comprising the prior CDK4 and 6 inhibitors comprises abemaciclib. In some further embodiments, the therapy comprising the prior CDK4 and 6 inhibitors comprises palbociclib. In some even further embodiments, the therapy comprising the prior CDK4 and 6 inhibitors comprises ribociclib.

[0009] In some further embodiments, the treatment method includes patients having advanced or metastatic breast cancer and who have previously received CDK4 and CDK6 inhibitor therapy, including abemaciclib. In such further embodiments, the prior therapy including abemaciclib may have been administered as: (i) in combination with endocrine therapy (e.g., tamoxifen or an aromatase inhibitor) as adjuvant therapy in adult patients with HR+, HER2- lymph node-positive early breast cancer at high risk of recurrence and with a Ki-67 score ≥20% as determined by FDA-approved testing; (ii) in combination with an aromatase inhibitor as initial endocrine-based therapy for postmenopausal women with HR+, HER2- advanced or metastatic breast cancer; (iii) in combination with fulvestrant for women with HR+, HER2- advanced or metastatic breast cancer; or (iv) as monotherapy for adult patients with HR+, HER2- advanced or metastatic breast cancer whose disease has progressed after endocrine therapy.

[0010] In some further embodiments, the treatment method includes patients having advanced or metastatic breast cancer and who have previously received CDK4 and CDK6 inhibitor therapy, including palbociclib. In such further embodiments, the prior therapy including palbociclib may have been administered (i) in combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of postmenopausal women with HR+, HER2- advanced or metastatic breast cancer, or (ii) in combination with fulvestrant for the treatment of women with HR+, HER2- advanced or metastatic breast cancer after endocrine therapy.

[0011] In some further embodiments, the treatment method includes patients having advanced or metastatic breast cancer and who have previously received CDK4 and CDK6 inhibitor therapy, including ribociclib. In such further embodiments, the prior therapy including ribociclib may have been administered (i) in combination with an aromatase inhibitor as initial endocrine-based therapy for premenopausal / perimenopausal or postmenopausal women having HR+, HER2- advanced or metastatic breast cancer, or (ii) in combination with fulvestrant as initial endocrine-based therapy or after disease progression during endocrine therapy for postmenopausal women having HR+, HER2- advanced or metastatic breast cancer.

[0012] In some further embodiments, the method according to any of the above embodiments and models includes administering abemaciclib as an oral dose of 150 mg twice daily on days 1 to 28 of each 28-day cycle. In further embodiments, the method includes administering fulvestran as an intramuscular dose of 500 mg on days 1 and 15 of the first 28-day cycle (cycle 1), and on day 1 of the second and any subsequent 28-day cycles (cycle 2 and subsequent cycles).

[0013] In another aspect, the Disclosure provides a method for treating patients with hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer who have been previously treated with a therapy comprising CDK4 and 6 inhibitors selected from abemaciclib, ribociclib, and palbociclib, the method comprising administering an effective dose of abemaciclib to the patient in combination with fulvestrant, the abemaciclib being administered twice daily as an oral dose of 150 mg on days 1 to 28 of each 28-day cycle, and the fulvestrant being administered as an intramuscular dose of 500 mg on days 1 and 15 of the first 28-day cycle, and on day 1 of the second and any subsequent 28-day cycles.

[0014] In any of the above embodiments and examples, the method may include administering CDK4 and CDK6 inhibitors simultaneously with, separately from, or sequentially in combination with fulvestrant.

[0015] In any of the above embodiments and models, the method can be administered for a sufficient duration to provide progression-free survival for the patient.

[0016] In all of the above embodiments and designs, the patient is a human being. In further embodiments, the patient may be an adult male, or an adult premenopausal, perimenopausal, or postmenopausal woman.

[0017] In another aspect, the disclosure provides CDK4 and CDK6 inhibitors for use concurrently with, separately, or sequentially in combination with fulvestrant in the treatment of patients with hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer who have previously received therapy including CDK4 and CDK6 inhibitors.

[0018] In another aspect, the Disclosure provides concurrent, separate, or sequential combinations of therapeutically effective doses of CDK4 and 6 inhibitors and fulvestrant for a period sufficient to provide progression-free survival in patients with HR+, HER2-, advanced or metastatic breast cancer whose disease progresses during or after prior therapy with CDK4 and 6 inhibitors.

[0019] In another aspect, the disclosure provides CDK4 and 6 inhibitors for use concurrently, separately, or sequentially with fulvestrant for the treatment of patients with HR+, HER2-, advanced or metastatic breast cancer whose disease progresses during or after prior therapy with CDK4 and 6 inhibitors.

[0020] In another embodiment, the Disclosure provides the use of CDK4 and 6 inhibitors in the manufacture of a drug for the treatment of patients with HR+, HER2-, advanced or metastatic breast cancer who have received prior therapy with CDK4 and 6 inhibitors, the drug being administered concurrently with, separately, or sequentially with fulvestrant. In some embodiments, the patient experienced disease progression during prior therapy with CDK4 and 6 inhibitors.

[0021] In another aspect, the Disclosure provides the use of CDK4 and 6 inhibitors in the manufacture of a drug for the treatment of patients with HR+, HER2-, advanced or metastatic breast cancer whose disease has relapsed during or after prior therapy with endocrine therapy for adjuvant treatment of early breast cancer, the drug being administered concurrently, separately, or sequentially with fulvestrant.

[0022] These aspects, as well as other aspects and embodiments, will become apparent in light of the following description. [Modes for carrying out the invention]

[0023] Disclosed herein are methods, uses, and compositions for the treatment of patients who have previously been treated with a CDK4 and CDK6 inhibitor-containing therapy, comprising administering CDK4 and CDK6 inhibitors to patients who have hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer, in combination with fulvestrant. While there has been considerable interest in and increasing use of CDK4 and CDK6 inhibitor-containing therapies in the treatment of breast cancer, there is no clinical evidence to guide standard care for patients whose metastatic disease has recurred or progressed during or after treatment with a CDK4 and CDK6-containing therapy. For example, the 2020 ESMO and 2021 NCCN clinical guidelines support the use of options including (i) endocrine therapy alone (e.g., aromatase inhibitors (AIs), selective estrogen receptor modifiers (SERMs or SERDs)), (ii) endocrine therapy in combination with PI3K pathway blockade (e.g., everolimus or alpelisib if PIK3CA mutations leading to drug selection are detected), (iii) cytotoxic therapy, and (iv) participation in clinical trials. Therefore, there is little data to help identify and define the optimal therapy for patients with HR+, HER2- advanced or metastatic breast cancer, either as monotherapy or in combination with ET, following adjuvant therapy or first-line therapy including CDK4 and CDK6 inhibitors. There is an unmet need to improve outcomes for such patients.

[0024] In a general embodiment, the present disclosure relates to a method for treating patients with hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer who have been previously treated with a therapy comprising CDK4 and 6 inhibitors, including administering the CDK4 and 6 inhibitors in combination with fulvestrant.

[0025] The treatment methods and methods for treating patients according to various aspects and embodiments of this disclosure include patients who have received prior therapies including CDK4 and 6 inhibitors. “Previously treated” or “prior therapy” with CDK4 and 6 inhibitors according to the aspects and embodiments disclosed herein encompasses the administration of any prior therapy for the treatment of HR+, HER2- breast cancer (e.g., early, advanced, or metastatic breast cancer) including CDK4 and 6 inhibitors. In some embodiments, the prior therapy including CDK4 and 6 inhibitors includes the treatment of early HR+, HER2- breast cancer. In some embodiments, the prior CDK4 and 6 inhibitor treatment for early HR+, HER2- breast cancer includes adjuvant therapy, which includes administering CDK4 and 6 inhibitors to the patient in combination with endocrine therapy, on an optional basis. In some further embodiments, the prior adjuvant therapy is administered to patients with lymph node-positive early breast cancer at high risk of recurrence. In some further embodiments, the prior adjuvant therapy is administered to patients with early breast cancer having a Ki-67 score of at least 20% or higher, as determined by an FDA-approved trial. In some further embodiments, the prior adjuvant therapy is administered to patients with lymph node-positive early breast cancer at high risk of recurrence, as determined by four or more positive axillary lymph nodes (≧4pALN), or one to three positive axillary lymph nodes (1 to 3pALN) and tumor grade 3 and / or tumor size ≧5 cm. In some further embodiments, the prior adjuvant therapy is administered to patients with lymph node-positive early breast cancer at high risk of recurrence, as determined by one to three positive axillary lymph nodes (1 to 3pALN), Ki-67 ≧20%, and no grade 3 tumors and tumor size not ≧5 cm.

[0026] In some embodiments, therapies comprising prior CDK4 and 6 inhibitors include the initial or primary treatment of progressive or metastatic HR+, HER2− breast cancer. In some embodiments, the initial or primary treatment of progressive or metastatic HR+, HER2− breast cancer comprises administering to a patient a CDK4 and 6 inhibitor, optionally in combination with endocrine therapy. In some further embodiments, the primary treatment comprises administering palbociclib in combination with endocrine therapy. In some further embodiments, the primary treatment comprises administering ribociclib in combination with endocrine therapy. In some further embodiments, the primary treatment comprises administering abemaciclib in combination with endocrine therapy.

[0027] In some preferred embodiments, therapies comprising prior CDK4 and 6 inhibitors can be an incomplete treatment course. In some preferred embodiments, therapies comprising prior CDK4 and 6 inhibitors can be an incomplete treatment course in which disease progression occurs during the treatment of progressive or metastatic breast cancer. In some preferred embodiments, therapies comprising prior CDK4 and 6 inhibitors can be an incomplete treatment course in which the disease recurs during adjuvant treatment of early breast cancer. In some preferred embodiments, therapies comprising prior CDK4 and 6 inhibitors can be a completed treatment course. In some preferred embodiments, therapies comprising prior CDK4 and 6 inhibitors can be a completed treatment course in which the disease recurs after adjuvant treatment of early breast cancer. In some embodiments, therapies comprising prior CDK4 and 6 inhibitors are discontinued for a period sufficient to effect clearance of the prior therapy from the patient (e.g., 1, 2, 3, 4, 5, 6, 7, 10, 14, 21 days or more) prior to the sequential administration of CDK4 and 6 inhibitors according to the present disclosure.

[0028] As used herein, "therapy comprising a CDK4 and 6 inhibitor" refers to a treatment or therapeutic intervention that includes administration of a CDK4 and 6 inhibitor to a patient. In some embodiments, the therapy comprising a CDK4 and 6 inhibitor may include administration of the CDK4 and 6 inhibitor as a monotherapy. In some alternative embodiments, the therapy comprising a CDK4 and 6 inhibitor may include administration of the CDK4 and 6 inhibitor in combination with one or more other active agents. In some further embodiments, the therapy comprising a CDK4 and 6 inhibitor includes a CDK4 and 6 inhibitor in combination with an endocrine therapy.

[0029] "CDK4 and 6 inhibitor" or alternatively "CDK4 / 6 inhibitor" refers to a molecule that inhibits the activity of D-type cyclins (e.g., cyclin D3) and cyclin-dependent kinases (CDK4 and 6) protein complexes (e.g., cyclin D:CDK4 and 6 complexes), and generally functions to block the transition from the G1 phase to the S phase of the cell cycle by inhibiting kinase activity. In some embodiments of the present disclosure, the CDK4 and 6 inhibitor is palbociclib, ribociclib, or abemaciclib.

[0030] Palbociclib [6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(piperazin-1-yl)pyridin-2-yl]amino}pyrido[2,3,-d]pyrimidin-7(8H)-one] is indicated for the treatment of HR+, HER2- advanced or metastatic breast cancer in (i) combination with an aromatase inhibitor as initial endocrine-based therapy in postmenopausal women or men, or (ii) in combination with fulvestrant in patients with disease progression after endocrine therapy. Palbociclib has the following chemical structure.

Chemical Structure

[0031] Palbociclib is administered orally and is available in capsule form (125 mg, 100 mg, and 75 mg). The recommended starting dose is 125 mg once daily for 21 days, followed by a 7-day rest period. Palbociclib can be prepared as a free base or as pharmaceutically acceptable salts, including mono- and di-adductor salts such as monoisethionate, polymorphic isethionate, or hydrochloride (see, for example, WO2003 / 062236, WO2005 / 005426, WO2008 / 032157, U.S. Patents 6,936,612, 7,208,489, 7,345,171, 7,456,168, 7,781,583, and 7,863,278). Palbociclib in its free base form may be anhydrous or may contain varying amounts of water or one or more solvents. (See, for example, U.S. Patent No. 10,723,730).

[0032] Ribociclib [7-cyclopentyl-N,N-dimethyl-2-{[5-(piperazin-1-yl)pyridine-2-yl]amino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide] is indicated for the treatment of HR+, HER2- advanced or metastatic breast cancer in (i) in combination with an aromatase inhibitor as initial endocrine-based therapy in premenopausal / perimenopausal or postmenopausal women, or (ii) in combination with fulvestrant as initial endocrine-based therapy in postmenopausal women, or after disease progression during endocrine therapy. Ribociclib has the following chemical structure. [ka]

[0033] Ribociclib is administered orally and is available as tablets (200 mg, equivalent to 254.40 mg of ribociclib succinate). The recommended starting dose is 600 mg (3 x 200 mg tablets) once daily for 21 days, followed by a 7-day rest period. Ribociclib can be prepared as a free base or as a pharmaceutically acceptable salt containing ribociclib succinate (see, for example, U.S. Patents 9,868,739 and 9,193,732).

[0034] Abemaciclib (LY28352l9), including its salt forms [5-(4-ethyl-piperazin-1-ylmethyl)-pyridine-2-yl]-[5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-3H-benzimidazole)-5-yl)-pyrimidine-2-yl]amine, hydrochloride, and mesylate, as well as methods for preparing and using the compound, including for the treatment of cancer, particularly breast cancer, are disclosed in WO2010 / 075074. Methods for using abemaciclib in combination with endocrine therapy as adjuvant treatment for adult patients diagnosed with early-stage breast cancer with HR+, HER2-, lymph node-positive, high risk of recurrence, and a Ki-67 score ≥20% are disclosed in WO2018 / 204138. Abemaciclib has the following structure: [ka]

[0035] Abemaciclib is approved for the treatment of several breast cancer indications, including (i) in combination with endocrine therapy (tamoxifen or aromatase inhibitor) as adjuvant therapy for adult patients with early-stage breast cancer that is HR+, HER2-, lymph node-positive, at high risk of recurrence, and has a Ki-67 score ≥20% as determined by FDA-approved testing; (ii) in combination with an aromatase inhibitor as initial endocrine-based therapy for postmenopausal women and men with HR+, HER2-, advanced or metastatic breast cancer; (iii) in combination with fulvestrant for adult patients with HR+, HER2-, advanced or metastatic breast cancer whose disease has progressed after endocrine therapy; and (iv) as monotherapy for adult patients with HR+, HER2-, advanced or metastatic breast cancer whose disease has progressed after endocrine therapy and prior chemotherapy in a metastatic setting.

[0036] In embodiments and examples comprising abemaciclib, the following dosages may be used according to the methods and uses described herein. In some preferred embodiments, abemaciclib, or a pharmaceutically acceptable salt thereof, is administered twice daily in doses of 50 mg to 200 mg. Preferably, abemaciclib, or a pharmaceutically acceptable salt thereof, is administered twice daily in doses of 100 mg to 150 mg. More preferably, abemaciclib, or a pharmaceutically acceptable salt thereof, is administered twice daily in doses of 200 mg. More preferably, abemaciclib, or a pharmaceutically acceptable salt thereof, is administered twice daily in doses of 150 mg over a 28-day cycle. More preferably, abemaciclib, or a pharmaceutically acceptable salt thereof, is administered twice daily in doses of 100 mg over a 28-day cycle. More preferably, abemaciclib, or a pharmaceutically acceptable salt thereof, is administered twice daily in doses of 50 mg over a 28-day cycle. Preferably, abemaciclib is administered orally. More preferably, abemaciclib is administered in capsule form. Even more preferably, abemaciclib is administered in tablet form.

[0037] Fulvestrant is indicated for the treatment of advanced or metastatic breast cancer, is prescribed as an injectable (intravenous (IV) or intramuscular (IM)) drug, and has the following chemical structure: [ka]

[0038] Preferably, fulvestrant is administered as, for example, 500 mg once a month by injection, as indicated on the approved label, with an additional loading dose of 500 mg on day 15 of the first administration cycle. More preferably, fulvestrant is administered as an intramuscular dose of 500 mg on days 1 and 15 of the first 28-day cycle, and on day 1 of the second and any subsequent 28-day cycles.

[0039] According to the embodiments and models described herein, the methods and uses are administered to patients who have received prior therapy including CDK4 and CDK6 inhibitors. In some embodiments, the prior therapy including CDK4 and CDK6 inhibitors is in combination with one or more endocrine therapies, such as abemaciclib, ribociclib, or palbociclib, which may be applied to the treatment of advanced or metastatic breast cancer. As used herein, the term “endocrine therapy” means tamoxifen or a pharmaceutically acceptable salt thereof, anastrozole, letrozole, or exemestane. In some embodiments, the endocrine therapy may include fulvestrant.

[0040] In such embodiments, endocrine therapy is administered prior to the treatment in accordance with the guidance and instructions for the approved label of the specific endocrine therapy. For example, tamoxifen or a pharmaceutically acceptable salt thereof may be administered at 20–40 mg / day. Doses exceeding 20 mg should be administered in divided doses, morning and evening. Oral administration is preferred. For example, anastrazole may be administered at 1 mg / day. Oral administration is preferred. For example, letrozole may be administered at 2.5 mg / day. Oral administration is preferred. For example, exemestane may be administered at 25 mg / day. Oral administration is preferred.

[0041] Therefore, previously administered CDK4 and CDK6 therapies can be administered in combination with endocrine therapies according to the approved label of the specific endocrine therapy, as described on the approved label of the specific CDK4 and CDK6 inhibitor.

[0042] Generally, as those skilled in the art will understand, the CDK4 and 6 inhibitors according to the embodiments and models of this disclosure may be prepared and administered as inhibitor compounds or as pharmaceutically acceptable salts thereof. In some embodiments, abemaciclib may be prepared and / or administered as a free base. In some other embodiments, abemaciclib may be prepared and / or administered as a pharmaceutically acceptable salt, such as hydrochloride or mesylate. In some embodiments, ribociclib may be prepared and / or administered as a free base. In some other embodiments, ribociclib may be prepared and / or administered as a pharmaceutically acceptable salt, such as ribociclib succinate. In some embodiments, palbociclib may be prepared and / or administered as a free base. In some other embodiments, palbociclib may be prepared and / or administered as a pharmaceutically acceptable salt, such as isethionate or hydrochloride. In addition to the preparation of specific pharmaceutically acceptable salts of the CDK4 and 6 inhibitors referred to herein, the formation of pharmaceutically acceptable salts is generally well known. For example, see Gould, PL, “Salt selection for basic drugs,” International Journal of Pharmaceutics, 33:201-217 (1986), Bastin, RJ, et al., “Salt Selection and Optimization Procedures for Pharmaceutical New Chemical Entities,” Organic Process Research and Development, 4:427-435 (2000), and Berge, SM, et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Sciences, 66:1-19 (1977).

[0043] As used herein, the term “patient” refers to a human being. In certain embodiments, the patient may be an adult male or an adult premenopausal, perimenopause, or postmenopausal woman having or being diagnosed with HR+, HER2- advanced or metastatic breast cancer. In further embodiments, the patient may have HR+, HER2- advanced or metastatic breast cancer and have been previously treated with a therapy comprising CDK4 and CDK6 inhibitors in accordance with this disclosure.

[0044] As used herein, the terms “cancer” and “malignant” refer to or describe a physiological condition in a patient typically characterized by uncontrolled cell proliferation.

[0045] As used herein, the term “effective dose” refers to the amount or dosage of a CDK4 and 6 inhibitor (e.g., abemaciclib, palbociclib, or ribociclib) and the amount or dosage of fulvestrant that produces an effective response in a patient undergoing treatment.

[0046] As used herein, the terms “effective response” or “responsiveness” of a patient to treatment with combination therapy refer to the clinical or therapeutic benefit provided to a patient upon administration of a CDK4 and 6 inhibitor (e.g., abemaciclib, palbociclib, or ribociclib) or a pharmaceutically acceptable salt thereof, and fulvestrant. For example, an effective response may include, but is not limited to, any one or more of the following: progression-free survival (PFS) (e.g., based on investigator assessment or blinded independent central review (BICR)), overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR), disease control rate (DCR), duration of response (DoR), safety, patient-reported outcomes (PRO), pharmacokinetics (PK), or best combined response (BOR), which may include complete response (CR), partial response (PR), or stable disease (SD). Therefore, an effective response is not limited to curing, eliminating, or improving the disease or disease-related clinical symptoms.

[0047] As used herein, the term “in combination with ~” means administering a CDK4 and 6 inhibitor (e.g., abemaciclib) or a pharmaceutically acceptable salt thereof with an endocrine therapy (e.g., fulvestrant) simultaneously or sequentially in any order, for example, one drug may be administered before, concurrently with, or after the administration of another drug, or in any combination thereof, at repeated intervals during a single or more standard treatment course.

[0048] As used herein, the term “early” means cancer that may have spread to nearby lymph nodes but has not spread to more distant parts of the body. In various embodiments of the methods and uses described herein, treatment of early breast cancer may be referred to as “adjuvant therapy.”

[0049] As used herein, the terms “advanced” or “metastatic” mean cancer that has spread to one or more parts of the body that were not the site of the original cancerous tissue. In various embodiments of the methods and uses described herein, the initial treatment of advanced or metastatic breast cancer with CDK4 and 6 inhibitor therapy may be referred to as “initial treatment” or “first-line treatment.”

[0050] As used herein, the terms “to treat” or “to cure” mean the administration of one or more drugs to a patient. These terms may also be used in relation to reducing, inhibiting, reducing, stopping, or relieving a disease, or to delay the onset of the biological symptoms of disease progression.

[0051] As used herein, the term “adjunctive therapy” means the administration of one or more drugs to a patient after surgical resection of one or more cancerous tumors, for the purpose of reducing the likelihood or severity of disease recurrence, or delaying the onset of biological symptoms of disease recurrence, when all detectable and resectable disease (e.g., cancer) has been removed from the patient, but a statistical risk of recurrence due to latent disease remains.

[0052] The "Ki67 antigen" or simply "Ki67" (also known as the antigen identified by the monoclonal antibody Ki-67) refers to a nucleoprotein encoded by the MKI67 gene, which is expressed in all cell cycle phases except G0 and has been reported as an independent prognostic factor in early breast cancer (Dowsett et al. 2011). In HR+ breast cancer, patients with high levels of Ki67 (e.g., Ki67 thresholds in the range of 20% to 29%) have been shown to have a higher disease recurrence rate while receiving adjuvant endocrine therapy postoperatively.

[0053] The following are further nominal embodiments of the present invention: 1. Use of CDK4 and 6 inhibitors in the manufacture of drugs for the treatment of patients with hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer after prior therapy including CDK4 and 6 inhibitors, wherein the drugs are administered concurrently, separately, or sequentially in combination with fulvestrant. 2. The use according to Embodiment 1, wherein the previous therapy containing CDK4 and 6 inhibitors contained abemaciclib, palbociclib, or ribociclib. 3. The use described in embodiment 2, wherein the previous therapy containing CDK4 and 6 inhibitors contained abemaciclib. 4. The use according to embodiment 2, wherein the previous therapy containing CDK4 and 6 inhibitors contained palbociclib. 5. The use according to embodiment 2, wherein the previous therapy containing CDK4 and 6 inhibitors contained ribociclib. 6. The use described in any one of embodiments 1 to 5, wherein the previous therapy containing CDK4 and 6 inhibitors was a combination of CDK4 / 6 inhibitors and endocrine therapy for adjuvant treatment of early breast cancer. 7. The use according to aspect 6, wherein prior adjuvant therapy included endocrine therapy selected from tamoxifen and an aromatase inhibitor. 8. The use described in any one of embodiments 6 to 7, wherein previous adjuvant therapy was administered to a patient at high risk of recurrence. 9. The method according to any one of embodiments 6 to 8, wherein prior adjuvant therapy was administered to a patient having a Ki-67 score ≥ 20% as determined by an FDA-approved test. 10. The use according to any one of embodiments 1 to 5, wherein the previous therapy including CDK4 and 6 inhibitors was a combination of CDK4 / 6 inhibitors and endocrine therapy for the initial treatment of advanced or metastatic breast cancer. 11. The use according to any one of embodiments 1 to 5, wherein the prior therapy including CDK4 and 6 inhibitors was a combination of a CDK4 / 6 inhibitor and an aromatase inhibitor for the initial treatment of advanced or metastatic breast cancer. 12. The use according to embodiment 11, wherein the aromatase inhibitor is selected from letrozole, anastrozole, or exemestane. 13. The use according to any one of embodiments 1 to 12, wherein the CDK4 and CDK6 inhibitor administered in combination with fulvestrant is selected from abemaciclib, palbociclib, and ribociclib. 14. The use according to embodiment 13, wherein the CDK4 and CDK6 inhibitor is abemaciclib. 15. The use according to embodiment 13, wherein the CDK4 and 6 inhibitor is palbociclib. 16. The use according to embodiment 13, wherein the CDK4 and 6 inhibitor is ribociclib. 17. The use according to embodiment 14, comprising administering abemaciclib as an oral dose of 150 mg twice daily on days 1 to 28 of each 28-day cycle. 18. The use according to embodiment 14 or 17, wherein fulvestrant is administered as an intramuscular dose of 500 mg on the 1st and 15th days of the first 28-day cycle (cycle 1), and on the 1st day of the second and any subsequent 28-day cycles (cycle 2 and subsequent cycles). 19. Use of abemaciclib in the manufacture of a drug for the treatment of patients with hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer following prior therapy including CDK4 and 6 inhibitors, wherein abemaciclib is administered twice daily as an oral dose of 150 mg on days 1 to 28 of each 28-day cycle, and fulvestrant is administered as an intramuscular dose of 500 mg on days 1 and 15 of the first 28-day cycle, and on day 1 of the second and any subsequent 28-day cycles, and the prior therapy including CDK4 and 6 inhibitors is abemaciclib in combination with tamoxifen or an aromatase inhibitor. 20. The use according to any one of embodiments 1 to 19, wherein the administration is made for a sufficient amount of time to provide progression-free survival. 21. Use as described in any one of the embodiments 1 to 20, wherein the patient is an adult male or an adult premenopausal, perimenopausal, or postmenopausal woman.

[0054] The following examples are intended solely to illustrate various aspects and embodiments of the Disclosure and should not be considered to limit the scope of the Disclosure.

[0055] Example 1. Sequential treatment with abemaciclib in conjunction with endocrine therapy inhibits cell proliferation in cells that previously had resistance to CDK4 and CDK6 inhibitors. Resistant breast cancer cells are prepared by treating breast cancer cell lines for 120–144 hours with a CDK4 and CDK6 inhibitor (either abemaciclib or palbociclib) in combination with 4-OH-tamoxifen (tamoxifen). Cells are sorted and screened for resistant cells, defined as geminin-positive (GEM+), a marker of S / G2 / M cell cycle accumulation. To confirm the resistance phenotype, cell lines are treated with tamoxifen and a CDK4 and CDK6 inhibitor (either abemaciclib or palbociclib) used to promote resistance.

[0056] Sequential therapy with CDK4 and CDK6 inhibitors. The resistant cancer cells generated by the above method are treated with abemaciclib in combination with endocrine therapy (ET) containing either fulvestrant or tamoxifen, or with palbociclib in combination with either fulvestrant or tamoxifen. Cell proliferation and viability are evaluated by Geminin / Ki67, Annexin V, and colony formation assays. The mechanism of resistance and the efficacy of sequential treatment with CDK4 and CDK6 inhibitors in combination with either fulvestrant or tamoxifen are characterized by Western blotting and RNA-seq analysis.

[0057] Cancer cell lines resistant to palbociclib and tamoxifen show decreased %GEM+ and colony-forming ability, decreased Ki67 levels, and increased apoptosis when sequentially treated with abemaciclib and ET. In contrast, abemaciclib and tamoxifen-resistant cell lines do not show similar inhibitory effects when sequentially treated with palbociclib and ET. Western blot analysis demonstrates that both palbociclib and abemaciclib-resistant cells show increased levels of CDK6 and pERK compared to controls. Treatment of palbociclib-resistant cells with abemaciclib and ET is effective not only in reducing FOXM1, a regulator of senescence and apoptosis, but also in reducing cyclin A, a marker of mitosis, which is consistent with the decrease in the %GEM+ cell subpopulation in palbociclib and ET-resistant cells. Treatment of abemaciclib-resistant cells with palbociclib and ET in combination does not show similar effects.

[0058] Cancer cell lines resistant to palbociclib and tamoxifen show reduced proliferation, decreased pRb signaling, and induction of the androgen response when sequentially treated with abemaciclib and ET. Treatment of abemaciclib-resistant cells with palbociclib and ET does not show similar effects on proliferation, pRb signaling, or the androgen response.

[0059] This example demonstrates that cancer cells resistant to combination therapy with CDK4 and 6 inhibitors and ET (e.g., tamoxifen) are susceptible to sequential treatment with abemaciclib in combination with ET, and that this provides a treatment option for patients with advanced or metastatic breast cancer who are resistant to previous therapies including CDK4 and 6 inhibitors.

[0060] Example 2. A randomized phase 3 trial of fulvestrant in combination with or without abemaciclib in participants with HR+, HER2-, advanced or metastatic breast cancer that has progressed during or after treatment with adjuvant or first-line therapy with CDK4 and 6 inhibitors and endocrine therapy. As detailed below, the clinical trial will be conducted as a phase 3, global, multicenter, randomized, double-blind, placebo-controlled trial in participants with HR+, HER2-, advanced or metastatic breast cancer. This trial will enroll adults who have experienced disease progression during first-line therapy (initial treatment for advanced or metastatic breast cancer) with CDK4 and 6 inhibitors and aromatase inhibitors (AIs), or adults who have relapsed during or after treatment with CDK4 and 6 inhibitors in combination with endocrine therapy (ET) in an adjuvant setting.

[0061] This trial will include approximately 350 participants who will be randomly assigned to one of two intervention groups: Group A: abemaciclib and fulvestrant, or Group B: placebo and fulvestrant. [Table 1]

[0062] Patient randomization is 1:1 and stratified by the following factors: geography (USA, East Asia, or other (including the EU)); presence of visceral metastases (yes or no); duration of previous CDK4 and 6 inhibitor-based regimens (2 levels, based on adjuvant / first-line therapy), if prior treatment was metastatic, duration less than 12 months; or if treated in an adjuvant setting, disease recurrence during the CDK4 and 6 inhibitor-based regimen, or if prior treatment was first-line / metastatic, ≥ 12 months; or if treated in an adjuvant setting, disease recurrence after completion of the CDK4 and 6 inhibitor-based regimen.

[0063] The primary endpoint is progression-free survival (PFS) as assessed by the principal investigator. Participants will receive treatment until disease progression or other discontinuation criteria are met. Secondary endpoints include overall survival (OS), blinded independent central review PFS (BICR), objective response rate (ORR), clinical benefit rate (CBR), disease control rate (DCR), duration of response (DoR), safety, patient-reported outcomes (PRO), and pharmacokinetics (PK).

[0064] The primary endpoint, Physician-Assessed PFS, is defined as the time from randomization to the first occurrence of documented disease progression as determined by Physician Assessment according to RECIST 1.1, or, in the absence of documented progressive disease, to death from any cause. PFS is compared between treatment groups using a stratified log-rank test stratified by the randomization stratum. Corresponding hazard ratios between treatment groups are estimated using a stratified Cox regression model (Cox 1972) stratified by the randomization stratum. PFS curves, median PFS, and PFS rates at various time points at 95% CI for each treatment group are estimated using the Kaplan-Meier method (Kaplan and Meier 1958).

[0065] An interim effectiveness analysis of PFS is performed when approximately 176 PFS events are observed in a controlled Type I error via the sequential monitoring approach of DeMets and Lan (1994) using an O'Brien-Fleming type expenditure function.

[0066] Secondary endpoints: Objective response rate (ORR), disease control rate (DCR), and clinical benefit rate (CBR).

[0067] Objective response rate (ORR) is defined as the number of participants who achieved a best overall response (BOR) of complete response (CR) or partial response (PR) divided by the total number of participants randomized to the corresponding treatment group. Confirmation of CR or PR is not required.

[0068] The disease control rate (DCR) is defined as the number of participants who achieved complete response (CR), partial response (PR), or stable disease (SD) (BOR) divided by the total number of participants randomized to the corresponding treatment group (ITT population). Confirmation of CR or PR is not required.

[0069] The Clinical Benchmark Rate (CBR) is defined as the number of participants who achieved a Complete Complete Reaction (CR) or Partial Progression (PR) (BOR), or a standard deviation (SD) of 6 months, divided by the total number of participants randomized to the corresponding treatment group (ITT population). Confirmation of CR or PR is not required. For each of these rates, a point estimate and a 95% confidence interval (using a binomial normal approximation) are calculated for each treatment group. A stratified test is performed to compare these rates across treatment groups using the Cochran-Mantel-Haenszel test, which adjusts for randomization.

[0070] As used herein, the term “duration of response” is defined, in accordance with the RECIST 1.1 criteria, as the time from the date of the first measurement in which the CR or PR criterion (whichever is recorded first) is met, to the first date on which the disease relapses or objective progression is observed, or to the date of death from any cause in the absence of objectively determined disease progression or relapse.

[0071] Overall survival (OS) is a secondary endpoint that is a particular focus of this study and is defined as the time from randomization to death from any cause. If a patient is alive or could not be followed up at the time of data analysis, OS data is censored at the last known date the patient was alive. [Table 2]

[0072] The treatment cycle is defined as a 28-day interval. The 28-day cycle is maintained throughout the treatment period, regardless of any interruption of administration. Participants begin the medication assigned to C1D1 treatment. All efforts are made to maintain the 28-day + / - 7-day cycle of fulvestrant administration. If a delay is necessary, administration will be resumed at the earliest medically appropriate time, based on the judgment of the clinical trial investigator. Additional clinic visits may be required for administration. Treatment will continue until progression, unacceptable toxicity, or other discontinuation criteria are met.

[0073] Abemaciclib. For the approved HR+, HER2- MBC indication, the recommended starting dose of abemaciclib in combination with fulvestrant is 150 mg BID, based on the Phase 3 clinical trial MONARCH (Sledge et al. 2017), which showed that 150 mg BID of abemaciclib in combination with fulvestrant demonstrated a manageable safety profile and provided clinically meaningful PFS and OS benefits compared to fulvestrant / placebo (Verzenio package insert, 2019; Verzenios SmPC, 2018) in patients with HR+, HER2- advanced or metastatic breast cancer.

[0074] Fulvestrant. The recommended dose of fulvestrant in combination with abemaciclib is consistent with the approved monotherapy dose of fulvestrant. Study participants will receive 500 mg of fulvestrant IM on days 1 and 15 of cycle 1, and thereafter from day 1 of cycle 2 onwards, according to the dosing information provided on the approved local label.

[0075] Standard medication. Assignment to either abemaciclib (Group A) or placebo (Group B) will be blinded to the principal investigator and participants. The blinded clinical trial drug will be administered at an initial dose of 150 mg twice daily, provided as a 50 mg tablet. The blinded clinical trial drug must be taken twice daily at the same time each day (with at least approximately 6 hours between doses) with 6-8 ounces of water. Participants should be instructed to swallow the tablet whole and not chew or crush it.

[0076] During the trial treatment period, participants will return to the clinic every two weeks (14 ± 3 days) for the first two cycles, and then monthly (28 ± 7 days) from cycle 3 onwards until the start of short-term follow-up. The duration of this trial is not predefined, as patients will continue treatment until disease progression or discontinuation occurs for any reason.

[0077] Tumor response. Tumor response according to RECIST 1.1 should be assessed approximately every 8 weeks for the first 12 months, and then approximately every 12 weeks (compared to day 1 of cycle 1) until the participant objectively experiences disease progression, death, or completion of the study (assessment after final OS data).

[0078] Short-term and long-term follow-up. Participants who discontinue the trial intervention will return for short-term follow-up visits at the clinic. Short-term follow-up visits will take place 30 days (±7 days) after the decision to discontinue all trial treatments is made. After the short-term follow-up visits, all participants will enter the long-term follow-up period. Long-term follow-up will begin the day after the completion of the short-term follow-up visits and will continue until the participant dies, withdraws from the trial, or the trial is completed. During long-term follow-up, visits should be made approximately every 2-3 months (Q60-90D). This trial period is not predefined because participants remain in long-term follow-up until they die, withdraw from the trial, or the trial is completed.

[0079] Treatment in the clinical trial group (abemaciclib and fulvestrant combination) is expected to be well-tolerated, achieve statistically significant primary endpoints, and / or slow disease progression. Prolonged disease management may also delay the need for cytotoxic chemotherapy.

[0080] Inclusion criteria for participants. Eligible participants to be included in the examination must meet all of the following inclusion criteria.

[0081] Age. At the time of signing the informed consent form, the person must be 18 years of age or older (or the age permitted by local regulations, whichever is higher).

[0082] Participant type and disease characteristics. Participants are diagnosed with breast cancer as HR+, HER2-. To meet the requirements for HR+ disease immunohistochemistry (IHC), expression of at least one hormone receptor (estrogen receptor [ER] or progesterone receptor [PgR]) must be shown, as defined in the relevant American Society of Clinical Oncology (ASCO) / American College of Pathology (CAP) guidelines (Hammond et al. 2010). To meet the requirements for HER2- disease: IHC or in-situ hybridization must not demonstrate HER2 overexpression at initial diagnosis or subsequent biopsy, as defined in the relevant ASCO / CAP guidelines (Wolff et al. 2018).

[0083] Participants have either a curative surgical treatment or a progressive disease that is not affected by metastatic disease.

[0084] Participants have radiological evidence of disease progression or recurrence either during or after treatment with a CDK4 and 6 inhibitor (palbociclib, ribociclib, or abemaciclib) and AI as initial treatment for advanced disease, or with a CDK4 and 6 inhibitor (palbociclib, ribociclib, or abemaciclib) and ET as adjuvant therapy for early breast cancer.

[0085] Participants have either a measurable disease or an unmeasurable but evaluable disease. Measurable, unmeasurable, and evaluable diseases are defined according to the criteria for evaluating solid tumor response (RECIST version 1.1 [v1.1], Eisenhauer et al. 2009).

[0086] Participants have a performance status (PS) of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale (Oken et al 1982).

[0087] Participants must be deemed suitable for treatment by extraterrestrial beings (ETs).

[0088] Participants had discontinued previous treatment and had recovered to at least Grade 1 from the strong effects of treatment, except for residual alopecia and peripheral neuropathy. The required therapy washout period before receiving the investigational drug is summarized in Table 3. [Table 3]

[0089] Participants must have adequate organ function, as summarized in Table 4: [Table 4]

[0090] Male participants must agree to use hormone suppression with a gonadotropin-releasing hormone agonist such as goserelin or leuprolide (administered monthly and started at least 28 days before day 1 of cycle 1). Men are eligible to participate if they agree to refrain from sperm donation during the treatment period. Contraception requirements for male participants receiving fulvestrant must follow the approved local label.

[0091] Female participants must be postmenopausal, either due to surgical / spontaneous menopause or ovarian suppression with a gonadotropin-releasing hormone agonist such as goserelin or leuprolide (administered monthly, initiated at least 28 days before day 1 of cycle 1). Postmenopausal status due to surgical / spontaneous menopause requires at least one of the following: (a) prior bilateral oophorectomy, (b) age ≥ 55 years with at least 12 months of amenorrhea or a diagnosis of menopause, or (c) age ≥ 40 and < 55 years with at least 12 months of amenorrhea (without chemotherapy, tamoxifen, toremifene, or ovarian suppression), and a postmenopausal FSH range (≥ 40 mIU / mL).

[0092] Women of childbearing potential (WOCBPs) must have a negative pregnancy test before starting treatment, specifically a negative serum pregnancy test at the screening visit, followed by a negative urine pregnancy test 48 hours prior to their first exposure to the study drug. WOCBPs must agree to use two effective forms of contraception to prevent pregnancy during their study treatment for three weeks after the last dose of the blinded study drug and for two years after the last dose of fulvestrant (or according to the locally approved fulvestrant label), with at least one of these forms being highly effective (failure rate less than 1%).

[0093] Exclusion criteria Participants will be excluded if they have certain medical conditions or are receiving certain prior or concomitant therapies. Participants will be excluded if they are enrolled in any other clinical trial, including any other type of medical research, that is deemed scientifically or medically incompatible with this study. Pregnant or breastfeeding women will be excluded. Any patient with known or suspected hypersensitivity reactions or intolerance to the investigational drug or any excipient (e.g., lactose) will be excluded, unless otherwise deemed appropriate by the principal investigator.

[0094] The following participants will be excluded due to their medical conditions: • Visceral origin, lymphatic spread, or intrathecal dissemination and metastasis. Visceral origin refers not merely to the presence of visceral metastasis, but to severe organ dysfunction assessed by symptoms and signs, clinical laboratory findings, and rapid disease progression. • Participants have symptomatic or untreated central nervous system (CNS) metastases. Participants who have been treated for CNS metastases are eligible if: a. Having completed prior therapy (including radiation and / or surgery) ≥ 28 days prior to the first dose of the investigational treatment, and b. Not having received corticosteroids and / or anticonvulsants for at least 14 days prior to the first dose of the study treatment, c. The disease is asymptomatic and has been stable on X-ray examinations via repeated imaging for at least 28 days prior to consent (repeated imaging should be performed during the trial screening). • A history of any of the following conditions within the past 12 months: cardiovascular syncope, pathological ventricular arrhythmia (including but not limited to ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest. Exception: Patients who have had atrial fibrillation under control for 30 days or more prior to randomization are eligible. The principal investigator of the clinical trial has a serious pre-existing medical condition that would prevent participation in this study (e.g., severe renal impairment [e.g., estimated creatinine clearance <30 mL / min], active symptoms of ILD / pneumonia], severe dyspnea requiring rest or oxygen therapy, a history of major surgical resection including the stomach or small intestine, or a pre-existing Crohn's disease or ulcerative colitis, or a pre-existing chronic condition causing clinically significant diarrhea). • A history of other cancers (excluding non-melanoma skin cancer or cervical carcinoma in situ) unless the cancer has not been in complete remission for at least three years without treatment. • You have a known active systemic infection (e.g., a bacterial, fungal, or detectable viral infection requiring systemic therapy). a) Participants with uncontrolled human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS)-defining disease are ineligible. Participants with known HIV infection and a CD4+ T cell (CD4+) count of ≥350 cells / μL are ineligible. b) Participants with hepatitis B are not eligible unless their viral load is below a quantitative level. c) Participants with known hepatitis C are ineligible unless they have completed curative antiviral therapy and their viral load is below quantitative levels. d) Screening for HIV, coronavirus disease 2019 (COVID-19), hepatitis B, or hepatitis C is not necessary. The following participants were included in the pre-exclusion therapy or combination therapy group: • The patient is receiving a systemic therapy line intervening between disease relapse / progression and trial screening. • Receiving two or more lines of therapy for progressive or metastatic disease. • Has a history of chemotherapy for MBC. • Previous treatment with a CDK4 and CDK6 inhibitor-based regimen other than those specified. Prior treatment with CDK4 and CDK6 inhibitors in two or more settings (e.g., adjuvant and subsequent metastatic) is not permitted. • Previously treated with fulvestrant, clinical trial-intensive ER instructional therapy (including SERD and non-SERD), any PI3K inhibitor, mTOR inhibitor, or AKT inhibitor. • At the discretion of the clinical trial investigator, these therapies are approved and available within the available area for those with known pathogenic germ cell mutations suitable for PARP inhibitors. • Patients initiated a bisphosphonate or an approved RANK ligand (RANK-L) targeted therapy (e.g., denosumab) within 7 days prior to randomization. • The patient is simultaneously receiving exogenous reproductive hormone therapy (e.g., birth control pills, hormone replacement therapy, or megestrol acetate). The appropriate washout period between the last dose and randomization is at the medical discretion of the clinical trial physician (e.g., 7 days or 5 times the half-life elimination rule). Note: Topical vaginal estrogen therapy is permitted if all other non-hormonal options have been exhausted. • Has undergone autologous stem cell transplantation or allogeneic stem cell transplantation.

Claims

1. A therapeutic agent for treating patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer who have previously been treated with a therapy comprising a CDK4 and 6 inhibitor, the therapeutic agent comprising a CDK4 and 6 inhibitor in combination with fulvestrant.

2. 2. The method of claim 1, wherein the previous therapy comprising a CDK4 and 6 inhibitor included abemaciclib, palbociclib, or ribociclib.

3. The method of claim 2, wherein the previous therapy comprising a CDK4 and 6 inhibitor included abemaciclib.

4. The therapeutic agent of claim 2, wherein the previous therapy comprising a CDK4 and 6 inhibitor included palbociclib.

5. 3. The therapeutic agent of claim 2, wherein the previous therapy comprising a CDK4 and 6 inhibitor included ribociclib.

6. The method of claim 1, wherein the previous therapy comprising a CDK4 and 6 inhibitor was a combination of a CDK4 and 6 inhibitor and endocrine therapy for the adjuvant treatment of early stage breast cancer.

7. 7. The method of claim 6, wherein the previous adjuvant treatment included endocrine therapy selected from tamoxifen and an aromatase inhibitor.

8. The method of claim 6, wherein the previous adjuvant treatment was administered to a patient at high risk of recurrence.

9. 7. The method of claim 6, wherein the prior adjunctive therapy was administered to a patient with a Ki-67 score ≧20% as determined by an FDA-approved test.

10. The method of claim 1, wherein the previous therapy comprising a CDK4 and 6 inhibitor was a combination of a CDK4 and 6 inhibitor and endocrine therapy for the initial treatment of advanced or metastatic breast cancer.

11. The method of claim 10, wherein the previous therapy comprising a CDK4 and 6 inhibitor was administered in combination with an aromatase inhibitor.

12. 12. The method of claim 11, wherein the aromatase inhibitor previously administered in combination with the therapy comprising the CDK4 and 6 inhibitor comprised letrozole, anastrozole, or exemestane.

13. The therapeutic agent according to any one of claims 1 to 12, wherein the CDK4 and 6 inhibitor is selected from abemaciclib, palbociclib, and ribociclib.

14. The method of claim 13, wherein the CDK4 and 6 inhibitor is abemaciclib.

15. The therapeutic agent of claim 13, wherein the CDK4 and 6 inhibitor is palbociclib.

16. The therapeutic agent of claim 13, wherein the CDK4 and 6 inhibitor is ribociclib.

17. The method of claim 14, wherein abemaciclib is administered as an oral dose of 150 mg twice daily on days 1 to 28 of each 28-day cycle.

18. 18. The method of claim 17, wherein fulvestrant is administered as an intramuscular dose of 500 mg on days 1 and 15 of the first 28-day cycle (cycle 1) and on day 1 of the second and any subsequent 28-day cycles (cycle 2 and any subsequent cycles).

19. A therapeutic agent comprising abemaciclib in combination with fulvestrant for the treatment of patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer who have been previously treated with a therapy comprising a CDK4 and 6 inhibitor selected from abemaciclib, ribociclib, and palbociclib, wherein abemaciclib is administered as a 150 mg oral dose twice daily on days 1-28 of each 28-day cycle, and fulvestrant is administered as a 500 mg intramuscular dose on days 1 and 15 of the first 28-day cycle and on day 1 of the second and any subsequent 28-day cycle.

20. A therapeutic agent comprising abemaciclib in simultaneous, separate, or sequential combination with fulvestrant for the treatment of patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer whose disease has recurred on or after prior therapy with abemaciclib in combination with tamoxifen or an aromatase inhibitor, wherein abemaciclib is administered as a 150 mg oral dose twice daily on days 1-28 of each 28-day cycle, and fulvestrant is administered as a 500 mg intramuscular dose on days 1 and 15 of the first 28-day cycle and on day 1 of the second and any subsequent 28-day cycle.

21. 21. The therapeutic agent of any one of claims 1 to 12, 19 or 20 for use for a time sufficient to provide progression-free survival.

22. 21. The method of any one of claims 1 to 12, 19 or 20, wherein the patient is an adult male or an adult pre-, peri- or post-menopausal female.

23. The therapeutic agent according to any one of claims 1 to 12 or 19, wherein the combination with fulvestrant is simultaneous, separate or sequential combination.

24. Use of a CDK4 and 6 inhibitor in the manufacture of a medicament for the treatment of patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer after a previous therapy including a CDK4 and 6 inhibitor, wherein the medicament is administered simultaneously, separately, or in sequential combination with fulvestrant.