Combination therapy comprising GDC-9545 and a CDK4 / 6 inhibitor for the treatment of breast cancer

Abstract

Provided herein is a combination therapy comprising GDC‑9545 and a CDK4 / 6 inhibitor for the treatment of locally advanced breast cancer or metastatic breast cancer.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 023,501, filed May 12, 2020, which is incorporated herein by reference in its entirety and for all purposes. Technical Field

[0003] Provided herein are combination therapies comprising GDC-9545 or a pharmaceutically acceptable salt thereof and a CDK4 / 6 inhibitor (eg, palbociclib) for treating breast cancer. Background Art

[0004] Although endocrine therapy is effective for ER-positive (ER+) breast cancer, many patients eventually relapse or develop resistance. One such resistance mechanism involves mutations in ESR1, which drives ER-dependent transcription and proliferation in the absence of estrogen.

[0005] Therefore, clinically active agents for the treatment of recurrent or resistant ER-positive breast cancer are urgently needed. Summary of the invention

[0006] Solutions to the above-referenced problems and other problems in the art are provided herein.

[0007] Embodiments of the present invention may be more fully understood by referring to the detailed description and examples, which are intended to illustrate non-limiting embodiments. BRIEF DESCRIPTION OF THE DRAWINGS

[0008] Figure 1 Depicted is a study timeline of the patients described herein treated with combination therapy of GDC-9545 and palbociclib. uPR = unconfirmed partial response; cPR = confirmed partial response.

[0009] Figure 2 Tumor responses of patients treated with GDC-9545 and GDC-9545 and palbociclib are depicted. DETAILED DESCRIPTION

[0010] Unless otherwise defined, all scientific and technical terms used herein have the same meaning as those generally understood by those of ordinary skill in the art to which the present invention belongs. See, for example: Singleton et al., DICTIONARY OF MICROBIOLOGY AND MOLECULAR BIOLOGY, 2nd edition, J. Wiley & Sons (New York, NY 1994); Sambrook et al., MOLECULAR CLONING, A LABORATORY MANUAL, Cold Springs Harbor Press (Cold Springs Harbor, NY 1989). Methods, devices and materials similar or equivalent to the methods, devices and materials described herein can be used in the practice of the present invention.

[0011] The following definitions are provided to facilitate understanding of some of the terms frequently used herein and are not intended to limit the scope of the present disclosure.All references cited herein are incorporated by reference in their entirety.

[0012] As used herein, unless otherwise indicated, the terms "about" and "approximately" when referring to the dosage, amount or weight percentage of the ingredients of the composition or dosage form, mean a dosage, amount or weight percentage recognized by those of ordinary skill in the art that provides a pharmacological effect equivalent to that obtained by the specified dosage, amount or weight percentage. The equivalent dosage, amount or weight percentage may be within the range of 30%, 20%, 15%, 10%, 5%, 1% or less of the specified dosage, amount or weight percentage.

[0013] "GDC-9545" refers to a compound having the following structure:

[0014]

[0015] It has the chemical name 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol. GDC-9545 is also known as giredestrant. In one embodiment, GDC-9545 is a tartrate salt.

[0016] "Palbociclib" refers to a compound having the following structure:

[0017]

[0018] Its chemical name is 6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(piperazin-1-yl)pyridin-2-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one. Palbociclib is an exemplary "CDK4 / 6 inhibitor" - a class of agents that target cyclin-dependent protein kinases 4 and 6 (CDK4 and CDK6, respectively).

[0019] Other exemplary CDK4 / 6 inhibitors include, but are not limited to: ribociclib (succinic acid-7-cyclopentyl-N,N-dimethyl-2-{[5-(piperazin-1-yl)pyridin-2-yl]amino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (1 / 1); Abemaciclib, (2-pyrimidinamine, N-[5-[(4-ethyl-1-piperazinyl)methyl]-2-pyridinyl]-5-fluoro-4-[4-fluoro-2-methyl-1-(1-methylethyl)-1H-benzimidazol-6-yl], sold); and Trilaciclib (2'-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-7',8'-dihydro-6'H-spiro(cyclohexane-1,9'-pyrazino(1',2':1,5)pyrrolo(2,3-d)pyrimidine)-6'-one).

[0020] "Time to worsening of pain intensity" is the time to the first documented increase of at least 2 points from the baseline measurement (eg, by using the Brief Pain Inventory-Short Form (BPI-SF) questionnaire).

[0021] "Time to worsening of pain presence and interference" is the time to first documented increase of at least 10 points from baseline measurements (eg, by using the European Organization for Research on Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) linearly transformed pain scale).

[0022] "Time to deterioration in physical function" is the time to the first documented decrease of at least 10 points from the baseline measurement (eg, by using the EORTC QLQ-C30 linearly transformed physical function scale score).

[0023] "Time to deterioration in role functioning" is the time to the first documented decrease of at least 10 points from the baseline measurement (eg, by using the EORTC QLQ-C30 linearly transformed role functioning scale score).

[0024] “Time to deterioration in global health status and quality of life” or “GHS / QoL” was defined as the time to first documented decrease of 10 points from baseline measurement (eg, by using the EORTC QLQ-C30 linear transformation of the GHS / QoL scale score).

[0025] “Overall survival” or “OS” was defined as the time from enrollment to death from any cause.

[0026] “Objective response rate” or “ORR” is the percentage of patients who had a confirmed complete response or partial response as determined by the investigator according to RECIST v1.1 within two consecutive periods of ≥4 weeks.

[0027] “Time to progression” or “TTP” refers to the time from randomization to objective tumor progression.

[0028] “Duration of response” or “DOR” is the time from the first documented objective response to disease progression or death from any cause, whichever occurs first, as determined by the investigator according to RECIST v1.1.

[0029] “Progression-free survival” or “PFS” is the time from enrollment to the date of the first documented disease progression or death from any cause, whichever occurs first, as determined by the investigator according to RECIST v1.1.

[0030] “Clinical benefit rate” or “CBR” is the percentage of patients with stable disease for at least 24 weeks or with a confirmed complete response or partial response as determined by the investigator according to RECIST v1.1.

[0031] "Complete response" or "CR" refers to the disappearance of all target and non-target lesions and, if applicable, normalization of tumor marker levels.

[0032] "Partial response" or "non-CR / non-PD" means that one or more non-target lesions persist and / or (if applicable) tumor marker levels remain above normal limits. PR can also refer to a ≥30% decrease in the sum of the diameters of target lesions, the appearance of new lesions in the absence of CR, and clear progression of non-target lesions.

[0033] “Progressive disease” or “PD” was defined as an increase of ≥20% in the sum of the diameters of target lesions, unequivocal progression of nontarget lesions, and / or the appearance of new lesions.

[0034] "Stable disease" or "SD" refers to tumors that have neither shrunk sufficiently to qualify as a CR or PR nor increased sufficiently to qualify as a PD.

[0035] The term "locally advanced breast cancer" refers to cancer that started in the breast and spread to nearby tissue or lymph nodes but has not spread to other parts of the body.

[0036] The term "metastatic breast cancer" refers to cancer that has spread from the breast to other parts of the body, such as the bones, liver, lungs, or brain. Metastatic breast cancer may also be called stage IV breast cancer.

[0037] The term "treatment" refers to a clinical intervention intended to change the natural course of the patient or cell being treated during the course of clinical pathology. Desirable therapeutic effects include reducing the rate of disease progression, slowing down or alleviating the disease state, and alleviating or improving prognosis. For example, if one or more symptoms associated with breast cancer as described herein are alleviated or eliminated, including but not limited to reducing cancer cell proliferation (or destroying cancer cells), alleviating the symptoms caused by the disease, improving the quality of life of patients suffering from the disease, reducing the dosage of other drugs required for treating the disease and / or prolonging the survival period of the patient, the patient is successfully "treated".

[0038] The term "delayed progression" of disease refers to postponing, hindering, slowing down, slowing down, stabilizing and / or delaying the development of breast cancer as described herein. This delay can have different time lengths, specifically depending on the cancer medical history and / or patient to be treated. It is obvious to those skilled in the art that sufficient or significant delay can actually cover prevention, because the patient will not suffer from cancer.

[0039] An "effective amount" is at least the minimum amount required to achieve a measurable improvement or prevention of breast cancer as described herein. The effective amount herein may vary according to factors such as the patient's disease state, age, sex, and weight, and the ability of the agent to elicit an expected response in the patient. An effective amount is also the amount in which the beneficial effects of treatment exceed any toxic or deleterious effects of treatment. Beneficial or desired clinical results include results such as: eliminating or reducing risk, reducing severity, delaying the onset of disease (including biochemical, histological, and / or behavioral symptoms of disease occurring during disease development, its complications, and intermediate pathological phenotypes), reducing one or more symptoms caused by the disease, improving the quality of life of patients suffering from the disease, reducing the dose of other drugs required to treat the disease, enhancing the effect of another drug (such as by targeting), delaying disease progression, and / or prolonging survival. In some embodiments, an effective amount of a drug may have the following effects: reducing the number of cancer cells; reducing tumor size; inhibiting (i.e., slowing down or stopping) the infiltration of cancer cells into surrounding organs; inhibiting (i.e., slowing down or stopping) tumor metastasis; inhibiting (i.e., slowing down or stopping) tumor growth; and / or alleviating one or more of the symptoms associated with the disease. An effective amount may be administered once or multiple times. The effective amount of a drug, compound, pharmaceutical composition or combination therapy as described herein can be an amount sufficient to treat directly or indirectly. As understood in a clinical setting, a drug, compound or pharmaceutical composition that can or cannot reach an effective amount in combination with another drug, compound or pharmaceutical composition or combination therapy. Therefore, an "effective amount" can be considered in the case of administering one or more therapeutic agents, and if it can be obtained or achieve a desired result in combination with one or more other agents, a single agent that can be considered to give an effective amount.

[0040] As used herein, "E2 inhibition score" refers to a numerical value reflecting the aggregated expression level of a predetermined gene set, the inhibition of which reflects estrogen receptor (ER) pathway activity.

[0041] As used herein, "E2 induction score" refers to a numerical value reflecting the aggregated expression level of a predetermined gene set, the induction of which reflects the estrogen receptor (ER) pathway activity.

[0042] As used herein, "ER pathway activity score" refers to a numerical value that reflects the mathematical difference between the E2 induction score and the E2 inhibition score.

[0043] "Administration period" or "cycle" refers to a time period including the administration of one or more agents described herein (i.e., GDC-9545 or a pharmaceutically acceptable salt thereof or palbociclib) and an optional time period not including the administration of one or more of the agents described herein. For example, the total length of a cycle may be 28 days, and includes 21 days of administration of one or more agents and a 7-day rest period. "Rest period" refers to a time period during which at least one of the agents described herein (e.g., GDC-9545 or a pharmaceutically acceptable salt thereof or palbociclib) is not administered. In one embodiment, a rest period refers to a time period during which no agent described herein (e.g., GDC-9545 or a pharmaceutically acceptable salt thereof or palbociclib) is administered. In some cases, the rest period provided herein may include the administration of another agent that is not GDC-9545 or a pharmaceutically acceptable salt thereof or palbociclib. In such cases, the administration of another agent during the rest period should not interfere with or impair the administration of the agents described herein.

[0044] A "dosing regimen" refers to a period of administration of an agent described herein that includes one or more cycles, wherein each cycle may include administration of an agent described herein in different amounts at different times.

[0045] "Once daily" (QD) means that the compound is administered once per day.

[0046] "PO" refers to oral administration of an agent described herein.

[0047] Graded adverse events refer to severity grading levels determined by NCI CTCAE. In one embodiment, adverse events are graded according to the following table.

[0048]

[0049] Combination therapy

[0050] Provided herein is a combination therapy comprising GDC-9545 or a pharmaceutically acceptable salt thereof (e.g., GDC-9545 tartrate) and a CDK4 / 6 inhibitor. In one embodiment, the combination therapy can be used to treat certain types of breast cancer described herein. For example, in one embodiment, the combination therapy described herein can be used to treat estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) breast cancer. In another embodiment, the combination therapy described herein can be used to treat ER+, HER2-locally advanced breast cancer (laBC) or ER+, HER2-metastatic breast cancer (mBC). In one such embodiment, the combination therapy described herein can be used to treat ER+, HER2-laBC. In one such embodiment, the combination therapy described herein can be used to treat ER+, HER2-mBC.

[0051] In another aspect, provided herein is a combination therapy comprising GDC-9545 or a pharmaceutically acceptable salt thereof (eg, GDC-9545 tartrate) and palbociclib. As used herein, "palbociclib" refers to the free base and any pharmaceutically acceptable salt of palbociclib.

[0052] The combination therapy described herein can be provided in the form of a kit comprising one or more of the agents for administration. In one embodiment, the kit comprises GDC-9545 or a pharmaceutically acceptable salt thereof for administration in combination with palbociclib as described herein. In another embodiment, the kit comprises GDC-9545 or a pharmaceutically acceptable salt thereof packaged with palbociclib, wherein the kit comprises a separately formulated dose of each agent. In yet another embodiment, the kit comprises GDC-9545 or a pharmaceutically acceptable salt thereof co-formulated with palbociclib.

[0053] Treatment

[0054] Provided herein is a method for treating such a cancer of a patient suffering from ER+, HER2-1aBC or mBC. In one embodiment, the method includes treating such a cancer of a patient suffering from ER+, HER2-1aBC or mBC by administering a combination therapy as described herein to the patient over a 28-day cycle.

[0055] Further provided herein are methods of treating such cancer in a patient having ER+, HER2- laBC or mBC, wherein the method comprises administering to the patient a combination therapy comprising GDC-9545, or a pharmaceutically acceptable salt thereof, and palbociclib, wherein the combination therapy is administered over one or more 28-day cycles.

[0056] Further provided herein are methods of treating such cancers in patients suffering from ER+, HER2-1aBC or mBC, wherein the method comprises administering to the patient a combination therapy described herein comprising a dosing regimen comprising: (i) administering GDC-9545, or a pharmaceutically acceptable salt thereof, once daily on days 1-28 of the first 28-day cycle; and (ii) administering palbociclib once daily on days 1-21 of the first 28-day cycle.

[0057] In one embodiment, GDC-9545 or a pharmaceutically acceptable salt thereof is administered in a fixed dose or once daily administration. In one embodiment, it is administered orally (PO), wherein GDC-9545 or a pharmaceutically acceptable salt thereof is formulated as a tablet or capsule. In one embodiment, GDC-9545 or a pharmaceutically acceptable salt thereof is administered once daily in an amount of about 1 mg-100 mg, 1 mg-50 mg, 1 mg-30 mg, 10 mg-100 mg, 10 mg-50 mg or 10 mg-30 mg. In another embodiment, GDC-9545 or a pharmaceutically acceptable salt thereof is administered in an amount of about 1, 5, 10, 15, 20, 25, 30, 50 or 100 mg. In yet another embodiment, GDC-9545 or a pharmaceutically acceptable salt thereof is administered in an amount of about 10, 30, 50 or 100 mg. In yet another embodiment, GDC-9545 or a pharmaceutically acceptable salt thereof is administered in an amount of about 30 mg.

[0058] In one embodiment, palbociclib is administered according to the package insert. In a preferred embodiment, palbociclib is administered in an amount of 125 mg.

[0059] Further provided herein is a method for treating such cancer in a patient with ER+, HER2-1aBC or mBC, wherein the method comprises administering to the patient a combination therapy as described herein comprising a dosing regimen comprising: (i) administering 30 mg of GDC-9545 or a pharmaceutically acceptable salt thereof once daily on days 1-28 of the first 28-day cycle; and (ii) administering 125 mg of palbociclib once daily on days 1-21 of the first 28-day cycle. In one such embodiment, the dosing regimen comprises 2 or more cycles as described herein.

[0060] The method for treating breast cancer provided herein may include administering the combination therapy described herein as part of a dosing regimen. In one embodiment, the dosing regimen comprises one or more cycles. In another embodiment, the dosing regimen comprises at least 2 cycles. On the other hand, provided herein is a dosing regimen comprising 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 30, 36, 42, 48, 54, 60, 66 or 72 cycles. In another embodiment, the dosing regimen comprises about 2-72, 2-66, 2-60, 2-54, 2-48, 2-42, 2-36, 2-30, 2-24, 2-18 or 2-12 cycles. In one embodiment, the dosing regimen includes administering the combination therapy described herein in any number of cycles until the expected response (e.g., PFS, OS, ORR, DOR, CBR) reaches the expected result (e.g., an increase in PFS, OS, ORR, DOR, CBR compared to a control described herein). In another embodiment, the dosing regimen includes administering the combination therapy described herein in any number of cycles until toxicity occurs or the patient additionally experiences one or more adverse events (AEs) that prevent further administration. In yet another embodiment, the dosing regimen includes administering the combination therapy described herein in any number of cycles until disease progression.

[0061] In one embodiment, the patient is a postmenopausal female. In one such embodiment, the patient is (i) ≥ 60 years old; (ii) < 60 years old and has ≥ 12 months of amenorrhea, plus follicle stimulating hormone (FSH) and plasma estradiol levels within the postmenopausal range as assessed by local laboratories in the absence of oral contraceptives, hormone replacement therapy, or gonadotropin-releasing hormone agonists or antagonists; or (iii) has undergone a documented bilateral oophorectomy.

[0062] In another embodiment, the patient is a premenopausal or perimenopausal (i.e., non-postmenopausal) female. In one such embodiment, the patient is treated with an LHRH agonist in combination with a combination therapy described herein. LHRH agonist therapy may begin 28 days prior to Day 1 of Cycle 1. In one embodiment, an LHRH agonist is administered on Day 1 of each cycle.

[0063] In another embodiment, the patient is male.In one such embodiment, the patient is treated with an LHRH agonist in combination with a combination therapy described herein.

[0064] In one embodiment, the patient described herein has been tested for the presence of estrogen receptor, prostaglandin receptor or Ki67. In one embodiment, the patient described herein suffers from a recorded ER positive tumor according to the American Society of Clinical Oncology / American Pathologists Association Guide. In one such embodiment, the patient described herein suffers from a recorded HER2 negative tumor. In one embodiment, the patient described herein has previously been treated with an aromatase inhibitor (e.g., anastrozole, exemestane or letrozole) or a CDK4 / 6 inhibitor (e.g., palbociclib) or a combination thereof. In one such embodiment, the patient has no disease recurrence during or within 12 months of completing such treatment with an aromatase inhibitor or a CDK4 / 6 inhibitor).

[0065] In one embodiment, the patient described herein has not been treated. In another embodiment, the patient described herein has not received previous chemotherapy before the combination therapy is administered. In another embodiment, the patient described herein has not been treated with an aromatase inhibitor or a CDK4 / 6 inhibitor or a combination thereof. In one such embodiment, the CDK4 / 6 inhibitor is palbociclib. In another such embodiment, the aromatase inhibitor is anastrozole, exemestane or letrozole. In one embodiment, the patient described herein has not been treated with letrozole or palbociclib before. In another embodiment, the patient described herein has not received surgery, chemotherapy or radiotherapy for at least 14 days before the combination therapy described herein is administered. In another embodiment, the patient described herein has not been treated with SERD (e.g., fulvestrant) or tamoxifen before. In another embodiment, the patient may have been treated with tamoxifen before, provided that the patient has not shown disease recurrence within the first 24 months of treatment with tamoxifen.

[0066] In one embodiment of the methods described herein, the patient has been treated with one or more cancer therapies prior to administering the combination therapy described herein. In one embodiment of the methods described herein, patients with breast cancer as described herein are resistant to one or more cancer therapies. In one embodiment of the methods described herein, resistance to cancer therapy includes recurrence of cancer or refractory cancer. Recurrence can refer to the reappearance of cancer at the original site or a new site after treatment. In one embodiment of the methods described herein, resistance to cancer therapy includes cancer progression during treatment with anticancer therapy. In some embodiments of the methods described herein, resistance to cancer therapy includes cancer that is unresponsive to treatment. Cancer may be resistant at the beginning of treatment, or resistant during treatment. In some embodiments of the methods described herein, cancer is in early or late stages.

[0067] Systemic chemotherapy is considered a standard of care (SOC) for mBC patients, although there is no standard regimen or sequence. In one embodiment of the methods described herein, the patients described herein have been treated with one or more of the therapies selected from the group consisting of anastrozole, letrozole, exemestane, everolimus, palbociclib and letrozole, fulvestrant, tamoxifen, toremifene, megestrol acetate, fluoxetine, ethinyl estradiol doxorubicin, pegylated liposomal doxorubicin, epirubicin, cyclophosphamide, docetaxel, paclitaxel, albumin-bound paclitaxel, methotrexate, 5-fluorouracil (5-FU), methotrexate and 5-fluorouracil (5-FU), carboplatin, cisplatin, capecitabine, gemcitabine, vinorelbine, eribulin, ixabepilone, trastuzumab and pertuzumab, or a combination thereof before administering the combination therapy described herein.

[0068] In one embodiment of the methods described herein, the patient described herein may have IaBC or mBC described herein that is resistant to one or more single-agent therapies selected from the group consisting of anastrozole, letrozole, exemestane, everolimus, palbociclib and letrozole, fulvestrant, tamoxifen, toremifene, megestrol acetate, fluoxetine, ethinyl estradiol doxorubicin, pegylated liposomal doxorubicin, epirubicin, cyclophosphamide, docetaxel, paclitaxel, nab-paclitaxel, methotrexate, 5-fluorouracil (5-FU), methotrexate and 5-fluorouracil (5-FU), carboplatin, cisplatin, capecitabine, gemcitabine, vinorelbine, eribulin, ixabepilone, trastuzumab and pertuzumab, or a combination thereof.

[0069] In one embodiment of the methods described herein, a patient as described herein may have undergone surgical treatment, such as breast-conserving surgery (i.e., a lumpectomy focused on removing the primary tumor with margins) or more extensive surgery (i.e., a mastectomy aimed at completely removing all breast tissue), prior to administration of the combination therapy described herein. In another embodiment, a patient as described herein may undergo surgical treatment after treatment with the combination therapy described herein.

[0070] Radiation therapy is also applied to the breast / chest wall and / or regional lymph nodes after surgery, and its goal is to kill the microscopic cancer cells left after surgery. In the case of breast-conserving surgery, radiotherapy is applied to the remaining breast tissue and sometimes to regional lymph nodes (including axillary lymph nodes). In the case of mastectomy, if there are factors that predict a higher risk of local recurrence, radiation can still be applied. In some embodiments of the method provided herein, the patient as described herein can receive radiation therapy before applying the combination therapy as described herein. In other embodiments of the method provided herein, the patient as described herein can receive radiation therapy after applying the combination therapy as described herein.

[0071] In some embodiments, the patients described herein have a history of other malignancies within 5 years prior to administration of the combination therapy described herein. In some embodiments, the patients described herein have no active inflammatory bowel disease, chronic diarrhea, short bowel syndrome, or major upper gastrointestinal surgery including gastrectomy. In some embodiments, the patients described herein do not have heart disease or heart dysfunction.

[0072] In one embodiment, compared to a control (e.g., non-treatment, standard of care (SOC) treatment or a combination of palbociclib and letrozole), the treatment performed with a combination therapy according to the methods provided herein increases the patient's OS. In one embodiment, compared to a control (e.g., non-treatment, standard of care (SOC) treatment or a combination of palbociclib and letrozole), the treatment performed with a combination therapy according to the methods provided herein increases the patient's OS by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 24 or more months compared to a control.

[0073] In one embodiment, according to the method provided herein, combination therapy is used for treatment, and the ORR amount of the patient is increased. In one such embodiment, the treatment performed with combination therapy according to the method provided herein results in more complete responses (CR) or partial responses (PR) in patients than in controls. In another embodiment, after combination therapy is used for treatment according to the method provided herein, the TTP of the patient increases. In another embodiment, compared with controls (e.g., non-treatment, standard of care (SOC) treatment or a combination of palbociclib and letrozole), the response duration of the combination therapy increases. In one such embodiment, the response duration increases by at least 1-3, 2-6, 3-8, 4-10, 5-12, 6-15, 8-20 or 1-24 months. In another embodiment, compared with controls (e.g., non-treatment, standard of care (SOC) treatment or a combination of palbociclib and letrozole), the patient described herein has an increased clinical benefit rate. In another embodiment, compared with controls (e.g., non-treatment, standard of care (SOC) treatment or a combination of palbociclib and letrozole), the patient has an increased progression-free survival period.

[0074] In one embodiment provided herein, after treatment with the combination therapy according to the methods provided herein, the patient is diagnosed with CR. In one embodiment provided herein, after treatment with the combination therapy according to the methods provided herein, the patient is diagnosed with PR. In one embodiment provided herein, after treatment with the combination therapy according to the methods provided herein, the patient is diagnosed with SD.

[0075] Further provided herein is the use of a combination therapy described herein comprising GDC-9545 described herein, or a pharmaceutically acceptable salt thereof, and palbociclib for treating laBC or mBC described herein.

[0076] Further provided herein are the use of the combination therapy described herein comprising GDC-9545 as described herein or a pharmaceutically acceptable salt thereof and palbociclib for treating mBC as described herein. Further provided herein are the use of the combination therapy described herein comprising GDC-9545 as described herein or a pharmaceutically acceptable salt thereof and palbociclib for treating laBC as described herein.

[0077] Further provided herein is the use of the combination therapy described herein comprising GDC-9545 or a pharmaceutically acceptable salt thereof and palbociclib as described herein for the preparation of a medicament for treating laBC or mBC as described herein. Further provided herein is the use of the combination therapy described herein comprising GDC-9545 or a pharmaceutically acceptable salt thereof and palbociclib as described herein for the preparation of a medicament for treating mBC as described herein. Further provided herein is the use of the combination therapy described herein comprising GDC-9545 or a pharmaceutically acceptable salt thereof and palbociclib as described herein for the preparation of a medicament for treating laBC as described herein.

[0078] Also provided herein are methods for inhibiting tumor growth or producing tumor regression in patients described herein, which are achieved by administering the combination therapy described herein. In one embodiment, a method for inhibiting tumor growth in a patient with laBC described herein is provided herein, the method comprising administering a combination therapy comprising administering GDC-9545 or a pharmaceutically acceptable salt thereof and palbociclib within one or more 28-day cycles described herein. In one embodiment, a method for inhibiting tumor growth in a patient with mBC described herein is provided herein, the method comprising administering a combination therapy comprising administering GDC-9545 or a pharmaceutically acceptable salt thereof and palbociclib within one or more 28-day cycles described herein.

[0079] In one embodiment, provided herein is a method of producing or improving tumor regression in a patient with mBC as described herein, the method comprising administering a combination therapy comprising administering GDC-9545 or a pharmaceutically acceptable salt thereof and palbociclib within one or more 28-day cycles as described herein. In one embodiment, provided herein is a method of producing or improving tumor regression in a patient with laBC as described herein, the method comprising administering a combination therapy comprising administering GDC-9545 or a pharmaceutically acceptable salt thereof and palbociclib within one or more 28-day cycles as described herein.

[0080] The development of combination therapy presents challenges, including, for example, the selection of agents for combination therapy that can improve efficacy while maintaining acceptable toxicity. A particular challenge is the need to distinguish the incremental toxicity of the combination. In one embodiment of the methods described herein, the combination therapy described herein (e.g., GDC-9545 or a pharmaceutically acceptable salt thereof and palbociclib) is administered with a dosing regimen comprising a staggered dosing schedule. In one such embodiment, the number or frequency of adverse events (AEs) in patients is reduced compared to controls (e.g., SOC therapy or palbociclib and letrozole).

[0081] In one embodiment of the methods described herein, the dosing regimen reduces the number or frequency of Grade 2 or Grade 3 or higher adverse events compared to the administration of palbociclib and letrozole. In one such embodiment, the dosing regimen eliminates the number or frequency of Grade 3 or higher AEs.

[0082] In another embodiment of the methods described herein, the administration reduces the number or frequency of Grade 2 or Grade 3 or higher adverse events compared to administration of either agent alone.

[0083] As is generally known, when an adverse event occurs, there are four options: (1) continue the original treatment with optional concomitant therapy; (2) adjust the dose of one or more agents in the dosing regimen; (3) suspend the administration of one or more agents in the dosing regimen; or (4) discontinue the administration of one or more agents in the dosing regimen.

[0084] In one embodiment of the methods described herein, the patient described herein experiences one or more adverse events including the following: fatigue, cough, pain, arthralgia, neutropenia, bradycardia, diarrhea, constipation, dizziness, nausea, anemia, weakness, thrombocytopenia, or pruritus. In one such embodiment, the patient described herein experiences the same level or reduced level / severity of one or more such AEs. In another embodiment, the patient described herein experiences reduced severity of one or more such AEs. In one embodiment, the patient described herein has reduced severity of neutropenia, diarrhea, or bradycardia compared to the control. In one such embodiment, the control is (i) either agent alone; (ii) palbociclib and letrozole; or (iii) SOC therapy.

[0085] In one embodiment, after administration of the combination therapy, the patient described herein has the same level or a reduced level of neutropenia compared to the control. In one such embodiment, the control is palbociclib alone; GDC-9545 alone or a pharmaceutically acceptable salt thereof; palbociclib and letrozole; or SOC therapy. In another embodiment, the control is palbociclib alone or palbociclib and letrozole. In yet another embodiment, after administration of the combination therapy, the patient described herein has the same level or a reduced level of bradycardia compared to the control. In another embodiment, the control is GDC-9545 alone or a pharmaceutically acceptable salt thereof or palbociclib and letrozole.

[0086] In one embodiment, a patient described herein who is treated with a combination therapy described herein experiences a relative reduction in one or more adverse events, as described herein.

[0087] In one embodiment of the methods described herein, patients described herein experience adverse events, including diarrhea. In one embodiment of the methods described herein, less than 75%, 60%, 50%, 40%, 33%, 25%, 20%, 12% or 5% of all patients treated experience neutropenia, diarrhea or bradycardia after treatment with the combination therapy described herein. In one embodiment of the methods described herein, less than 85%, 75%, 60%, 50%, 40%, 33%, 25%, 20%, 17%, 10% or 5% of all patients treated experience diarrhea described herein after treatment with the combination therapy described herein. In one embodiment of the methods described herein, less than 60%, 50%, 45%, 33%, 25%, 10% or 5% of all patients treated experience neutropenia after treatment with the combination therapy described herein. In one embodiment of the methods described herein, less than 75%, 60%, 50%, 40%, 33%, 25%, 20%, 15%, 10% or 8% of all patients treated experience bradycardia as described herein after treatment with the combination therapy described herein. In some embodiments, when a patient experiences one or more AEs selected from the group consisting of neutropenia, diarrhea and bradycardia due to treatment with the combination therapy described herein, the severity of the AE is Grade 2 or lower. In one embodiment, the patient described herein does not experience one or more AEs selected from the group consisting of neutropenia, diarrhea and bradycardia due to treatment with the combination therapy described herein, and the severity of the AE is greater than Grade 2.

[0088] Biomarkers

[0089] Breast cancer is a heterogeneous disease with many different subtypes defined by molecular markers and various mutational signatures. Diagnostic methods or kits can be used to test ER+HER2-laBC or mBC in patients described herein to inform treatment or predict the responsiveness of patients to the combination therapies described herein. In one embodiment, patients can be tested by determining ER pathway activity scores, such as those described in U.S. Patent Application Publication 20200082944. In some embodiments, patient samples are collected and tested to determine ER pathway activity scores. The score can be calculated using the 41 gene signature by subtracting the E2 repression score (as determined by the average z-score expression of genes listed in AGR3, AMZ1, AREG, C5AR2, CELSR2, CT62, FKBP4, FMN1, GREB1, IGFBP4, NOS1AP, NXPH3, OLFM1, PGR, PPM1J, RAPGEFL1, RBM24, RERG, RET, SGK3, SLC9A3R1, TFF1, and ZNF703) from the E2 induction score (as determined by the average z-score expression of genes listed in AGR3, AMZ1, AREG, C5AR2, CELSR2, CT62, FKBP4, FMN1, GREB1, IGFBP4, NOS1AP, NXPH3, OLFM1, PGR, PPM1J, RAPGEFL1, RBM24, RERG, RET, SGK3, SLC9A3R1, TFF1, and ZNF703).

[0090] In one embodiment, the sample from the patient used to determine the ER pathway activity score is a tumor tissue sample (eg, formalin-fixed paraffin-embedded (FFPE), fresh frozen (FF), archived, fresh, or frozen tumor tissue specimen).

[0091] In some cases, a combination therapy described herein is administered to a patient described herein, wherein the measured ER pathway activity score is between about -1.0 and about -0.2 (e.g., between about -0.9 and about -0.2, such as between about -0.8 and about -0.2, such as between about -0.7 and about -0.2, such as between about -0.6 and about -0.2, such as between about -0.5 and about -0.2, such as between about -0.4 and about -0.2, or such as between about -0.3 and about -0.2). In some cases, the ER activity score from a sample may be less than -1.0.

[0092] In some embodiments, additional biomarker assessments may be performed on samples from patients described herein to determine factors that may be associated with the safety and efficacy of the study treatment.

[0093] In one embodiment of the methods described herein, DNA can be obtained from blood samples and tumor tissues of patients described herein using NGS, whole genome sequencing (WGS), other methods, or a combination thereof. Such samples can be analyzed to identify germline (e.g., BRCA1 / 2) and somatic changes that predict response to study drugs, are associated with progression to more severe disease states, are associated with acquired resistance to study drugs, or can increase knowledge and understanding of disease biology.

[0094] Example:

[0095] Exemplary embodiments of the present invention are provided below.

[0096] Example No. 1. A method for treating estrogen receptor-positive and HER2-negative locally advanced breast cancer (laBC) or metastatic breast cancer (mBC) in a patient with receptor-positive and HER2-negative laBC or mBC, the method comprising administering to the patient a combination therapy comprising GDC-9545 or a pharmaceutically acceptable salt thereof and a CDK4 / 6 inhibitor, wherein the combination therapy is administered over a 28-day cycle.

[0097] Example No. 2. A method for treating estrogen receptor-positive and HER2-negative locally advanced breast cancer (laBC) or metastatic breast cancer (mBC) in a patient with receptor-positive and HER2-negative laBC or mBC, the method comprising administering to the patient a combination therapy comprising GDC-9545 or a pharmaceutically acceptable salt thereof and palbociclib, wherein the combination therapy is administered over one or more 28-day cycles.

[0098] Example No. 3. A method of treating estrogen receptor-positive and HER2-negative locally advanced breast cancer (laBC) or metastatic breast cancer (mBC) in a patient with receptor-positive and HER2-negative laBC or mBC, the method comprising administering to the patient a combination therapy comprising a dosing regimen comprising:

[0099] (i) administering GDC-9545 or a pharmaceutically acceptable salt thereof once daily on days 1 to 28 of the first 28-day cycle; and

[0100] (ii) administering palbociclib once daily on days 1-21 of the first 28-day cycle.

[0101] Embodiment No. 4. The method of embodiment 1, wherein the CDK4 / 6 inhibitor is palbociclib.

[0102] Embodiment No. 5. The method of any one of Embodiments 1 to 4, wherein GDC-9545 or a pharmaceutically acceptable salt thereof is administered in an amount of about 10 mg to about 100 mg.

[0103] Embodiment No. 6. The method of Embodiment 5, wherein GDC-9545 or a pharmaceutically acceptable salt thereof is administered in an amount of about 10, 30, 50 or 100 mg.

[0104] Embodiment No. 7. The method of Embodiment 5, wherein GDC-9545 or a pharmaceutically acceptable salt thereof is administered in an amount of about 30 mg.

[0105] Embodiment No. 8. The method of any one of Embodiments 2 to 7, wherein palbociclib is administered in an amount of about 125 mg.

[0106] Embodiment No. 9. A method as described in any one of Embodiments 3 to 8, wherein the dosing regimen comprises 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 30, 36, 42, 48, 54, 60, 66 or 72 cycles.

[0107] Embodiment No. 10. The method of any one of embodiments 3 to 8, wherein the dosing regimen comprises about 2-72, 2-66, 2-60, 2-54, 2-48, 2-42, 2-36, 2-30, 2-24, 2-18 or 2-12 cycles.

[0108] Embodiment No. 11. The method of any one of Embodiments 1 to 8, wherein the patient is premenopausal.

[0109] Embodiment No. 12. The method of any one of Embodiments 1 to 8, wherein the patient is male.

[0110] Embodiment No. 13. The method of embodiment 11 or 12, wherein luteinizing hormone releasing hormone (LHRH) is further administered to the patient.

[0111] Embodiment No. 14. The method of Embodiment 13, wherein LHRH is administered to the patient on the first day of each cycle.

[0112] Embodiment No. 15. The method of any one of embodiments 1 to 14, wherein the patient is tested for the presence or absence of a mutation in one or more of an estrogen receptor, a prostaglandin receptor, or Ki67.

[0113] Embodiment No. 16. The method of any one of embodiments 1 to 15, wherein the patient has reduced adverse events (AEs) compared to a control.

[0114] Embodiment No. 17. The method of Embodiment 16, wherein the control is letrozole administered in combination with palbociclib.

[0115] Embodiment No. 18. The method of any one of Embodiments 16 to 17, wherein the number or frequency of Grade 3 or higher AEs is reduced.

[0116] Embodiment No. 19. A method as described in any one of embodiments 16 to 18, wherein the patient has a reduced severity of one or more AEs compared to the control, wherein the one or more AEs are selected from the group consisting of fatigue, cough, pain, arthralgia, neutropenia, bradycardia, diarrhea, constipation, dizziness, nausea, anemia, weakness, thrombocytopenia or pruritus.

[0117] Embodiment No. 20. The method of any one of embodiments 1 to 19, wherein said patient has the same level or a reduced level of neutropenia after administration of said combination therapy compared to said control.

[0118] Embodiment No. 21. The method of any one of embodiments 1 to 20, wherein said patient has the same level or a reduced level of bradycardia after administration of said combination therapy compared to said control.

[0119] Embodiment No. 22. The method of any one of embodiments 1 to 21, wherein the patient's overall survival (OS) is increased compared to a control.

[0120] Embodiment No. 23. The method of embodiment 22, wherein the patient has an increase of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 24 or more months compared to a control.

[0121] Embodiment No. 24. The method of any one of embodiments 1 to 23, wherein the objective response rate of said patients to said combination therapy results in more patients having a complete response (CR) or a partial response (PR) than a control.

[0122] Embodiment No. 25. The method of any one of embodiments 1 to 24, wherein the duration of response to the combination therapy is increased compared to a control.

[0123] Embodiment No. 26. The method of embodiment 25, wherein the duration of response is increased by at least 1-3, 2-6, 3-8, 4-10, 5-12, 6-15, 8-20 or 1-24 months.

[0124] Embodiment No. 27. The method of any one of embodiments 1 to 26, wherein the patient has an increased clinical benefit rate compared to a control.

[0125] Embodiment No. 28. The method of any one of embodiments 1 to 27, wherein the patient has increased progression-free survival compared to a control.

[0126] Embodiment No. 29. A method as described in Embodiment 28, wherein the increase is at least 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 36, 42, 48, 50, 54, 60, 66 or 72 months.

[0127] Embodiment No. 30. A method as described in any one of Embodiments 1 to 29, wherein the patient has a reduction in the time to deterioration in: (i) pain intensity; (ii) pain presence and interference; (iii) physical function; (iv) role function; (v) global health status and quality of life; or (vi) a combination thereof.

[0128] Embodiment No. 31. The method of any one of embodiments 22 to 30, wherein the control is palbociclib alone or palbociclib administered in combination with letrozole.

[0129] Embodiment No. 32. The method of any one of Embodiments 1 to 31, wherein the patient is postmenopausal.

[0130] Embodiment No. 33. The method of embodiment 32, wherein the patient has undergone bilateral oophorectomy.

[0131] Embodiment No. 34. The method of any one of Embodiments 1 to 33, wherein the patient has not received prior chemotherapy prior to administration of the combination therapy.

[0132] Embodiment No. 35. The method of any one of embodiments 1 to 33, wherein the patient has been previously treated with tamoxifen.

[0133] Embodiment No. 36. The method of any one of embodiments 1 to 33, wherein the patient has been previously treated with an aromatase inhibitor or a CDK4 / 6 inhibitor or a combination thereof.

[0134] Embodiment No. 37. The method of any one of embodiments 1 to 33, wherein the patient has not been previously treated with an aromatase inhibitor or a CDK4 / 6 inhibitor or a combination thereof.

[0135] Embodiment No. 38. The method of any one of Embodiments 1 to 33, wherein the patient has not undergone surgery, chemotherapy, or radiation therapy for at least 14 days prior to administration of the combination therapy.

[0136] Embodiment No. 39. The method of any one of Embodiments 1 to 33, wherein the patient does not have heart disease or heart dysfunction.

[0137] Example No. 40. Use of a combination therapy comprising GDC-9545 or a pharmaceutically acceptable salt thereof and palbociclib for treating laBC or mBC as described herein.

[0138] Example No. 41. Use of a combination therapy comprising GDC-9545 or a pharmaceutically acceptable salt thereof and palbociclib in the preparation of a medicament for the treatment of laBC or mBC.

[0139] Example No. 42. A method of inhibiting tumor growth in a patient with laBC or mBC, the method comprising administering a combination therapy comprising GDC-9545 or a pharmaceutically acceptable salt thereof and palbociclib in one or more 28-day cycles.

[0140] Example No. 43. A method of producing or improving tumor regression in a patient with laBC or mBC, the method comprising administering a combination therapy comprising GDC-9545 or a pharmaceutically acceptable salt thereof and palbociclib in one or more 28-day cycles.

[0141] The following examples are offered by way of illustration only and not limitation.

[0142] Examples:

[0143] Patients: Eligible patients had ER+(HER2-) metastatic breast cancer, received ≤2 lines of prior therapy in the advanced or metastatic setting, and had received adjuvant endocrine therapy for ≥24 months and / or relapsed or progressed on endocrine therapy in the incurable, locally advanced or metastatic setting and had a clinical benefit from therapy (i.e., tumor response or disease stabilization for at least 6 months). Patients receiving palbociclib were not allowed to have prior treatment with a CDK4 / 6i.

[0144] Table 1: Basic information of patients and disease manifestations.

[0145]

[0146]

[0147] Safety. Treatment-emergent AEs (TEAEs) were reported in 78% and 96% of patients treated in Cohorts A and B, respectively. In Cohort A, 58% of patients experienced AEs related to GDC-9545; these were generally Grade 1-2, with the exception of three Grade 3 events: fatigue, elevated transaminases, and diarrhea. No patient discontinued study treatment due to an AE. In Cohort B, 58% of patients experienced AEs related to GDC-9545; AEs were Grade 1 or 2 in severity, with the exception of one SAE of Grade 3 QT prolongation and T-wave inversion reported in a 69-year-old female. This patient had a baseline QTcF of 441ms, and at the Cycle 6 Day 1 visit, her QTcF was 506ms, but she was asymptomatic. This case was confounded by the patient's history of preexisting coronary artery disease (coronary artery stenosis 30%-50%), right bundle branch block, and possible concurrent use of pregabalin. Treatment with palbociclib and GDC-9545 was discontinued in response to QT prolongation, which resolved approximately 16 days after onset.

[0148] The AE of bradycardia was reported in three patients (8%) in cohort A and 15 patients (31%) in cohort B; all patients were grade 1 and asymptomatic, except for one patient (cohort B) who experienced grade 2 bradycardia, who also experienced grade 2 dizziness. ECG data showed similar changes in heart rate in cohorts A and B, with no further changes in heart rate after the addition of palbociclib. After completion of treatment, heart rate (HR) changes returned to baseline. For patients with baseline HR ≥ 60 bpm, the mean maximum HR changes in the two cohorts were 19 and 20 beats per minute (bpm), respectively, and for patients with baseline HR < 60 bpm, the mean maximum HR changes in cohorts A and B were 13 bpm, respectively.

[0149] Table 2: All adverse events occurring in ≥10% of patients

[0150]

[0151] Pharmacokinetics. Exposures of GDC-9545 in combination with palbociclib were generally comparable to those observed with GDC-9545 alone. The PK of palbociclib was not altered when coadministered with GDC-9545 and was consistent with reported values.

[0152] Pharmacodynamic effects. Reduced ER (10 / 12, 83%), PR (7 / 8, 88%), and Ki67 (9 / 12, 75%) protein levels, as well as ER pathway signature scores (8 / 12, 67%) were observed in evaluable paired pre-treatment and on-treatment biopsies (n=12) (Guan et al., Cell, 2019).

[0153] A decrease from baseline in ctDNA ESR1 mutant allele frequency was observed in all patients in both cohorts (n=26).

[0154] Clinical Activity. In Cohort A, 22 / 40 (55%) patients achieved clinical benefit, defined as a CR, PR, or first progressive disease observed at or after Week 24. Partial responses were observed in 4 / 31 (13%) patients with measurable disease at baseline. In Cohort B, 35 / 48 (81%) patients achieved clinical benefit, and 14 / 45 (33%) achieved a PR. In both cohorts, clinical benefit was observed in patients who had received prior fulvestrant therapy [2 / 7 (29%) and 2 / 3 (67%) in Cohorts A and B, respectively] and in patients with detectable ESR1 mutations at enrollment [8 / 13 (62%) and 11 / 11 (100%)].

[0155] Table 3: Efficacy Results

[0156]

[0157] In this specification and claims, unless the context requires otherwise, the words "comprises," "comprising," and "containing" are used in a non-exclusive sense. It should be understood that the embodiments described herein include "consisting of" and / or "consisting essentially of" the embodiments.

[0158] If a range of values ​​is provided, it is understood that each intervening value (to one-tenth of the unit of the lower limit, unless the context clearly dictates otherwise) between the upper and lower limits of the range, as well as any other specified or intervening value in the specified range, is encompassed herein. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed herein, subject to any explicitly excluded limits in the specified ranges. Where the stated range includes one or both limits, ranges excluding one or both of those included limits are also encompassed herein.

[0159] Many variations and other embodiments of the invention set forth herein will come to mind to those skilled in the art to which the present invention relates, with the benefit of the above description and the teachings presented in the associated drawings. Therefore, it should be understood that the present invention is not limited to the specific embodiments disclosed, and variations and other embodiments are intended to be included within the scope of the appended claims. Although specific terms are employed herein, these terms are used only in a general and descriptive sense and not for purposes of limitation.

Claims

1. Use of a combination product comprising GDC-9545 or a pharmaceutically acceptable salt thereof and palbociclib in the preparation of a medicament for a method of treating estrogen receptor-positive and HER2-negative locally advanced breast cancer (laBC) or metastatic breast cancer (mBC) in a patient with estrogen receptor-positive and HER2-negative laBC or mBC, the method comprising administering to the patient a combination therapy comprising GDC-9545 or a pharmaceutically acceptable salt thereof and palbociclib, wherein the combination therapy is administered over one or more 28-day cycles.

2. The use of claim 1, wherein the method comprises administering to the patient a combination therapy comprising a dosing regimen comprising: (i) administering GDC-9545 or a pharmaceutically acceptable salt thereof QD on Days 1-28 of the first 28-day cycle; and (ii) administering palbociclib QD on Days 1-21 of the first 28-day cycle.

3. The use according to any one of claims 1 to 2, wherein GDC-9545 or a pharmaceutically acceptable salt thereof is administered in an amount of 10 mg to 100 mg.

4. The use according to any one of claims 1 to 2, wherein GDC-9545 or a pharmaceutically acceptable salt thereof is administered in an amount of 10, 30, 50 or 100 mg.

5. The use according to any one of claims 1 to 2, wherein GDC-9545 or a pharmaceutically acceptable salt thereof is administered in an amount of 30 mg.

6. The use according to any one of claims 1 to 2, wherein palbociclib is administered in an amount of 125 mg.

7. The use of claim 2, wherein the dosing regimen comprises 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 30, 36, 42, 48, 54, 60, 66 or 72 cycles.

8. The use according to claim 2, wherein the dosing regimen comprises 2-72, 2-66, 2-60, 2-54, 2-48, 2-42, 2-36, 2-30, 2-24, 2-18 or 2-12 cycles.

9. The use according to claim 2, wherein the patient is premenopausal.

10. The use according to claim 2, wherein the patient is male.

11. The use according to claim 9 or 10, wherein the patient is further administered luteinizing hormone releasing hormone (LHRH) and wherein LHRH is administered on the first day of each cycle.

12. The use according to any one of claims 1 to 2, wherein the patient is tested for the presence of a mutation in one or more of an estrogen receptor, a prostaglandin receptor or Ki67.

13. The use according to claim 2, wherein the patient has reduced adverse events (AEs) compared to a control.

14. The use according to claim 13, wherein the control is letrozole administered in combination with palbociclib.

15. The use according to any one of claims 13 to 14, wherein the patient has a reduced severity of one or more AEs selected from the group consisting of fatigue, cough, pain, arthralgia, neutropenia, bradycardia, diarrhea, constipation, dizziness, nausea, anemia, asthenia, thrombocytopenia or pruritus compared to the control.

16. The method of any one of claims 1 to 2, wherein the patient has a reduction in time to deterioration in: (i) pain intensity; (ii) pain presence and interference; (iii) physical function; (iv) role function; (v) overall health status and quality of life; or (vi) a combination thereof.

17. The use according to any one of claims 1 to 2, wherein the patient is postmenopausal.

18. The use according to claim 17, wherein the patient has undergone bilateral oophorectomy.

19. The use according to any one of claims 1 to 2, wherein the patient has not received previous chemotherapy prior to administration of the combination therapy.

20. The use according to any one of claims 1 to 2, wherein the patient has been previously treated with tamoxifen.

21. The use according to any one of claims 1 to 2, wherein the patient has been previously treated with an aromatase inhibitor or a CDK4 / 6 inhibitor or a combination thereof.

22. The use according to any one of claims 1 to 2, wherein the patient has not been previously treated with an aromatase inhibitor or a CDK4 / 6 inhibitor or a combination thereof.

23. The use according to any one of claims 1 to 2, wherein the patient has not undergone surgery, chemotherapy or radiotherapy for at least 14 days prior to administration of the combination therapy.

24. The use according to any one of claims 1 to 2, wherein the patient does not have heart disease or heart dysfunction.

25. Use of a combination product comprising GDC-9545 or a pharmaceutically acceptable salt thereof and palbociclib in the preparation of a medicament for a method of inhibiting tumor growth in patients with estrogen receptor-positive and HER2-negative laBC or mBC, the method comprising administering a combination therapy comprising GDC-9545 or a pharmaceutically acceptable salt thereof and palbociclib in one or more 28-day cycles.

26. Use of a combination product comprising GDC-9545 or a pharmaceutically acceptable salt thereof and palbociclib in the preparation of a medicament for a method for producing or improving tumor regression in patients with estrogen receptor-positive and HER2-negative laBC or mBC, the method comprising administering a combination therapy comprising GDC-9545 or a pharmaceutically acceptable salt thereof and palbociclib in one or more 28-day cycles.

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