Methods of treating breast cancer using selective estrogen receptor degradation agents (SERDs)

Abstract

The present specification relates to methods of treating hormone receptor positive (HR +), human epidermal growth factor receptor 2 negative (HER2-), metastatic, or localized region recurrent breast cancer comprising administering to a patient suffering from such cancer a next generation selective estrogen receptor degrading agent (ngSERD), such as carmistrant, such as carmistrant. Characterized in that the cancer has relapsed or progressed after at least one past endocrine treatment line.

Description

Technical Field

[0001] This specification relates to methods for treating hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), metastatic or locally recurrent breast cancer, including administering a next-generation selective estrogen receptor degrader (ngSERD) to a patient suffering from such cancer, characterized in that the cancer has recurred or progressed after at least one prior line of endocrine therapy. This specification also relates to the use of ngSERD for treating such breast cancer and the use of ngSERD for manufacturing a medicament for treating such breast cancer. Background Art

[0002] Breast cancer is the most frequently diagnosed malignancy among women globally and is a leading cause of cancer mortality among women globally. Locally advanced (inoperable) and / or metastatic breast cancer (MBC) remains largely incurable. Recent advances in MBC treatment suggest that the concept of MBC as a chronic disease that can be controlled long-term by sequential treatment is realistic, at least for certain subgroups (see, e.g., Harbeck and Gnant, Lancet 2017; 389(10074):1134-50). Thus, the treatment goal is to prolong progression-free survival (PFS) and overall survival (OS), while maintaining quality of life.

[0003] Hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) tumors account for more than two-thirds of all breast cancers (see https: / / seer.cancer.gov / statfacts / html / breast-subtypes.html, accessed on October 31, 2022). Endocrine therapy (ET) has been the backbone of treatment for HR+ breast cancer for decades, although the use of standard treatments, monotherapies or combinations, and the preferred ET have evolved over time. One class of ET (selective estrogen receptor modulators (SERMs)) binds to the estrogen receptor (ER), thereby preventing the breast tumor growth stimulation provided by the binding of endogenous estrogen to the ER. Examples of SERMs approved by the FDA for the treatment of breast cancer include tamoxifen and toremifene. A second class of ET (aromatase inhibitors (AIs)) blocks the activity of aromatase and, in doing so, blocks estrogen biosynthesis. Thus, AI treatment prevents the activation of ER mediated by estrogen, although, unlike in the case of SERMs, which directly block ligand / receptor interactions, AIs deplete the ligand pool available for receptor activation. Examples of AIs approved by the FDA for the treatment of breast cancer include anastrazole and letrazole. AIs are primarily used in postmenopausal women, although they can be used in a premenopausal setting if combined with ovarian activity inhibitors such as goserelin or leuprolide. A third class of ET is selective estrogen receptor degraders (SERDs). Fulvestrant (e.g. ) is the only SERD currently approved for clinical use. Although, like SERMs, fulvestrant binds to the estrogen receptor, it does not mimic estrogen and is therefore referred to as a pure antiestrogen. In addition, the binding of fulvestrant to the ER causes the degradation of the estrogen receptor. The clinical use of fulvestrant has been better understood in recent years, which has led to its use in earlier lines of treatment. One factor that may slow the initial uptake of fulvestrant in the clinic is the fact that it is administered as an intramuscular injection on a monthly basis. This fact, along with the realization that more frequent dosing of oral next-generation SERDs may provide greater net degradation of the estrogen receptor over time, has led to great interest in the development of oral next-generation SERDs.

[0004] Mutations in estrogen receptor (ESR1m) that affect the ligand-binding domain of ERα cause constitutively active, estrogen-independent ER signaling, which counteracts the effects of AIs and SERMs. Clinically, ESR1m is associated with acquired AI resistance, most commonly in patients who have been treated with AIs in the advanced breast cancer setting. Today, in many countries, the majority of patients with advanced breast cancer receive AIs in combination with CDK4 / 6i rather than as monotherapy, and translational studies from PALOMA-3 and MONARCH-3 have shown that ESR1m is frequently acquired in patients treated with CDK4 / 6 inhibitor + ET (see, e.g., Goetz et al., J. Clin. Oncol. 2020; 38(suppl 15): 3519; O'Leary et al., Cancer Discovery 2018; 11: 1390). Multiple lines of evidence, including real-world data, suggest that ESR1m is also associated with poor treatment outcomes in both PFS and OS, mainly due to the lack of effective treatment options to address this driver mutation (Lei et al., J. Cancer Metastasis Treat. 2019; 5: 38). The emergence of ESR1m is also associated with more aggressive disease features, including the development of visceral metastases (see, e.g., Reinert T. et al., Front Oncol 2017; 7: 26).

[0005] The CDK4 / 6 cell cycle pathway, consisting of cyclin D-CDK4 / 6-INK4-Rb (Rb, retinoblastoma protein), is frequently mutated in breast cancer, and pathway overactivation causes cells to erroneously progress through the G1 / S checkpoint and proliferate. Estrogen itself is mitogenic, leading to increased activity of both cyclin D1 and CDK4 / 6 and promoting the excessive proliferation of hormone-regulated breast cancer. Rb is a tumor suppressor protein that blocks cell cycle progression when it binds to the E2 transcription factor (E2F). Therefore, targeting CDK4 / 6 is indicated as a desirable option for intervening in the overactivated cyclin D-CDK4 / 6-INK4-Rb pathway in HR+ breast cancer because it allows Rb to remain functional and helps control cell growth. Thus, CDK4 / 6 inhibitors have been found to be particularly useful agents for treating advanced HR+, HER2− breast cancer and have been widely adopted in clinical practice, most commonly in combination with ET. Targeting components of the cyclin D-CDK4 / 6-INK4-Rb pathway also helps circumvent resistance to antiestrogens.

[0006] Although CDK4 / 6 inhibitors have proven highly effective in the clinic for patients with ER+ breast cancer, intrinsic or developed resistance to these drugs is common. Approximately 20% of breast cancer patients treated with CDK4 / 6 inhibitors do not respond to treatment. The tumors of these patients already harbor mutations that allow them to evade the action of CDK4 / 6 inhibitors and proliferate in the presence of the drugs. This intrinsic resistance to CDK4 / 6 inhibitors typically involves activation of the cyclin D-CDK4 / 6-Rb pathway. Resistance to CDK4 / 6 inhibitors acquired after an initial response can manifest in multiple ways, including activation of the cyclin D-CDK4 / 6-Rb pathway, activation of other proliferative pathways, alterations in the tumor microenvironment, and modulation of tumor metabolism. Within 2 years of starting treatment in the PALOMA-2 trial, more than 30% of the enrolled patients developed resistance to the CDK4 / 6 inhibitor palbociclib. The treatment of CDK4 / 6-resistant HR+ / HER2− breast cancer represents a significant unmet medical need.

[0007] Next-generation oral selective estrogen receptor degraders (ngSERDs) are designed to be the backbone endocrine therapy for patients with HR+ breast cancer by delivering more potent blockade of ER signaling than existing therapies and addressing key mechanisms of resistance. Camizestrant (AZD9833) is an ngSERD for the treatment of ER+ breast cancer that has demonstrated selective ERα degradation, pure ER antagonism, and significant antitumor activity in both ESR1 wild-type (ESR1wt) and mutant (ESR1m) tumors, as well as encouraging clinical activity in early clinical trials.

[0008] As described above, current guidelines recommend combining endocrine therapies such as AIs or SERDs with inhibitors of cyclin-dependent kinases 4 and 6 (CDK4 / 6i) as first-line (1L) treatment for HR+ / HER− breast cancer (see, for example, Cardoso F et al., Ann. Oncol. 2020; S0923-7534,(20),42460-3). Unfortunately, most patients ultimately experience cancer progression on CDK4 / 6 inhibitor + ET and die of their disease. Once patients experience disease progression on 1L CDK4 / 6i-based treatment, subsequent endocrine-based therapies may have limited efficacy and challenging tolerability profiles. Many patients ultimately are treated with chemotherapy. However, drug resistance ultimately develops, leading to disease progression (i.e., where the growth of the cancer is not adequately or fully controlled by the previously administered drug regimen, e.g., as evaluated by radiological or other analytical methods).

[0009] In addition to intrinsic and acquired resistance features, the presence of lung and / or liver metastases is an important prognostic factor in advanced breast cancer, indicating aggressive and refractory disease.

[0010] Accordingly, improved treatment methods are needed to treat HR+, HER2− breast cancer, particularly in those patients with locally advanced breast cancer or metastatic breast cancer that has recurred or progressed after at least one prior line of endocrine therapy. One aim of the present specification is to provide a new method of treating such patients. SUMMARY OF THE INVENTION

[0011] In a first aspect, the present specification provides a method of treating hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2−), metastatic or locally regionally recurrent breast cancer, comprising administering to a patient having such cancer a therapeutically effective amount of a next-generation selective estrogen receptor degrader (ngSERD), wherein the cancer has recurred or progressed after at least one prior line of endocrine therapy.

[0012] In this and other aspects detailed below, “recurrence” or “progression” of cancer is after prior treatment with endocrine therapy (ET), optionally a SERM or an aromatase inhibitor. The patient being treated may also have received chemotherapy and / or CDK4 / 6 inhibitor therapy and will receive no more than one line of ET or chemotherapy for treatment of advanced disease. CDK4 / 6 inhibitors are typically administered in combination with ET, such as in combination with an AI.

[0013] The term “treatment” refers to at least partially alleviating, inhibiting, preventing, and / or ameliorating a disorder, condition, or disease (such as breast cancer). The term “cancer treatment” includes both ex vivo and in vivo treatment, including in warm-blooded animals (such as humans). The effectiveness of cancer treatment can be evaluated in a variety of ways, including but not limited to: inhibition of cancer cell proliferation (including reversal of cancer growth); promotion of cancer cell death (e.g., by promoting apoptosis or another cell death mechanism); improvement of symptoms; duration of remission from treatment; delay of disease progression; and extension of survival. Treatment can also be evaluated based on the nature and extent of side effects associated with the treatment. In addition, effectiveness can be evaluated based on biomarkers such as the expression or phosphorylation level of a protein known to be associated with a particular biological phenomenon. Other evaluations of effectiveness are known to those skilled in the art.

[0014] The term "therapeutically effective amount" refers to an amount of a compound or combination of compounds as described herein that is sufficient to achieve the intended application, including but not limited to the treatment of a disease. The therapeutically effective amount can vary depending on the intended application (in vitro or in vivo), or the subject to be treated and the disease condition (e.g., the weight, age, and sex of the subject), the severity of the disease condition, the mode of administration, etc., which can be readily determined by one of ordinary skill in the art. The term also applies to the dose that will induce a specific response in a target cell (e.g., the amount of apoptosis). The specific dose will vary depending on the particular compound selected, the dosing regimen to be followed, whether the compound is administered in combination with other compounds, the time of administration, the tissue to which it is administered, and the physical delivery system carrying the compound.

[0015] "Hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) breast cancer" refers to a tumor that expresses one or both of estrogen receptor (ER) and / or progesterone receptor (PgR) (i.e., HR+) and has low levels or no human epidermal growth factor receptor on its cell surface (i.e., HER2-). These terms are well known to those skilled in the art.

[0016] In a related aspect, the present specification provides an ngSERD for treating HR+, HER2- metastatic or locally recurrent breast cancer, characterized in that the breast cancer has recurred or progressed after at least one prior line of endocrine therapy.

[0017] In a related aspect, the present specification provides an ngSERD for manufacturing a medicament for treating HR+, HER2-, metastatic or locally recurrent breast cancer, wherein the medicament is for treating breast cancer that has recurred or progressed after at least one prior line of endocrine therapy.

[0018] In an aspect according to the present specification, the breast cancer has recurred or progressed after at least one line of endocrine therapy, optionally wherein the endocrine therapy is selected from AI or SERM therapy.

[0019] In an aspect according to the present specification, the breast cancer has recurred or progressed after at least one line of treatment with a CDK4 / 6 inhibitor. In such aspects, the CDK4 / 6 inhibitor can be administered in combination with an endocrine therapy such as an aromatase inhibitor.

[0020] In an aspect according to the present specification, the patient has breast cancer with a mutation in the estrogen receptor (ESR1m), i.e., the breast cancer is ESR1m breast cancer.

[0021] In an aspect according to the present specification, the patient has visceral metastases (e.g., metastases to the liver and / or lungs).

[0022] In aspects according to the present specification, the ngSERD in a method for treating, a treatment method, or the manufacture of a medicament for treatment is camizestrant (AZD9833, N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)pyridin-3-amine) or a pharmaceutically acceptable salt thereof. In such aspects, camizestrant or a pharmaceutically acceptable salt thereof may be administered orally at a dose of 75 mg or 150 mg per day. In some aspects, the ngSERD used in a method for treating, a treatment method, or the manufacture of a medicament for treatment is camizestrant in its non-salt form (i.e., as its free base).

[0023] In aspects according to the present specification, the ngSERD in a method for treating, a treatment method, or the manufacture of a medicament provides an improvement in progression-free survival (PFS) relative to that observed with standard of care (SoC). In such aspects, the SoC may be fulvestrant.

[0024] In aspects according to the present specification, the ngSERD in a method for treating, a treatment method, or a medicament comprising the ngSERD provides an improvement in overall survival (OS) relative to standard of care.

[0025] In aspects according to the present specification, the ngSERD in a method for treating, a treatment method, or a medicament comprising the ngSERD provides an improvement in objective response rate (ORR) relative to standard of care.

[0026] In aspects according to the present specification, the ngSERD in a method for treating, a treatment method, or a medicament comprising the ngSERD provides an improvement in 24-week clinical benefit rate (CBR 24 ) relative to standard of care.

[0027] In aspects according to the present specification, the ngSERD in a method for treating, a treatment method, or a medicament comprising the ngSERD causes clearance of mutations in the estrogen receptor of the tumor. In such aspects, clearance of ESR1m is measured in a blood sample analyzing circulating tumor DNA, or clearance of ESR1m is measured in a tumor biopsy obtained from a patient. In such aspects, the presence of ESR1m may be identified by analyzing a tumor biopsy. In such aspects, clearance of mutations in the estrogen receptor is increased relative to that observed with treatment with fulvestrant.

[0028] In aspects according to this specification, the ngSERD in a treatment, in a method of treatment, or in a medicament comprising an ngSERD does not cause any clinically significant treatment-related adverse effects (TRAE).

[0029] In one aspect according to this specification, there is provided a kit comprising a medicament containing an ngSERD and instructions for using the medicament to treat HR+ / HER2-metastatic or locally recurrent breast cancer in a patient, wherein the cancer of the patient has recurred or progressed after at least one prior line of endocrine therapy.

[0030] In one aspect according to this specification, there is provided a pharmaceutical composition comprising an ngSERD and at least one pharmaceutically acceptable excipient, the pharmaceutical composition being for treating HR+ / HER2-metastatic or locally recurrent breast cancer in a patient, wherein the cancer of the patient has recurred or progressed after at least one prior line of endocrine therapy.

[0031] Drawings

[0032] For easier understanding of the present invention, reference is made to the following drawings herein.

[0033] Figure 1 : Shows Kaplan–Meyer curves of the probability of progression-free survival evaluated by the investigator versus time (in months) of treatment with fulvestrant ((F) 500 mg, once-monthly injection) or camizestrant ((C) administered once-daily as 75 mg or 150 mg tablets). Compared with fulvestrant, both doses of camizestrant delivered a clinically meaningful improvement in PFS. The proportions of patients progression-free at 12 m were 23.8%, 34.3% and 44.5% for fulvestrant, 75 mg camizestrant and 150 mg camizestrant, respectively.

[0034] Figure 2 : Shows Kaplan–Meyer curves of the probability of progression-free survival evaluated by blinded independent central review (BICR) versus time (in months) of treatment with fulvestrant ((F) 500 mg, once-monthly injection) or camizestrant ((C) administered once-daily as 75 mg or 150 mg tablets). Compared with fulvestrant, both doses of camizestrant delivered a clinically meaningful improvement in PFS. The discordance in progression at the patient level between BICR and investigator assessment was consistent with those commonly observed (see K Borradaile et al., Cancer Research 2009:62(2 Suppl): Abstract No. 2081).

[0035] Figure 3: A Kaplan Meyer curve showing the probability of progression-free survival over time (in months) for patients who had received prior CDK4 / 6 inhibitor treatment. In this subgroup of patients who had received prior CDK4 / 6i treatment, both 75 mg and 150 mg camizestrant treatments produced improvements comparable to fulvestrant treatment, with hazard ratios (HRs) of 0.49 and 0.68, respectively.

[0036] Figure 4 : A Kaplan Meyer curve showing the probability of progression-free survival over time (in months) for patients who had lung metastases and / or liver metastases before the start of treatment. In this subgroup, both 75 mg and 150 mg camizestrant treatments produced improvements comparable to fulvestrant treatment, with HRs of 0.43 and 0.55, respectively.

[0037] Figure 5 : A Kaplan Meyer curve showing the probability of progression-free survival over time (in months) for patients who had estrogen receptor mutations (ESR1m) before the start of treatment. In this subgroup, both 75 mg and 150 mg camizestrant treatments produced improvements comparable to fulvestrant treatment, with HRs of 0.33 and 0.55, respectively.

[0038] Figure 6 : Changes in the total variant allele frequency (sVAF%) of ESR1m ctDNA by treatment group and visit (comparison of samples collected at screening and on day 1 of cycle 1 before treatment, and comparison of samples collected on day 1 of cycle 1 and on day 1 of cycle x). Variants defined as ESR1m are E380Q, V422del, S463P, L536H / P / R, Y537C / D / N / S. Dots represent individual patients, boxes represent the upper quartile, median quartile, and lower quartile, and whiskers represent the 1.5 interquartile range. Treatment with 75 mg and 150 mg camizestrant resulted in a 100% or near 100% reduction in the levels of ESR1m at all time points. In contrast, although a reduction in ESR1m ctDNA was observed in the fulvestrant group, the degree of reduction was lower than that observed with camizestrant. Detailed implementation

[0039] Estrogen receptor-α is a recognized drug target in breast cancer, and ET is the main treatment modality. ET includes SERMs (such as tamoxifen), SERDs (fulvestrant), and AIs (such as non-steroidal AIs anastrozole and letrozole, and the steroidal AI exemestane). It is recognized that CDK4 / 6 inhibitors (palbociclib, ribociclib, or abemaciclib) enhance the efficacy of ET in untreated and previously treated HR+ / HER2− metastatic breast cancer (MBC) by prolonging progression-free survival (PFS) and overall survival (OS). Current treatment guidelines recommend the combination of an AI with a CDK4 / 6 inhibitor as the standard treatment in the first-line (1L) HR+ / HER2− MBC setting for most postmenopausal women in many regions, in combination with an LHRH agonist for premenopausal women, and preferably in combination with an LHRH agonist for men. As of the day of writing, three CDK4 / 6 inhibitors are approved for the treatment of HR+, HER2− breast cancer, namely palbociclib, abemaciclib, and ribociclib.

[0040] Unfortunately, most patients ultimately have cancer progression on CDK4 / 6 inhibitor + AI and die from their disease. Once patients progress on 1L CDK4 / 6 inhibitor-based therapy, subsequent endocrine-based therapies have limited efficacy and challenging tolerability profiles. Most patients may ultimately be treated with chemotherapy. Thus, improved therapies are needed for patients who progress after treatment with an AI and a CDK4 / 6i. Treatment of HR+, HER2− advanced breast cancer patients with CDK4 / 6 inhibitor resistance, whose tumors have estrogen receptor mutations (i.e., have an ESR1m status), or whose tumors have metastasized to the lung and / or liver (or have these and additional visceral metastases) is particularly challenging. One aim of the present specification is to provide new treatment options for such groups of patients.

[0041] In a first embodiment, the present specification provides a method of treating hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−), metastatic or locally regionally recurrent breast cancer, comprising administering to a patient suffering from such cancer a therapeutically effective amount of a next-generation selective estrogen receptor degrader (ngSERD), characterized in that the cancer has recurred or progressed after at least one prior line of endocrine therapy. In an embodiment, the prior endocrine therapy is selected from aromatase or SERM therapy, optionally wherein the prior treatment comprises administration of an aromatase inhibitor selected from anastrozole, letrozole, or exemestane and / or a selective estrogen receptor modulator (SERM) such as tamoxifen.

[0042] In a related embodiment, the present specification provides an ngSERD for treating HR+, HER2-metastatic or locally recurrent breast cancer, characterized in that the breast cancer has recurred or progressed after at least one prior line of endocrine therapy.

[0043] In a related embodiment, the present specification provides an ngSERD for manufacturing a medicament for treating HR+, HER2-, metastatic or locally recurrent breast cancer, wherein the medicament is for treating breast cancer that has recurred or progressed after at least one prior line of endocrine therapy. In a related embodiment, the present specification provides a kit that includes a medicament containing an ngSERD and instructions for using the pharmaceutical composition to treat HR+ / HER2-metastatic or locally recurrent breast cancer in a patient, wherein the cancer of the patient has recurred or progressed after at least one prior line of endocrine therapy.

[0044] In a related embodiment, the present specification provides a pharmaceutical composition that includes an ngSERD and at least one pharmaceutically acceptable excipient, and the pharmaceutical composition is for treating HR+ / HER2-metastatic or locally recurrent breast cancer in a patient, wherein the cancer of the patient has recurred or progressed after at least one prior line of endocrine therapy.

[0045] To avoid doubt, the embodiments provided below relate to further characterizing features of embodiments related to treatment methods, the ngSERDs used, the ngSERDs for manufacturing medicaments for treatment, kits and compositions for use in embodiments elsewhere in the present specification (such as those directly above), and their features can be incorporated into these general embodiments. For example, the reader will understand that an embodiment relating to a treatment method with certain characterizing features can continue reading to the ngSERD for treating the same condition in a patient with the same characterizing features and results, etc.

[0046] As described above, SERDs bind to the estrogen receptor, causing its degradation and thus downregulation. The first-generation SERD, fulvestrant, is administered by monthly injection, and it is hypothesized that next-generation oral SERDs may provide benefits for the treatment of HR+, HER2-breast cancer by providing a greater net degradation of the estrogen receptor and higher net systemic concentrations resulting from more frequent administration.

[0047] In embodiments, the ngSERD can be selected from camizestrant or a pharmaceutically acceptable salt thereof, giredestrant or a pharmaceutically acceptable salt thereof, imlunestrant or a pharmaceutically acceptable salt thereof, and elacestrant or a pharmaceutically acceptable salt thereof. In embodiments of the present specification, the ngSERD can be used in the form of a free base or in the form of a pharmaceutically acceptable salt or prodrug. The term "pharmaceutically acceptable" as used herein is used to indicate that an object (such as a salt, a dosage form [such as a tablet or capsule], or an excipient [such as a diluent or carrier]) is suitable for a patient. A list of examples of pharmaceutically acceptable salts can be found in "Handbook of Pharmaceutical Salts: Properties, Selection and Use", edited by P.H. Stahl and C.G. Wermuth, Weinheim / Zurich: Wiley-VCH / VFiCA, 2002 or subsequent editions.

[0048] In embodiments, the ngSERD is camizestrant or a pharmaceutically acceptable salt thereof.

[0049] In embodiments, the ngSERD is giredestrant or a pharmaceutically acceptable salt thereof.

[0050] In embodiments, the ngSERD is imlunestrant or a pharmaceutically acceptable salt thereof.

[0051] In embodiments, the ER PROTAC can be used in place of the ngSERD. In embodiments, the ER PROTAC can be ARV-471.

[0052] Camizestrant (AZD9833) has the following chemical structure:

[0053]

[0054] The chemical name of the free base of camizestrant is known to be N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)pyridin-3-amine. Camizestrant is disclosed in WO2018077630A1.

[0055] Giredestrant (GDC-9545) has the following chemical structure:

[0056]

[0057] The chemical name of the free base of giredestrant is known as 3-[(1R,3R)-1-[2,6-difluoro-4-[[1-(3-fluoropropyl)azetidin-3-yl]amino]phenyl]-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]-2,2-difluoropropan-1-ol. Giredestrant is disclosed in WO2016097072A1.

[0058] Elacestrant (LY-3484356) has the following chemical structure:

[0059]

[0060] The chemical name of the free base of elacestrant is known as (5R)-5-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-chromeno[4,3-c]quinolin-2-ol. Elacestrant is disclosed in WO2020014435.

[0061] ARV-471 (disclosed in WO2018102725) has the following chemical structure:

[0062]

[0063] In an embodiment, camizestrant or a pharmaceutically acceptable salt thereof is administered to a subject at a daily dose of 75 mg or 150 mg.

[0064] The nature of HR+, HER2-, metastatic or locally recurrent breast cancer can be further defined based on the prior treatment the patient has received, the mutational status of the cancer, the response characteristics of the cancer to prior endocrine therapy, or the presence of visceral metastases (such as the presence of metastases in the liver and / or lungs). Such parameters can be prognostic of response to treatment.

[0065] In embodiments of the present specification, the ngSERD for the treatment method, for use in treatment or for use in manufacturing the drug, kit or pharmaceutical composition delivered an improvement in time to disease progression or progression-free survival (PFS) relative to the time to disease progression or progression-free survival (PFS) obtained with fulvestrant (first-generation SERD). In such embodiments, the PFS improvement is relative to the improvement observed with standard treatment, i.e., fulvestrant administered monthly by injection at an approved dose of 500 mg. Clinical activity evaluated by PFS can be determined by the standard assessment of tumor response according to RECIST 1.1 (Eisenhauser et al., Eur J Cancer January 2009;45(2):228-47). The RECIST criteria can be evaluated by the attending physician / investigator or by a blinded independent central review (BICR).

[0066] In the SERENA-2 clinical trial (further details of which are provided below), the efficacy of administering camizestrant once daily as a treatment for patients with HR+, HER2− metastatic or locally recurrent breast cancer that has recurred or progressed after at least one prior line of endocrine therapy, in tablet form at doses of 75 mg and 150 mg, was evaluated. Patients in the control group in this study were treated with the standard therapy fulvestrant (first-generation SERD), a 500 mg injection once monthly. The study was dedicated to differentiating camizestrant and the standard therapy, fulvestrant (F), treatment groups, but not to differentiating the 75 mg and 150 mg camizestrant dose cohorts.

[0067] Fulvestrant, used as the standard therapy comparator group in this study, delivered a median PFS of 3.7 months (90% CI). In contrast, the 75 mg and 150 mg camizestrant groups delivered median PFS values of 7.2 months and 7.7 months (90% CI) and hazard ratios of 0.58 (p = 0.0124) and 0.67 (p = 0.0161), respectively, as determined by the investigators (see Figure 1 ). The proportions of patients without progression at 12 m for fulvestrant, 75 mg camizestrant, and 150 mg camizestrant were 23.8%, 34.3%, and 44.5%, respectively. It was thus determined that, in all patients in the clinical trial, relative to fulvestrant, both camizestrant treatment groups achieved a clinically meaningful improvement in PFS, independent of pre-treatment, estrogen receptor mutation status (ESR1m), or the presence of visceral metastases. In an embodiment, PFS according to the RECIST 1.1 criteria is determined by the attending physician or investigator.

[0068] When the PFS in the SERENA-2 study was evaluated by blinded independent central assessment according to the RECIST 1.1 criteria, fulvestrant (as used as the standard therapy comparator group in the study) delivered a median PFS of 3.7 months (90% CI). In contrast, the 75 mg and 150 mg camizestrant groups delivered median PFS values of 7.4 months and 12.7 months (90% CI) and hazard ratios of 0.56 (p = 0.0079) and 0.47 (p < 0.001), respectively, as determined by the BICR (see Figure 2 ).

[0069] Thus, the improvement in PFS observed by the investigators or the BICR under the RECIST 1.1 criteria indicates that, in both camizestrant groups (75 mg and 150 mg), the improvement in PFS in the overall patient population in the SERENA-2 study was at least 3.5 months. As noted above, the study was not dedicated to differentiating the camizestrant groups, but rather to differentiating the camizestrant treatment group and the fulvestrant group.

[0070] Accordingly, in embodiments, the present specification provides a method of treating hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), metastatic or locally recurrent breast cancer, comprising administering to a patient having such cancer a therapeutically effective amount of a next-generation selective estrogen receptor degrader (ngSERD), characterized in that the cancer has recurred or progressed after at least one prior line of endocrine therapy, wherein the method prolongs the time to disease progression as compared to that observed with fulvestrant treatment.

[0071] Accordingly, in embodiments, the present specification provides a method of treating hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), metastatic or locally recurrent breast cancer, comprising administering camizestrant to a patient having such cancer, characterized in that the cancer has recurred or progressed after at least one prior line of endocrine therapy, wherein the method prolongs the progression-free survival as compared to that observed with fulvestrant treatment.

[0072] In embodiments, the present specification provides a method of treating hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), metastatic or locally recurrent breast cancer, comprising administering to a patient having such cancer a therapeutically effective amount of camizestrant, characterized in that the cancer has recurred or progressed after at least one prior line of endocrine therapy, wherein the method prolongs the progression-free survival as compared to that observed with fulvestrant treatment, and wherein the hazard ratio for disease progression relative to fulvestrant is 0.67 or lower. In such embodiments, the hazard ratio for disease progression with camizestrant treatment relative to fulvestrant is 0.58 or lower, such as 0.56 or lower or 0.47 or lower. In the SERENA-2 trial detailed herein, the hazard ratios obtained with camizestrant treatment relative to fulvestrant were all statistically significant and were associated with a clinically meaningful improvement in progression-free survival as compared to that observed with standard therapy.

[0073] In embodiments, the present specification provides a method of treating hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), metastatic or locally recurrent breast cancer, comprising administering to a patient having such cancer a therapeutically effective amount of camizestrant, characterized in that the cancer has recurred or progressed after at least one prior line of endocrine therapy, wherein the time to disease progression is at least 5 months, such as 6 months or longer, 7 months or longer, 8 months or longer, 9 months or longer or 12 months or longer. The time to disease progression obtained with camizestrant treatment was statistically significant and represented a meaningful improvement as compared to that observed with standard treatment, the approved dose of fulvestrant.

[0074] Accordingly, in an embodiment, the present specification provides a method for treating hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), metastatic or locally recurrent breast cancer, comprising administering camizestrant to a patient having such cancer, characterized in that the cancer has recurred or progressed after at least one prior line of endocrine therapy, wherein camizestrant is administered once daily at a dose of 75 mg or 150 mg, and wherein the hazard ratio for disease progression from camizestrant treatment is 0.67 or lower, 0.58 or lower, 0.56 or lower, or 0.47 or lower relative to fulvestrant treatment.

[0075] In an embodiment, the present specification provides a method for treating hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), metastatic or locally recurrent breast cancer, comprising administering camizestrant to a patient having such cancer, characterized in that the cancer has recurred or progressed after at least one prior line of endocrine therapy, and wherein the median progression-free survival delivered by camizestrant treatment is at least 5 months, such as 6 months or longer, 7 months or longer, 8 months or longer, 9 months or longer, or 12 months or longer.

[0076] In an embodiment, the present specification provides a method for treating hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), metastatic or locally recurrent breast cancer, comprising administering camizestrant to a patient having such cancer, characterized in that the cancer has recurred or progressed after at least one prior line of endocrine therapy, wherein the method delivers an improvement in progression-free survival. In an embodiment, the improvement in progression-free survival is relative to that obtainable with fulvestrant treatment. In an embodiment, the prolongation of PFS from the use of camizestrant is at least 1 month relative to fulvestrant, such as 2 months or longer, 3 months or longer, or 4 months or longer.

[0077] In an embodiment, the present specification provides a method for treating hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), metastatic or locally recurrent breast cancer, comprising administering camizestrant to a patient having such cancer, characterized in that the cancer has recurred or progressed after at least one prior line of endocrine therapy, and wherein the median time to disease progression obtained from camizestrant treatment is prolonged by at least two months, optionally for a period of at least 3.5 months, relative to that observed with fulvestrant treatment.

[0078] In embodiments where the treatment method provides an improvement in PFS, disease progression was evaluated based on the RECIST 1.1 criteria. In embodiments, the evaluation of disease progression by the RECIST 1.1 criteria was performed by the investigator or the attending physician. In embodiments, the evaluation of disease progression by the RECIST 1.1 criteria was performed by a blinded independent central review (BICR).

[0079] In embodiments, at least one prior endocrine therapy line can be aromatase inhibitor therapy, i.e., treatment with anastrozole or letrozole or exemestane. In embodiments, at least one prior endocrine therapy line can be SERM therapy, optionally tamoxifen therapy.

[0080] In embodiments, the present specification provides a method of treating hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), metastatic or locally regionally recurrent breast cancer, comprising administering camizestrant to a patient having such cancer, characterized in that the cancer has recurred or progressed after at least one prior endocrine therapy line, and wherein the treatment delivers an improvement in overall survival.

[0081] In embodiments, the present specification provides a method of treating hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), metastatic or locally regionally recurrent breast cancer, comprising administering camizestrant to a patient having such cancer, characterized in that the cancer has recurred or progressed after at least one prior endocrine therapy line, wherein the treatment delivers an improvement in the objective response rate (ORR) relative to that obtainable with fulvestrant treatment. The ORR is defined as the percentage of patients with at least 1 investigator-assessed visit response with a complete response (CR) or partial response (PR) before any evidence of progression. The complete or partial response is evaluated according to the RECIST 1.1 criteria detailed below. In embodiments, the ORR derived from the treatment method is at least 15.7%, such as 20.3%. The ORR data obtained from the SERENA-2 study are provided in Table 1 below.

[0082] A complete response indicates the disappearance of all target lesions (TLs) from baseline. Any pathologic lymph node selected as a TL must have a short axis reduction of <10 mm. A partial response indicates a reduction in the sum of the TL diameters of at least 30%, referenced to the sum of the baseline diameters. Other evaluations of target lesions include stable disease (SD), which indicates neither sufficient shrinkage to meet the requirements for PR nor sufficient increase to meet the requirements for progressive disease (PD), and progressive disease, which indicates at least a 20% increase in the sum of the TL diameters, referenced to the smallest sum in the study (if this is the smallest in the study, this includes the baseline sum), and in addition to the 20% relative increase, the sum must demonstrate an absolute increase of at least 5 mm. Further information regarding the evaluation of target and non-target lesions is provided below.

[0083] Table 1: Objective Response Rate, Patients with Measurable Disease 。

[0084]

[0085] In an embodiment, the present specification provides a method for treating hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), metastatic or locally recurrent breast cancer, comprising administering camizestrant to a patient having such cancer, characterized in that the cancer has recurred or progressed after at least one prior endocrine treatment line, and wherein the treatment delivers an improvement in the 24-week clinical benefit rate (CBR 24 ) relative to that obtained from fulvestrant treatment.

[0086] In an embodiment, the present specification provides a method for treating hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), metastatic or locally recurrent breast cancer, comprising administering camizestrant to a patient having such cancer, characterized in that the cancer has recurred or progressed after at least one prior endocrine treatment line, and wherein the treatment delivers at least 48%, such as 52%, of the 24-week clinical benefit rate (CBR 24 ).

[0087] CBR 24 is defined as the percentage of patients having a best objective response (BoR) of CR or PR within the first 25 weeks (to allow for later assessment within the evaluation window) or having SD (without subsequent cancer treatment) at least 23 weeks after the start of treatment (to allow for early assessment within the evaluation window). CBR is defined based on the investigator's assessment of RECIST 1.1.

[0088] Table 2: 24-week Clinical Benefit Rate (CBR 24 )

[0089]

[0090] In an embodiment, the present specification provides a method for treating hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), metastatic or locally recurrent breast cancer, comprising administering camizestrant to a patient having such cancer, characterized in that the cancer has recurred or progressed after at least one prior line of endocrine therapy and one prior line of therapy with a CDK4 / 6 inhibitor. In an embodiment, the patient's disease has recurred or progressed after treatment with palbociclib. In an embodiment, the patient's disease has recurred or progressed after treatment with abemaciclib. In an embodiment, the patient's disease has recurred or progressed after treatment with ribociclib.

[0091] In an embodiment, the present specification provides a method for treating hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), metastatic or locally recurrent breast cancer, comprising administering camizestrant to a patient having such cancer, characterized in that the cancer has recurred or progressed after at least one prior line of endocrine therapy and one prior line of therapy with a CDK4 / 6 inhibitor, wherein the median time to progression is extended by at least three months relative to that observed with fulvestrant treatment.

[0092] In an embodiment, the present specification provides a method for treating hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), metastatic or locally recurrent breast cancer, comprising administering camizestrant to a patient in need thereof, characterized in that the patient's cancer has recurred or progressed after at least one prior line of endocrine therapy and one prior line of therapy with a CDK4 / 6 inhibitor, wherein the hazard ratio for disease progression from camizestrant treatment is 0.68 or less, such as 0.49, relative to fulvestrant treatment.

[0093] In an embodiment, the present specification provides a method for treating hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), metastatic or locally recurrent breast cancer, comprising administering camizestrant to a patient in need thereof, characterized in that the patient's cancer has recurred or progressed after at least one prior line of endocrine therapy and one prior line of therapy with a CDK4 / 6 inhibitor, wherein the time to disease progression is at least 3.8 months, such as 5.8 months.

[0094] Table 3: Progression-free survival of patients with a disease that has progressed or recurred after at least one prior line of endocrine therapy and one prior line of therapy with a CDK4 / 6 inhibitor

[0095] n = the number of patients with the said characteristics in each group

[0096] In an embodiment, the present specification provides a method for treating hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), metastatic or locally recurrent breast cancer, comprising administering camizestrant to a patient having such cancer, wherein the cancer has recurred or progressed after at least one prior endocrine therapy line and one prior chemotherapy treatment line.

[0097] In an embodiment, the present specification provides a method for treating hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), metastatic or locally recurrent breast cancer, comprising administering camizestrant to a patient having such cancer, wherein the cancer has not been previously treated with fulvestrant, any other oral SERD, or any related therapy (e.g., ER proteolysis targeting chimera [PROTAC] and / or selective ER covalent antagonist [SERCA] in a metastatic setting).

[0098] In an embodiment, the present specification provides a method for treating hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), metastatic or locally recurrent breast cancer, comprising administering camizestrant to a patient having such cancer, wherein the cancer has recurred or progressed after at least one prior endocrine therapy line and the patient has visceral metastases prior to initiation of camizestrant treatment.

[0099] In an embodiment, the present specification provides a method for treating hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), metastatic or locally recurrent breast cancer, comprising administering camizestrant to a patient having such cancer, wherein the cancer has recurred or progressed after at least one prior endocrine therapy line and the patient has been identified as having metastases to the liver and / or lungs prior to initiation of camizestrant treatment.

[0100] In an embodiment, the present specification provides a method for treating hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), metastatic or locally recurrent breast cancer, comprising administering camizestrant to a patient having such cancer, wherein the cancer has recurred or progressed after at least one prior endocrine therapy line and the patient has been identified as having metastases to the liver and / or lungs prior to initiation of camizestrant treatment, wherein the median time to progression is extended by at least three months relative to that observed with fulvestrant treatment, e.g., extended by 3.6 months or 5.2 months.

[0101] In an embodiment, the present specification provides a method for treating hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), metastatic or locally recurrent breast cancer, comprising administering camizestrant to a patient suffering from such cancer, characterized in that the cancer has recurred or progressed after at least one prior endocrine therapy line, and the patient has been identified as having metastases to the liver and / or lungs before initiation of camizestrant treatment, wherein the hazard ratio of disease progression from camizestrant treatment is 0.55 or less, such as 0.43, relative to fulvestrant treatment.

[0102] In an embodiment, the present specification provides a method for treating hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), metastatic or locally recurrent breast cancer, comprising administering camizestrant to a patient suffering from such cancer, characterized in that the cancer has recurred or progressed after at least one prior endocrine therapy line, and the patient has been identified as having metastases to the liver and / or lungs before initiation of camizestrant treatment, wherein the time to disease progression is at least 5.6 months, such as 7.2 months.

[0103] Table 4: Progression-Free Survival of Patients with a Disease that has progressed or recurred after at least one prior line of endocrine therapy and has had metastases to the liver and / or lungs prior to initiation of treatment with camizestrant

[0104]

[0105] In an embodiment, the present specification provides a method for treating hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), metastatic or locally recurrent breast cancer, comprising administering camizestrant to a patient suffering from such cancer, characterized in that the cancer has recurred or progressed after at least one prior endocrine therapy line, and the patient has been identified as having estrogen receptor mutant breast cancer. In an embodiment, the estrogen receptor mutations are selected from E380Q, V422del, S463P, L536H, L536P, L536R, Y537C, Y537D, Y537N, Y537S, and D538G.

[0106] In an embodiment, the present specification provides a method for treating hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), metastatic or locally recurrent breast cancer, comprising administering camizestrant to a patient suffering from such cancer, characterized in that the cancer has recurred or progressed after at least one prior endocrine therapy line, and the cancer has been identified as expressing ESR1m.

[0107] In an embodiment, the present specification provides a method for treating hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), metastatic or locally recurrent breast cancer, comprising administering camizestrant to a patient suffering from such cancer, characterized in that the cancer has recurred or progressed after at least one prior line of endocrine therapy, and the patient has been identified as having ESR1m breast cancer, wherein the median time to disease progression is extended by at least three months relative to that observed with fulvestrant treatment, for example, extended by 4.1 months or 7.0 months.

[0108] In an embodiment, the present specification provides a method for treating hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), metastatic or locally recurrent breast cancer, comprising administering camizestrant to a patient suffering from such cancer, characterized in that the cancer has recurred or progressed after at least one prior line of endocrine therapy, and the patient has been identified as having ESR1m breast cancer, wherein the hazard ratio of disease progression from camizestrant treatment is 0.55 or less relative to fulvestrant treatment, for example, 0.33.

[0109] In an embodiment, the present specification provides a method for treating hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), metastatic or locally recurrent breast cancer, comprising administering camizestrant to a patient suffering from such cancer, characterized in that the cancer has recurred or progressed after at least one prior line of endocrine therapy, and the patient has been identified as having ESR1m breast cancer, wherein the time to disease progression is at least 6.3 months, for example, 9.2 months.

[0110] In an embodiment, the presence of estrogen receptor mutations in the patient's cancer or the identification of the ESR1m status of breast cancer is based on a circulating tumor DNA test. In an embodiment, the presence of estrogen receptor mutations in the patient's cancer or the identification of the ESR1m status of breast cancer is based on the analysis of the presence of ESR1m in a tumor biopsy.

[0111] Table 5: Progression-Free Survival of Patients with a Disease that has progressed or recurred after at least one prior line of endocrine therapy, and the patient has breast cancer with estrogen receptor mutations 。

[0112]

[0113]

[0114] In one embodiment, the present specification provides an ngSERD (such as camizestrant or a pharmaceutically acceptable salt thereof, which is optionally orally administered once daily at a dose of 75 mg or 150 mg) for the treatment of HR+, HER2-metastatic or locally recurrent breast cancer, characterized in that the breast cancer has recurred or progressed after at least one prior line of endocrine therapy.

[0115] In one embodiment, the present specification provides an ngSERD (such as camizestrant or a pharmaceutically acceptable salt thereof, which is optionally orally administered once daily at a dose of 75 mg or 150 mg) for the treatment of HR+, HER2-metastatic or locally recurrent breast cancer, characterized in that the breast cancer has recurred or progressed after at least one prior line of endocrine therapy, and:

[0116] a) The use delivers an improvement in the median time to disease progression of at least 3.5 months compared to that observed with fulvestrant treatment; and / or

[0117] b) The hazard ratio of ngSERD treatment is less than or equal to 0.67 compared to fulvestrant treatment;

[0118] and / or

[0119] c) The use delivers a median time to disease progression of at least 7 months.

[0120] In one embodiment, the present specification provides an ngSERD (such as camizestrant or a pharmaceutically acceptable salt thereof, which is optionally orally administered once daily at a dose of 75 mg or 150 mg) for the treatment of HR+, HER2-metastatic or locally recurrent breast cancer, characterized in that the breast cancer has recurred or progressed after at least one prior line of endocrine therapy and at least one prior line of treatment with a CDK4 / 6 inhibitor.

[0121] In one embodiment, the present specification provides an ngSERD (such as camizestrant or a pharmaceutically acceptable salt thereof, which is optionally orally administered once daily at a dose of 75 mg or 150 mg) for the treatment of HR+, HER2-metastatic or locally recurrent breast cancer, characterized in that the breast cancer has recurred or progressed after at least one prior line of endocrine therapy and at least one prior line of treatment with a CDK4 / 6 inhibitor, and:

[0122] a) The use delivers an improvement in the median time to disease progression that is at least 1.7 months more than that observed with fulvestrant treatment; and / or

[0123] b) The hazard ratio of ngSERD treatment is less than or equal to 0.68 compared to fulvestrant treatment;

[0124] and / or

[0125] c) The use delivers a median time to disease progression of at least 3.8 months.

[0126] In one embodiment, the present specification provides an ngSERD (such as camizestrant or a pharmaceutically acceptable salt thereof, which is optionally orally administered once daily at a dose of 75 mg or 150 mg) for treating HR+, HER2-metastatic or locally recurrent breast cancer, characterized in that the breast cancer has recurred or progressed after at least one prior line of endocrine therapy and the cancer has been identified as having visceral metastases.

[0127] In one embodiment, the present specification provides an ngSERD (such as camizestrant or a pharmaceutically acceptable salt thereof, which is optionally orally administered once daily at a dose of 75 mg or 150 mg) for treating HR+, HER2-metastatic or locally recurrent breast cancer, characterized in that the breast cancer has recurred or progressed after at least one prior line of endocrine therapy and the cancer has been identified as having visceral metastases, and:

[0128] a) The use delivers an improvement in median time to disease progression of at least 3.6 months more than that observed with treatment with fulvestrant; and / or

[0129] b) The hazard ratio for ngSERD treatment is less than or equal to 0.55 relative to fulvestrant treatment;

[0130] and / or

[0131] c) The use delivers a median time to disease progression of at least 5.6 months.

[0132] In one embodiment, the present specification provides an ngSERD (such as camizestrant or a pharmaceutically acceptable salt thereof, which is optionally orally administered once daily at a dose of 75 mg or 150 mg) for treating HR+, HER2-metastatic or locally recurrent breast cancer, characterized in that the breast cancer has recurred or progressed after at least one prior line of endocrine therapy, and wherein the cancer has been identified as having a mutation in the estrogen receptor (such as estrogen receptor mutations selected from E380Q, V422del, S463P, L536H, L536P, L536R, Y537C, Y537D, Y537N, Y537S and D538G).

[0133] In one embodiment, the present specification provides an ngSERD (such as camizestrant or a pharmaceutically acceptable salt thereof, which is optionally orally administered once daily at a dose of 75 mg or 150 mg) for the treatment of HR+, HER2-metastatic or locally recurrent breast cancer, characterized in that the breast cancer has recurred or progressed after at least one prior line of endocrine therapy, and wherein the cancer has been identified as having a mutation in the estrogen receptor (such as an estrogen receptor mutation selected from E380Q, V422del, S463P, L536H, L536P, L536R, Y537C, Y537D, Y537N, Y537S, and D538G) based on testing of a sample obtained from the patient (such as where the sample is a tumor biopsy or a blood sample) (such as testing by analysis of circulating tumor DNA).

[0134] In one embodiment, the present specification provides an ngSERD (such as camizestrant or a pharmaceutically acceptable salt thereof, which is optionally orally administered once daily at a dose of 75 mg or 150 mg) for the treatment of HR+, HER2-metastatic or locally recurrent breast cancer, characterized in that the breast cancer has recurred or progressed after at least one prior line of endocrine therapy, and the use improves overall survival relative to treatment with fulvestrant.

[0135] In one embodiment, the present specification provides camizestrant or a pharmaceutically acceptable salt thereof for the treatment of HR+, HER2-, metastatic or locally recurrent breast cancer, characterized in that the cancer has recurred or progressed after at least one prior line of endocrine therapy, wherein:

[0136] a) The use delivers an improvement in the median time to disease progression of at least 3.5 months relative to that observed with treatment with fulvestrant; and / or

[0137] b) The hazard ratio for treatment with camizestrant is less than or equal to 0.67 relative to fulvestrant treatment; and / or

[0138] c) The use delivers a median time to disease progression of at least 7 months.

[0139] In one embodiment, the present specification provides an ngSERD (such as camizestrant or a pharmaceutically acceptable salt thereof, which is optionally orally administered once daily in an amount of 75 mg or 150 mg) for manufacturing a medicament for the treatment of HR+, HER2-, metastatic or locally recurrent breast cancer, wherein the medicament is for the treatment of breast cancer that has recurred or progressed after at least one prior line of endocrine therapy.

[0140] In one embodiment, the present specification provides an ngSERD for manufacturing a medicament for treating HR+, HER2-metastatic or locally recurrent breast cancer (such as camizestrant or a pharmaceutically acceptable salt thereof, which is optionally orally administered once daily at a dose of 75 mg or 150 mg), characterized in that the breast cancer has recurred or progressed after at least one prior line of endocrine therapy, and wherein the medicament for use delivers:

[0141] a) an improvement in the median time to disease progression of at least 3.5 months relative to that observed with fulvestrant treatment; and / or

[0142] b) a hazard ratio of less than or equal to 0.67 for ngSERD treatment relative to fulvestrant treatment;

[0143] and / or

[0144] c) a median time to disease progression of at least 7 months.

[0145] In one embodiment, the present specification provides an ngSERD for manufacturing a medicament for treating HR+, HER2-metastatic or locally recurrent breast cancer (such as camizestrant or a pharmaceutically acceptable salt thereof, which is optionally orally administered once daily at a dose of 75 mg or 150 mg), characterized in that the breast cancer has recurred or progressed after at least one prior line of endocrine therapy and at least one prior line of treatment with a CDK4 / 6 inhibitor.

[0146] In one embodiment, the present specification provides an ngSERD for manufacturing a medicament for treating HR+, HER2-metastatic or locally recurrent breast cancer (such as camizestrant or a pharmaceutically acceptable salt thereof, which is optionally orally administered once daily at a dose of 75 mg or 150 mg), characterized in that the breast cancer has recurred or progressed after at least one prior line of endocrine therapy and at least one prior line of treatment with a CDK4 / 6 inhibitor, and wherein the medicament for use delivers:

[0147] a) an improvement in the median time to disease progression of at least 1.7 months more than that observed with fulvestrant treatment; and / or

[0148] b) a hazard ratio of less than or equal to 0.68 for ngSERD treatment relative to fulvestrant treatment; and / or

[0149] c) a median time to disease progression of at least 3.8 months.

[0150] In one embodiment, the present specification provides an ngSERD for manufacturing a medicament for treating HR+, HER2-metastatic or locally recurrent breast cancer (such as camizestrant or a pharmaceutically acceptable salt thereof, which is optionally orally administered once daily at a dose of 75 mg or 150 mg), characterized in that the breast cancer has recurred or progressed after at least one prior endocrine therapy line and the cancer has been identified as having visceral metastases.

[0151] In one embodiment, the present specification provides an ngSERD for manufacturing a medicament for treating HR+, HER2-metastatic or locally recurrent breast cancer (such as camizestrant or a pharmaceutically acceptable salt thereof, which is optionally orally administered once daily at a dose of 75 mg or 150 mg), characterized in that the breast cancer has recurred or progressed after at least one prior endocrine therapy line and the cancer has been identified as having visceral metastases, and wherein the drug delivery for use:

[0152] a) an improvement in the median time to disease progression of at least 3.6 months more than that observed with fulvestrant treatment; and / or

[0153] b) a hazard ratio of less than or equal to 0.55 for ngSERD treatment relative to fulvestrant treatment; and / or

[0154] c) a median time to disease progression of at least 5.6 months.

[0155] In one embodiment, the present specification provides an ngSERD for manufacturing a medicament for treating HR+, HER2-metastatic or locally recurrent breast cancer (such as camizestrant or a pharmaceutically acceptable salt thereof, which is optionally orally administered once daily at a dose of 75 mg or 150 mg), characterized in that the breast cancer has recurred or progressed after at least one prior endocrine therapy line, and wherein the cancer has been identified as having a mutation in the estrogen receptor (such as estrogen receptor mutations selected from E380Q, V422del, S463P, L536H, L536P, L536R, Y537C, Y537D, Y537N, Y537S and D538G).

[0156] In one embodiment, the present specification provides an ngSERD for manufacturing a medicament for treating HR+, HER2− metastatic or locally recurrent breast cancer (such as camizestrant or a pharmaceutically acceptable salt thereof, which is optionally orally administered once daily at a dose of 75 mg or 150 mg), characterized in that the breast cancer has recurred or progressed after at least one prior line of endocrine therapy, and wherein the cancer has been identified as having a mutation in the estrogen receptor (such as an estrogen receptor mutation selected from E380Q, V422del, S463P, L536H, L536P, L536R, Y537C, Y537D, Y537N, Y537S, and D538G) based on testing of a sample obtained from the patient (such as where the sample is a tumor biopsy or a blood sample) (such as testing by analysis of circulating tumor DNA).

[0157] In one embodiment, the present specification provides an ngSERD for manufacturing a medicament for treating HR+, HER2− metastatic or locally recurrent breast cancer (such as camizestrant or a pharmaceutically acceptable salt thereof, which is optionally orally administered once daily at a dose of 75 mg or 150 mg), characterized in that the breast cancer has recurred or progressed after at least one prior line of endocrine therapy, and that the use improves overall survival relative to treatment with fulvestrant.

[0158] In one embodiment, the present specification provides an ngSERD for manufacturing a medicament for treating HR+, HER2− metastatic or locally recurrent breast cancer (such as camizestrant or a pharmaceutically acceptable salt thereof, which is optionally orally administered once daily at a dose of 75 mg or 150 mg), characterized in that the cancer has recurred or progressed after at least one prior line of endocrine therapy, and wherein the drug delivery for use:

[0159] a) an improvement in the median time to disease progression of at least 3.5 months relative to that observed with treatment with fulvestrant; and / or

[0160] b) a hazard ratio of less than or equal to 0.67 for treatment with camizestrant relative to fulvestrant treatment; and / or

[0161] c) a median time to disease progression of at least 7 months.

[0162] In one embodiment, there is provided a pharmaceutical composition for treating HR+, human epidermal growth factor receptor 2 negative (HER2-), metastatic or locally recurrent breast cancer, the pharmaceutical composition comprising an ngSERD (such as camizestrant or a pharmaceutically acceptable salt thereof, which is optionally orally administered once daily at a dose of 75 mg or 150 mg) and at least one pharmaceutically acceptable excipient, characterized in that the cancer has recurred or progressed after at least one prior line of endocrine therapy.

[0163] In one embodiment, there is provided a pharmaceutical composition for treating HR+, human epidermal growth factor receptor 2 negative (HER2-), metastatic or locally recurrent breast cancer, the pharmaceutical composition comprising an ngSERD (such as camizestrant or a pharmaceutically acceptable salt thereof, which is optionally orally administered once daily at a dose of 75 mg or 150 mg) and at least one pharmaceutically acceptable excipient, characterized in that the breast cancer has recurred or progressed after at least one prior line of endocrine therapy, and:

[0164] a) the use delivers an improvement in the median time to disease progression of at least 3.5 months more than that observed with treatment with fulvestrant; and / or

[0165] b) the hazard ratio for ngSERD treatment is less than or equal to 0.67 relative to fulvestrant treatment;

[0166] and / or

[0167] c) the use delivers a median time to disease progression of at least 7 months.

[0168] In one embodiment, there is provided a pharmaceutical composition for treating HR+, human epidermal growth factor receptor 2 negative (HER2-), metastatic or locally recurrent breast cancer, the pharmaceutical composition comprising an ngSERD (such as camizestrant or a pharmaceutically acceptable salt thereof, which is optionally orally administered once daily at a dose of 75 mg or 150 mg) and at least one pharmaceutically acceptable excipient, characterized in that the breast cancer has recurred or progressed after at least one prior line of endocrine therapy and at least one prior line of treatment with a CDK4 / 6 inhibitor.

[0169] In one embodiment, there is provided a pharmaceutical composition for treating HR+, human epidermal growth factor receptor 2 negative (HER2-), metastatic or locally recurrent breast cancer, the pharmaceutical composition comprising an ngSERD (such as camizestrant or a pharmaceutically acceptable salt thereof, which is optionally orally administered once daily at a dose of 75 mg or 150 mg) and at least one pharmaceutically acceptable excipient, characterized in that the breast cancer has recurred or progressed after at least one prior line of endocrine therapy and at least one prior line of therapy with a CDK4 / 6 inhibitor, and:

[0170] a) the use delivers an improvement in the median time to disease progression of at least 1.7 months more than that observed with treatment with fulvestrant; and / or

[0171] b) the hazard ratio for ngSERD treatment is less than or equal to 0.68 relative to fulvestrant treatment;

[0172] and / or

[0173] c) the use delivers a median time to disease progression of at least 3.8 months.

[0174] In one embodiment, there is provided a pharmaceutical composition for treating HR+, human epidermal growth factor receptor 2 negative (HER2-), metastatic or locally recurrent breast cancer, the pharmaceutical composition comprising an ngSERD (such as camizestrant or a pharmaceutically acceptable salt thereof, which is optionally orally administered once daily at a dose of 75 mg or 150 mg) and at least one pharmaceutically acceptable excipient, characterized in that the breast cancer has recurred or progressed after at least one prior line of endocrine therapy and the cancer has been identified as having visceral metastases.

[0175] In one embodiment, there is provided a pharmaceutical composition for treating HR+, human epidermal growth factor receptor 2 negative (HER2-), metastatic or locally recurrent breast cancer, the pharmaceutical composition comprising an ngSERD (such as camizestrant or a pharmaceutically acceptable salt thereof, which is optionally orally administered once daily at a dose of 75 mg or 150 mg) and at least one pharmaceutically acceptable excipient, characterized in that the breast cancer has recurred or progressed after at least one prior line of endocrine therapy and the cancer has been identified as having visceral metastases, and:

[0176] a) the use delivers an improvement in the median time to disease progression of at least 3.6 months more than that observed with treatment with fulvestrant; and / or

[0177] b) the hazard ratio for ngSERD treatment is less than or equal to 0.55 relative to fulvestrant treatment;

[0178] and / or

[0179] c) This use delivers a median time to disease progression of at least 5.6 months.

[0180] In one embodiment, there is provided a pharmaceutical composition for treating HR+, human epidermal growth factor receptor 2 negative (HER2-), metastatic or locally recurrent breast cancer, the pharmaceutical composition comprising an ngSERD (such as camizestrant or a pharmaceutically acceptable salt thereof, which is optionally orally administered once daily at a dose of 75 mg or 150 mg) and at least one pharmaceutically acceptable excipient, characterized in that the breast cancer has recurred or progressed after at least one prior line of endocrine therapy, and wherein the cancer has been identified as having a mutation in the estrogen receptor (such as an estrogen receptor mutation selected from E380Q, V422del, S463P, L536H, L536P, L536R, Y537C, Y537D, Y537N, Y537S, and D538G).

[0181] In one embodiment, there is provided a pharmaceutical composition for treating HR+, human epidermal growth factor receptor 2 negative (HER2-), metastatic or locally recurrent breast cancer, the pharmaceutical composition comprising an ngSERD (such as camizestrant or a pharmaceutically acceptable salt thereof, which is optionally orally administered once daily at a dose of 75 mg or 150 mg) and at least one pharmaceutically acceptable excipient, characterized in that the breast cancer has recurred or progressed after at least one prior line of endocrine therapy, and wherein the cancer has been identified as having a mutation in the estrogen receptor (such as an estrogen receptor mutation selected from E380Q, V422del, S463P, L536H, L536P, L536R, Y537C, Y537D, Y537N, Y537S, and D538G) based on testing of a sample obtained from the patient (such as where the sample is a tumor biopsy or a blood sample) (such as testing by analysis of circulating tumor DNA).

[0182] In one embodiment, there is provided a pharmaceutical composition for treating HR+, human epidermal growth factor receptor 2 negative (HER2-), metastatic or locally recurrent breast cancer, the pharmaceutical composition comprising an ngSERD (such as camizestrant or a pharmaceutically acceptable salt thereof, which is optionally orally administered once daily at a dose of 75 mg or 150 mg) and at least one pharmaceutically acceptable excipient, characterized in that the breast cancer has recurred or progressed after at least one prior line of endocrine therapy, and that this use improves overall survival relative to treatment with fulvestrant.

[0183] In one embodiment, a pharmaceutical composition for treating HR+, human epidermal growth factor receptor 2 negative (HER2-), metastatic or locally recurrent breast cancer is provided. The pharmaceutical composition comprises an ngSERD (such as camizestrant or a pharmaceutically acceptable salt thereof, which is optionally orally administered once daily at a dose of 75 mg or 150 mg) and at least one pharmaceutically acceptable excipient, characterized in that the cancer has recurred or progressed after at least one prior line of endocrine therapy, wherein:

[0184] a) relative to that observed with fulvestrant treatment, the use delivers an improvement in the median time to disease progression of at least 3.5 months; and / or

[0185] b) relative to fulvestrant treatment, the hazard ratio for treatment with camizestrant is less than or equal to 0.67; and / or

[0186] c) the use delivers a median time to disease progression of at least 7 months.

[0187] In one embodiment, a kit is provided that comprises a medicament containing an ngSERD and instructions for using the pharmaceutical composition to treat HR+ / HER2- metastatic or locally recurrent breast cancer in a patient whose cancer has recurred or progressed after at least one prior line of endocrine therapy.

[0188] In one embodiment, a kit is provided that comprises a medicament containing an ngSERD and instructions for using the pharmaceutical composition to treat HR+ / HER2- metastatic or locally recurrent breast cancer, characterized in that the cancer has recurred or progressed after at least one prior line of endocrine therapy, wherein the use of the kit delivers:

[0189] a) a median time to disease progression that is at least 3.5 months more than that observed with fulvestrant treatment; and / or

[0190] b) relative to fulvestrant treatment, the hazard ratio for ngSERD treatment is less than or equal to 0.67;

[0191] and / or

[0192] c) a median time to disease progression of at least 7 months.

[0193] In one embodiment, a kit is provided that comprises a medicament containing an ngSERD and instructions for using the pharmaceutical composition to treat HR+ / HER2- metastatic or locally recurrent breast cancer in a patient whose cancer has recurred or progressed after at least one prior line of endocrine therapy and at least one prior line of treatment with a CDK4 / 6 inhibitor.

[0194] In one embodiment, a kit is provided that includes a drug containing ngSERD and instructions for using the pharmaceutical composition to treat HR+ / HER2− metastatic or locally recurrent breast cancer, characterized in that the cancer has recurred or progressed after at least one prior line of endocrine therapy, wherein the use of the kit delivers:

[0195] a) The median time to disease progression is at least 1.7 months more than that observed with fulvestrant treatment; and / or

[0196] b) The hazard ratio for ngSERD treatment is less than or equal to 0.68 relative to fulvestrant treatment;

[0197] and / or

[0198] c) The median time to disease progression is at least 3.8 months.

[0199] In one embodiment, a kit is provided that includes a drug containing ngSERD and instructions for using the pharmaceutical composition to treat HR+ / HER2− metastatic or locally recurrent breast cancer in a patient, the cancer of which has recurred or progressed after at least one prior line of endocrine therapy and the cancer has been identified as having visceral metastases.

[0200] In one embodiment, a kit is provided that includes a drug containing ngSERD and instructions for using the pharmaceutical composition to treat HR+ / HER2− metastatic or locally recurrent breast cancer, characterized in that the cancer has recurred or progressed after at least one prior line of endocrine therapy, wherein the use of the kit delivers:

[0201] a) The median time to disease progression is at least 3.6 months more than that observed with fulvestrant treatment; and / or

[0202] b) The hazard ratio for ngSERD treatment is less than or equal to 0.55 relative to fulvestrant treatment;

[0203] and / or

[0204] c) The median time to disease progression is at least 5.6 months.

[0205] In one embodiment, a kit is provided that includes a drug containing ngSERD and instructions for using the pharmaceutical composition to treat HR+ / HER2-metastatic or locally recurrent breast cancer in a patient whose cancer has recurred or progressed after at least one prior line of endocrine therapy and whose cancer has been identified as having a mutation in the estrogen receptor (such as an estrogen receptor mutation selected from E380Q, V422del, S463P, L536H, L536P, L536R, Y537C, Y537D, Y537N, Y537S, and D538G).

[0206] In one embodiment, a kit is provided that includes a drug containing ngSERD and instructions for using the pharmaceutical composition to treat HR+ / HER2-metastatic or locally recurrent breast cancer in a patient whose cancer has recurred or progressed after at least one prior line of endocrine therapy and whose cancer has been identified as having a mutation in the estrogen receptor (such as an estrogen receptor mutation selected from E380Q, V422del, S463P, L536H, L536P, L536R, Y537C, Y537D, Y537N, Y537S, and D538G) based on testing (such as testing by analyzing circulating tumor DNA) of a sample obtained from the patient (such as where the sample is a tumor biopsy or a blood sample).

[0207] In one embodiment, a kit is provided that includes a drug containing ngSERD and instructions for using the pharmaceutical composition to treat HR+ / HER2-metastatic or locally recurrent breast cancer in a patient whose cancer has recurred or progressed after at least one prior line of endocrine therapy, and wherein the use improves overall survival relative to treatment with fulvestrant.

[0208] In one embodiment, a pharmaceutical composition for treating HR+, human epidermal growth factor receptor 2 negative (HER2-), metastatic or locally recurrent breast cancer is provided, the pharmaceutical composition comprising ngSERD (such as camizestrant or a pharmaceutically acceptable salt thereof, which is optionally orally administered once daily at a dose of 75 mg or 150 mg) and at least one pharmaceutically acceptable excipient, characterized in that the cancer has recurred or progressed after at least one prior line of endocrine therapy, wherein the use of the kit delivers:

[0209] a) an improvement in the median time to disease progression of 3.5 months relative to that observed with treatment with fulvestrant; and / or

[0210] b) a hazard ratio for treatment with camizestrant less than or equal to 0.67 relative to fulvestrant treatment; and / or

[0211] c) The use delivers a median time to disease progression of at least 7 months.

[0212] In one embodiment, a kit is provided that comprises a pharmaceutical composition containing camizestrant and at least one pharmaceutically acceptable excipient, and instructions for using the pharmaceutical composition to treat HR+, HER2−, metastatic or locally recurrent breast cancer, wherein the cancer has recurred or progressed after at least one prior line of endocrine therapy, and wherein the use of the kit delivers:

[0213] a) An improvement in the median time to disease progression of 3.5 months relative to that observed with fulvestrant treatment; and / or

[0214] b) A hazard ratio of less than or equal to 0.67 for treatment with camizestrant relative to fulvestrant treatment; and / or

[0215] c) A median time to disease progression of at least 7 months.

[0216] Further details of the SERENA-2 clinical trial protocol are provided below. The trial began with three doses of camizestrant (AZD9833), namely 75 mg, 150 mg, and 300 mg, but only 20 patients were recruited in the 300 mg group before it was stopped. Therefore, no results are provided for the 300 mg group.

[0217] Examples

[0218] Abbreviations。B = Blood; BoR = Best Objective Response; CA15-3 = Cancer Antigen 15-3; BICR = Blind Independent Central Review; CBR24 = Clinical Benefit Rate at 24 Weeks; CSP = Clinical Study Protocol; CTC = Circulating Tumor Cells; ctDNA = Circulating Tumor DNA; Cx = Cycle x; Dx = Day x; DoR = Duration of Response; ECG = Electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EORTC = European Organization for Research and Treatment of Cancer; EORTC QLQ BR23 = EORTC Quality of Life Questionnaire - Breast Cancer Module; EORTC QLQ C30 = EORTC Quality of Life Questionnaire - Core Questionnaire, EOT = End of Treatment; EQ 5D 5L = European Five-Dimension Five-Level Health Scale; HRQoL = Health-Related Quality of Life; ICF = Informed Consent Form; IM = Intramuscular; ITT = Intention to Treat; NEI VFQ-25 = National Eye Institute Visual Function Questionnaire 25-Item; ORR = Objective Response Rate; OS = Overall Survival; PFS = Progression-Free Survival; PGI-BR = Patient's Global Impression of Benefit-Risk; PGIC = Patient's Global Impression of Change; PGIS = Patient's Global Impression of Severity; PGI TT = Patient's Global Impression of Tolerability to Treatment; PgR = Progesterone Receptor; PK = Pharmacokinetics; PO = Oral (by mouth); PRO = Patient-Reported Outcome; RECIST = Response Evaluation Criteria in Solid Tumors; SAE = Serious Adverse Event; SRC = Safety Review Committee; U = Urine; ULN = Upper Limit of Normal; WHO = World Health Organization.

[0219] Summary of the Invention 。

[0220] A randomized, open-label, parallel-group, multicenter phase 2 study was conducted according to the following protocol and activity plan to compare the efficacy and safety of oral AZD9833 with fulvestrant in women with advanced estrogen receptor-positive, HER2-negative breast cancer. The study evaluated the efficacy and safety of AZD9833 (75 mg, 150 mg, and 300 mg, orally [PO]) administered once daily as a single therapy compared with fulvestrant administered according to its label (i.e., by slow IM injection into the buttocks in two 5 mL injections (1 injection per buttock) at days 1, 15, 29, and every 4 weeks thereafter, with each injection taking 1 to 2 minutes).

[0221] Table 6 : Activity Schedule

[0222]

[0223]

[0224] a Height will be measured only at screening.

[0225] b Collect pharmacokinetic samples only from patients treated with AZD9833.

[0226] c The time window for tumor imaging is ±7 days. Assessments are to be conducted until disease progression. d Bone scan / skeletal survey (C1D1) should be performed within 12 weeks of treatment initiation.

[0227] e Starting from Week 25 (C7), samples are to be collected every 8 weeks (D1 of every 2nd cycle) and the HRQoL questionnaire is to be completed, in line with tumor RECIST assessments.

[0228] f PRO interviews will be conducted only for patients enrolled in the United States, the United Kingdom, and Spain. The interviews will be conducted by phone.

[0229] The first interview will occur at baseline (before the first dose during the screening period). The vendor conducting the interview will be notified within one day after identifying eligible patients and the planned C1D1 date. Best efforts will be made to schedule all interviews within the allowed window. The second interview will be conducted 4 weeks (±7 days) after C1D1, and the third interview will be conducted 12 weeks (±21 days) after C1D1.

[0230] g The time window for echocardiograms at Visits C2D1, C5D1, and every 3rd cycle thereafter, as well as the 28-day follow-up echocardiogram, is ±7 days

[0231] Table 7: Objectives and Endpoints Objectives and Endpoints

[0232]

[0233] Objectives and Endpoints

[0234]

[0235] Overall Study Design .

[0236] This is a randomized, open-label, parallel-group, multicenter Phase 2 study to compare the efficacy and safety of once-daily PO AZD9833 versus IM fulvestrant in women with advanced estrogen receptor-positive HER2-negative breast cancer. Postmenopausal women with histologically or cytologically confirmed metastatic or locoregional recurrent disease who meet all inclusion criteria and do not meet any exclusion criteria will be included prior to randomization. Randomization will be stratified according to prior CDK4 / 6 inhibitor use and the presence of lung metastases and / or liver metastases.

[0237] After screening visits and confirmation of eligibility, patients will be randomly assigned in a 1:1:1:1 ratio to receive one of the following 4 treatments, including a 4-week treatment cycle until disease progression (assessed by the investigator according to the Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1):

[0238] · AZD9833 (75 mg, PO, once daily)

[0239] · AZD9833 (150 mg, PO, once daily)

[0240] · AZD9833 (300 mg, PO, once daily)

[0241] · Fulvestrant (500 mg IM, on days 1, 15, 29, and every 4 weeks thereafter)

[0242] During the treatment period, patients will attend the following visits:

[0243] · Days 1, 8, and 15 of Cycle 1

[0244] · Day 1 of each subsequent cycle until treatment discontinuation

[0245] After the treatment period, patients will attend 2 safety follow-up visits (at treatment discontinuation and 28 days later), and survival will continue to be followed up. Throughout the study, patients are required to report adverse events (AEs) and the use of concomitant medications.

[0246] Safety assessments (physical examination, vital signs, electrocardiogram [ECG], clinical safety laboratory assessments) will be performed at screening, on day 1 of each cycle (up to cycle 6) and every 2 cycles (from cycle 6 onwards), and at the end-of-treatment (EOT) visit. Echocardiography will be performed at screening, on day 1 of cycles 2 and 5, every 3 cycles thereafter, and at the 28-day follow-up visit. Safety assessments will also be performed on day 8 of cycle 1 (vital signs and ECG in triplicate), day 15 of cycle 1 (vital signs, ECG, clinical chemistry, hematology, and urinalysis), and at the 28-day safety follow-up (physical examination and vital signs).

[0247] Tumor imaging will be performed at screening and every 8 weeks from week 9 until disease progression according to RECIST version 1.1 to evaluate tumor response.

[0248] Patients will complete health-related quality of life (HRQoL) questionnaires on day 1 of cycles 1, 2, and 4, then every 8 weeks (on day 1 of every 2nd cycle) starting from week 25 (cycle 7), in line with tumor imaging, at EOT and / or disease progression, and at the 28-day safety follow-up.

[0249] Blood and plasma samples for circulating tumor (ctDNA) and cancer antigen 15-3 (CA15-3) analysis will be collected at screening, on Day 1 and Day 15 of Cycle 1, on Day 1 of Cycles 2 to 5, every 8 weeks (on Day 1 of every second cycle) starting from Week 25 (Cycle 7), in accordance with tumor imaging, at EOT and / or at disease progression.

[0250] Blood samples for circulating tumor cells (CTC) will be collected at screening, on Day 1 of Cycles 1, 2 and 4, and at EOT.

[0251] For patients receiving AZD9833, blood samples will be collected on Day 15 of Cycle 1 and Day 1 of Cycle 2 for pharmacokinetic (PK) assessment.

[0252] For patients who provide specific consent, the following optional assessments will be performed:

[0253] · Up to 12 patients will be selected per treatment group such that they are suitable for providing paired tumor biopsy samples at 1 time before treatment and at 1 time during treatment. If it becomes clinically infeasible to provide paired biopsies during the course of care for the selected patients, patients may be replaced until up to 12 evaluable biopsy pairs are collected within each treatment group.

[0254] · On Day 1 of Cycle 1 or during a subsequent study period, optional blood samples will be collected before dosing for future genetic studies.

[0255] Number of Patients The study will screen approximately 360 patients (assuming a 20% screening failure rate) in order to randomly assign 288 patients in a 1:1:1:1 ratio to 4 treatment groups:

[0256] · AZD9833 75 mg: 72 patients

[0257] · AZD9833 150 mg: 72 patients

[0258] · AZD9833 300 mg: 72 patients (recruitment for this group was stopped after 20 patients)

[0259] · Fulvestrant: 72 patients

[0260] Treatment and treatment duration. Patients will receive study treatment until objective disease progression (according to RECIST version 1.1) or other discontinuation criteria are met.

[0261] AZD9833 will be administered once daily:

[0262] · 75 mg: 3 × 25 mg tablets.

[0263] · 150 mg: 1 × 100 mg tablet + 2 × 25 mg tablets.

[0264] · 300 mg: 3 × 100 mg tablets.

[0265] Fulvestrant will be administered on Day 1, Day 15 (±1 day), Day 29 (±3 days), and every 4 weeks thereafter:

[0266] · 500 mg: 2 × 5 ml IM injection.

[0267] The study treatments are summarized in Table 8.

[0268] Table 8 : Study Treatments

[0269]

[0270]

[0271] Study Population . Anticipated approval of protocol deviations (also known as protocol waivers or exemptions) to the inclusion / exclusion criteria is not permitted. Every patient should meet all inclusion criteria for the study and not meet any exclusion criteria in order to be assigned / randomized to a study intervention. Patients who are enrolled and do not meet the entry requirements are screening failures. In this protocol, "enrolled" patients are defined as those who have signed the informed consent. "Randomized" patients are defined as those who have undergone randomization and received a randomization number. Patients are eligible for inclusion in the study only if all of the following inclusion criteria apply and no exclusion criteria apply.

[0272] Inclusion Criteria . Informed consent. Provide a signed and dated written informed consent prior to any mandatory study-specific procedures, sampling, and analysis. Patients are also required to consent to provide an archived tumor biopsy. For consenting patients, provide a signed and dated written genetic informed consent prior to collection of samples for genetic analysis.

[0273] Age and gender. Female patients at least 18 years of age.

[0274] Menopausal status. Postmenopausal is defined as meeting at least 1 of the following criteria:

[0275] · Has undergone bilateral oophorectomy.

[0276] · Age ≥ 60 years.

[0277] · Age ≥ 50 years and cessation of regular menses ≥ 12 months and has an intact uterus in the absence of gonadotropin-releasing hormone (GnRH) agonists, oral contraceptives, or hormone replacement therapy.

[0278] · In the absence of gonadotropin-releasing hormone (GnRH) agonists, oral contraceptives, or hormone replacement therapy, aged < 50 years and having had amenorrhea for ≥ 12 months and follicle-stimulating hormone (FSH) and estradiol levels within the postmenopausal range (using the range from the local laboratory facility) and having an intact uterus.

[0279] Disease characteristics. Histological or cytological confirmation of breast adenocarcinoma. The ER-positive status of the primary or metastatic tumor tissue was recorded according to local laboratory parameters, and those laboratory parameters conform to recognized diagnostic guidelines (e.g., the American Society of Clinical Oncology / American Society of Pathology guidelines for immunohistochemical testing of estrogen and progesterone receptors in breast cancer, [Hammond et al. 2010]).

[0280] The recorded HER2-negative status is defined as an immunohistochemistry (IHC) score of 0 or 1+ or negative by in situ hybridization (ISH; FISH / CISH / SISH); if the IHC is 2+, ISH is required to be negative. When available, the assessment of ER and HER2 status should be based on the most recent tumor biopsy sample. According to local laboratory parameters, and those laboratory parameters conform to recognized diagnostic guidelines (e.g., the American Society of Clinical Oncology / American Society of Pathology guidelines for immunohistochemical testing of estrogen and progesterone receptors in breast cancer, [Hammond et al. 2010]).

[0281] Applicable to metastatic disease or locally recurrent disease treated with fulvestrant.

[0282] Radiological or other objective evidence of progression at or after the last systemic treatment before the start of study treatment. Isolated tumor marker progression is not considered objective evidence of progression.

[0283] Patients must have:

[0284] · At least 1 previously unirradiated lesion that can be accurately measured by computed tomography (CT) or magnetic resonance imaging (MRI) applicable to precise repeated measurements at baseline with a longest diameter ≥ 10 mm (except for lymph nodes that must have a short axis ≥ 15 mm), or

[0285] · In the absence of measurable disease as defined above, at least 1 lytic or mixed (lytic + sclerotic) bone lesion that can be continuously evaluated by CT or MRI; patients with only sclerotic / osteoblastic bone lesions in the absence of measurable disease are ineligible.

[0286] The Eastern Cooperative Oncology Group (ECOG) / World Health Organization (WHO) performance status is 0 to 1, without deterioration in the previous 2 weeks, and the minimum life expectancy is 12 weeks.

[0287] Previous chemotherapy, endocrine therapy, and other anti-cancer treatments. Previous endocrine therapy is as follows:

[0288] · Recurrence or progression on at least one line of endocrine therapy.

[0289] · No more than 1 line of endocrine therapy for advanced disease.

[0290] · No more than 1 line of chemotherapy for advanced disease. A chemotherapy line in advanced disease is an anti-cancer regimen that contains at least one cytotoxic chemotherapy agent and is given for 21 days or longer. If a cytotoxic chemotherapy regimen is stopped for reasons other than disease progression and lasts less than 21 days, that regimen does not count as a previous chemotherapy line. Repeated administration of the same anti-cancer regimen on separate occasions does not count as a new chemotherapy line.

[0291] · Previous treatment with CDK4 / 6 inhibitors is allowed.

[0292] · No previous treatment with fulvestrant, oral SERD, or related therapies (e.g., ER, proteolysis-targeting chimera [PROTAC], selective ER covalent antagonist [SERCA] in the metastatic setting).

[0293] Inclusion criteria for paired tumor biopsies. Diseases applicable to paired baseline and on-treatment tumor biopsies. Excluded from the study subgroup. Previous tamoxifen: 4 months should pass from the last tamoxifen administration to the biopsy in the study before dosing. Provide signed, written, and dated informed consent for tumor biopsy.

[0294] Exclusion Criteria If any of the following exclusion criteria are met, the patient must not enter the study.

[0295] Previous / concomitant therapies. Intervention with any of the following:

[0296] · Any cytotoxic chemotherapy, investigational agent, or other anti-cancer drug for the treatment of breast cancer from a previous treatment regimen or clinical study within 14 days of the first dose of study treatment.

[0297] · Use of systemic estrogen-containing hormone replacement therapy within 6 months before the first dose of study treatment.

[0298] · Drugs or supplements known to be strong inhibitors / inducers of cytochrome P450 (CYP) 3A4 / 5, sensitive CYP2B6 substrates, and drugs that are substrates of CYP2C9 and / or CYP2C19 (which have a narrow therapeutic index), namely warfarin (and other coumarin-derived vitamin K antagonist anticoagulants) and phenytoin, or drugs that cannot be discontinued within the washout period specified in Appendix B prior to the first dose of the investigational treatment.

[0299] · Drugs known to prolong QT and with a known risk of torsade de pointes ventricular tachycardia, as indicated in Appendix B1.

[0300] · Radiation therapy, limited radiation fields for palliation within 1 week of the first dose of the investigational treatment, and / or radiation to more than 30% of the bone marrow or wide radiation fields within 4 weeks of the first dose of the investigational treatment.

[0301] · Major surgery or significant traumatic injury (as judged by the investigator) within 4 weeks of the first dose of the investigational treatment, or any surgery expected to require major surgery and / or general anesthesia during the study.

[0302] Medical conditions. At the start of the investigational treatment, any unresolved toxicity from prior treatment greater than CTCAE grade 1, except for alopecia and chemotherapy-related peripheral neuropathy.

[0303] Presence of life-threatening metastatic visceral disease or uncontrolled CNS metastatic disease as judged by the investigator. Patients with spinal cord compression and / or brain metastases may be enrolled if they have been definitively treated (e.g., surgery or radiation therapy) and are on stable steroids for at least 4 weeks prior to the start of the investigational treatment.

[0304] Any of the following criteria:

[0305] · Any evidence of severe or uncontrolled systemic disease, including uncontrolled hypertension and active bleeding diathesis, or an infection, for example, requiring intravenous antibiotic treatment, which in the investigator's opinion would make the patient ineligible to participate in the study or would jeopardize compliance with the protocol.

[0306] · Immunocompromised patients, such as patients known to be seropositive for human immunodeficiency virus (HIV).

[0307] · Patients known to have active hepatitis (i.e., hepatitis B or C) Any of the following cardiovascular criteria:

[0308] · Mean resting QTcF > 470 ms, obtained from screening ECGs in triplicate.

[0309] · Resting heart rate < 45 bpm

[0310] · Any clinically important abnormality in the rhythm, conduction, or morphology of the resting ECG (e.g., complete left bundle branch block, second- and third-degree heart block), or clinically significant sinus pause, or sick sinus syndrome. Patients with controlled atrial fibrillation may be enrolled.

[0311] · Any factor that increases the risk of QTc prolongation or arrhythmia events, such as symptomatic heart failure, congenital long QT syndrome, direct family history of long QT syndrome, or unexplained sudden death <40 years of age; hypertrophic cardiomyopathy and clinically significant valvular stenosis; clinically significant hypokalemia, hyperkalemia, hypomagnesemia, hypermagnesemia, hypocalcemia, and hypercalcemia.

[0312] · Left ventricular ejection fraction <50%, and / or having experienced any of the following surgeries or conditions within the previous 6 months: coronary artery bypass grafting, angioplasty, vascular stenting, myocardial infarction, unstable angina, congestive heart failure New York Heart Association (NYHA) ≥ grade 2, stroke, or transient ischemic attack.

[0313] · Uncontrolled hypertension. Patients with hypertension may be eligible, but blood pressure must be adequately controlled at baseline. Patients may be rescreened regarding blood pressure requirements.

[0314] · Symptomatic hypotension

[0315] Insufficient bone marrow reserve or organ function demonstrated by any of the following laboratory values:

[0316] · Absolute neutrophil count (ANC) <1.5 × 109 / L

[0317] · Platelet count <100 × 109 / L

[0318] · Hemoglobin (Hb) <90 g / L

[0319] · Alanine aminotransferase (ALT) >2.5 × upper limit of normal (ULN)

[0320] · Aspartate aminotransferase (AST) >2.5 × ULN

[0321] · Total bilirubin (TBL) >1.5 × ULN or >3 × ULN in the presence of documented Gilbert syndrome (unconjugated hyperbilirubinemia)

[0322] · Estimated glomerular filtration rate (eGFR) <50 mL / min

[0323] · Refractory nausea and vomiting, uncontrolled chronic gastrointestinal diseases, inability to swallow the formulated product, or prior significant bowel resection that may interfere with the adequate absorption of AZD9833.

[0324] Other exclusions:

[0325] · History of hypersensitivity to the active or inactive excipients of AZD9833 or fulvestrant.

[0326] · Involvement in the planning and conduct of the study (applied to personnel at AstraZeneca and / or at the study centers).

[0327] · Prior randomization in this study.

[0328] · If, in the judgment of the investigator, the patient is unlikely to comply with the study protocol, restrictions, and requirements, the patient should not participate in the study.

[0329] · Male patients are excluded from this study.

[0330] · Women of childbearing potential are excluded from this study.

[0331] Lifestyle Restrictions During the study, patients should avoid consuming large amounts of grapefruit and Seville oranges (and other products containing these fruits [e.g., grapefruit juice or marmalade]) (e.g., no more than a small glass of grapefruit juice [120 mL], half a grapefruit, or 1 to 2 teaspoons [15 g] of Seville orange marmalade per day). There are no food restrictions for AZD9833 (i.e., AZD9833 can be taken with or without food). There are no food restrictions for fulvestrant.

[0332] Measures to Minimize Bias: Randomization and Blinding This is an open-label study. All patients will receive active treatment. Since the study treatment will not be blinded to the investigator, BICR for tumor scans will be performed to provide an independent tumor response assessment in addition to the investigator's response evaluation. To reduce potential bias during the study, eligible patients will be randomly assigned at a ratio of 1:1:1:1 to receive one of the 4 study treatments.

[0333] Patients will be randomized as they become eligible. Once a patient's eligibility is confirmed, the investigator (or designee) will notify the centralized IWRS. Randomization should be performed as close as possible to the start of study treatment, with a maximum delay of 3 days. Randomization will be stratified based on 2 stratification factors:

[0334] · Prior use of CDK4 / 6 inhibitors in any setting (yes / no)

[0335] · Presence of lung metastases and / or liver metastases (yes / no)

[0336] The control of the first factor (i.e., prior use of CDK4 / 6 inhibitors) will be such that each stratum will include 32 to up to 40 patients in each treatment group (out of 72 planned patients) to ensure that approximately 50% of the patients in each treatment group have not used CDK4 / 6 inhibitors at the final analysis. The upper limit will allow up to 40 patients to be enrolled in each stratum, but not exceed the total planned for each treatment group. There is no mandatory upper limit for the second stratification factor (i.e., the presence of lung metastases and / or liver metastases).

[0337] Efficacy Assessment Assessment of tumor response. Tumor response assessment according to version 1.1 of RECIST will be used to determine the clinical activity (assessed by PFS) and anti-tumor activity (assessed by ORR, clinical benefit rate [CBR]) of AZD9833 and fulvestrant.

[0338] Tumor imaging. Tumor imaging should be performed according to the SoA (Table 6). Baseline tumor assessment should cover all regions known to have a predilection for metastases in the disease being evaluated and should additionally study regions that may be involved based on the signs and symptoms of individual patients. Baseline assessment should be performed no more than 28 days before the start of study treatment and, ideally, as close as possible to the start of study treatment.

[0339] If an unplanned assessment is performed and the patient has not progressed, every effort should be made to perform a follow-up assessment at their planned visit. Follow this schedule to minimize any inadvertent bias caused by some patients being evaluated at a different frequency than other patients.

[0340] Investigator assessment of tumor response according to version 1.1 of RECIST. Tumor response will be assessed by the investigator according to version 1.1 of RECIST (Eisenhauer et al. 2009). Based on the investigator's review of the imaging scans, the evaluation of TL, NTL, and new lesions will be used to determine the overall visit response for each patient. Then the overall visit response for each visit will be used to determine whether and when the patient has progressed (according to RECIST) and their best objective response to study treatment.

[0341] Blinded independent central assessment of tumor evaluation. Encoded copies of all imaging evaluations (regardless of format and including unplanned visit scans) will be sent to a designated contract research organization (CRO) for central analysis. The results of this independent review will not be communicated to the investigator, and patient management will be based only on the results of the RECIST assessment performed by the investigator. Imaging scans will be reviewed by 2 independent radiologists using version 1.1 of RECIST and adjudicated if necessary (i.e., 2 reviewers will review the scans and, in the case of disagreement, a separate reviewer will perform the adjudication). Study treatment will be blinded to the independent reviewers.

[0342] The BICR will be conducted on an ongoing basis throughout the study. Where possible, scans will be performed in batches and a series of evaluations for an inpatient will be read together. For each patient, the BICR will define the overall visit response (i.e., the response overall obtained at each visit by assessing TL, NTL, and new lesions), and no procedural derivation of the overall visit response will be required.

[0343] Bone scan or skeletal survey. All patients should have a baseline bone scan or skeletal survey no more than 12 weeks prior to and as close as possible to the start of study treatment. Additional in-study bone scans or skeletal surveys may be performed if clinically indicated. Bone lesions identified on the isotope bone scan at baseline and confirmed by CT, MRI, or X-ray should be recorded as NTL and followed up by the same method (CT, MRI, or X-ray) as indicated in the SoA (Table 6).

[0344] Survival follow-up. After discontinuation of study treatment, the survival status of patients will be followed up by telephone every 12 weeks until the clinical study database is closed. Any new anti-cancer treatment initiated by a patient during the survival follow-up period will be recorded in the clinical database. For each survival analysis, survival follow-up telephone calls will be made within weeks after the DCO date.

[0345] Post-primary analysis. At the time of the final analysis, the clinical study database will be close to new data. However, if in the opinion of the investigator, a patient will continue to benefit from study treatment, the patient will be allowed to continue receiving study treatment beyond database closure.

[0346] Clinical Outcome Assessment . Performance status. The performance status will be evaluated at the visits indicated in the SoA (Table 6) according to the following ECOG / WHO criteria:

[0347] · Fully active, able to carry out all pre-disease activities without restriction.

[0348] · Limited to strenuous physical activity but can walk around and is able to perform light or sedentary work (e.g., light housework, office work).

[0349] · Able to walk around and able to take care of oneself but unable to perform any work activities. Able to get out of bed for more than 50% of the waking hours.

[0350] · Only able to perform limited self-care, bedridden or in a wheelchair for more than 50% of the waking hours.

[0351] · Completely disabled. Unable to perform any self-care. Completely confined to bed or chair.

[0352] Health-related quality of life questionnaires. PRO measures will be used to examine the impact of treatment on symptoms, function, and HRQoL, and to help understand the benefit / risk assessment from the patient's perspective. In this study, the following PRO measures will be administered according to the SoA (Table 6) and in the following order:

[0353] · European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - Core 30 (EORTC QLQ-C30)

[0354] · EORTC Quality of Life Questionnaire - Breast Cancer Module (EORTC QLQ-BR23)

[0355] · National Eye Institute Visual Function Questionnaire-25 (NEIVFQ-25)

[0356] · EuroQol Five-Dimension Five-Level (EQ-5D-5L)

[0357] · Patient Global Impression of Severity (PGIS)

[0358] · Patient Global Impression of Change (PGIC) (not applicable at baseline, i.e., Day 1 of Cycle 1)

[0359] · Patient Global Impression of Treatment Tolerability (PGI-TT)

[0360] · Patient Global Impression of Benefit-Risk (PGI-BR) (not applicable at baseline, i.e., Day 1 of Cycle 1)

[0361] Safety Assessment 。All planned time points for safety assessments are provided in the SoA (Table 6). Table 9 provides a list of clinical safety laboratory tests to be performed and the SoA regarding time and frequency.

[0362] Table 9: Laboratory Safety Variables

[0363] Hematology (Whole Blood) Clinical Chemistry (Serum or Plasma) B-Hemoglobin (Hb) S / P-Creatinine B-White Blood Cell Count S / P-Bilirubin, Total (TBL) B-Hematocrit S / P-Conjugated Bilirubin B-Red Blood Cell Count S / P-Unconjugated Bilirubin B-White Blood Cell Differential Count (Absolute Count) S / P-Alkaline Phosphatase (ALP) Neutrophils S / P-Aspartate Aminotransferase (AST) Lymphocytes S / P-Alanine Aminotransferase (ALT) Monocytes S / P-Creatine Kinase (CK) Basophils S / P-Albumin Eosinophils S / P-Calcium, Total B-Platelet Count S / P-Potassium S / P-Sodium Coagulation Parameters S / P-Glucose Activated Partial Thromboplastin Time (aPTT) S / P-Magnesium International Normalized Ratio (INR) S / P-Phosphate S / P-Urea Nitrogen Urine Analysis S / P-Protein, Total U-Glucose S / P-Troponin U-Protein S / P-NT-proBNP U-Blood

[0364] Pharmacokinetics 。Approximately 2 mL of venous blood samples will be collected from patients receiving AZD9833 for measuring the plasma concentration of AZD9833 and, if applicable, the plasma concentration of metabolites specified in the SoA (Table 6).

[0365] If necessary and agreed between the investigator and the sponsor, samples may be collected at additional time points during the study or no further samples will be collected. Instructions for the collection and handling of biological samples will be provided by the sponsor or the analytical testing center. The actual date and time (24-hour clock time) of each sample will be recorded.

[0366] Samples collected for analysis of the plasma concentration of AZD9833 may also be used to evaluate safety or efficacy aspects related to concerns that arise during or after the study (i.e., if needed, PK samples may be re - used).

[0367] Genetics Patients will have the opportunity to participate in optional genetic exploratory studies. DNA will be collected and stored according to local and ethical regulations in each country for future exploratory studies of genes / genetic variants that may affect response to treatment. After signing a separate consent for the optional genetic study, 6 mL of blood samples will be collected according to the inclusion criteria and SoA (Table 6). If for any reason, blood samples are not drawn on Day 1 according to the SoA, they can be obtained at any time up to the last study visit. Although genotype is a stable parameter, early sample collection is preferred to avoid introducing bias by excluding subjects who may be withdrawn due to AEs. It will be important to include such subjects in any genetic analysis. During the study, only 1 sample per subject should be collected for genetic research.

[0368] Biomarkers Biomarkers will be tested in plasma, blood, and tumor samples for secondary and exploratory purposes to study predictive markers of response to and / or acquired resistance to AZD9833, and to evaluate the impact of tumor mutation status on treatment response and acquired resistance.

[0369] The following samples are required for biomarker research and will be collected from all patients in the study as specified in the SoA (Table 6).

[0370] · Blood and plasma samples for ctDNA

[0371] · Blood samples for the tumor marker CA15 - 3

[0372] · Blood samples for CTC

[0373] · Archived tumor tissue samples

[0374] The following samples for biomarker research are optional and will be collected from patients in the study, if possible, as specified in the SoA (Table 6).

[0375] · Paired tumor biopsy samples; pre - treatment and during treatment. Samples will be collected from up to 12 patients in each treatment group (with tumors amenable to biopsy).

[0376] · Additional tumor biopsy samples may be collected at the time of progression.

[0377] Blood samples for circulating tumor DNA. At screening, a 20 mL whole blood sample is obtained for the isolation of plasma and buffy coat to enable the assessment, analysis, and interpretation of circulating tumor DNA. At all other time points indicated in the SoA (Table 1), 10 mL blood samples are obtained to provide plasma only.

[0378] The samples will be used for the extraction and analysis of ctDNA, for the analysis of predictive and pharmacodynamic biomarkers to interrogate changes in frequency, levels, specific genetic alterations, and potential resistance mechanisms.

[0379] Blood samples for the tumor marker CA15-3. Approximately 2 mL blood samples are obtained at each time point indicated in the SoA (Table 6) for cancer antigen CA15-3 assessment. The samples will be analyzed in a local laboratory located at or near the investigator site. Sample tubes and sample sizes may vary according to the laboratory methods used and the center's routine practice.

[0380] Circulating tumor cells. As indicated in the SoA (Table 6), a 10 mL blood sample is obtained at each time point. These samples will be obtained to obtain a preliminary assessment of AZD9833 activity in the tumor by evaluating changes in pharmacodynamic biomarkers, which may include but are not limited to total counts, and the expression levels of ER, Ki67 protein, and ER-regulated genes.

[0381] Archived tumor tissue. When available, formalin-fixed archived tumor tissue embedded in paraffin blocks will be retrieved (for all patients). If baseline biopsy samples can also be collected, archived diagnostic tumor material still needs to be retrieved to provide data on how the tumor has evolved since diagnosis. Archived samples may be derived from the primary tumor and / or metastatic sites, and whenever possible, recently obtained archived samples are required.

[0382] If this is not possible, if tumor blocks cannot be submitted, at least 20 slides of freshly prepared unstained 5-micron sections from archived tumor blocks are accepted. From the submitted archived tumor blocks, cores may be removed to construct tissue microarrays for subsequent biomarker analysis. The remaining portion of the tumor block may be returned to the institution.

[0383] Tumor biopsies of selected patients. Optional paired tumor biopsies will be collected from up to 12 eligible patients in each treatment group. Paired tumor biopsies will be obtained from patients with accessible tumors who consent to provide biopsy samples. An accessible lesion is defined as a tumor lesion from which repeat biopsies are possible. Paired biopsies of bone tissue are not permitted. Pretreatment biopsies can be performed as close as possible to the start of treatment during screening, ideally no more than 6 weeks before treatment begins. Biopsy samples at the time of treatment can be obtained on Day 1 (±7 days) of Cycle 2, but if AstraZeneca agrees, both pretreatment and at-treatment samples can be obtained outside of this time window. Biopsies before dosing and at the time of treatment should be obtained from the same tumor lesion. Whenever possible, biopsies should be performed within 1 hour to 12 hours of the last AZD9833 dose. Further tumor biopsies can also be performed at the time of disease progression or at the end of treatment.

[0384] Biomarkers to be studied using tumor samples may include but are not necessarily limited to: ER, PgR, Ki67, genomic / genetic alterations, and other ER-regulated gene expressions. Whenever feasible, collection of tumor biopsies at the time of disease progression is encouraged. The sample will be used to study changes in pathway signal transduction and potential resistance mechanisms (i.e., evidence of genetic alterations or alternative pathway activation).

[0385] Statistical Methods All efficacy analyses will be conducted on the full analysis set (FAS). The primary analysis for the formal comparison of AZD9833 with fulvestrant is applicable only to the AZD9833 75mg and 150mg treatment groups, and pairwise comparisons refer only to the AZD9833 doses 75mg and 150mg. Results of all statistical analyses will be presented using 90% confidence intervals (CI) and two-sided p-values. The treatment comparisons of interest are the comparisons of AZD9833 at each dose level with fulvestrant. Data generated from the AZD9833 300mg treatment group will be appropriately summarized and reported, but will not contribute to event triggering for the following analysis time points.

[0386] For the primary analysis, the null hypothesis to be tested is no treatment effect (i.e., no difference in PFS between patients treated with any dose of AZD9833 and patients treated with fulvestrant).

[0387] · H0: PFS HR AZD9833 / 氟维司群 = 1

[0388] · H1: PFS HR AZD9833 / 氟维司群 ≠ 1

[0389] Each dose of AZD9833 of interest will be compared to fulvestrant in a pairwise comparison. Since this is a Phase 2 study, no adjustment for multiplicity will be made. The primary endpoint will be based on the investigator's assessment of progression, as defined by RECIST version 1.1. A sensitivity analysis will be performed based on blinded independent central review (BICR) scans.

[0390] For the pairwise comparisons of the 75 mg and 150 mg AZD9833 doses to fulvestrant (approximately 75% maturity), the analysis of the primary endpoint of PFS (as assessed by the investigator) will be performed when study enrollment has been completed and at least 108 events have occurred. Further analyses of PFS may be performed at subsequent time points based on more mature data, particularly in subgroups of interest.

[0391] A sample size of approximately 288 patients will be required, randomized in equal proportions to 4 treatment groups, to observe a total of at least 108 PFS events in each pairwise comparison to fulvestrant. An HR of 0.59 for each pairwise treatment comparison to fulvestrant is of interest. Assuming a median PFS of 5 months will be observed on fulvestrant, this corresponds to an increase in median PFS of 3.5 months compared to fulvestrant. If the true treatment effect is the hypothesized HR = 0.59, at least 108 events in each pairwise comparison of an AZD9833 dose of interest to fulvestrant will provide 86% power at a two-sided 10% significance level.

[0392] The objective response rate (ORR) between AZD9833 (at each dose level) and fulvestrant will be compared using a logistic regression model adjusted for prior use of CDK4 / 6 inhibitors and the presence of lung metastases and / or liver metastases.

[0393] The change in tumor size from baseline and the best change in tumor size from baseline at 16 weeks will also be summarized and presented by randomized treatment group.

[0394] Overall survival (OS) data will be analyzed at the time of the primary analysis of PFS and the same methodology and model will be used (as long as there are sufficient events for a meaningful analysis). Further survival analyses may be performed after 50% and 75% of the patients have died, or according to other appropriate levels of maturity.

[0395] CBR24 will be summarized by treatment group and analyzed using a logistic regression model (similar to the analysis of ORR).

[0396] All safety analyses will be performed on the safety analysis set. Safety data will not be formally analyzed.

[0397] Populations for analysis. For the purposes of analysis, the following populations are defined in Table 10.

[0398] Table 10 : Study Population

[0399]

[0400] Statistical analysis. All sponsor personnel involved in the study will remain blinded to the overall efficacy data until after the database lock for the primary analysis. After the database lock for the primary analysis, all study team members will be unblinded.

[0401] Efficacy analysis. All efficacy analyses will be performed on the FAS. The primary analysis for the formal comparison of AZD9833 with fulvestrant will apply only to the AZD9833 75 mg and 150 mg treatment groups, and the pairwise comparisons will refer only to the AZD9833 doses 75 mg and 150 mg. The results of all statistical analyses will be presented using 90% CI and two-sided p-values. The treatment comparisons of interest are the comparisons of AZD9833 with fulvestrant at each dose level. The data generated from the AZD9833 300 mg treatment group will be appropriately summarized and reported.

[0402] Investigator assessment of tumor response according to RECIST version 1.1. Based on the investigator's review of imaging scans, the measurement of TL (where appropriate), NTL, and new lesions will be used to determine the overall visit response for each patient according to RECIST version 1.1: patients will be procedurally assigned an overall visit response of complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) according to their disease status compared to baseline and previous assessments. The efficacy endpoints of PFS, CBR24, ORR, and DoR will be procedurally derived from the overall visit response determined for each visit. The endpoint of the percentage change in the sum of TL will be procedurally derived from the TL tumor measurements.

[0403] Blinded independent central review of tumor response. The sensitivity analysis for the primary endpoint of this study will be based on the BICR of the radiological scans. For each patient, the BICR will define the overall visit response data (i.e., the response overall obtained by assessing TL, NTL, and new lesions at each visit), and no procedural derivation of the visit response will be required. PFS will be procedurally derived from the overall visit response determined for each visit. The BICR for all patients will be performed at the final database lock for the primary analysis of PFS. The BICR will cover all available scans up to the corresponding DCO.

[0404] Primary endpoint: Progression-free survival. For each pairwise comparison of each AZD9833 dose with fulvestrant (at approximately 75% maturity), the analysis of the primary endpoint of PFS (as assessed by the investigator) will be conducted when the study recruitment has been completed and at least 108 events have occurred. Further analysis of PFS may also be conducted at subsequent time points based on more mature data, particularly in subgroups of interest.

[0405] PFS is defined as the time from the date of randomization to the date of objective disease progression or death (due to any cause in the absence of progression), regardless of whether the patient withdraws from randomized treatment or receives another anti-cancer treatment prior to progression (i.e., the date of the PFS event or censoring - the date of randomization + 1).

[0406] Patients who have not progressed or died at the time of analysis will be censored at the date of their most recent evaluable assessment (according to version 1.1 of RECIST). However, if a patient progresses or dies immediately following 2 or more consecutive missed visits, the patient will be censored at the most recent evaluable assessment (according to RECIST 1.1) prior to the 2 missed visits. PFS time will always be based on scan / assessment dates and not on visit dates.

[0407] PFS will be analyzed based on the FAS, using the Cox proportional hazards model, taking into account the treatment effect and including aspects of the stratification factors; prior use of CDK4 / 6 inhibitor (yes / no) and the presence of lung metastases and / or liver metastases (yes / no). A stratified log-rank test adjusted for prior use of CDK4 / 6 inhibitor and the presence of lung metastases and / or liver metastases will be used to compare all AZD9833 doses with fulvestrant.

[0408] The stratification variables in the statistical modeling will be based on the values entered into the IWRS at the time of randomization, even if these values are subsequently found to be incorrect. A sensitivity analysis may be conducted based on the correct allocation if deemed necessary.

[0409] The HR for each treatment compared to fulvestrant will be estimated, along with their 90% CI and two-sided p-values.

[0410] The Kaplan-Meier plots for PFS will be presented by treatment group. The number and percentage of patients who experienced a PFS event, along with a summary of the event type (progression or death), the median PFS, and the proportion of patients without progression at 6 months and 1 year for each treatment group will be provided.

[0411] The hypothesis of proportionality will be evaluated, and if there is evidence of non-proportionality, time-dependent covariates will be fitted to assess the extent to which it represents random variation. Full details will be provided in the SAP.

[0412] For the sensitivity analysis of the primary endpoint, the above analysis method will be repeated based on BICR.

[0413] The collected RECIST v1.1 data (investigator-determined and BICR) for all randomized patients will be listed.

[0414] Subgroup analysis. For the patient subgroup of "previous CDK4 / 6 inhibitor use (yes / no)", the primary endpoint will also be summarized and analyzed, provided that there are sufficient events for a meaningful analysis; if not, a descriptive summary will be provided. Further subgroups of interest can be defined based on patient characteristics at baseline, and these will be illustrated in a forest plot comparing HR and 90% CI. Subgroups of interest and any sensitivity analysis will be fully defined in the SAP.

[0415] Secondary endpoint: Objective response rate. The ORR is defined as the percentage of patients with at least 1 investigator-assessed visit response with CR or PR before any evidence of progression. The ORR will be based on the subset of FAS with measurable disease at baseline. Responses do not need to be confirmed to be included in the calculation of the ORR.

[0416] The ORR between AZD9833 (at each dose level) and fulvestrant will be compared using a logistic regression model adjusted for previous CDK4 / 6 inhibitor use and the presence of lung metastases and / or liver metastases. The results of the analysis will be presented in the form of odds for each treatment comparison and its associated characteristic likelihood 90% CI and two-sided p-value (based on twice the change in log-likelihood resulting from adding the treatment factor to the model).

[0417] Summaries representing the number and percentage of patients with tumor responses (CR / PR) will be generated, and these will include the frequencies of confirmed complete and partial responses, as well as unconfirmed complete and partial responses, disease stability, progressive disease, and non-evaluable.

[0418] Secondary endpoint: Duration of response. The DoR will be defined as the time from the date of the first recorded response until the date of recorded progression or death in the absence of disease progression. The time to initial response will be defined as the most recent date among the dates contributing to the visit response for PR or CR. If a patient does not progress or die after a response, their DoR will use the PFS censoring time. Descriptive data on the duration of response for responding patients will be provided, including the relevant Kaplan-Meier curves.

[0419] Secondary endpoint: change in tumor size. One of the secondary outcome variables in the secondary outcome variables of this study is the percentage change in the sum of the TL diameters from baseline at 16 weeks. Based on the RECIST measurements performed at baseline and at 16 weeks, the percentage change in tumor size at 16 weeks will be obtained for each patient. Tumor size is the sum of the longest diameters of the TLs. TLs are measurable tumor lesions. The RECIST baseline is defined as the last evaluable assessment before randomization.

[0420] Secondary endpoint: best percentage change. The absolute change and percentage change in the sum of tumor sizes from baseline will be calculated at each visit. The best change in tumor size (i.e., depth of response) is the greatest decrease from baseline or the smallest increase from baseline in the absence of a decrease, and will include the earliest death in the absence of progression, any evidence of progression, the initiation of subsequent anti-cancer therapy, or all assessments prior to the last evaluable RECIST assessment if the patient has not died, progressed, or initiated subsequent anti-cancer therapy.

[0421] Absolute values, changes in tumor size from baseline, and percentage changes in tumor size from baseline will be summarized using descriptive statistics and presented for each time point and by randomized treatment group. The change in tumor size from baseline and the best change in tumor size from baseline at 16 weeks will also be summarized and presented by randomized treatment group. The normality of the data will be evaluated and, if appropriate, the effect of AZD9833 on the percentage change in tumor size will be estimated from an analysis of covariance (ANCOVA) model. The number of patients, unadjusted means, and least-squares means (LSmeans) for each treatment group will be presented, as well as the differences in LSmeans, 90% CIs, and corresponding two-sided p-values. If the assumptions are not met, appropriate transformations of the study data will be investigated, the full details of which will be provided in the SAP. Tumor size will also be illustrated using waterfall plots and spider plots segmented by appropriate handling.

[0422] Secondary endpoint: overall survival. OS is defined as the time from the date of randomization until death from any cause, regardless of whether the patient withdraws from randomized treatment or receives another anti-cancer therapy. Any patients whose death is unknown at the time of analysis will be censored based on the last recorded date on which the patient was known to be alive.

[0423] Note: Survival follow-up phone calls will be made within one week after the DCO date used for analysis, and these patients will be censored at the DCO date if it is confirmed that the patient is alive or if the date of death is after the DCO date.

[0424] OS data will be analyzed at the time of the PFS primary analysis and will use the same methodology and model (as long as there are sufficient events available for a meaningful analysis [> 20% maturity in OS], if not, a descriptive summary will be provided). Further survival analyses can be performed after 50% and 75% of the patients have died.

[0425] Secondary endpoint: Clinical Benefit Rate at 24 weeks. CBR24 is defined as the percentage of patients with a best objective response (BoR) of CR or PR within the first 25 weeks (to allow for later assessments within the evaluation window) or with SD (without subsequent cancer treatment) at least 23 weeks after treatment initiation (to allow for early assessments within the evaluation window). CBR will be defined based on the investigator's RECIST assessment, will be summarized by treatment group, and analyzed using a logistic regression model (similar to the analysis of ORR).

[0426] Results obtained from the clinical trial protocol are presented in Figures 1 to 6 below.

Claims

1. A method for treating HR+, HER2−, metastatic or locally recurrent breast cancer, the method comprising administering a therapeutically effective amount of ngSERD to a patient suffering from such cancer, characterized in that The cancer has recurred or progressed after at least one prior line of endocrine therapy.

2. The treatment method according to claim 1, wherein: a) The median time to disease progression is at least 3.5 months more than that observed with fulvestrant treatment; and / or b) The hazard ratio of ngSERD treatment is less than or equal to 0.67 relative to fulvestrant treatment; and / or c) The median time to disease progression is at least 7 months.

3. The treatment method according to claim 1, wherein the cancer has recurred or progressed after at least one prior line of treatment with a CDK4 / 6 inhibitor.

4. The treatment method according to claim 3, wherein: a) The median time to disease progression is at least 1.7 months more than that observed with fulvestrant treatment; and / or b) The hazard ratio of ngSERD treatment is less than or equal to 0.68 relative to fulvestrant treatment; and / or c) The median time to disease progression is at least 3.8 months.

5. The treatment method according to claim 1, wherein the cancer has been identified as having visceral metastases.

6. The treatment method according to claim 5, wherein: a) The median time to disease progression is at least 3.6 months more than that observed with fulvestrant treatment; and / or b) The hazard ratio of ngSERD treatment is less than or equal to 0.55 relative to fulvestrant treatment; and / or c) The median time to disease progression is at least 5.6 months.

7. The treatment method according to claim 1, wherein the cancer has been identified as having a mutation in estrogen receptor α.

8. The treatment method according to claim 7, wherein the cancer has been identified as having a mutation in estrogen receptor α, and the mutation is selected from E380Q, V422del, S463P, L536H, L536P, L536R, Y537C, Y537D, Y537N, Y537S, and D538G.

9. The treatment method according to claim 7 or claim 8, wherein the identification of the mutation in estrogen receptor α is based on testing of a sample obtained from the patient.

10. The treatment method according to claim 9, wherein the sample obtained from the patient is a tumor biopsy or a blood sample.

11. The treatment method according to claim 10, wherein the identification of the mutation in estrogen receptor α is performed by analyzing circulating tumor DNA.

12. The treatment method according to any one of claims 7 to 11, wherein: a) The median time to disease progression is at least 4 months more than that observed with fulvestrant treatment; and / or b) The hazard ratio of ngSERD treatment is less than or equal to 0.55 relative to fulvestrant treatment; and / or c) The median time to disease progression is at least 6.3 months.

13. The treatment method according to any one of the preceding claims, wherein the ngSERD is camizestrant or a pharmaceutically acceptable salt thereof.

14. The treatment method according to claim 13, wherein the camizestrant or a pharmaceutically acceptable salt thereof is orally administered once a day at a dose of 75 mg.

15. The treatment method according to claim 13, wherein the camizestrant or a pharmaceutically acceptable salt thereof is orally administered once a day at a dose of 150 mg.

16. The treatment method according to any one of the preceding claims, wherein the method improves the overall survival compared to the treatment with fulvestrant.

17. The treatment method according to any one of claims 1 to 15, wherein the method delivers an improvement in the 24-week clinical benefit rate compared to fulvestrant.

18. The treatment method according to any one of claims 1 to 15, wherein the method delivers an improvement in the objective response rate compared to fulvestrant.

19. Camizestrant or a pharmaceutically acceptable salt thereof for the treatment of HR+, HER2−, metastatic or locally recurrent breast cancer, characterized in that The cancer has recurred or progressed after at least one previous line of endocrine therapy, wherein: a) The use delivers an improvement in the median time to disease progression of at least 3.5 months compared to that observed with treatment with fulvestrant; and / or b) The hazard ratio of treatment with camizestrant is less than or equal to 0.67 compared to fulvestrant treatment; and / or c) The use delivers a median time to disease progression of at least 7 months.

20. Carmisertib or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for the treatment of HR+, HER2−, metastatic or locally recurrent breast cancer, characterised in that The cancer has recurred or progressed after at least one previous line of endocrine therapy, and wherein the drug for use delivers: a) An improvement in the median time to disease progression of at least 3.5 months compared to that observed with treatment with fulvestrant; and / or b) A hazard ratio of treatment with camizestrant that is less than or equal to 0.67 compared to fulvestrant treatment; and / or c) A median time to disease progression of at least 7 months.

21. A pharmaceutical composition, the pharmaceutical composition comprising camizestrant for treating HR+, human epidermal growth factor receptor 2 negative HER2−, metastatic or locally recurrent breast cancer and at least one pharmaceutically acceptable excipient, characterized in that The cancer has recurred or progressed after at least one previous line of endocrine therapy, wherein the pharmaceutical composition for use delivers: a) An improvement in the median time to disease progression of at least 3.5 months compared to that observed with treatment with fulvestrant; and / or b) A hazard ratio of treatment with camizestrant that is less than or equal to 0.67 compared to fulvestrant treatment; and / or c) A median time to disease progression of at least 7 months.

22. A kit, the kit comprising a pharmaceutical composition containing camizestrant and at least one pharmaceutically acceptable excipient, and instructions for using the pharmaceutical composition to treat HR+, HER2−, metastatic or locally recurrent breast cancer, characterized in that The cancer has recurred or progressed after at least one previous line of endocrine therapy, wherein the use of the kit delivers: a) An improvement in the median time to disease progression of 3.5 months compared to that observed with treatment with fulvestrant; and / or b) A hazard ratio of treatment with camizestrant that is less than or equal to 0.67 compared to fulvestrant treatment; and / or c) A median time to disease progression of at least 7 months.

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