Treatment of breast cancer with selective estrogen receptor degraders (SERDs)

Abstract

The present disclosure relates to a method for treating hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), metastatic or locally recurrent breast cancer, comprising administering to a patient afflicted with such cancer a next-generation selective estrogen receptor degrading drug (ngSERD), e.g., camizestrant, wherein the cancer has recurred or progressed after at least one prior course of endocrine therapy.

Description

[Technical Field]

[0001] This document relates to a method of treating hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), metastatic or locally recurrent breast cancer, comprising administering a next-generation selective estrogen receptor degrading drug (ngSERD) to a patient afflicted with such cancer, wherein the cancer has recurred or progressed after at least one prior course of endocrine therapy. This document also relates to the use of ngSERD for use in treating such breast cancer, and for the manufacture of a medicament for treating such breast cancer. [Background technology]

[0002] Breast cancer is the most frequently diagnosed malignancy in women worldwide and the leading cause of cancer mortality among women worldwide. Locally advanced (inoperable) and / or metastatic breast cancer (MBC) remains essentially incurable. Recent advances in MBC therapy have demonstrated that the concept of MBC as a chronic disease controlled by continuous therapy over an extended period of time is realistic, at least for certain subgroups (see, e.g., Harbeck and Gnant, Lancet 2017;389(10074):1134-50). Therefore, 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 (https: / / seer.cancer.gov / statfacts / html / breast-subtypes.html, accessed October 31, 2022). Endocrine therapy (ET) has been the mainstay and standard of care for HR+ breast cancer for decades, but preferred ETs have evolved over time, used as monotherapy or in combination. One class of ETs, selective estrogen receptor modulators (SERMs), bind to the estrogen receptor (ER), thereby preventing the stimulation of breast tumor growth that would otherwise occur through 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. Aromatase inhibitors (AIs), a second class of ETs, block the activity of the aromatase enzyme, thereby blocking estrogen biosynthesis. Thus, instead of directly blocking the ligand / receptor interaction as in the case of SERMs, Ai therapy prevents estrogen-mediated activation of the ER, depleting the pool of ligands available for receptor activation. Examples of Ai approved by the FDA for the treatment of breast cancer include anastrazole and letrazole. Ai are primarily used in postmenopausal women, but can be used in premenopausal settings when combined with ovarian activity suppressors such as goserelin or leuprolide. The third class of ETs is selective estrogen receptor degraders (SERDs). Fulvestrant (e.g., Faslodex®) is the only SERD currently approved for clinical use. Like SERMs, fulvestrant binds to the estrogen receptor but does not mimic estrogen; therefore, it is referred to as a pure antiestrogen. Furthermore, fulvestrant's binding to the ER causes estrogen receptor degradation. The clinical utility of fulvestrant has become better understood in recent years, leading to its use in early-stage therapeutic strategies.One factor that likely slowed the early clinical use of fulvestrant is the fact that it is administered as a monthly intramuscular injection. This fact, along with the recognition that more frequent administration of oral next-generation SERDs may result in greater net degradation of the estrogen receptor over time, has spurred significant interest in the development of oral next-generation SERDs.

[0004] Mutations in the estrogen receptor (ESR1m) affecting the ligand-binding domain of ERα result in constitutively active, estrogen-independent ER signaling, thereby counteracting the effects of anti-inflammatory drugs (AIs) and SERMs. Clinically, ESR1m is associated with acquired resistance to AIs, most commonly occurring in patients treated with AIs in the setting of advanced breast cancer. Today, in many countries, the majority of patients with advanced breast cancer receive AIs in combination with CDK4 / 6 inhibitors rather than as monotherapy. The PALOMA-3 and MONARCH-3 translational studies have shown that ESR1m is frequently acquired in patients treated with CDK4 / 6 inhibitors plus ET (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 terms of both PFS and OS, primarily due to the lack of effective treatment options to address this driving 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 overactivation of the pathway causes cells to mistakenly progress through the G1 / S checkpoint and proliferate. Estrogen itself is mitogenic and increases both cyclin D1 and CDK4 / 6 activity, promoting hyperproliferation in hormone-regulated breast cancer. Rb is a tumor suppressor protein that blocks cell cycle progression when bound to E2 transcription factors (E2Fs). Therefore, targeting CDK4 / 6 has been shown to be a desirable option for intervening in the overactivated cyclin D-CDK4 / 6-INK4-Rb pathway in HR+ breast cancer, as Rb remains functional and can help control cell proliferation. Therefore, CDK4 / 6 inhibitors have been found to be particularly useful drugs for the treatment of 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 to circumvent resistance to antiestrogens.

[0006] Although CDK4 / 6 inhibitors have proven highly effective in clinical trials for ER+ breast cancer patients, spontaneous or acquired resistance to these drugs is common. Approximately 20% of breast cancer patients treated with CDK4 / 6 inhibitors fail treatment. These patients' tumors harbor mutations that allow them to evade the effects of CDK4 / 6 inhibitors and grow in their presence. This spontaneous resistance to CDK4 / 6 inhibitors is generally associated with activation of the cyclin D-CDK4 / 6-Rb pathway. Acquired resistance to CDK4 / 6 inhibitors after an initial response can manifest in several ways, including activation of cyclin D-CDK4 / 6-Rb, activation of other growth pathways, changes in the tumor microenvironment, and modulation of tumor metabolism. Within two years of initiating treatment in the PALOMA-2 trial, more than 30% of enrolled patients developed resistance to the CDK4 / 6 inhibitor palbociclib. Treatment of CDK4 / 6-resistant HR+ / HER2- breast cancer represents a significant unmet medical need.

[0007] Next-generation oral selective estrogen receptor degraders (ngSERDs) aim to become the mainstay endocrine therapy for patients with HR+ breast cancer by blocking ER signaling to a greater extent than current 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 ESR1 wild-type (ESR1wt) and mutant (ESR1m) tumors, and has shown promising clinical activity in early clinical trials.

[0008] As mentioned above, current guidelines recommend combining endocrine therapy, such as an AI or SERD, with a cyclin-dependent kinase 4 and 6 inhibitor (CDK4 / 6i) as first-line (1L) therapy for HR+ / HER- breast cancer (e.g., Cardoso F et al. Ann. Oncol. 2020;S0923-7534,(20),42460-3). Unfortunately, most patients ultimately progress with CDK4 / 6 inhibitor plus ET and die of their disease. Once a patient progresses on 1L CDK4 / 6i-based therapy, subsequent endocrine-based therapies may have limited efficacy and challenging tolerability profiles. Many patients are eventually treated with chemotherapy. However, drug resistance eventually develops, leading to disease progression (i.e., cancer growth is not adequately or not controlled at all by the previously administered drug regimen, as assessed, for example, by radiological or other analytical means).

[0009] In addition to the innate and acquired resistance profile, the presence of lung and / or liver metastases is an important prognostic factor in advanced breast cancer, indicating an aggressive and difficult-to-treat disease.

[0010] Thus, there is a need for improved therapeutic approaches for the treatment of HR+, HER2- breast cancer, particularly in patients with locally advanced or metastatic breast cancer that has recurred or progressed after at least one prior course of endocrine therapy. It is an object of the present specification to provide new therapeutic methods for such patients. Summary of the Invention

[0011] In a first aspect, the description 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 a therapeutically effective amount of a next-generation selective estrogen receptor degrading drug (ngSERD) to a patient afflicted with such cancer, wherein the cancer has recurred or progressed after at least one prior course of endocrine therapy.

[0012] In this embodiment and other embodiments detailed below, the "recurrence" or "progression" of cancer is after prior treatment with endocrine therapy (ET), optionally a SERM or an aromatase inhibitor. The treated patient may also have received chemotherapy and / or CDK4 / 6 inhibitor therapy and may have received no more than one ET or chemotherapy regimen for the treatment of progressive disease. The CDK4 / 6 inhibitor is typically administered in combination with ET, e.g., in combination with an AI.

[0013] The terms "treat," "treating," and "treatment" refer to at least partially alleviating, inhibiting, preventing, and / or ameliorating a condition, disorder, or disease, such as breast cancer. The term "cancer treatment" includes both in vitro treatment and in vivo treatment, including treatment in a warm-blooded animal such as a human. The effectiveness of cancer treatment can be evaluated in various ways, including, but not limited to: inhibition of cancer cell growth (including reversal of cancer growth); promotion of cancer cell death (e.g., by promoting apoptosis or another cell death mechanism); symptom improvement; duration of response to treatment; delay in disease progression; and prolongation of survival. Treatment can also be evaluated in terms of the nature and extent of side effects associated with treatment. Furthermore, effectiveness can be evaluated in terms of biomarkers, such as levels of expression or phosphorylation of proteins known to be associated with particular biological phenomena. Other evaluations of effectiveness are known to those of skill in the art.

[0014] The term "therapeutically effective amount" refers to an amount of a compound or combination of compounds described herein sufficient to affect the intended use, including but not limited to disease treatment. A therapeutically effective amount may vary depending on the intended use (in vitro or in vivo), or the subject and disease state being treated (e.g., the subject's weight, age, and sex), the severity of the disease state, the mode of administration, etc., and can be readily determined by one of ordinary skill in the art. The term also applies to a dose that induces a particular response (e.g., magnitude of apoptosis) in target cells. Specific doses 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 timing of administration, the tissue to which it is administered, and the physical delivery system by which the compound is delivered.

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

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

[0017] In a related aspect, the description provides an ngSERD for use in the manufacture of a medicament for the treatment of HR+, HER2-, metastatic, or locally recurrent breast cancer, wherein the medicament is being used to treat breast cancer that has recurred or progressed after at least one prior course of endocrine therapy.

[0018] In embodiments according to the present invention, the breast cancer has recurred or progressed after at least one course of endocrine therapy, and optionally the endocrine therapy is selected from an AI or a SERM therapy.

[0019] In embodiments herein, the breast cancer has recurred or progressed after at least one course of therapy with a CDK4 / 6 inhibitor. In such embodiments, the CDK4 / 6 inhibitor may have been administered in combination with an endocrine therapy, such as an aromatase inhibitor.

[0020] In embodiments according to the present invention, the patient has breast cancer that has a mutation in the estrogen receptor (ESR1m), ie, the breast cancer is ESR1m breast cancer.

[0021] In embodiments according to the present invention, the patient has visceral metastases (eg, metastases to the liver and / or lungs).

[0022] In embodiments herein, the ngSERD for use in therapy, for use in a method of treatment, or for use in a process for manufacturing a medicament for use in therapy 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 embodiments, camizestrant or a pharmaceutically acceptable salt thereof may be administered at a dose of 75 mg or 150 mg daily. In some embodiments, the ngSERD for use in therapy, for use in a method of treatment, or for use in a process for manufacturing a medicament for use in therapy is camizestrant in its non-salt form (i.e., as its free base).

[0023] In embodiments according to the present specification, the ngSERD for use in a treatment, method of treatment, or manufacture of a medicament improves progression-free survival (PFS) relative to the PFS observed with the standard of care (SoC). In such embodiments, the SoC can be fulvestrant.

[0024] In embodiments according to the present specification, the ngSERD for use in a treatment, for use in a method of treatment, or for use in a medicament comprising the ngSERD improves overall survival (OS) relative to standard of care.

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

[0026] In embodiments according to the present disclosure, the ngSERD for use in a treatment, for use in a method of treatment, or for use in a medicament comprising the ngSERD, has a clinical benefit rate (CBR) at 24 weeks. 24) versus standard treatment.

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

[0028] In embodiments herein, the ngSERD for use in a treatment, for use in a method of treatment, or for use in a medicament comprising the ngSERD does not cause clinically significant treatment-related adverse effects (TRAEs).

[0029] In an embodiment according to the present specification, a kit is provided that includes a medicament comprising an ngSERD and instructions for using the medicament in the treatment of HR+ / HER2- metastatic or locally recurrent breast cancer in patients whose cancer has recurred or progressed after at least one prior course of endocrine therapy.

[0030] In an embodiment according to the present specification, a pharmaceutical composition is provided comprising an ngSERD and at least one pharmaceutically acceptable excipient for use in treating HR+ / HER2- metastatic or locally recurrent breast cancer in patients whose cancer has recurred or progressed after at least one prior course of endocrine therapy. [Brief explanation of the drawings]

[0031] In order that the present invention may be more readily understood, reference is made herein to the following drawings: [Figure 1] Kaplan-Meier curves showing investigator-assessed progression-free survival probability versus time on treatment (months) with fulvestrant ((F) 500 mg monthly injection) or camizestrant ((C) 75 mg or 150 mg once-daily tablets). Both doses of camizestrant provide clinically meaningful improvements in PFS over fulvestrant. The proportion of patients who were progression-free at 12 months was 23.8%, 34.3%, and 44.5% for fulvestrant, camizestrant 75 mg, and camizestrant 150 mg, respectively. [Figure 2] Kaplan-Meier curves showing progression-free survival probability assessed by blinded independent central review (BICR) versus time on treatment (months) with fulvestrant ((F) 500 mg monthly injection) or camizestrant ((C) 75 mg or 150 mg once-daily tablets). Both doses of camizestrant are seen to provide clinically meaningful improvements in PFS over fulvestrant. Patient-level discrepancies in progression between BICR and investigator assessments are consistent with those generally observed (see K Borradaile et al., Cancer Research 2009:62(2 Suppl):Abstract No. 2081). [Figure 3] Kaplan-Meier curves showing the probability of progression-free survival versus time (months) for patients who had received prior CDK4 / 6 inhibitor treatment. In this subgroup who had received prior CDK4 / 6i treatment, both camizestrant 75 mg and 150 mg treatments provided improvements comparable to fulvestrant treatment, with HRs of 0.49 and 0.68, respectively. [Figure 4]1 is a Kaplan-Meier curve showing the probability of progression-free survival versus time (in months) for patients who had lung and / or liver metastases before treatment initiation. In this subgroup, both camizestrant 75 mg and 150 mg treatments resulted in improvements comparable to fulvestrant treatment, with HRs of 0.43 and 0.55, respectively. [Figure 5] Kaplan-Meier curves showing the probability of progression-free survival versus time (months) for patients who had an estrogen receptor mutation (ESR1m) before treatment initiation. In this subgroup, both camizestrant 75 mg and 150 mg treatments resulted in improvements comparable to fulvestrant treatment, with HRs of 0.33 and 0.55, respectively. [Figure 6] Change in ESR1m ctDNA total mutant allele frequency (sVAF%) by treatment group and visit (pretreatment is the comparison of samples collected at screening with samples collected on cycle 1 day 1; CxD1 is the comparison of samples collected on cycle 1 day 1 with samples collected on cycle x day 1). Mutations defined as ESR1m are E380Q, V422del, S463P, L536H / P / R, and Y537C / D / N / S. Points represent individual patients; boxes represent upper, median, and lower quartiles; whiskers represent the 1.5 interquartile range. Treatment with camizestrant 75 mg and 150 mg reduced ESR1m levels by 100% or nearly 100% at all time points. In contrast, a decrease in ESR1m ctDNA is observed in the fulvestrant group, but the degree of decrease is lower than that observed with kamizestrant. DETAILED DESCRIPTION OF THE INVENTION

[0032] Estrogen receptor-α is a well-established drug target in breast cancer, and ET is the mainstay of treatment. ETs include SERMs (e.g., tamoxifen), SERDs (fulvestrant), and AIs (e.g., the non-steroidal AIs anastrozole and letrozole, and the steroidal AI exemestane). It has been well documented that CDK4 / 6 inhibitors (palbociclib, ribociclib, or abemaciclib) enhance the efficacy of ET in previously untreated and previously treated HR+ / HER2- metastatic breast cancer (MBC) by extending progression-free survival (PFS) and overall survival (OS). Current treatment guidelines across many regions recommend AIs in combination with CDK4 / 6 inhibitors as standard of care in the first-line (1L) HR+ / HER2- MBC setting for most postmenopausal and premenopausal women, and preferably for men, in combination with an LHRH agonist. At the date of writing, three CDK4 / 6 inhibitors, namely palbociclib, abemaciclib, and ribociclib, are approved for the treatment of HR+, HER2- breast cancer.

[0033] Unfortunately, most patients ultimately progress with CDK4 / 6 inhibitors plus AIs and die from their disease. Once patients progress on first-line CDK4 / 6 inhibitor-based therapy, subsequent endocrine-based therapies have limited efficacy and challenging tolerability profiles. Most patients may eventually be treated with chemotherapy. Therefore, improved therapies for patients who progress after treatment with an AI and a CDK4 / 6i are needed. Treating HR+, HER2- advanced breast cancer patients who are CDK4 / 6 inhibitor-resistant, have tumors with estrogen receptor mutations (i.e., ESR1m status), or have tumors that have metastasized to the lung and / or liver (or visceral metastases in addition to these) is particularly challenging. The purpose of this document is to provide new treatment options for this patient population.

[0034] In a first embodiment, the present disclosure 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 a therapeutically effective amount of a next-generation selective estrogen receptor degrading drug (ngSERD) to a patient afflicted with such cancer, wherein the cancer has recurred or progressed after at least one prior course of endocrine therapy. In an embodiment, the prior endocrine therapy is selected from aromatase or SERM therapy, and optionally, the prior therapy included administration of an aromatase inhibitor selected from anastrazole, letrozole, or exemestane and / or a selective estrogen receptor modulator (SERM), such as tamoxifen.

[0035] In related embodiments, the description provides an ngSERD for use in treating HR+, HER2- metastatic or locally recurrent breast cancer, wherein the breast cancer has recurred or progressed after at least one prior course of endocrine therapy.

[0036] In related embodiments, the description provides an ngSERD for use in the manufacture of a medicament for the treatment of HR+, HER2-, metastatic or locally recurrent breast cancer, where the medicament is being used to treat breast cancer that has recurred or progressed after at least one prior course of endocrine therapy. In related embodiments, the description provides a kit comprising a medicament containing ngSERD and instructions for use of the pharmaceutical composition in the treatment of HR+ / HER2- metastatic or locally recurrent breast cancer in patients whose cancer has recurred or progressed after at least one prior course of endocrine therapy.

[0037] In a related embodiment, the description provides a pharmaceutical composition comprising an ngSERD and at least one pharmaceutically acceptable excipient for use in treating HR+ / HER2- metastatic or locally recurrent breast cancer in patients whose cancer has recurred or progressed after at least one prior course of endocrine therapy.

[0038] For the avoidance of doubt, the embodiments provided below relate to additional characteristic features of embodiments relating to methods of treatment, ngSERD for use, ngSERD for use in the manufacture of a medicament for treatment, kits and compositions for use in other embodiments herein (e.g., the embodiment immediately above), which may be incorporated into these general embodiments. For example, the reader will understand that an embodiment relating to a method of treatment having particular characteristic features can be translated to ngSERD for use in treating the same condition in a patient with the same characteristic features, outcome, etc.

[0039] As mentioned above, SERDs downregulate estrogen receptors by binding to them and degrading them. The first-generation SERD, fulvestrant, is administered as a monthly injection, and it is hypothesized that next-generation oral SERDs may be useful in treating HR+, HER2- breast cancer because they result in greater net degradation of estrogen receptors through more frequent administration and higher net systemic concentrations.

[0040] In embodiments, the ngSERD may be selected from camizestrant or a pharmaceutically acceptable salt thereof, gildestrant or a pharmaceutically acceptable salt thereof, imrunestrant or a pharmaceutically acceptable salt thereof, and elacestrant or a pharmaceutically acceptable salt thereof. In embodiments herein, the ngSERD may be used in the form of a free base or a pharmaceutically acceptable salt or prodrug. The term "pharmaceutically acceptable" is used herein to specify that an object (e.g., a salt, a dosage form (e.g., a tablet or capsule), or an excipient (e.g., a diluent or carrier)) is suitable for use in patients. An exemplary list of pharmaceutically acceptable salts may be found in "Handbook of Pharmaceutical Salts: Properties, Selection and Use," P.H. Stahl and C.G. Wermuth, editors, Weinheim / Zurich: Wiley-VCH / VFiCA, 2002 or later editions.

[0041] In an embodiment, the ngSERD is camizestrant or a pharmaceutically acceptable salt thereof.

[0042] In an embodiment, the ngSERD is giledestrant or a pharmaceutically acceptable salt thereof.

[0043] In an embodiment, the ngSERD is imrunestrant or a pharmaceutically acceptable salt thereof.

[0044] In embodiments, an ER PROTAC may be used in place of ngSERD. In embodiments, the ER PROTAC may be ARV-471.

[0045] Camizestrant (AZD9833) has the following chemical structure:

[0046] [ka]

[0047] The free base of camizestrant is known by the chemical name 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 WO 2018077630(A1).

[0048] Giledestrant (GDC-9545) has the following chemical structure:

[0049] [ka]

[0050] The free base of giledestrant is known by the chemical name 3-[(1R,3R)-1-[2,6-difluoro-4-[[1-(3-fluoropropyl)azetidin-3-yl]amino]phenyl]-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]-2,2-difluoropropan-1-ol. Giledestrant is disclosed in WO 2016097072(A1).

[0051] Imulnestrand (LY-3484356) has the following chemical structure:

[0052] [ka]

[0053] The free base of imrunestrant is known by the chemical name 5R-5-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-chromeno[4,3-c]quinolin-2-ol. Imulnestrant is disclosed in WO2020014435.

[0054] ARV-471 is disclosed in WO2018102725 and has the following chemical structure:

[0055] [ka]

[0056] In embodiments, camizestrant or a pharmaceutically acceptable salt thereof is administered to a subject at a daily dosage of 75 mg or 150 mg.

[0057] The nature of HR+, HER2-, metastatic, or locally recurrent breast cancer can be further defined in terms of prior treatments the patient has received, the mutational status of the cancer, the response profile 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 may be predictive of treatment success.

[0058] In embodiments herein, the therapeutic method, ngSERD, for use in treatment or for use in the manufacture of a medicament, kit, or pharmaceutical composition for use, improves the time to disease progression or progression-free survival (PFS) relative to the PFS obtained from the use of fulvestrant (a first-generation SERD). In such embodiments, the improvement in PFS is relative to the improvement in PFS observed with standard treatment, i.e., fulvestrant administered by monthly injection at the approved dose of 500 mg. Clinical activity, as assessed by PFS, can be determined by standard assessment of tumor response according to RECIST 1.1 (Eisenhauser et al., Eur J Cancer 2009 Jan;45(2):228-47). RECIST criteria can be assessed by the treating physician / investigator or by blinded independent central review (BICR).

[0059] The SERENA-2 clinical trial, further details of which are provided below, evaluated the efficacy of camizestrant administered once daily in tablet form at doses of 75 mg and 150 mg for the treatment of patients with HR+, HER2- metastatic or locally recurrent breast cancer that had recurred or progressed after at least one prior line of endocrine therapy. Control patients in the study were treated with monthly 500 mg injections of fulvestrant, a standard-of-care first-generation SERD. The study was able to distinguish between the camizestrant treatment group and the standard-of-care fulvestrant (F) treatment group, but was unable to distinguish between the 75 mg and 150 mg camizestrant cohorts.

[0060] Fulvestrant, used as the standard-of-care comparator in this study, provided a median PFS of 3.7 months (90% CI). In contrast, the 75 mg and 150 mg camizestrant treatment groups provided investigator-assessed median PFS of 7.2 and 7.7 months (90% CI), respectively, with hazard ratios of 0.58 (p=0.0124) and 0.67 (p=0.0161) (see Figure 1). The proportions of patients who were progression-free at 12 months were 23.8%, 34.3%, and 44.5% for fulvestrant, 75 mg camizestrant, and 150 mg camizestrant, respectively. Thus, a clinically meaningful improvement in PFS was demonstrated for both camizestrant treatment arms versus fulvestrant across all patients in the clinical trial, regardless of prior treatment, estrogen receptor mutation status (ESR1m), or the presence of visceral metastases. In an embodiment, PFS by RECIST 1.1 criteria is assessed by the treating physician or investigator.

[0061] When PFS in the SERENA-2 trial was assessed according to RECIST 1.1 criteria by blinded independent central review, fulvestrant, used in this study as the standard-of-care comparator, provided a median PFS of 3.7 months (90% CI). In contrast, the 75 mg and 150 mg camizestrant treatment groups provided median PFS (90% CI) of 7.4 and 12.7 months, respectively, and hazard ratios of 0.56 (p=0.0079) and 0.47 (p<0.001), as assessed by BICR (see Figure 2).

[0062] Therefore, the improvement in PFS observed under RECIST 1.1 criteria by either the investigator or BICR represents an improvement in PFS in the overall population of participants in SERENA-2 of at least 3.5 months in both camizestrant groups (75 mg and 150 mg). As noted above, the study was unable to distinguish between the camizestrant treatment groups, but was able to distinguish between the camizestrant treatment group and the fulvestrant group.

[0063] Thus, 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 afflicted with such cancer a therapeutically effective amount of a next-generation selective estrogen receptor degrading drug (ngSERD), wherein the cancer has recurred or progressed after at least one prior line of endocrine therapy, and wherein the method extends the time to disease progression relative to the time to disease progression observed with fulvestrant treatment.

[0064] Thus, in an embodiment, the present disclosure 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 afflicted with such cancer, wherein the cancer has recurred or progressed after at least one prior course of endocrine therapy, and wherein the method extends progression-free survival relative to the progression-free survival observed with fulvestrant treatment.

[0065] In embodiments, the present disclosure 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 a therapeutically effective amount of camizestrant to a patient suffering from such cancer, wherein the cancer has recurred or progressed after at least one prior course of endocrine therapy, and wherein the method extends progression-free survival relative to progression-free survival observed with fulvestrant treatment, and wherein the hazard ratio for disease progression relative to fulvestrant is 0.67 or less. In such embodiments, the hazard ratio for disease progression with camizestrant treatment relative to fulvestrant is 0.58 or less, e.g., 0.56 or less, or less than 0.47. In the SERENA-2 trial detailed herein, the hazard ratios obtained for camizestrant treatment relative to fulvestrant were all statistically significant and associated with clinically meaningful improvements in progression-free survival relative to progression-free survival observed with standard of care treatment.

[0066] In embodiments, the present disclosure 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 a therapeutically effective amount of camizestrant to a patient suffering from such cancer, wherein the cancer has recurred or progressed after at least one prior course of endocrine therapy, and the time to disease progression is at least 5 months, e.g., 6 months or more, 7 months or more, 8 months or more, 9 months or more, or 12 months or more. The time to disease progression obtained from camizestrant treatment is statistically significant and represents a significant improvement over the time to disease progression observed with the standard of care, fulvestrant, at its approved dose.

[0067] Thus, 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, wherein the cancer has recurred or progressed after at least one prior 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 with camizestrant treatment relative to fulvestrant is 0.67 or less, 0.58 or less, 0.56 or less, or 0.47 or less.

[0068] In embodiments, the present disclosure 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 afflicted with such cancer, wherein the cancer has recurred or progressed after at least one prior course of endocrine therapy, and wherein the median progression-free survival with camizestrant treatment is at least 5 months, e.g., 6 months or more, 7 months or more, 8 months or more, 9 months or more, or 12 months or more.

[0069] In an embodiment, the present disclosure 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, wherein the cancer has recurred or progressed after at least one prior course of endocrine therapy, and wherein the method improves progression-free survival. In an embodiment, the improvement in progression-free survival is relative to the improvement in progression-free survival achieved with fulvestrant therapy. In an embodiment, the extension of PFS with the use of camizestrant relative to the use of fulvestrant is at least 1 month, e.g., 2 months or more, 3 months or more, or 4 months or more.

[0070] In embodiments, the present disclosure 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 afflicted with such cancer, wherein the cancer has recurred or progressed after at least one prior endocrine therapy, and wherein the median time to disease progression resulting from treatment with camizestrant is extended by at least 2 months, optionally at least 3.5 months, relative to the median time observed with treatment with fulvestrant.

[0071] In embodiments in which a treatment method improves PFS, disease progression is assessed according to RECIST 1.1 criteria. In embodiments, assessment of disease progression according to RECIST 1.1 criteria is performed by the investigator or treating physician. In embodiments, assessment of disease progression according to RECIST 1.1 criteria is performed by blinded independent central review (BICR).

[0072] In embodiments, the at least one prior endocrine therapy regimen may be an aromatase inhibitor regimen, i.e., anastrazole or letrazole or exemestane regimen. In embodiments, the at least one prior endocrine therapy regimen may be a SERM regimen, optionally with tamoxifen.

[0073] In embodiments, provided herein is 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 afflicted with such cancer, wherein the cancer has recurred or progressed after at least one prior course of endocrine therapy, and wherein the treatment improves overall survival.

[0074] In an embodiment, the present disclosure 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, wherein the cancer has recurred or progressed after at least one prior course of endocrine therapy, and wherein the treatment improves the objective response rate (ORR) relative to the ORR achieved with fulvestrant treatment. ORR is defined as the percentage of patients who achieved a complete response (CR) or partial response (PR) at at least one investigator-assessed visit prior to any evidence of progression. A complete or partial response is assessed according to RECIST 1.1 criteria, as detailed below. In an embodiment, the ORR achieved with this treatment method is at least 15.7%, e.g., 20.3%. ORR data from the SERENA-2 trial are provided in Table 1 below.

[0075] A complete response means the disappearance of all target lesions (TL) since baseline. All pathological lymph nodes selected as TLs must have a shrinkage of <10 mm in the short axis. A partial response means a reduction of at least 30% in the sum of TL diameters, relative to the baseline sum of diameters. Other evaluations of target lesions include stable disease (SD), which shows neither sufficient shrinkage to be considered a PR nor sufficient increase to be considered progressive disease (PD), and progressive disease, which shows an increase of at least 20% in the sum of TL diameters, relative to the smallest sum on study (including the baseline sum, if it is the smallest on study), and in addition to a relative increase of 20%, the sum must also show an absolute increase of at least 5 mm. Further information regarding the evaluation of target and non-target lesions is provided below.

[0076] [Table 1]

[0077] In embodiments, described herein is 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 afflicted with such cancer, characterized in that the cancer has recurred or progressed after at least one prior course of endocrine therapy, and wherein the treatment results in a clinical benefit rate at 24 weeks (CBR). 24 ) compared with BR obtained from fulvestrant treatment 24 To provide a treatment method for improving the above.

[0078] In embodiments, described herein is 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 afflicted with such cancer, characterized in that the cancer has recurred or progressed after at least one prior course of endocrine therapy, and wherein the treatment results in a 24-week clinical benefit rate (CBR) of at least 48%, e.g., 52%. 24 ) to provide a method of treatment.

[0079] CBR 24 CBR is defined as the percentage of patients with a best objective response (BoR) of CR or PR in the first 25 weeks (allowing for late evaluation within the evaluation window) or SD (no subsequent cancer therapy) for at least 23 weeks after initiation of treatment (allowing for early evaluation within the evaluation window). CBR is defined based on investigator's assessment of RECIST 1.1.

[0080] [Table 2]

[0081] In embodiments, provided herein are methods 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 afflicted with such cancer, wherein the cancer has recurred or progressed after at least one prior course of endocrine therapy and one prior course of therapy with a CDK4 / 6 inhibitor. In embodiments, the patient's disease has recurred or progressed after therapy with palbociclib. In embodiments, the patient's disease has recurred or progressed after therapy with abemaciclib. In embodiments, the patient's disease has recurred or progressed after therapy with ribociclib.

[0082] In embodiments, the present disclosure 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 afflicted with such cancer, wherein the cancer has recurred or progressed after at least one prior course of endocrine therapy and one prior course of therapy with a CDK4 / 6 inhibitor, and wherein the median time to progression is extended by at least 3 months relative to the median time observed with fulvestrant treatment.

[0083] 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 subject in need thereof, wherein the subject's cancer has recurred or progressed after at least one prior course of endocrine therapy and one prior course of therapy with a CDK4 / 6 inhibitor, and wherein the hazard ratio for disease progression with camizestrant treatment relative to fulvestrant treatment is 0.68 or less, e.g., 0.49.

[0084] 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 subject in need thereof, wherein the subject's cancer has recurred or progressed after at least one prior course of endocrine therapy and one prior course of therapy with a CDK4 / 6 inhibitor, and the time to disease progression is at least 3.8 months, e.g., 5.8 months.

[0085] [Table 3] n = number of patients in each group with the described characteristics

[0086] In embodiments, provided herein is 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 afflicted with such cancer, wherein the cancer has recurred or progressed after at least one prior course of endocrine therapy and one prior course of chemotherapy.

[0087] In embodiments, provided herein is 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 afflicted with such cancer, wherein the cancer has not received prior treatment 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 the metastatic setting).

[0088] In embodiments, the present disclosure 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 afflicted with such cancer, wherein the cancer has recurred or progressed after at least one prior course of endocrine therapy, and the patient has visceral metastases prior to initiating camizestrant treatment.

[0089] In embodiments, the present disclosure 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 afflicted with such cancer, wherein the cancer has recurred or progressed after at least one prior course of endocrine therapy, and the patient has been identified as having liver and / or lung metastases prior to initiating camizestrant treatment.

[0090] In embodiments, the present disclosure 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 afflicted with such cancer, wherein the cancer has recurred or progressed after at least one prior course of endocrine therapy and the patient has been identified as having liver and / or lung metastases prior to initiating camizestrant treatment, and wherein the median time to progression is extended by at least 3 months, e.g., 3.6 months or 5.2 months, relative to the median time observed with fulvestrant treatment.

[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 suffering from such cancer, wherein the cancer has recurred or progressed after at least one prior course of endocrine therapy and the patient has been identified as having liver and / or lung metastases prior to initiating camizestrant treatment, and wherein the hazard ratio for disease progression with camizestrant treatment relative to fulvestrant treatment is 0.55 or less, e.g., 0.43.

[0092] In embodiments, the present disclosure 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 subject afflicted with such cancer, wherein the cancer has recurred or progressed after at least one prior course of endocrine therapy and the patient has been identified as having liver and / or lung metastases prior to initiating camizestrant treatment, and wherein the time to disease progression is at least 5.6 months, e.g., 7.2 months.

[0093] [Table 4]

[0094] In embodiments, the present disclosure 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 afflicted with such cancer, wherein the cancer has recurred or progressed after at least one prior course of endocrine therapy, and the patient has been identified as having breast cancer with an estrogen receptor mutation. In embodiments, the estrogen receptor mutation is selected from E380Q, V422del, S463P, L536H, L536P, L536R, Y537C, Y537D, Y537N, Y537S, and D538G.

[0095] In embodiments, the present disclosure 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 afflicted with such cancer, wherein the cancer has recurred or progressed after at least one prior course of endocrine therapy, and the cancer has been identified as expressing ESR1m.

[0096] In embodiments, the present disclosure 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 afflicted with such cancer, wherein the cancer has recurred or progressed after at least one prior course of endocrine therapy and the patient has been identified as having ESR1m breast cancer, and wherein the median time to disease progression is extended by at least 3 months, e.g., 4.1 months or 7.0 months, relative to the median observed with fulvestrant treatment.

[0097] In embodiments, the present disclosure 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 afflicted with such cancer, wherein the cancer has recurred or progressed after at least one prior course of endocrine therapy and the patient has been identified as having ESR1m breast cancer, and wherein the hazard ratio for disease progression with camizestrant treatment relative to fulvestrant treatment is 0.55 or less, e.g., 0.33.

[0098] In embodiments, the present disclosure 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 afflicted with such cancer, wherein the cancer has recurred or progressed after at least one prior course of endocrine therapy and the patient has been identified as having ESR1m breast cancer, and wherein the time to disease progression is at least 6.3 months, e.g., 9.2 months.

[0099] In embodiments, determining the presence of an estrogen receptor mutation in a patient's cancer or the ESR1m status of the breast cancer is based on circulating tumor DNA testing. In embodiments, determining the presence of an estrogen receptor mutation in a patient's cancer or the ESR1m status of the breast cancer is based on analysis of a tumor biopsy for the presence of ESR1m.

[0100] [Table 5]

[0101] In one embodiment, the description provides an ngSERD (e.g., camizestrant or a pharmaceutically acceptable salt thereof, optionally administered orally once daily at a dose of 75 mg or 150 mg) for use in treating HR+, HER2- metastatic or locally recurrent breast cancer, wherein the breast cancer has recurred or progressed after at least one prior course of endocrine therapy.

[0102] In one embodiment, the description provides an ngSERD (e.g., camizestrant or a pharmaceutically acceptable salt thereof, optionally administered orally once daily at a dose of 75 mg or 150 mg) for use in treating HR+, HER2- metastatic or locally recurrent breast cancer, characterized in that the breast cancer has recurred or progressed after at least one prior course of endocrine therapy; a) its use improves the median time to disease progression by at least 3.5 months relative to the median observed with fulvestrant treatment; and / or b) the hazard ratio for ngSERD treatment versus fulvestrant is 0.67 or less; and / or c) providing an ngSERD whose use results in a median time to disease progression of at least 7 months;

[0103] In one embodiment, the description provides an ngSERD (e.g., camizestrant or a pharmaceutically acceptable salt thereof, optionally administered orally once daily at a dose of 75 mg or 150 mg) for use in treating HR+, HER2- metastatic or locally recurrent breast cancer, wherein the breast cancer has recurred or progressed after at least one prior course of endocrine therapy and at least one prior course of therapy with a CDK4 / 6 inhibitor.

[0104] In one embodiment, the description provides an ngSERD (e.g., camizestrant or a pharmaceutically acceptable salt thereof, optionally administered orally once daily at a dose of 75 mg or 150 mg) for use in treating HR+, HER2- metastatic or locally recurrent breast cancer, wherein the breast cancer has recurred or progressed after at least one prior course of endocrine therapy and at least one prior course of therapy with a CDK4 / 6 inhibitor; a) its use improves the median time to disease progression by at least 1.7 months above the median observed with fulvestrant treatment, and / or b) the hazard ratio for ngSERD treatment versus fulvestrant is 0.68 or less; and / or c) providing an ngSERD whose use results in a median time to disease progression of at least 3.8 months;

[0105] In one embodiment, the description provides an ngSERD (e.g., camizestrant or a pharmaceutically acceptable salt thereof, optionally administered orally once daily at a dose of 75 mg or 150 mg) for use in treating HR+, HER2- metastatic or locally recurrent breast cancer, wherein the breast cancer has recurred or progressed after at least one prior course of endocrine therapy, and the cancer has been identified as having visceral metastases.

[0106] In one embodiment, the description provides an ngSERD (e.g., camizestrant or a pharmaceutically acceptable salt thereof, optionally administered orally once daily at a dose of 75 mg or 150 mg) for use in treating HR+, HER2- metastatic or locally recurrent breast cancer, characterized in that the breast cancer has recurred or progressed after at least one prior course of endocrine therapy, and the cancer has been identified as having visceral metastases; a) its use improves the median time to disease progression by at least 3.6 months beyond the median observed with fulvestrant treatment; and / or b) the hazard ratio for ngSERD treatment versus fulvestrant is 0.55 or less; and / or c) providing an ngSERD whose use results in a median time to disease progression of at least 5.6 months;

[0107] In one embodiment, the description provides an ngSERD (e.g., camizestrant or a pharmaceutically acceptable salt thereof, optionally administered orally once daily at a dose of 75 mg or 150 mg) for use in treating HR+, HER2- metastatic or locally recurrent breast cancer, wherein the breast cancer has recurred or progressed after at least one prior course of endocrine therapy, and the cancer has been identified as having an estrogen receptor mutation (e.g., a mutation in the estrogen receptor selected from E380Q, V422del, S463P, L536H, L536P, L536R, Y537C, Y537D, Y537N, Y537S, and D538G).

[0108] In one embodiment, the description provides an ngSERD (e.g., camizestrant or a pharmaceutically acceptable salt thereof, optionally administered orally once daily at a dose of 75 mg or 150 mg) for use in treating HR+, HER2- metastatic or locally recurrent breast cancer, wherein the breast cancer has recurred or progressed after at least one prior course of endocrine therapy, and the cancer has been identified as having an estrogen receptor mutation (e.g., a mutation in the estrogen receptor selected from E380Q, V422del, S463P, L536H, L536P, L536R, Y537C, Y537D, Y537N, Y537S, and D538G) based on testing of a sample obtained from the patient (e.g., testing performed by analyzing circulating tumor DNA), and the sample is, for example, a tumor biopsy or a blood sample.

[0109] In one embodiment, the description provides an ngSERD (e.g., camizestrant or a pharmaceutically acceptable salt thereof, optionally administered orally once daily at a dose of 75 mg or 150 mg) for use in treating HR+, HER2- metastatic or locally recurrent breast cancer, characterized in that the breast cancer has recurred or progressed after at least one prior course of endocrine therapy, and wherein use of the ngSERD improves overall survival relative to treatment with fulvestrant.

[0110] In one embodiment, the present description provides camizestrant, or a pharmaceutically acceptable salt thereof, for use in the treatment of HR+, HER2-, metastatic or locally recurrent breast cancer, wherein the cancer has recurred or progressed after at least one prior course of endocrine therapy; a) its use improves the median time to disease progression by at least 3.5 months relative to the median observed with fulvestrant treatment; and / or b) the hazard ratio for the use of camizestrant treatment versus fulvestrant treatment is 0.67 or less; and / or c) providing camizestrant or a pharmaceutically acceptable salt thereof, the use of which results in a median time to disease progression of at least 7 months;

[0111] In one embodiment, the description provides an ngSERD (e.g., camizestrant or a pharmaceutically acceptable salt thereof, optionally administered orally once daily at a dose of 75 mg or 150 mg) for use in the manufacture of a medicament for the treatment of HR+, HER2-, metastatic, or locally recurrent breast cancer, wherein the medicament is for use in the treatment of breast cancer that has recurred or progressed after at least one prior course of endocrine therapy.

[0112] In one embodiment, the description provides a ngSERD (e.g., camizestrant or a pharmaceutically acceptable salt thereof, optionally administered orally once daily at a dose of 75 mg or 150 mg) for use in the manufacture of a medicament 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 course of endocrine therapy, wherein the medicament for use: a) an improvement of at least 3.5 months in the median time to disease progression relative to the median observed with fulvestrant treatment, and / or b) a hazard ratio of 0.67 or less for the treatment of ngSERD versus the treatment of fulvestrant; and / or c) Provide an ngSERD with a median time to disease progression of at least 7 months.

[0113] In one embodiment, the description provides an ngSERD (e.g., camizestrant or a pharmaceutically acceptable salt thereof, optionally administered orally once daily at a dose of 75 mg or 150 mg) for use in the manufacture of a medicament for the treatment of HR+, HER2- metastatic or locally recurrent breast cancer, wherein the breast cancer has recurred or progressed after at least one prior course of endocrine therapy and at least one prior course of therapy with a CDK4 / 6 inhibitor.

[0114] In one embodiment, the description provides a ngSERD (e.g., camizestrant or a pharmaceutically acceptable salt thereof, optionally administered orally once daily at a dose of 75 mg or 150 mg) for use in the manufacture of a medicament for the treatment of HR+, HER2- metastatic or locally recurrent breast cancer, wherein the breast cancer has recurred or progressed after at least one prior course of endocrine therapy and at least one prior course of therapy with a CDK4 / 6 inhibitor, and wherein the medicament for use: a) an improvement in the median time to disease progression that is at least 1.7 months longer than the median observed with fulvestrant treatment, and / or b) a hazard ratio of 0.68 or less for the treatment of ngSERD versus the treatment of fulvestrant; and / or c) Provide an ngSERD that results in a median time to disease progression of at least 3.8 months.

[0115] In one embodiment, the description provides an ngSERD (e.g., camizestrant or a pharmaceutically acceptable salt thereof, optionally administered orally once daily at a dose of 75 mg or 150 mg) for use in the manufacture of a medicament for the treatment of HR+, HER2- metastatic or locally recurrent breast cancer, wherein the breast cancer has recurred or progressed after at least one prior course of endocrine therapy, and the cancer has been identified as having visceral metastases.

[0116] In one embodiment, the description provides a ngSERD (e.g., camizestrant or a pharmaceutically acceptable salt thereof, optionally administered orally once daily at a dose of 75 mg or 150 mg) for use in the manufacture of a medicament for the treatment of HR+, HER2- metastatic or locally recurrent breast cancer, wherein the breast cancer has recurred or progressed after at least one prior course of endocrine therapy, and the cancer has been identified as having visceral metastases, wherein the medicament for use: a) an improvement in the median time to disease progression that is at least 3.6 months longer than the median observed with fulvestrant treatment, and / or b) a hazard ratio of 0.55 or less for the treatment of ngSERD versus the treatment of fulvestrant; and / or c) Provide an ngSERD that results in a median time to disease progression of at least 5.6 months.

[0117] In one embodiment, the description provides an ngSERD (e.g., camizestrant or a pharmaceutically acceptable salt thereof, optionally administered orally once daily at a dose of 75 mg or 150 mg) for use in the manufacture of a medicament for the treatment of HR+, HER2- metastatic or locally recurrent breast cancer, wherein the breast cancer has recurred or progressed after at least one prior course of endocrine therapy, and the cancer has been identified as having an estrogen receptor mutation (e.g., a mutation in the estrogen receptor selected from E380Q, V422del, S463P, L536H, L536P, L536R, Y537C, Y537D, Y537N, Y537S, and D538G).

[0118] In one embodiment, the description provides an ngSERD (e.g., camizestrant or a pharmaceutically acceptable salt thereof, optionally administered orally once daily at a dose of 75 mg or 150 mg) for use in the manufacture of a medicament for the treatment of HR+, HER2- metastatic or locally recurrent breast cancer, wherein the breast cancer has recurred or progressed after at least one course of endocrine therapy, and the cancer has been identified as having an estrogen receptor mutation (e.g., a mutation in the estrogen receptor selected from E380Q, V422del, S463P, L536H, L536P, L536R, Y537C, Y537D, Y537N, Y537S, and D538G) based on testing of a sample obtained from the patient (e.g., testing performed by analyzing circulating tumor DNA), and the sample is, for example, a tumor biopsy or a blood sample.

[0119] In one embodiment, the description provides an ngSERD (e.g., camizestrant or a pharmaceutically acceptable salt thereof, optionally administered orally once daily at a dose of 75 mg or 150 mg) for use in the manufacture of a medicament for the treatment of HR+, HER2- metastatic or locally recurrent breast cancer, wherein the breast cancer has recurred or progressed after at least one prior course of endocrine therapy, and wherein use results in improved overall survival relative to treatment with fulvestrant.

[0120] In one embodiment, the description provides a ngSERD (e.g., camizestrant or a pharmaceutically acceptable salt thereof, optionally administered orally once daily at a dose of 75 mg or 150 mg) for use in the manufacture of a medicament for the treatment of HR+, HER2- metastatic or locally recurrent breast cancer, wherein the cancer has recurred or progressed after at least one prior course of endocrine therapy, and wherein the medicament for use: a) an improvement in median time to disease progression of at least 3.5 months relative to the median observed with fulvestrant treatment, and / or b) a hazard ratio of camizestrant treatment use versus fulvestrant treatment of 0.67 or less, and / or c) Provide an ngSERD with a median time to disease progression of at least 7 months.

[0121] In one embodiment, a pharmaceutical composition is provided comprising an ngSERD (e.g., camizestrant or a pharmaceutically acceptable salt thereof, optionally administered orally once daily at a dose of 75 mg or 150 mg) and at least one pharmaceutically acceptable excipient for use in treating HR+, human epidermal growth factor receptor 2-negative HER2-, metastatic or locally recurrent breast cancer, wherein the cancer has recurred or progressed after at least one prior course of endocrine therapy.

[0122] In one embodiment, a pharmaceutical composition comprising an ngSERD (e.g., camizestrant or a pharmaceutically acceptable salt thereof, optionally administered orally once daily at a dose of 75 mg or 150 mg) and at least one pharmaceutically acceptable excipient for use in the treatment of HR+, human epidermal growth factor receptor 2-negative HER2-, metastatic or locally recurrent breast cancer, characterized in that the breast cancer has recurred or progressed after at least one prior course of endocrine therapy; a) its use improves the median time to disease progression by at least 3.5 months beyond the median observed with fulvestrant treatment; and / or b) the hazard ratio for treatment with ngSERD is 0.67 or less compared to treatment with fulvestrant; and / or c) providing a pharmaceutical composition, the use of which results in a median time to disease progression of at least 7 months;

[0123] In one embodiment, a pharmaceutical composition is provided comprising an ngSERD (e.g., camizestrant or a pharmaceutically acceptable salt thereof, optionally administered orally once daily at a dose of 75 mg or 150 mg) and at least one pharmaceutically acceptable excipient for use in treating HR+, human epidermal growth factor receptor 2-negative HER2-, metastatic or locally recurrent breast cancer, wherein the breast cancer has recurred or progressed after at least one prior course of endocrine therapy and at least one prior course of therapy using a CDK4 / 6 inhibitor.

[0124] In one embodiment, a pharmaceutical composition comprising an ngSERD (e.g., camizestrant or a pharmaceutically acceptable salt thereof, optionally administered orally once daily at a dose of 75 mg or 150 mg) and at least one pharmaceutically acceptable excipient for use in treating HR+, human epidermal growth factor receptor 2-negative HER2-, metastatic or locally recurrent breast cancer, wherein the breast cancer has recurred or progressed after at least one prior course of endocrine therapy and at least one prior course of therapy with a CDK4 / 6 inhibitor; a) its use improves the median time to disease progression by at least 1.7 months above the median observed with fulvestrant treatment, and / or b) the hazard ratio for treatment with ngSERD is 0.68 or less compared to treatment with fulvestrant; and / or c) providing a pharmaceutical composition, the use of which results in a median time to disease progression of at least 3.8 months.

[0125] In one embodiment, a pharmaceutical composition is provided comprising an ngSERD (e.g., camizestrant or a pharmaceutically acceptable salt thereof, optionally administered orally once daily at a dose of 75 mg or 150 mg) and at least one pharmaceutically acceptable excipient for use in treating HR+, human epidermal growth factor receptor 2-negative HER2-, metastatic or locally recurrent breast cancer, wherein the breast cancer has recurred or progressed after at least one prior course of endocrine therapy, and the cancer has been identified as having visceral metastases.

[0126] In one embodiment, a pharmaceutical composition comprising an ngSERD (e.g., camizestrant or a pharmaceutically acceptable salt thereof, optionally administered orally once daily at a dose of 75 mg or 150 mg) and at least one pharmaceutically acceptable excipient for use in treating HR+, human epidermal growth factor receptor 2-negative HER2-, metastatic or locally recurrent breast cancer, wherein the breast cancer has recurred or progressed after at least one prior course of endocrine therapy, and the cancer has been identified as having visceral metastases; a) its use improves the median time to disease progression by at least 3.6 months beyond the median observed with fulvestrant treatment; and / or b) the hazard ratio for treatment with ngSERD is 0.55 or less compared to treatment with fulvestrant; and / or c) providing a pharmaceutical composition, the use of which results in a median time to disease progression of at least 5.6 months;

[0127] In one embodiment, a pharmaceutical composition is provided comprising an ngSERD (e.g., camizestrant or a pharmaceutically acceptable salt thereof, optionally administered orally once daily at a dose of 75 mg or 150 mg) and at least one pharmaceutically acceptable excipient for use in treating HR+, human epidermal growth factor receptor 2-negative HER2-, metastatic or locally recurrent breast cancer, wherein the breast cancer has recurred or progressed after at least one prior course of endocrine therapy, and the cancer has been identified as having an estrogen receptor mutation (e.g., a mutation in the estrogen receptor selected from E380Q, V422del, S463P, L536H, L536P, L536R, Y537C, Y537D, Y537N, Y537S, and D538G).

[0128] In one embodiment, a pharmaceutical composition is provided comprising an ngSERD (e.g., camizestrant or a pharmaceutically acceptable salt thereof, optionally administered orally once daily at a dose of 75 mg or 150 mg) and at least one pharmaceutically acceptable excipient for use in treating HR+, human epidermal growth factor receptor 2-negative, HER2-, metastatic, or locally recurrent breast cancer, wherein the breast cancer has recurred or progressed after at least one prior course of endocrine therapy, and the cancer has been identified as having an estrogen receptor mutation (e.g., a mutation in the estrogen receptor selected from E380Q, V422del, S463P, L536H, L536P, L536R, Y537C, Y537D, Y537N, Y537S, and D538G) based on testing of a sample obtained from the patient (e.g., testing performed by analyzing circulating tumor DNA), wherein the sample is, for example, a tumor biopsy or a blood sample.

[0129] In one embodiment, a pharmaceutical composition is provided comprising an ngSERD (e.g., camizestrant or a pharmaceutically acceptable salt thereof, optionally administered orally once daily at a dose of 75 mg or 150 mg) and at least one pharmaceutically acceptable excipient for use in treating HR+, human epidermal growth factor receptor 2-negative HER2-, metastatic or locally recurrent breast cancer, characterized in that the breast cancer has recurred or progressed after at least one prior course of endocrine therapy, and wherein use of the pharmaceutical composition results in improved overall survival relative to treatment with fulvestrant.

[0130] In one embodiment, a pharmaceutical composition comprising an ngSERD (e.g., camizestrant or a pharmaceutically acceptable salt thereof, optionally administered orally once daily at a dose of 75 mg or 150 mg) and at least one pharmaceutically acceptable excipient for use in treating HR+, human epidermal growth factor receptor 2-negative HER2-, metastatic or locally recurrent breast cancer, characterized in that the cancer has recurred or progressed after at least one prior course of endocrine therapy; a) its use improves the median time to disease progression by at least 3.5 months relative to the median observed with fulvestrant treatment; and / or b) The hazard ratio for the use of camizestrant treatment versus fulvestrant treatment is 0.67 or less, and / or c) providing a pharmaceutical composition, the use of which results in a median time to disease progression of at least 7 months;

[0131] In one embodiment, a kit is provided that includes a pharmaceutical composition containing an ngSERD and instructions for using the pharmaceutical composition in the treatment of HR+ / HER2- metastatic or locally recurrent breast cancer in patients whose cancer has recurred or progressed after at least one prior course of endocrine therapy.

[0132] In one embodiment, a kit comprising a medicament containing ngSERD and instructions for use of the pharmaceutical composition in 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 course of endocrine therapy, wherein use of the kit results in: a) the median time to disease progression is at least 3.5 months longer than the median time observed with fulvestrant treatment, and / or b) the hazard ratio for treatment with ngSERD is 0.67 or less compared to treatment with fulvestrant; and / or c) providing a kit in which the median time to disease progression is at least 7 months.

[0133] In one embodiment, a kit is provided that includes a pharmaceutical composition containing an ngSERD and instructions for using the pharmaceutical composition in the treatment of HR+ / HER2- metastatic or locally recurrent breast cancer in patients whose cancer has recurred or progressed after at least one prior course of endocrine therapy and at least one prior course of therapy with a CDK4 / 6 inhibitor.

[0134] In one embodiment, a kit comprising a medicament containing ngSERD and instructions for use of the pharmaceutical composition in 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 course of endocrine therapy, wherein use of the kit results in: a) the median time to disease progression is at least 1.7 months longer than the median time observed with fulvestrant treatment, and / or b) the hazard ratio for treatment with ngSERD is 0.68 or less compared to treatment with fulvestrant; and / or c) providing a kit in which the median time to disease progression is at least 3.8 months.

[0135] In one embodiment, a kit is provided that includes a pharmaceutical containing an ngSERD and instructions for using the pharmaceutical composition in the treatment of HR+ / HER2- metastatic or locally recurrent breast cancer in patients whose cancer has recurred or progressed after at least one prior course of endocrine therapy and whose cancer has been identified as having visceral metastases.

[0136] In one embodiment, a kit comprising a medicament containing ngSERD and instructions for use of the pharmaceutical composition in 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 course of endocrine therapy, wherein use of the kit results in: a) the median time to disease progression is at least 3.6 months longer than the median time observed with fulvestrant treatment, and / or b) the hazard ratio for treatment with ngSERD is 0.55 or less compared to treatment with fulvestrant; and / or c) providing a kit in which the median time to disease progression is at least 5.6 months.

[0137] In one embodiment, a kit is provided that includes a pharmaceutical containing ngSERD and instructions for use of the pharmaceutical composition in the treatment of HR+ / HER2 metastatic or locally recurrent breast cancer in patients whose cancer has recurred or progressed after at least one prior course of endocrine therapy and whose cancer has been identified as having an estrogen receptor mutation (e.g., a mutation in the estrogen receptor selected from E380Q, V422del, S463P, L536H, L536P, L536R, Y537C, Y537D, Y537N, Y537S, and D538G).

[0138] In one embodiment, a kit is provided that includes a pharmaceutical composition containing ngSERD and instructions for use in treating HR+ / HER2 metastatic or locally recurrent breast cancer in patients whose cancer has recurred or progressed after at least one prior course of endocrine therapy and whose cancer has been identified as having an estrogen receptor mutation (e.g., a mutation in the estrogen receptor selected from E380Q, V422del, S463P, L536H, L536P, L536R, Y537C, Y537D, Y537N, Y537S, and D538G) based on testing of a sample obtained from the patient (e.g., testing performed by analyzing circulating tumor DNA), where the sample is, for example, a tumor biopsy or a blood sample.

[0139] In one embodiment, a kit is provided comprising a medicament containing ngSERD and instructions for use of the pharmaceutical composition in the treatment of HR+ / HER2- metastatic or locally recurrent breast cancer in patients whose cancer has recurred or progressed after at least one prior course of endocrine therapy, wherein use of the kit results in improved overall survival relative to treatment with fulvestrant.

[0140] In one embodiment, a pharmaceutical composition comprising an ngSERD (e.g., camizestrant or a pharmaceutically acceptable salt thereof, optionally administered orally once daily at a dose of 75 mg or 150 mg) and at least one pharmaceutically acceptable excipient for use in the treatment of HR+, human epidermal growth factor receptor 2-negative HER2-, metastatic or locally recurrent breast cancer, characterized in that the cancer has recurred or progressed after at least one prior course of endocrine therapy, wherein use of the kit results in: a) its use results in an improvement of 3.5 months in the median time to disease progression relative to the median observed with fulvestrant treatment; and / or b) The hazard ratio for the use of camizestrant treatment versus fulvestrant treatment is 0.67 or less, and / or c) providing a pharmaceutical composition, the use of which results in a median time to disease progression of at least 7 months;

[0141] In one embodiment, a kit comprising a pharmaceutical composition comprising camizestrant and at least one pharmaceutically acceptable excipient and instructions for use of the pharmaceutical composition in 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 course of endocrine therapy, wherein use of the kit results in: a) a 3.5 month improvement in median time to disease progression relative to the median observed with fulvestrant treatment; and / or b) The hazard ratio for the use of camizestrant treatment versus fulvestrant treatment is 0.67 or less, and / or c) Providing a kit that provides a median time to disease progression of at least 7 months.

[0142] Further details regarding the SERENA-2 clinical trial protocol are provided below. The study began with three doses of camizestrant (AZD9833): 75 mg, 150 mg, and 300 mg; however, only 20 patients were recruited into the 300 mg group before it was discontinued. Therefore, results for the 300 mg group are not shown. [Example]

[0143] Abbreviations: B = blood; BoR = best objective response; CA15-3 = cancer antigen 15-3; BICR = blinded independent central review; CBR24 = clinical benefit rate at 24 weeks; CSP = clinical trial 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 Organisation 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 = EuroQol 5 Dimension 5 Level; HRQoL = health-related quality of life; ICF = informed consent form; IM = intramuscular; ITT: intention to treat; NEI VFQ-25 = National Eye Institute 25-Item Visual Function Questionnaire; ORR = Objective Response Rate; Os = Overall Survival; PFS = Progression-Free Survival; PGI-BR = Patient Global Impression of Benefit-Risk; PGIC = Patient Global Impression of Change; PGIS = Patient Global Impression of Severity; PGI TT = Patient Global Impression of Treatment Tolerability; PgR = Progesterone Receptor; PK = Pharmacokinetics; PO = Oral (per os); PRO = Patient-Reported Outcome; RECIST = Response Evaluation Criteria in Solid Tumors; SAE = Serious Adverse Event; SRC = Safety Review Committee; U = Urinary; ULN = Upper Limit of Reference; WHO = World Health Organization.

[0144] overview A randomized, open-label, parallel-group, multicenter, phase 2 study comparing the efficacy and safety of oral AZD9833 versus fulvestrant in women with advanced ER-positive, HER2-negative breast cancer was conducted according to the following protocol and schedule: The study evaluated the efficacy and safety of AZD9833 (75, 150, and 300 mg orally [PO]) administered once daily as monotherapy compared with fulvestrant administered according to its label (i.e., two 5-mL injections given slowly intramuscularly in the buttocks [1-2 minutes per injection], one in each buttock on days 1, 15, and 29, and every 4 weeks thereafter).

[0145] [Table 6-1]

[0146] [Table 6-2] a Height is measured at screening only. b Pharmacokinetic samples will be collected only for patients treated with AZD9833. c The time window for tumor imaging is ±7 days. Evaluations will be performed until disease progression. d A bone scan / skeletal survey must be performed within 12 weeks of starting treatment (C1D1). e Sampling and completion of HRQoL questionnaires will occur every 8 weeks (D1 of every second cycle) starting at week 25 (C7) to coincide with RECIST assessment of tumors. fPRO interviews will only be conducted for patients enrolled in the US, UK, and Spain. Interviews will be conducted by telephone. The first interview will be conducted at baseline (prior to the first dose during the screening period). The interviewing vendor will be notified upon identification of eligible patients and the scheduled C1D1 date. A best effort 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. g The time window for echocardiograms at visits C2D1, C5D1 and every third cycle thereafter, as well as the echocardiogram at 28-day follow-up, is ±7 days.

[0147] [Table 7]

[0148] Overall Study Design This is a randomized, open-label, parallel-group, multicenter phase 2 study to compare the efficacy and safety of daily oral (PO) AZD9833 versus intramuscular (IM) fulvestrant in women with advanced ER-positive, HER2-negative breast cancer. Postmenopausal women with histologically or cytologically confirmed metastatic or locally recurrent disease prior to randomization who meet all inclusion criteria and none of the exclusion criteria will be included. Randomization will be stratified according to prior CDK4 / 6 inhibitor use and the presence of liver and / or lung metastases.

[0149] After a screening visit and confirmation of eligibility, patients will be randomly assigned in a 1:1:1:1 ratio to receive one of the following four treatments, consisting of 4-week treatment cycles, until disease progression (as assessed by the investigator as defined by Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1): AZD9833 (75 mg PO once daily) ·AZD9833 (150mg, PO, once a day) ·AZD9833 (300mg, PO, once a day) Fulvestrant (500 mg IM on days 1, 15, and 29, and every 4 weeks thereafter)

[0150] During the treatment period, patients will visit the clinic on the following days: Days 1, 8, and 15 of Cycle 1 Day 1 of each subsequent cycle until treatment discontinuation

[0151] After the treatment period, patients will have two safety follow-up visits (at the time of treatment discontinuation and 28 days later) and will continue to be followed for survival. Throughout the study, patients will be asked to report adverse events (AEs) and concomitant medication use.

[0152] Safety assessments (physical examination, vital signs, electrocardiogram [ECG], clinical safety laboratory assessments) will be performed at screening, on Day 1 of every cycle (through Cycle 6) and every two cycles (from Cycle 6), and at the end-of-treatment (EOT) visit. Electrocardiograms will be performed at screening, on Day 1 of Cycles 2 and 5, every three cycles thereafter, and at the Day 28 follow-up visit. Safety assessments will also be performed on Day 8 of Cycle 1 (vital signs and triplicate ECG measurements), on Day 15 of Cycle 1 (vital signs, ECG, clinical chemistry, hematology, and urinalysis), and at the Day 28 safety follow-up (physical examination and vital signs).

[0153] Tumor imaging will be performed at screening and every 8 weeks from week 9 until disease progression for assessment of tumor response according to RECIST version 1.1.

[0154] Patients will complete health-related quality of life (HRQoL) questionnaires on Day 1 of Cycles 1, 2, and 4, then every 8 weeks (Day 1 of every second cycle) starting at Week 25 (Cycle 7) in conjunction with tumor imaging, at EOT and / or disease progression, and at the 28-day safety follow-up.

[0155] Blood and plasma samples for circulating tumor (ctDNA) and cancer antigen 15-3 (CA15-3) analysis will be collected at screening, days 1 and 15 of cycle 1, days 1 of cycles 2-5, every 8 weeks (day 1 of every 2 cycles) from week 25 (cycle 7) to coincide with tumor imaging, and at EOT and / or disease progression.

[0156] Blood samples for circulating tumor cells (CTCs) will be collected at screening, day 1 of cycles 1, 2, and 4, and at EOT.

[0157] For patients receiving AZD9833, blood samples will be collected on Day 15 of Cycle 1 and Day 1 of Cycle 2 for pharmacokinetic (PK) evaluation.

[0158] For patients who give specific consent, the following optional evaluations will be conducted. A maximum of 12 patients per treatment group will be selected to provide a set of tumor biopsies, one pre-treatment and one during treatment. If providing a set of biopsies becomes clinically impractical for a selected patient during the course of her treatment, patients may be substituted until up to 12 evaluable sets of biopsies are collected within each treatment group. Optional blood samples for future genetic studies will be collected pre-dose on Day 1 of Cycle 1 or thereafter during the study.

[0159] Number of Patients. The trial will screen approximately 360 patients (assuming a 20% screening failure rate) for randomization of 288 patients in a 1:1:1:1 ratio into four treatment arms: AZD9833 75mg: 72 patients AZD9833 150mg: 72 patients AZD9833 300 mg: 72 patients (NB recruitment in this group stopped after 20 patients). Fulvestrant: 72 patients

[0160] Treatment and Duration of Treatment. Patients will receive study treatment until objective disease progression (per RECIST version 1.1) or other discontinuation criteria are met.

[0161] AZD9833 is administered once daily. 75mg: 3 x 25mg tablets. 150mg: 1 x 100mg tablet + 2 x 25mg tablets. 300mg: 3 x 100mg tablets.

[0162] Fulvestrant will be administered on days 1, 15 (±1 day), 29 (±3 days), and every 4 weeks thereafter. · 500mg: 2 x 5ml IM injections.

[0163] The study treatments are summarized in Table 8.

[0164] [Table 8]

[0165] Study Population. Prospective approval of protocol deviations to the inclusion (inclusion) / exclusion criteria, also known as protocol waivers or exemptions, will not be permitted. Each patient must meet all of the inclusion criteria for this study and none of the exclusion criteria to be assigned / randomized to the study intervention. Patients who are enrolled and do not meet the participation requirements are screening failures. For the purposes of this protocol, an "enrolled" patient is defined as a patient who signs informed consent. A "randomized" patient is defined as a patient who undergoes randomization and receives a randomization number. Patients are eligible for inclusion in the study only if they meet all of the following inclusion criteria and none of the exclusion criteria.

[0166] Inclusion Criteria. Informed Consent. Signed and dated written informed consent is provided prior to all required study specific procedures, sampling, and analysis. Patients are also required to agree to provide an archival tumor biopsy. For consenting patients, signed and dated written genetic informed consent is provided prior to collection of samples for genetic analysis.

[0167] Age and sex: Female patients at least 18 years of age.

[0168] Menopausal status. Postmenopausal status is defined as meeting at least one of the following criteria: · Underwent bilateral oophorectomy. Age ≥ 60 years. Age ≥ 50 years, cessation of regular menstruation ≥ 12 months, intact uterus not receiving gonadotropin-releasing hormone (GnRH) agonists, oral contraception or hormone replacement therapy. Age ≤ 50 years, cessation of regular menstruation ≥ 12 months, follicle-stimulating hormone (FSH) and estradiol levels within the postmenopausal range (using local laboratory ranges), and an intact uterus not using gonadotropin-releasing hormone (GnRH) agonists, oral contraception, or hormone replacement therapy.

[0169] Disease characteristics: Histologic or cytologic confirmation of adenocarcinoma of the breast. ER-positive status of primary or metastatic tumor tissue documented according to local laboratory parameters, where the laboratory parameters conform to accepted diagnostic guidelines (e.g., American Society of Clinical Oncology / College of American Pathologists Guideline Recommendations for Immunohistochemical Testing of Estrogen and Progesterone Receptors in Breast Cancer, [Hammond et al. 2010]).

[0170] Documented HER2-negative status, defined as an immunohistochemistry (IHC) score of 0 or 1+ or a negative in situ hybridization (ISH; FISH / CISH / SISH), is required; if IHC 2+, a negative ISH is required. When available, assessment of ER and HER2 status should be based on the most recent tumor biopsy specimen according to local laboratory parameters, which follow accepted diagnostic guidelines (e.g., American Society of Clinical Oncology / College of American Pathologists Guideline Recommendations for Immunohistochemical Testing of Estrogen and Progesterone Receptors in Breast Cancer, [Hammond et al. 2010]).

[0171] Metastatic or locally recurrent disease suitable for treatment with fulvestrant.

[0172] Radiographic or other objective evidence of progression on or after the last systemic therapy prior to initiating study treatment. Marker progression alone is not considered objective evidence of progression.

[0173] The patient At least one lesion that can be accurately measured at baseline using computed tomography (CT) or magnetic resonance imaging (MRI) suitable for accurate repeated measurements, with a longest dimension ≥ 10 mm (excluding lymph nodes, which must have a short axis ≥ 15 mm), and that has not been previously irradiated; or At least one lytic or mixed (lytic + sclerotic) bone lesion suitable for serial evaluation by CT or MRI in the absence of measurable disease as defined above; patients with only sclerotic / osteoblastic bone lesions in the absence of measurable disease are not eligible.

[0174] Eastern Cooperative Oncology Group (ECOG) / World Health Organization (WHO) performance status of 0-1, no deterioration over the past 2 weeks, and a minimum life expectancy of 12 weeks.

[0175] Chemotherapy, endocrine therapy, and other anti-cancer therapy history. Endocrine therapy history is as follows: Relapse or progression on at least one line of endocrine therapy. No more than one endocrine therapy regimen for advanced disease. No more than one chemotherapy regimen for progressive disease. A chemotherapy regimen in progressive disease is an anticancer regimen that includes at least one cytotoxic chemotherapy agent and is administered for 21 days or more. If a cytotoxic chemotherapy regimen is discontinued for reasons other than disease progression and continues for less than 21 days, this regimen does not count as a prior chemotherapy regimen. Repeat administration of the same anticancer regimen on separate occasions does not count as a new chemotherapy regimen. -History of treatment with CDK4 / 6 inhibitors is permitted. · No prior treatment with fulvestrant, oral SERD, or related therapies (e.g., ER, proteolysis-targeting chimeras [PROTACs], selective ER covalent antagonists [SERCAs] in the metastatic setting).

[0176] Inclusion criteria for paired tumor biopsies. Disease suitable for paired baseline and on-treatment tumor biopsies. Washout from study subgroups. Tamoxifen history: 4 months elapsed between last tamoxifen dose and pre-study biopsy. Provision of signed, written, dated informed consent for tumor biopsy.

[0177] Exclusion Criteria: Patients will not be included in the study if they meet any of the following exclusion criteria:

[0178] Prior / concomitant therapy. Intervention with any of the following: Any cytotoxic chemotherapy, investigational drug, or other anti-cancer drug for the treatment of breast cancer in a prior treatment regimen or clinical trial within 14 days of the first dose of the study treatment. Use of systemic estrogen-containing hormone replacement therapy within 6 months of the first dose of study treatment. Medications or herbal 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 with narrow therapeutic indices, i.e., warfarin (and other coumarin-derived vitamin K antagonist anticoagulants) and phenytoin, or drugs that cannot be stopped within the washout period specified in Appendix B prior to the first dose of study treatment. · Drugs known to prolong the QT and with a known risk of torsade pointes, as listed in Appendix B 1. Limited-field radiation therapy for palliative care within 1 week of the first dose of study treatment, and / or extended-field radiation therapy to more than 30% of the bone marrow within 4 weeks of the first dose of study treatment. Major surgery or significant trauma as determined by the investigator within 4 weeks of the first dose of study treatment, or the anticipated need for major surgery and / or any surgery requiring general anesthesia during the study.

[0179] Medical Conditions: Any undetermined toxicity from prior treatment greater than CTCAE Grade 1 at the start of study treatment, excluding alopecia and chemotherapy-related peripheral neuropathy.

[0180] Presence of life-threatening metastatic visceral disease or uncontrolled CNS metastatic disease as determined 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 stable on steroids for at least 4 weeks prior to the start of study treatment.

[0181] Meets any of the following criteria: Any evidence of serious or uncontrolled systemic disease, including uncontrolled hypertension and active bleeding diathesis, or infection requiring intravenous antibiotic therapy, which, in the opinion of the investigator, would make the patient's participation in the study undesirable or compromise compliance with the protocol; Immunocompromised patients, for example, those known to be serologically positive for human immunodeficiency virus (HIV). Patients with known active hepatitis (i.e., hepatitis B or C)

[0182] Meets any of the following cardiovascular criteria: · Mean resting QTcF > 470 msec from screening triplicate ECG measurements. Resting heart rate <45 bpm Any clinically significant abnormality in cardiac rhythm, conduction, or morphology on resting ECG (e.g., complete left bundle branch block, second- and third-degree atrioventricular block), or clinically significant sinus pauses, or sick sinus syndrome. Patients with controlled atrial fibrillation may be enrolled. Any factor that increases the risk of QTc prolongation or the risk of arrhythmic events, such as symptomatic heart failure, congenital long QT syndrome, immediate family history of long QT syndrome, or sudden unexplained death before age 40, hypertrophic cardiomyopathy and clinically significant valvular stenosis, clinically significant hypokalemia, hyperkalemia, hypo- and hypermagnesemia, hypo- and hypercalcemia. Left ventricular ejection fraction <50%, and / or any of the following surgeries or conditions in the past 6 months: coronary artery bypass surgery, angioplasty, vascular stent, myocardial infarction, unstable angina, New York Heart Association (NYHA) grade ≥ 2 congestive heart failure, stroke, or transient ischemic attack. Uncontrolled hypertension. Hypertensive patients may be eligible, provided their blood pressure is adequately controlled at baseline. Patients may be rescreened for blood pressure requirements. Symptomatic hypotension

[0183] Inadequate bone marrow reserve or organ function as evidenced by any of the following laboratory findings: Absolute neutrophil count (ANC) < 1.5 × 109 / L ·Platelet count<100×109 / L Hemoglobin (Hb) < 90g / L Alanine aminotransferase (ALT) > 2.5 × upper limit of normal (ULN) Aspartate aminotransferase (AST) > 2.5 × ULN Total bilirubin (TBL) >1.5 x ULN, or total bilirubin (TBL) >3 x ULN if documented Gilbert syndrome (unconjugated hyperbilirubinemia) is present Estimated glomerular filtration rate (EGFr) < 50 mL / min ·Intractable nausea and vomiting, uncontrolled chronic gastrointestinal disease, inability to swallow formulated products, or history of significant bowel resection that would prevent adequate absorption of AZD9833.

[0184] Other exclusions: · History of hypersensitivity to AZD9833 or fulvestrant active or inactive excipients. · Involvement in the design and conduct of the trial (applies to both AstraZeneca staff and / or trial site staff). Prior randomization in this study. · The investigator's judgment that a patient should not participate in a study if the patient is unlikely to comply with study procedures, restrictions, and requirements. Male patients are excluded from this study. Women of childbearing potential are excluded from this study.

[0185] Lifestyle Restrictions. Patients must refrain from eating large amounts of grapefruit and Seville oranges (and other products containing these fruits [e.g., grapefruit juice or marmalade]) during the study (e.g., not exceeding one small glass of grapefruit juice [120 mL], half a grapefruit, or one to two teaspoons [15 g] of Seville orange marmalade per day). There are no food restrictions for AZD9833 (i.e., AZD9833 may be taken with or without food). There are no food restrictions for fulvestrant.

[0186] Measures to minimize bias: randomization and blinding. This is an open-label study. All patients will receive active treatment. Because the investigators will not be blinded to the study treatment, BICR of tumor scans will be performed to provide an independent assessment of tumor response in addition to the investigator's assessment of response. To reduce potential bias in the study, eligible patients will be randomly assigned in a 1:1:1:1 ratio to receive one of the four study treatments.

[0187] Patients will be randomized when they become eligible. Once patient eligibility is confirmed, the investigator (or designee) will notify the centralized IWRS. Randomization should occur as close as possible to the start of study treatment, with a maximum delay of 3 days. Randomization will be stratified based on the following two stratification factors: - History of CDK4 / 6 inhibitor use in any setting (yes / no) Presence of lung and / or liver metastases (yes / no)

[0188] To ensure that approximately 50% of patients in each treatment group are CDK4 / 6 inhibitor naive in the final analysis, the first factor (i.e., prior CDK4 / 6 inhibitor use) will be controlled so that each stratum will contain 32 to a maximum of 40 patients (out of 72 planned patients) per treatment group. An upper limit will allow enrollment of up to 40 patients per stratum, but not more than the planned total per treatment group. No upper limit will be placed on the second stratification factor (i.e., presence of lung and / or liver metastases).

[0189] Efficacy Assessment. Tumor Response Assessment. Tumor response assessment according to RECIST version 1.1 will be used to determine the clinical activity (assessed by PFS) and antitumor activity (assessed by ORR, clinical benefit rate [CBR]) of AZD9833 and fulvestrant.

[0190] Tumor Imaging. Tumor imaging should be performed in line with the SoA (Table 6). The baseline tumor assessment should encompass all areas of known propensity for metastasis in the disease under evaluation and should further examine areas that may be involved based on the individual patient's signs and symptoms. The baseline assessment should be performed within 28 days prior to the start of study treatment, ideally as close as possible to the start of study treatment.

[0191] If an unscheduled evaluation is performed and the patient does not progress, every attempt should be made to perform a subsequent evaluation at the patient's scheduled visit. This schedule should be followed to minimize any unintended bias caused by some patients being evaluated at a different frequency than others.

[0192] Investigator Assessment of Tumor Response According to RECIST Version 1.1. Tumor response will be assessed by the investigator according to RECIST Version 1.1 (Eisenhauer et al. 2009). From the investigator's review of imaging scans, assessments of TL, NTL, and new lesions will be used to determine each patient's overall visit response. The overall visit response at each visit will then be used to determine if and when the patient has progressed according to RECIST, as well as the patient's best objective response to study treatment.

[0193] Blinded independent central review of tumor assessments. Coded copies of all imaging assessments (regardless of modality and including scans at unscheduled visits) 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 solely on the results of the RECIST assessment performed by the investigator. Imaging scans will be reviewed by two independent radiologists using RECIST version 1.1 and adjudicated as necessary (i.e., two reviewers will review the scans, and in case of discrepancy, adjudication will be made by a separate reviewer). The independent reviewers will be blinded to the study treatment.

[0194] BICR is performed continuously throughout the study. When possible, scans are batched and serial assessments for each patient are read together. For each patient, BICR defines an overall visit response (i.e., the response achieved overall at each visit by assessing TL, NTL, and new lesions); the overall visit response does not need to be derived programmatically.

[0195] Bone Scan or Skeletal Survey. All patients must have a baseline bone scan or skeletal survey within 12 weeks and as close as possible to the start of study treatment. Additional on-study bone scans or skeletal surveys may be performed if clinically indicated. Bone lesions identified on isotopic bone scans at baseline and confirmed by CT, MRI, or X-ray must be recorded as NTLs as shown in the SoA (Table 6) and subsequently recorded by the same method (CT, MRI, or X-ray).

[0196] Survival Follow-up. After discontinuation of study treatment, patients' survival status will be followed by telephone every 12 weeks until the clinical trial database is closed. All new anti-cancer therapies initiated by patients during the survival follow-up period will be recorded in the clinical database. Survival follow-up calls will be conducted the week after the DCO date for each survival analysis.

[0197] Post-primary analysis. At the time of the final analysis, the clinical trial database will be updated with new data. However, patients will be allowed to continue receiving study treatment after the database is closed if, in the opinion of the investigator, they continue to receive study treatment benefit.

[0198] Clinical Outcome Assessments. Performance Status. Performance status will be assessed at the visits indicated in the SoA (Table 6) according to ECOG / WHO criteria as follows: · Fully active and able to continue all pre-disease activities without restrictions. Physically strenuous activity is limited, but the patient is able to walk and perform tasks of a light or sedentary nature (e.g., light housework, office work). Ambulatory and self-care, but unable to perform any occupational activities. Spends more than 50% of waking hours in a sitting position. Able to care for themselves only to a limited extent and spends more than 50% of their waking hours confined to a bed or chair Completely unable. Unable to care for himself at all. Totally confined to bed or chair.

[0199] Health-Related Quality of Life Questionnaire. PRO scales 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. The following PRO scales will be administered in this study in the following order, according to the SoA (Table 6): European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - Core Questionnaire (EORTC QLQ-C30) EORTC Quality of Life Questionnaire - Breast Cancer Module (EORTC QLQ-BR23) ·National Eye Institute 25-Item Visual Function Questionnaire(NEI VFQ-25) EuroQol 5-Dimension 5-Level (EQ-5D-5L) Patient Global Impression of Severity (PGIS) Patient Global Impression of Change (PGIC) (not applicable to baseline, i.e., Cycle 1 Day 1) Global Impression of Treatment Tolerability (PGI-TT) Patient Global Impression of Benefit-Risk (PGI-BR) (not applicable to baseline, i.e., Day 1 of Cycle 1).

[0200] Safety Assessments. The planned time points for all safety assessments are shown in the SoA (Table 6). Table 9 provides a list of clinical safety laboratory tests to be performed and the SoA for timing and frequency.

[0201] [Table 9]

[0202] Pharmacokinetics. Venous blood samples of approximately 2 mL will be collected from patients receiving AZD9833 as specified in the SoA (Table 6) for measurement of plasma concentrations of AZD9833 and metabolites, where appropriate.

[0203] Samples may be collected at additional time points, or not further collected during the study, if warranted and agreed upon between the investigator and sponsor. Instructions for collection and handling of biological samples will be provided by the sponsor or analytical test site. Record the actual date and time (24-hour clock time) of each sample.

[0204] Samples collected for analysis of AZD9833 plasma concentrations may also be used to assess aspects of safety or efficacy relevant to concerns that arise during or after the study (i.e., PK samples may be reused, if necessary).

[0205] Genetics. Patients will be offered the possibility of participating in optional genetic exploratory studies. DNA collection and storage will follow local ethical procedures for future exploratory research into genes / genetic variations that may affect response to treatment. After signing a separate consent for optional genetic studies, a 6 mL blood sample will be collected according to the inclusion criteria and SoA (Table 6). If, for any reason, a blood sample is not collected on day 1 according to the SoA, it may be collected at any time up to the final study visit. Although genotype is a stable parameter, early sample collection is preferred to avoid introducing bias by excluding subjects who may withdraw due to AEs, and it is important to include such subjects in any genetic analysis. Only one sample per subject should be collected for genetic studies during the study.

[0206] Biomarkers. Biomarkers will be tested in plasma, blood and tumor samples for secondary and exploratory purposes to investigate predictive markers of response and / or acquired resistance to AZD9833 and to assess the impact of tumor mutational status on response to treatment and acquired resistance.

[0207] The following samples for biomarker studies are required and will be collected from all patients in the study as specified in the SoA (Table 6). Blood and plasma samples for ctDNA Blood sample for tumor marker CA15-3 Blood samples for CTCs Archived tumor tissue samples

[0208] The following samples for biomarker studies are optional and will be collected from study patients, when possible, as specified in the SoA (Table 6). A set of tumor biopsy samples; pre- and during treatment. Samples will be collected from up to 12 patients per treatment group with tumors suitable for biopsy. Additional tumor biopsies may be taken at the time of progression.

[0209] Blood Samples for Circulating Tumor DNA. One 20 mL whole blood sample will be collected at screening to isolate plasma and buffy coat to allow for assessment, analysis, and interpretation of circulating tumor DNA. 10 mL blood samples will be collected at all other time points indicated in the SoA (Table 1) to provide plasma only.

[0210] Samples will be used for extraction and analysis of ctDNA for analysis of predictive and pharmacodynamic biomarkers to investigate changes in frequency, levels, specific genetic alterations and possible mechanisms of resistance.

[0211] Blood Samples for Tumor Marker CA15-3. Approximately 2 mL of blood samples will be collected for assessment of the cancer antigen CA15-3 at each of the time points indicated in the SoA (Table 6). Samples will be analyzed at the investigator's facility or a local laboratory nearby. Sample tubes and sample sizes may vary depending on the laboratory methods used and facility routines.

[0212] Circulating tumor cells. One 10 mL blood sample will be collected at each of the time points indicated in the SoA (Table 6). These samples will be collected to obtain a preliminary assessment of AZD9833 activity in the tumor by assessing changes in pharmacodynamic biomarkers, which may include, but are not limited to, ER, Ki67 protein, and the total number and expression levels of ER-regulated genes.

[0213] Archival Tumor Tissue. Archival tumor tissue, formalin-fixed and embedded in paraffin blocks, will be obtained for all patients, if available. While a baseline biopsy sample can also be obtained, obtaining archived diagnostic tumor material is still necessary to obtain data on how the tumor has progressed since diagnosis. Archival samples may be derived from the primary tumor and / or metastatic sites, with the most recently obtained archived sample being preferred, if possible.

[0214] If this is not possible, a minimum of 20 slides of freshly prepared, unstained 5-micron sections from an archived tumor block will be accepted if the tumor block cannot be submitted. Cores can be extracted from the archived tumor block to construct tissue microarrays for subsequent biomarker analysis. The remainder of the tumor block can be returned to the facility.

[0215] Tumor biopsies in selected patients. Optional paired tumor biopsies will be collected from up to 12 eligible patients in each treatment group. A paired tumor biopsy will be obtained from patients with accessible tumor who consent to providing a biopsy sample. Accessible lesions are defined as tumor lesions suitable for repeat biopsy. A paired biopsy of bone tissue will not be permitted. A pre-treatment biopsy may be obtained during screening as close as possible to the start of treatment, ideally within 6 weeks prior to treatment initiation. An on-treatment biopsy sample may be obtained on Day 1 (±7 days) of Cycle 2; however, if agreed with AstraZeneca, both pre- and on-treatment samples may be obtained outside this time window. Pre- and on-treatment biopsies must be taken from the same tumor lesion. Biopsies should be performed within 1-12 hours of the last AZD9833 dose, if possible. Further tumor biopsies may also be obtained at the time of disease progression or the end of treatment.

[0216] Biomarkers investigated using tumor samples may include, but are not necessarily limited to, ER, PgR, Ki67, genomic / genetic alterations, and other ER-regulated gene expression. When possible, tumor biopsies are recommended at the time of disease progression. These samples are used to investigate altered pathway signaling and possible mechanisms of resistance (i.e., evidence of genetic alterations or activation of alternative pathways).

[0217] Statistical methods. All efficacy analyses will be performed on the full analysis set (FAS). The primary analysis, a formal comparison of AZD9833 versus fulvestrant, will apply only to the 75 mg and 150 mg AZD9833 treatment groups, and pairwise comparisons will apply only to the 75 mg and 150 mg AZD9833 doses. Results of all statistical analyses will be presented using 90% confidence intervals (CI) and two-sided p-values. The treatment comparison of interest is AZD9833 versus fulvestrant at each dose level. Data from the AZD9833 300 mg treatment group will be summarized and reported where appropriate, but will not contribute to the event triggers for the following analyses.

[0218] In the primary analysis, the null hypothesis tested is that there is no treatment effect (i.e., no difference in PFS between patients treated with any dose of AZD9833 and those treated with fulvestrant). H0:PFS HR AZD 9833 / フルベストラント =1 H1:PFS HR AZD 9833 / フルベストラント ≠1

[0219] Each dose of AZD9833 will be compared to fulvestrant in a pairwise comparison. Because this is a Phase 2 study, no multiplicity adjustment will be performed. The primary endpoint is based on investigator assessment of progression as defined by RECIST version 1.1. A sensitivity analysis will be performed based on blinded independent central review (BICR) of scans.

[0220] Analysis of the primary endpoint of PFS (as assessed by the investigator) will occur when recruitment into the study is complete and at least 108 events have occurred for the pairwise comparisons of the 75 mg and 150 mg AZD9833 doses versus fulvestrant (approximately 75% maturity). Further analyses of PFS may also be performed at later time points based on more mature data, particularly in subgroups of interest.

[0221] To observe a total of at least 108 PFS events for each pairwise comparison versus fulvestrant, a sample size of approximately 288 patients randomized equally across the four treatment groups would be required. The HR of 0.59 for each pairwise treatment comparison versus fulvestrant is interesting. Assuming a median PFS of 5 months is observed with fulvestrant, this equates to a 3.5-month increase in median PFS versus fulvestrant. If the assumed true treatment effect is HR = 0.59, a minimum of 108 events for each pairwise comparison of AZD9833 doses versus fulvestrant would provide 86% power at a two-sided 10% significance level.

[0222] Objective response rates (ORR) will be compared between AZD9833 (at each dose level) and fulvestrant using a logistic regression model adjusting for prior CDK4 / 6 inhibitor use and the presence of lung and / or liver metastases.

[0223] The change from baseline in tumor size at week 16 and the best change from baseline in tumor size will also be summarized and presented by randomized treatment group.

[0224] Overall survival (OS) data will be analyzed at the time of the primary analysis of PFS, using the same methodology and model (if there are enough events available for a meaningful analysis). Further survival analyses may be performed after 50% and 75% of patients have died, or after other degrees of completion that may be appropriate.

[0225] CBR24 will be summarized by treatment group and analyzed using a logistic regression model (similar to the analysis of ORR).

[0226] All safety analyses will be performed in the safety analysis set. Safety data will not be formally analyzed.

[0227] Analysis Populations. For the purposes of analysis, the following populations are defined in Table 10:

[0228] [Table 10]

[0229] Statistical Analysis: All sponsor personnel involved in the study will remain blinded to the aggregated efficacy data until after database lock for the primary analysis, after which all study team members will be unblinded.

[0230] Efficacy Analyses. All efficacy analyses will be performed in the FAS. The primary analysis, a formal comparison of AZD9833 versus fulvestrant, will apply only to the 75 mg and 150 mg AZD9833 treatment groups, and pairwise comparisons will apply only to the 75 mg and 150 mg AZD9833 doses. Results of all statistical analyses will be presented using 90% CIs and two-sided p-values. The treatment comparison of interest will be AZD9833 versus fulvestrant at each dose level. Data from the 300 mg AZD9833 treatment group will be summarized and reported accordingly.

[0231] Investigator assessment of tumor response according to RECIST version 1.1. From the investigator's review of imaging scans, measurements of TL (if appropriate), NTL, and assessment of new lesions will be used to determine each patient's overall visit response according to RECIST version 1.1, and patients will be 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. Efficacy endpoints of PFS, CBR24, ORR, and DoR will be derived programmatically from the overall visit responses determined at each visit. The endpoint of percentage change in total TL will be derived programmatically from tumor measurements of TL.

[0232] Blinded independent central review of tumor response. Sensitivity analysis of the primary endpoint of this study is based on BICR of radiological scans. For each patient, BICR defines the overall visit response (i.e., the response obtained overall at each visit by assessing TL, NTL, and new lesions) data, and programmatic derivation of visit response is not required. PFS is programmatically derived from all visit responses assessed at each visit. For the primary analysis of PFS, BICR will be performed for all patients, and the database will be finally locked. BICR will cover all available scans up to each DCO.

[0233] Primary endpoint: progression-free survival. Analysis of the primary endpoint of PFS (as assessed by the investigator) will occur when recruitment into the study is complete and at least 108 events have occurred for each dose of AZD9833 versus fulvestrant pairwise comparison (approximately 75% completeness). Further analyses of PFS may also be performed at later time points based on more complete data, particularly in subgroups of interest.

[0234] PFS is defined as the time from the date of randomization to the date of objective disease progression or death (from any cause if there is no progression), regardless of whether the patient withdraws from randomized therapy or receives another anticancer therapy before progression (i.e., date of PFS event or censoring - date of randomization + 1).

[0235] Patients who have not progressed or died at the time of analysis are deleted as of the last date of evaluation from their last evaluable assessment (per RECIST version 1.1). However, if a patient progresses or dies shortly after missing two or more consecutive visits, the patient will be deleted as of their last evaluable assessment (per RECIST version 1.1) before the two missed visits. PFS times are always derived based on scan / assessment date, not visit date.

[0236] PFS will be analyzed based on the FAS using a Cox proportional hazards model, taking into account the effect of treatment and including stratification factors: prior use of CDK4 / 6 inhibitors (yes / no) and the presence of lung and / or liver metastases (yes / no). All AZD9833 doses will be compared to fulvestrant using a stratified log-rank test adjusting for prior use of CDK4 / 6 inhibitors and the presence of lung and / or liver metastases.

[0237] Stratification variables in statistical modeling will be based on the values ​​entered into the IWRS at the time of randomization, even if these values ​​are later found to be inaccurate. If deemed necessary, sensitivity analyses may be performed based on the correct allocation.

[0238] HRs for each treatment comparison to fulvestrant are estimated, along with 90% CIs and two-sided p-values.

[0239] Kaplan-Meier plots of PFS are shown by treatment group. A summary of the number and percentage of patients who experienced a PFS event and the type of event (progression or death) is shown for each treatment group, along with the median PFS and proportion of patients progression-free at 6 months and 1 year.

[0240] The assumption of proportionality is assessed, and if there is evidence of non-proportionality, a time-varying covariate is fitted to assess the extent to which this represents random variation. Full details are provided in SAP.

[0241] As a sensitivity analysis for the primary endpoint, the above analysis method will be repeated based on BICR.

[0242] Collected RECIST version 1.1 data (investigator-adjudicated and BICR) will be listed for all randomized patients.

[0243] Subgroup analysis. The subgroup of patients with prior CDK4 / 6 inhibitor use (yes / no) will also be analyzed, summarizing the primary endpoint, as long as there are enough events available for a meaningful analysis; otherwise, a narrative summary will be provided. Further subgroups of interest may be defined based on baseline patient characteristics, and these will be presented in forest plots comparing HRs and 90% CIs. Subgroups of interest will be fully defined in the SAP, along with any optional sensitivity analyses.

[0244] Secondary endpoint: Objective Response Rate. ORR is defined as the percentage of patients with at least one investigator-assessed response at a visit of CR or PR before any evidence of progression. ORR is 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 ORR.

[0245] ORRs are compared between AZD9833 (at each dose level) and fulvestrant using logistic regression models adjusting for prior CDK4 / 6 inhibitor use and the presence of lung and / or liver metastases. Results of the analysis are presented in terms of odds ratios for each treatment comparison, along with their associated profile likelihood 90% CI and two-sided p-values ​​(based on twice the log change in likelihood resulting from adding the treatment factor to the model).

[0246] Summaries will be generated showing the number and percentage of patients experiencing tumor response (CR / PR), including the frequency of confirmed complete and partial responses, as well as unconfirmed complete and partial responses, stable disease, progressive disease, and unevaluable disease.

[0247] Secondary endpoint: duration of response. DoR is defined as the time from the date of first documented response to the date of documented disease progression or date of death in the absence of disease progression. Time of first response is defined as the latest date attributable to a response at the first visit of PR or CR. If patients do not progress or die after a response, the censoring time of PFS will be used for their DoR. Descriptive data on duration of response in responding patients, including associated Kaplan-Meier curves, will be provided.

[0248] Secondary Endpoint: Change in Tumor Size. One of the secondary outcome variables for this study is the percentage change from baseline in the sum of the diameters of the TL at week 16. Based on RECIST measurements taken at baseline and week 16, a percentage change in tumor size at week 16 will be obtained for each patient. Tumor size is the sum of the longest diameters of the TL. The TL is a measurable tumor lesion. RECIST baseline is defined as the last evaluable assessment before randomization.

[0249] Secondary Endpoint: Best Percentage Change. Absolute and percentage change from baseline in sum of tumor size at each visit will be calculated. Best change in tumor size (i.e., depth of response) is the greatest reduction from baseline, or the smallest increase from baseline if there is no reduction, including the earliest death in the absence of progression, any evidence of progression, any assessment prior to initiation of subsequent anticancer therapy, or the last evaluable RECIST assessment if the patient has not died, progressed, or started subsequent anticancer therapy.

[0250] Absolute values, change from baseline in tumor size, and percentage change from baseline in tumor size are summarized using descriptive statistics and presented for each time point and by randomized treatment group. Change from baseline in tumor size at week 16 and best change from baseline in tumor size are also summarized and presented by randomized treatment group. Normality of the data is assessed, and the effect of AZD9833 on percentage change in tumor size is estimated from an analysis of covariance (ANCOVA) model, where appropriate. Numbers of patients, unadjusted means, and least-squares means (LS means) for each treatment group are presented, along with the difference in LS means, 90% CI, and corresponding two-sided p-values. Where assumptions are not met, appropriate transformations of the data are considered, and full details are provided in SAP. Tumor sizes are also presented graphically using waterfall and spider plots, separated by treatment as appropriate.

[0251] Secondary endpoint: overall survival. OS is defined as the time from the date of randomization to death from any cause, regardless of whether the patient withdraws from randomized therapy or receives another anticancer therapy. All patients not known to have died at the time of analysis will be removed based on the last recorded date the patient was known to be alive.

[0252] NOTE: Survival follow-up calls will be conducted the week following the DCO date for analysis, and patients will be dropped on the day of DCO if they are confirmed alive or if their date of death is after the DCO date.

[0253] OS data will be analyzed at the time of the primary analysis of PFS, using the same methodology and model (if there are enough events available for a meaningful analysis [>20% completeness in OS]; if not, a narrative summary will be provided). Further survival analyses may be performed after 50% and 75% of patients have died.

[0254] 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 in the first 25 weeks (to allow for later evaluation within the evaluation window) or with SD (no subsequent cancer therapy) for at least 23 weeks after the start of treatment (to allow for early evaluation within the evaluation window). CBR will be defined based on investigator assessment of RECIST, summarized by treatment group, and analyzed using a logistic regression model (similar to the analysis of ORR).

[0255] The results obtained from the described clinical trial protocol are shown in Figures 1 to 6.

Claims

1. A method for treating HR+, HER2-, metastatic or locally recurrent breast cancer, comprising administering a therapeutically effective amount of ngSERD to a patient afflicted with such cancer, wherein the cancer has recurred or progressed after at least one prior course of endocrine therapy.

2. a) the median time to disease progression is at least 3.5 months longer than that observed with fulvestrant treatment, and / or b) the hazard ratio for treatment of ngSERD is 0.67 or less compared to treatment with fulvestrant; and / or c) the median time to disease progression is at least 7 months.

3. 10. The method of claim 1, wherein the cancer has recurred or progressed after at least one prior course of therapy with a CDK4 / 6 inhibitor.

4. a) the median time to disease progression is at least 1.7 months longer than that observed with fulvestrant treatment, and / or b) the hazard ratio for treatment of ngSERD is 0.68 or less compared to treatment with fulvestrant; and / or c) the median time to disease progression is at least 3.8 months.

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

6. a) the median time to disease progression is at least 3.6 months longer than that observed with fulvestrant treatment, and / or b) the hazard ratio for treatment of ngSERD is 0.55 or less compared to treatment with fulvestrant; and / or c) the median time to disease progression is at least 5.6 months.

7. The method of claim 1 , wherein the cancer has been identified as having an estrogen receptor alpha mutation.

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

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

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

11. The method of claim 10, wherein the identification of the mutation in estrogen receptor alpha is carried out by analyzing circulating tumor DNA.

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

13. The method of any one of claims 1 to 12, wherein the ngSERD is camizestrant or a pharmaceutically acceptable salt thereof.

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

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

16. 16. The method of treatment according to any one of claims 1 to 15, wherein said method improves overall survival relative to treatment with fulvestrant.

17. The method of any one of claims 1 to 15, wherein the method improves the clinical benefit rate compared to fulvestrant at 24 weeks.

18. The method of any one of claims 1 to 15, wherein the objective response rate is improved relative to fulvestrant.

19. 1. Camizestrant, or a pharmaceutically acceptable salt thereof, for use in the treatment of HR+, HER2-, metastatic or locally recurrent breast cancer, wherein the cancer has recurred or progressed after at least one prior course of endocrine therapy; a) said use results in an improvement in the median time to disease progression of at least 3.5 months relative to the median observed with fulvestrant treatment; and / or b) the hazard ratio for the use of camizestrant treatment versus fulvestrant treatment is 0.67 or less; and / or c) Camizestrant or a pharmaceutically acceptable salt thereof, wherein said use results in a median time to disease progression of at least 7 months.

20. 1. Camizestrant or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament, said medicament being for use in the treatment of HR+, HER2-, metastatic or locally recurrent breast cancer, wherein said cancer has recurred or progressed after at least one prior course of endocrine therapy, wherein said medicament for use a) an improvement in the median time to disease progression of at least 3.5 months relative to the median observed with fulvestrant treatment, and / or b) a hazard ratio of camizestrant treatment use versus fulvestrant treatment of 0.67 or less; and / or c) Camizestrant or a pharmaceutically acceptable salt thereof, which provides a median time to disease progression of at least 7 months.

21. 1. A pharmaceutical composition comprising camizestrant and at least one pharmaceutically acceptable excipient for use in the treatment of HR+, human epidermal growth factor receptor 2-negative HER2-, metastatic or locally recurrent breast cancer, wherein said cancer has recurred or progressed after at least one prior course of endocrine therapy, wherein said pharmaceutical composition for use: a) an improvement of at least 3.5 months in the median time to disease progression relative to the median observed with fulvestrant treatment; and / or b) a hazard ratio of camizestrant treatment use versus fulvestrant treatment of 0.67 or less; and / or c) A pharmaceutical composition that provides a median time to disease progression of at least 7 months.

22. 1. A kit comprising a pharmaceutical composition comprising camizestrant and at least one pharmaceutically acceptable excipient, and instructions for use of said pharmaceutical composition in the treatment of HR+, HER2-, metastatic or locally recurrent breast cancer, wherein said cancer has recurred or progressed after at least one prior course of endocrine therapy, and wherein use of said kit results in: a) an improvement of 3.5 months in the median time to disease progression relative to the median observed with fulvestrant treatment, and / or b) a hazard ratio of camizestrant treatment use versus fulvestrant treatment of 0.67 or less; and / or c) A kit that provides a median time to disease progression of at least 7 months.

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