Method of increasing time to second progression and time to first subsequent chemotherapy

Abstract

The present disclosure relates to methods of increasing time to second progression or death and time to first subsequent chemotherapy in subjects having advanced breast cancer using therapeutic combinations of capivasertib and fulvestrant.

Description

A METHOD OF INCREASING TIME TO SECOND PROGRESSION AND TIME TO FIRST SUBSEQUENT CHEMOTHERAPY CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to United States Provisional Patent Application No.63 / 645,571, filed 10 May 2024, the disclosure of which is incorporated by reference herein. FIELD

[0001] The present disclosure relates to methods of increasing time to second progression or death and time to first subsequent chemotherapy in subjects having advanced breast cancer using therapeutic combinations of capivasertib and fulvestrant. BACKGROUND

[0002] In women, breast cancer is both the most common cancer worldwide and the second cause of cancer death. Approximately 60% of premenopausal and 75% of postmenopausal breast cancer subjects have estrogen receptor-positive (ER+) carcinomas. Estrogen receptor (ER) expression and activation are important factors to control tumor growth and recurrence. Although there are several therapeutic approaches, endocrine therapy has become the standard adjuvant treatment for postmenopausal women with ER+ breast cancer. Drugs that selectively target ER, like the selective ER down-regulators (SERDs), such as fulvestrant, or the selective ER modulators (SERMs), such as tamoxifen or drugs that prevent estrogen biosynthesis, like aromatase inhibitors (AIs), are important therapeutic tools to block the ER signaling pathways that lead to cancer progression. Unless there is evidence of impending or actual visceral crisis, endocrine-based therapy is the preferred treatment modality because it has greater activity and better tolerability than cytotoxic chemotherapy. However, almost all tumors will become resistant to endocrine-based therapy and novel approaches are required to circumvent resistance, prolong the prechemotherapy window, and extend life.

[0003] The signaling pathway of phosphatidylinositol 3-kinase (PI3K) / protein kinase B (AKT) and mammalian target of rapamycin (mTOR) has been identified as playing a role in the development of resistance and is altered in approximately 50% of ER+ advanced breast cancer tumors. Mutations in exons 9 and 20 of PIK3CA, encoding the p110α subunit, are the most commonly found mutations but loss-of-function mutations in PTEN, a negative regulator of PI3K / AKT signaling, and activating mutations of AKT1 also occur. Increased activation of the PI3K / AKT pathway, via mTORC1 signaling, promotes tumor cell growth and survival, and results in ligand- independent activation of the ER and resistance to endocrine therapies. Alternatively, inhibition of the PI3K pathway produces compensatory increases in ligand-dependent ER transcription and increased ER signaling.

[0004] Therefore, a rationale exists for simultaneously inhibiting the ER and PI3K / AKT pathway in subjects with breast cancer.

[0005] AKT is a serine / threonine-specific protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, transcription, and cell migration. Mammalian cells express three closely related AKT isoforms that are encoded by different genes: AKT1 (protein kinase Bα), AKT2 (protein kinase Bβ), and AKT3 (protein kinase Bγ).

[0006] Capivasertib, sold under the brand name TRUQAP, is a potent, selective pan-AKT kinase inhibitor that has shown activity in preclinical models of both endocrine-sensitive and endocrine- resistant BC when combined with the selective ER degrader (SERD) fulvestrant.

[0007] Fulvestrant, sold under the brand name FASLODEX among others, is used to treat ER+ metastatic breast cancer that may also be HER2-negative, and hormone receptor (HR)-positive, HER2-negative locally advanced or metastatic breast cancer in combination with palbociclib (a CDK4 / 6 inhibitor). It is a selective estrogen receptor degrader (SERD), which works both by down-regulating and by degrading the estrogen receptor. SUMMARY

[0008] In some embodiments, the present disclosure provides a method of increasing the time to second progression or death (PFS2) in a subject having breast cancer, the method comprisingadministering to the subject a combination of capivasertib and fulvestrant wherein the breast cancer in the subject is a HR+, HER2- breast cancer. In some embodiments, PFS2 is increased by at least 15 % relative to fulvestrant monotherapy.

[0009] In some embodiments, the subject has a PIK3CA / AKT1 / PTEN-altered tumor. In some embodiments, the subject has a PIK3CA / AKT1 / PTEN-altered tumor and PFS2 is increased by at least 40 % relative to fulvestrant monotherapy.

[0010] In some embodiments, the method further comprises increasing time to first subsequent chemotherapy (TFSC) in the subject having breast cancer. In some embodiments, TFSC is increased by at least 50% relative to fulvestrant monotherapy. In some embodiments, TFSC is increased by at least 80 % relative to fulvestrant monotherapy and the subject has a PIK3CA / AKT1 / PTEN-altered tumor.

[0001] In some embodiments, the present disclosure provides a method of increasing TFSC in a subject in a subject having breast cancer, the method comprising administering to the subject a combination of capivasertib and fulvestrant, wherein the breast cancer in the subject is a HR+, HER2- breast cancer. In some embodiments, TFSC is increased by at least 50% relative to fulvestrant monotherapy. In some embodiments, the subject has a PIK3CA / AKT1 / PTEN-altered tumor. In some embodiments, the subject has a PIK3CA / AKT1 / PTEN-altered tumor and TFSC is increased by at least 80% relative to fulvestrant monotherapy. In some embodiments, the method further comprises increasing PFS2 by at least 40% relative to fulvestrant monotherapy when the subject has a PIK3CA / AKT1 / PTEN-altered tumor.

[0011] In some embodiments, the breast cancer is locally advanced or metastatic breast cancer. In some embodiments, the breast cancer has progressed following subject receiving at least one endocrine-based regimen in the metastatic setting, or wherein the breast cancer has recurred within 12 months of the subject receiving adjuvant therapy. In some embodiments, the subject has previously received treatment with a CDK4 / 6 inhibitor.

[0012] In some embodiments, the administration comprises intramuscular injections of fulvestrant and oral administration of capivasertib. In some embodiments, the administration comprises intramuscular injections of 500mg fulvestrant every 28 days. In some embodiments, the administration further comprises a 500mg loading dose of fulvestrant on day 15 of cycle 1. In some embodiments, the method comprises oral administration of 400mg capivasertib twice dailyon an intermittent weekly schedule of 4 days on and 3 days off. In some embodiments, the method comprises oral administration of 320mg capivasertib twice daily on an intermittent weekly schedule of 4 days on and 3 days off. In some embodiments, the method comprises oral administration of 200mg capivasertib twice daily on an intermittent weekly schedule of 4 days on and 3 days off. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Figure 1: Study design for the Phase 3 clinical trial of administration of capivasertib and fulvestrant.

[0002] Figures 2A and 2B: All post-study treatment-discontinuation therapies.

[0014] Figures 3A and 3B: First subsequent therapy post-discontinuation of study treatment.

[0015] Figures 4A and 4B: Progression-free survival 2 (PFS2) curves.

[0003] Figures 5A and 5B: Time to first subsequent chemotherapy (TFSC) curves. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0016] Unless otherwise defined herein, scientific and technical terms used in the present disclosure shall have the meanings that are commonly understood by one of ordinary skill in the art. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.

[0017] The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0018] The use of the term "or" in the claims is used to mean "and / or," unless explicitly indicated to refer only to alternatives or the alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and "and / or."

[0019] As used herein, the terms "comprising" (and any variant or form of comprising, such as "comprise" and "comprises"), "having" (and any variant or form of having, such as "have" and"has"), "including" (and any variant or form of including, such as "includes" and "include") or "containing" (and any variant or form of containing, such as "contains" and "contain") are inclusive or open-ended and do not exclude additional, unrecited, elements or method steps.

[0020] The use of the term "for example" and its corresponding abbreviation "e.g." means that the specific terms recited are representative examples and embodiments of the disclosure that are not intended to be limited to the specific examples referenced or cited unless explicitly stated otherwise.

[0021] As used herein, "about" can mean plus or minus 10% of the provided value. Where ranges are provided, they are inclusive of the boundary values. "About" can additionally or alternately mean either within 10% of the stated value, or within 5% of the stated value, or in some cases within 2.5% of the stated value; or "about" can mean rounded to the nearest significant digit.

[0022] As used herein, "between" is a range inclusive of the ends of the range. For example, a number between x and y explicitly includes the numbers x and y and any numbers that fall within x and y.

[0023] The term “effective amount” or “therapeutically effective amount” refers to that amount of a compound or combination of compounds as described herein that is sufficient to affect the intended application including, but not limited to, disease treatment. A therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated (e.g., the weight, age and gender of the subject), the severity of the disease condition, the manner of administration, etc. which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that will induce a particular response in target cells (e.g., the reduction of platelet adhesion and / or cell migration). The specific dose will vary depending on the particular compounds chosen, the dosing regimen to be followed, whether the compound is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which the compound is carried.

[0024] A “therapeutic effect” as that term is used herein, encompasses a therapeutic benefit and / or a prophylactic benefit. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0025] The terms “treat,” “treating,” and “treatment” refer to at least partially alleviating, inhibiting, and / or ameliorating a condition, disorder, or disease, such as advanced breast cancer. The effectiveness of treatment of advanced breast cancer can be assessed in a variety of ways, including but not limited to: inhibiting cancer cell proliferation (including the reversal of cancer growth); promoting cancer cell death (e.g., by promoting apoptosis or another cell death mechanism); improvement in symptoms; duration of response to the treatment; delay in progression of disease; and prolonging progression free survival (PFS).

[0026] The term “combination therapy” can refer to simultaneous, separate, or sequential administration of two or more therapeutic agents. In one embodiment, “combination” can refer to simultaneous administration (e.g., administration of both agents in a single dosage form). In another embodiment, “combination” refers to separate administration (e.g., administration of both agents in separate dosage forms, but at substantially the same time). In a further embodiment of the invention, “combination” refers to separate and sequential administration (e.g., where a first therapeutic agent is administered, followed by a delay, followed by administration of a second or further therapeutic agent). The two therapeutic agents (capivasertib and fulvestrant) may each be administered multiple times within a pre-defined treatment cycle. Where the administration is sequential or separate, the delay in administering the later component should be neither too long nor too short, so as not to lose the benefit of the combination.

[0027] The terms “co-administration,” “in combination with,” “simultaneous,” and “concurrent,” as used herein, encompass administration of two or more active pharmaceutical ingredients to a subject and include simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which two or more active pharmaceutical ingredients are present.

[0028] In the context of a clinical trial study, the term “progression free survival (PFS)” is defined as the time (usually measured in months) from randomization to either the first documented progression confirmed by RECIST version 1.1 criteria (see Eisenhauer et al., European Journal of Cancer (2009) 45:228-247, the content of which is hereby incorporated by reference in its entirety) or death from any cause. In a real-world clinical (non-trial) setting, PFS can be defined as the time from first administration of the monotherapy or combination therapy to either the first documented progression confirmed by RECIST version 1.1 criteria or death from any cause. In other words,PFS can also be defined as the time from start of treatment to either the first documented progression confirmed by RECIST version 1.1 criteria or death from any cause.

[0029] In the context of a clinical trial study, the term “time from randomization or start of treatment to second progression or death (PFS2)” is defined as the time (usually measured in months) from randomization until second progression on next-line treatment, as assessed by a clinician, or death due to any cause. In a real-world clinical (non-trial) setting, PFS2 can be defined as the time from first administration of the combination therapy until second progression on next- line treatment, as assessed by a clinician, or death due to any cause. In other words, PFS2 can also be defined as the time from start of treatment until second progression on next-line treatment, as assessed by a clinician, or death due to any cause.

[0030] In the context of a clinical trial study, the term “time to first subsequent chemotherapy (TFSC)” is defined as the time from the date of randomization to the earlier of start date of the first subsequent chemotherapy after discontinuation of randomized treatment, or death due to any cause. In a real-world clinical (non-trial) setting, TFSC can be defined as the time from first administration of the combination therapy until the start date of the first subsequent chemotherapy, or death due to any cause.

[0031] In some embodiments, the subject has a hormone receptor-positive (HR+), HER2-negative breast cancer, wherein the subject’s tumour cells do not comprise any of the following mutations (The human wild-type PIK3CA, AKT1 and PTEN genes are identified in Table 1): ^ E17K in the AKT1 gene; ^ Any of the mutations in the PIK3CA gene listed in Table 2; and ^ Any of the mutations in the PTEN gene listed in Table 3 or in Table 4. Table 1 Gene Full Name Ensemble Ref seq Transcript PIK3CA phosphatidylinositol-4,5-ENST00000263967NM_006218.2bisphosphate 3-kinase, catalytic subunit alpha AKT1 AKT serine / threonine kinase 1 ENST00000555528. NM_005163 5 PTEN phosphatase and tensin homolog ENST00000371953NM_000314.4

[0032] In some embodiments, the subject has a hormone receptor-positive (HR+), HER2-negative breast cancer, wherein the subject has a PIK3CA / AKT1 / PTEN-altered tumor.

[0033] As PIK3CA and AKT1 are oncogenes, mutations that result in activation of the protein affect the PI3K / AKT pathway. A non-limiting list of potential mutations in AKT1 and PIK3CA genes is provided in Table 2. Table 2 Gene Mutation Exon Comments AKT1 E17K 2 Hotspot mutation PIK3CA R88Q 1 PI3K-ABD (p85) binding domain PIK3CA N345K 4 PIK3CA C402R 7 PIK3CA E542K 9 Helical domain PIK3CA E545A 9 Helical domain PIK3CA E545D 9 Helical domain PIK3CA E545Q 9 Helical domain PIK3CA E545K 9 Helical domain PIK3CA E545G 9 Helical domain PIK3CA Q546E 9 Helical domain PIK3CA Q546K 9 Helical domain PIK3CA Q546R 9 Helical domain PIK3CA Q546P 9 Helical domain PIK3CA M1043V 20 PI3_PI4_Kinase domain PIK3CA M1043I 20 PI3_PI4_Kinase domain PIK3CA H1047Y 20 PI3_PI4_Kinase domain PIK3CA H1047R 20 PI3_PI4_Kinase domain PIK3CA H1047L 20 PI3_PI4_Kinase domain PIK3CA G1049R 20 PI3_PI4_Kinase domain

[0034] PTEN is a tumor suppressor gene, therefore gene alterations that result in loss of a functional protein affect the PI3K / AKT pathway. A non-limiting list of seven distinct criteria to identify such alterations by next-generation sequencing (NGS) was generated. Non-limiting detailsof the criteria to identify qualifying alterations in the PTEN gene are provided in Table 3. A non- limiting list of specific qualifying missense mutations are provided in Table 4. Table 3 Inclusion criteria for deleterious Additional information PTEN alterationsNonsense mutation Any nonsense mutation leads to interrupted translation / nonsense- mediated decay (NMD). i.e. creates a STOP codon Frameshift Mutation Any frameshift mutation usually leads to interrupted translation / NMD. i.e. insertion or deletion causing a frameshift in the coding sequence Splicing Mutation Mutations or deletion of any of the 4 bases that immediately flank coding exons (i.e. -2, -1, +1 or +2 to a coding exon) are expected to lead to incorrect splicing, which likely leads to a non-functional protein. Start Codon Mutation Any change to the recognised start codon (ATG / Methionine 1) for the main transcript should lead to loss of protein translation. Deep deletion Partial or entire PTEN homozygous gene deletion qualifies. Intragenic Rearrangement Any large-scale change within the PTEN gene considered to be disruptive, including rearrangements and fusion (with another gene) i.e. any rearrangement of the Note: duplication, gain or amplification do not qualify. PTEN locus clearly disruptive to the gene. Table 4 Gene Protein exon Additional information change PTEN C124R 5 Associated with Cowden Syndrome; in phosphatase p- loop PTEN C124S 5In phosphatase p-loopPTEN G129E 5 In phosphatase p-loop PTEN G129V 5 In phosphatase p-loop PTEN G129R 5 In phosphatase p-loop PTEN R130Q 5 Associated with Cowden Syndrome, commonly mutation position across multiple tumor types PTEN R130G 5 Associated with Cowden Syndrome, commonly mutation position across multiple tumor types PTEN R130L 5 Associated with Cowden Syndrome, commonly mutation position across multiple tumor types PTEN R130P 5 Associated with Cowden Syndrome, commonly mutation position across multiple tumor types PTEN C136R 5 Associated with hereditary cancer-predisposing syndrome, associated with hamartoma tumorsyndrome PTEN C136Y 5 Associated with Cowden Syndrome, associated with hereditary cancer-predisposing syndrome PTEN S170R 6 in TI-loop PTEN R173C 6 Located at the phosphatase-C2 domain

[0035] The sample obtained from the subject may be any sample type that contains breast tumour genomic material (e.g. tissue, blood, plasma or cell-free DNA). Preferably, the sample is a breast tumour tissue sample.

[0036] There are a variety of methods which are routinely used in the art to detect genetic mutations, and any suitable method can be used.

[0037] Next-generation sequencing (NGS) technologies can detect hundreds of alterations across multiple genes in a single test, and as the skilled person will be aware, NGS can be used to define tumour biomarker status. A single NGS assay can sensitively detect activating PIK3CA mutations and AKT1 mutations across their entire gene structures, as well as PTEN alterations and gene deletion.

[0038] In some embodiments, NGS is used to detect the presence or absence of any of the mutations detailed in Tables 2-4 in a sample containing tumour cells obtained from the subject. Preferably, the sample is a breast tumour tissue sample.

[0039] Commercially available NGS technologies include the FoundationOne®CDx (F1CDx) NGS Clinical Trial Assay from Foundation Medicine, Cambridge, MA, USA), which can be used to detect single-nucleotide variations, insertion and deletion alterations, and copy number alterations in DNA isolated from formalin-fixed paraffin-embedded tumour tissue specimens. The GuardantOMNI™ (Guardant Health, Redwood City, CA, USA) detects single-nucleotide variations, insertion and deletion alterations, copy number alterations, or fusions in 500 genes, including PIK3CA, AKT1, and PTEN alterations, using NGS of cfDNA extracted from plasma samples. Burning Rock Biotech Limited (Guangzhou, China) is developing a liquid biopsy approach, with NGS-based circulating tumour DNA (ctDNA) assays.

[0040] Jones R.H. et al. (Lancet Oncol, 21: 345–57 (2020)) describe using pyrosequencing and / or digital-droplet PCR [ddPCR] tests on tumour tissue or cell-free DNA [cfDNA]) or displayed loss of PTEN expression by immunohistochemistry to identify tumour PI3K / AKT / PTEN pathway status.

[0041] The subject has a hormone receptor-positive (HR+) breast cancer, meaning that the tumour cells express surface receptors that bind to the hormones estrogen and / or progesterone.

[0042] In one embodiment, the subject has estrogen receptor-positive (ER+) breast cancer (with or without co-expression of progesterone receptor). ER+ cancer can be defined as at least 10% of primary tumour or metastatic tumour cells staining positive for the estrogen receptor.

[0043] In some embodiments, the cancer is classified as a HER2-negative cancer, meaning that the tumour cells do not express human epidermal growth factor receptor 2 (HER2). This is histologically confirmed from biopsy taken at diagnosis or from metastasis. In one embodiment, HER2-negative is defined as immunohistochemistry (IHC) scores of 0, 1+, or 2+ and in situ hybridisation (ISH)-negative.

[0044] In some embodiments, the cancer is classified as an advanced breast cancer (ABC), meaning histologically confirmed, locally advanced (inoperable) or metastatic breast cancer, with radiological or objective evidence of recurrence or progression. either with recurrence or progression while on, or within 12 months of, the end of (neo)adjuvant treatment with a regimen containing an aromatase inhibitor (AI) either as a single agent or in combination.

[0045] Aromatase inhibitors (AIs) are one of the principal therapeutic approaches for estrogen receptor-positive (ER+) breast cancer in postmenopausal women. They block estrogen biosynthesis through aromatase inhibition, thus preventing tumour progression. Examples of AIs include anastrozole (sold under the brand name ARIMIDEX, among others), exemestane (sold under the brand name AROMASIN, among others) and letrozole (sold under the brand name FEMARA, among others).

[0046] The subject may or may not have been previously treated with a CDK4 / 6 inhibitor (e.g. (Palbociclib (sold under the brand name IBRANCE among others), ribociclib (sold under the brand names KISQALI and KRYXANA), abemaciclib (sold under the brand name VERZENIO among others)). CDK4 / 6 inhibitors are, in certain markets, approved treatment options in combination with an aromatase inhibitor or fulvestrant for subjects with advanced or metastatic HR+HER2-breast cancer who have received prior endocrine therapy and / or as initial endocrine-based therapy. In one embodiment, the subject has been previously treated with a CDK4 / 6 inhibitor.

[0047] In some embodiments, the present disclosure provides a method of increasing PFS2 in a subject having breast cancer, the method comprising administering to the subject a combination of capivasertib and fulvestrant wherein the breast cancer in the subject is a HR+, HER2- breast cancer.

[0048] In some embodiments, the present disclosure provides a method of increasing PFS2 in a subject having breast cancer, the method comprising administering to the subject a combination of capivasertib and fulvestrant wherein the breast cancer in the subject is a HR+, HER2- breast cancer wherein PFS2 is increased by at least about 5%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 100% relative to fulvestrant monotherapy. In some embodiments, PFS2 is increased by about 15% to about 20%. In some embodiments, PFS2 is increased by about 16% to about 19%.

[0049] In some embodiments, the present disclosure provides a method of increasing PFS2 in a subject having breast cancer, the method comprising administering to the subject a combination of capivasertib and fulvestrant wherein the breast cancer in the subject is a HR+, HER2- breast cancer, wherein PFS2 is increased by at least about 10%, at least about 11%, at least about 12%, about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, about 18%, at least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24% or at least about 25% relative to fulvestrant monotherapy, and wherein TFSC is increased by about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69% or about 70% relative to fulvestrant monotherapy.

[0050] In some embodiments, the present disclosure provides a method of increasing the time to second progression or death (PFS2) in a subject having breast cancer, the method comprising administering to the subject a combination of capivasertib and fulvestrant wherein the breast cancerin the subject is a HR+, HER2- breast cancer, wherein PFS2 is increased by about 15% to about 20% relative to fulvestrant monotherapy and wherein TFSC is increased by about 57% to about 65% relative to fulvestrant monotherapy. In some embodiments, the present disclosure provides a method of increasing the time to second progression or death (PFS2) in a subject having breast cancer, the method comprising administering to the subject a combination of capivasertib and fulvestrant wherein the breast cancer in the subject is a HR+, HER2- breast cancer, wherein PFS2 is increased by about 16% to about 19% relative to fulvestrant monotherapy and wherein TFSC is increased by about 60% to about 63% relative to fulvestrant monotherapy.

[0051] In some embodiments, the present disclosure provides a method of increasing TFSC in a subject having breast cancer, the method comprising administering to the subject a combination of capivasertib and fulvestrant wherein the breast cancer in the subject is a HR+, HER2- breast cancer.

[0052] In some embodiments, the present disclosure provides a method of increasing TFSC in a subject having breast cancer, the method comprising administering to the subject a combination of capivasertib and fulvestrant wherein the breast cancer in the subject is a HR+, HER2- breast cancer. In some embodiments, TFSC is increased by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 56%, at least about 57%, at least about 58%, at least about 59%, at least about 60%, at least about 61%, at least about 62%, at least about 63%, at least about 64%, at least about 65%, at least about 66%, at least about 67%, at least about 68%, at least about 69%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 100% relative to fulvestrant monotherapy. In some embodiments, TFSC is increased by about 57% to about 65% relative to fulvestrant monotherapy. In some embodiments, TFSC is increased by about 60% to about 63% relative to fulvestrant monotherapy.

[0053] In some embodiments, the present disclosure provides a method of increasing TFSC in a subject having breast cancer, the method comprising administering to the subject a combination of capivasertib and fulvestrant wherein the breast cancer in the subject is a HR+, HER2- breast cancer, wherein TFSC is increased by at least about 55%, at least about 56%, at least about 57%, at least about 58%, at least about 59%, at least about 60%, at least about 61%, at least about 62%, at least about 63%, at least about 64%, at least about 65%, at least about 66%, at least about 67%, at least about 68%, at least about 69% or at least about 70% relative to fulvestrant monotherapy andwherein PFS2 is increased by at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24% or at least about 25% relative to fulvestrant monotherapy.

[0054] In some embodiments, the present disclosure provides a method of increasing TFSC in a subject having breast cancer, the method comprising administering to the subject a combination of capivasertib and fulvestrant wherein the breast cancer in the subject is a HR+, HER2- breast cancer, wherein TFSC is increased by about 57% to about 65% relative to fulvestrant monotherapy and wherein PFS2 is increased by about 15% to about 20% relative to fulvestrant monotherapy. In some embodiments, the present disclosure provides a method of increasing TFSC in a subject having breast cancer, the method comprising administering to the subject a combination of capivasertib and fulvestrant wherein the breast cancer in the subject is a HR+, HER2- breast cancer, wherein TFSC is increased by about 60% to about 63% relative to fulvestrant monotherapy and wherein PFS2 is increased by about 16% to about 19% relative to fulvestrant monotherapy.

[0055] In some embodiments, the subject has a PIK3CA / AKT1 / PTEN-altered tumor. In some embodiments, the PIK3CA / AKT1 / PTEN-alteration is due to an insertion mutation. In some embodiments, the PIK3CA / AKT1 / PTEN-alteration is due to a deletion mutation. In some embodiments, the PIK3CA / AKT1 / PTEN-alteration is due to a substitution mutation. In some embodiments, the PIK3CA / AKT1 / PTEN-alteration is due to loss of the PTEN gene or loss of PTEN function. In some embodiments, the PIK3CA / AKT1 / PTEN-alteration is caused by a mutation which activates AKT1. In some embodiments, the PIK3CA / AKT1 / PTEN-alteration is caused by a mutation which activates PIK3CA.

[0056] In some embodiments, PIK3CA / AKT1 / PTEN status is identified by a testing panel that includes next-generation sequencing (NGS) assays. In some embodiments, tumors are considered as PI3K / AKT / PTEN pathway altered if NGS testing of tumor tissue or plasma identifies any of the following: ^ AKT1 E17K, ^ PIK3CA R88Q, N345K, C420R, exon 9 E542K, exon 9 E545K, exon 9 E545X, Q546X, M1043I, M1043V, exon 20 H1047R, exon 20 H1047L, exon 20 H1047X, or G1049R (in which X represents any change in amino acid residue), or^ A deleterious PTEN mutation or loss of the PTEN gene.

[0057] In some embodiments, tumors are considered as PIK3CA / AKT1 / PTEN altered if NGS testing of tumor tissue or plasma identifies any of the mutations identified in Table 2 or Table 4.

[0058] In some embodiments, the present disclosure provides a method of increasing PFS2 in a subject having breast cancer, the method comprising administering to the subject a combination of capivasertib and fulvestrant wherein the breast cancer in the subject is a HR+, HER2- breast cancer and wherein the subject has a PIK3CA / AKT1 / PTEN-altered tumor.

[0059] In some embodiments, the present disclosure provides a method of increasing PFS2 in a subject having breast cancer, the method comprising administering to the subject a combination of capivasertib and fulvestrant wherein the breast cancer in the subject is a HR+, HER2- breast cancer, wherein PFS2 is increased by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 36%, at least about 37%, at least about 38%, at least about 39%, at least about 40%, at least about 41%, at least about 42%, at least about 43%, at least about 44%, at least about 45%, at least about 46%, at least about 47%, at least about 48%, at least about 49%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or about 100% relative to fulvestrant monotherapy, and wherein the subject has a PIK3CA / AKT1 / PTEN-altered tumor. In some embodiments, PFS2 is increased by about 40% to about 47%. In some embodiments, PFS2 is increased by about 42% to about 45%.

[0060] In some embodiments, the present disclosure provides a method of increasing PFS2 in a subject having breast cancer, the method comprising administering to the subject a combination of capivasertib and fulvestrant wherein the breast cancer in the subject is a HR+, HER2- breast cancer, wherein PFS2 is increased by at least about 35%, at least about 36%, at least about 37%, at least about 38%, at least about 39%, at least about 40%, at least about 41%, at least about 42%, at least about 43%, at least about 44%, at least about 45%, at least about 46%, at least about 47%, at least about 48%, at least about 49% or at least about 50% relative to fulvestrant monotherapy, wherein TFSC is increased by at least about 75%, at least about 76%, at least about 77%, at least about 78%, at least about 79%, at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at leastabout 88%, at least about 89% or at least about 90% relative to fulvestrant monotherapy, and wherein the subject has a PIK3CA / AKT1 / PTEN-altered tumor.

[0061] In some embodiments, the present disclosure provides a method of increasing the time to second progression or death (PFS2) in a subject having breast cancer, the method comprising administering to the subject a combination of capivasertib and fulvestrant wherein the breast cancer in the subject is a HR+, HER2- breast cancer, wherein PFS2 is increased by about 40% to about 47% relative to fulvestrant monotherapy, wherein TFSC is increased by about 80% to about 87% relative to fulvestrant monotherapy, and wherein the subject has a PIK3CA / AKT1 / PTEN-altered tumor. In some embodiments, the present disclosure provides a method of increasing the time to second progression or death (PFS2) in a subject having breast cancer, the method comprising administering to the subject a combination of capivasertib and fulvestrant wherein the breast cancer in the subject is a HR+, HER2- breast cancer, wherein PFS2 is increased by about 42% to about 45% relative to fulvestrant monotherapy, wherein TFSC is increased by about 82% to about 85% relative to fulvestrant monotherapy, and wherein the subject has a PIK3CA / AKT1 / PTEN-altered tumor.

[0062] In some embodiments, the present disclosure provides a method of increasing TFSC in a subject having breast cancer, the method comprising administering to the subject a combination of capivasertib and fulvestrant wherein the breast cancer in the subject is a HR+, HER2- breast cancer and wherein the subject has a PIK3CA / AKT1 / PTEN-altered tumor.

[0063] In some embodiments, the present disclosure provides a method of increasing TFSC in a subject having breast cancer, the method comprising administering to the subject a combination of capivasertib and fulvestrant wherein the breast cancer in the subject is a HR+, HER2- breast cancer and wherein the subject has a PIK3CA / AKT1 / PTEN-altered tumor. In some embodiments, TFSC is increased by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 76%, at least about 77%, at least about 78%, at least about 79%, at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 95%, or about 100% relative to fulvestrant monotherapy. In some embodiments, TFSC is increased by about 80% to about 87% relative to fulvestrant monotherapy.In some embodiments, TFSC is increased by about 82% to about 85% relative to fulvestrant monotherapy.

[0064] In some embodiments, the present disclosure provides a method of increasing TFSC in a subject having breast cancer, the method comprising administering to the subject a combination of capivasertib and fulvestrant wherein the breast cancer in the subject is a HR+, HER2- breast cancer, wherein TFSC is increased by at least about 75%, at least about 76%, at least about 77%, at least about 78%, at least about 79%, at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89% or at least about 90% relative to fulvestrant monotherapy and wherein PFS2 is increased by at least about 35%, at least about 36%, at least about 37%, at least about 38%, at least about 39%, at least about 40%, at least about 41%, at least about 42%, at least about 43%, at least about 44%, at least about 45%, at least about 46%, at least about 47%, at least about 48%, at least about 49% or at least about 50% relative to fulvestrant monotherapy, and wherein the subject has a PIK3CA / AKT1 / PTEN-altered tumor.

[0065] In some embodiments, the present disclosure provides a method of increasing TFSC in a subject having breast cancer, the method comprising administering to the subject a combination of capivasertib and fulvestrant wherein the breast cancer in the subject is a HR+, HER2- breast cancer, wherein TFSC is increased by about 80% to about 87% relative to fulvestrant monotherapy, wherein PFS2 is increased by about 40% to about 47% relative to fulvestrant monotherapy and wherein the subject has a PIK3CA / AKT1 / PTEN-altered tumor. In some embodiments, the present disclosure provides a method of increasing TFSC in a subject having breast cancer, the method comprising administering to the subject a combination of capivasertib and fulvestrant wherein the breast cancer in the subject is a HR+, HER2- breast cancer, wherein TFSC is increased by about 82% to about 85% relative to fulvestrant monotherapy, wherein PFS2 is increased by about 42% to about 47% relative to fulvestrant monotherapy and wherein the subject has a PIK3CA / AKT1 / PTEN-altered tumor.

[0066] In some embodiments, the present disclosure provides a method of increasing PFS2 or TFSC in a subject having breast cancer, the method comprising administering to the subject a combination of capivasertib and fulvestrant wherein the administration comprises intramuscular injections of fulvestrant and oral administration of capivasertib, wherein the administration comprises intramuscular injections of 250mg-750mg, e.g., 500mg fulvestrant every 28 days,wherein the administration further comprises a 250mg-750mg, e.g., 500mg, loading dose of fulvestrant on day 15 of cycle 1 and wherein the method comprises oral administration of 200mg- 500mg, e.g., 400mg, capivasertib twice daily on an intermittent weekly schedule of 4 days on and 3 days off.

[0067] In some embodiments, the present disclosure provides a method of increasing PFS2 or TFSC in a subject having HR+, HER2- breast cancer, the method comprising administering to the subject a combination of capivasertib and fulvestrant wherein the administration comprises intramuscular injections of fulvestrant and oral administration of capivasertib, wherein the administration comprises intramuscular injections of 500mg fulvestrant every 28 days, wherein the administration further comprises a 500mg loading dose of fulvestrant on day 15 of cycle 1, and wherein the method comprises oral administration of 400mg capivasertib twice daily on an intermittent weekly schedule of 4 days on and 3 days off. In some embodiments, the present disclosure provides a method of increasing PFS2 or TFSC in a subject having HR+, HER2- breast cancer, the method comprising administering to the subject a combination of capivasertib and fulvestrant wherein the administration comprises intramuscular injections of fulvestrant and oral administration of capivasertib, wherein the administration comprises intramuscular injections of 500mg fulvestrant every 28 days, wherein the administration further comprises a 500mg loading dose of fulvestrant on day 15 of cycle 1, wherein the method comprises oral administration of 400mg capivasertib twice daily on an intermittent weekly schedule of 4 days on and 3 days off, and wherein the subject has a PIK3CA / AKT1 / PTEN-altered tumor.

[0068] In some embodiments, the present disclosure provides a method of increasing PFS2 or TFSC in a subject having HR+, HER2- breast cancer, the method comprising administering to the subject a combination of capivasertib and fulvestrant wherein the administration comprises intramuscular injections of fulvestrant and oral administration of capivasertib, wherein the administration comprises intramuscular injections of 500mg fulvestrant every 28 days, wherein the administration further comprises a 500mg loading dose of fulvestrant on day 15 of cycle 1, wherein the method comprises oral administration of 400mg capivasertib twice daily on an intermittent weekly schedule of 4 days on and 3 days off, wherein PFS2 is increased by about 10 to about 25% relative to fulvestrant monotherapy and wherein TFSC is increased by about 55 to about 70% relative to fulvestrant monotherapy. In some embodiments, the present disclosure provides a method of increasing PFS2 or TFSC in a subject having HR+, HER2- breast cancer, the methodcomprising administering to the subject a combination of capivasertib and fulvestrant wherein the administration comprises intramuscular injections of fulvestrant and oral administration of capivasertib, wherein the administration comprises intramuscular injections of 500mg fulvestrant every 28 days, wherein the administration further comprises a 500mg loading dose of fulvestrant on day 15 of cycle 1, wherein the method comprises oral administration of 400mg capivasertib twice daily on an intermittent weekly schedule of 4 days on and 3 days off, wherein the subject has a PIK3CA / AKT1 / PTEN-altered tumor, wherein PFS2 is increased by about 35 to about 50% relative to fulvestrant monotherapy and wherein TFSC is increased by about 75 to about 90% relative to fulvestrant monotherapy.

[0069] In some embodiments, the present disclosure provides a method of increasing PFS2 or TFSC in a subject having HR+, HER2- breast cancer, the method comprising administering to the subject a combination of capivasertib and fulvestrant wherein the administration comprises intramuscular injections of fulvestrant and oral administration of capivasertib, wherein the administration comprises intramuscular injections of 500mg fulvestrant every 28 days, wherein the administration further comprises a 500mg loading dose of fulvestrant on day 15 of cycle 1 and wherein the method comprises oral administration of 320mg capivasertib twice daily on an intermittent weekly schedule of 4 days on and 3 days off. In some embodiments, the present disclosure provides a method of increasing PFS2 or TFSC in a subject having HR+, HER2- breast cancer, the method comprising administering to the subject a combination of capivasertib and fulvestrant wherein the administration comprises intramuscular injections of fulvestrant and oral administration of capivasertib, wherein the administration comprises intramuscular injections of 500mg fulvestrant every 28 days, wherein the administration further comprises a 500mg loading dose of fulvestrant on day 15 of cycle 1, wherein the method comprises oral administration of 320mg capivasertib twice daily on an intermittent weekly schedule of 4 days on and 3 days off, and wherein the subject has a PIK3CA / AKT1 / PTEN-altered tumor.

[0070] In some embodiments, the present disclosure provides a method of increasing PFS2 or TFSC in a subject having HR+, HER2- breast cancer, the method comprising administering to the subject a combination of capivasertib and fulvestrant wherein the administration comprises intramuscular injections of fulvestrant and oral administration of capivasertib, wherein the administration comprises intramuscular injections of 500mg fulvestrant every 28 days, wherein the administration further comprises a 500mg loading dose of fulvestrant on day 15 of cycle 1 andwherein the method comprises oral administration of 200mg capivasertib twice daily on an intermittent weekly schedule of 4 days on and 3 days off. In some embodiments, the present disclosure provides a method of increasing PFS2 or TFSC in a subject having HR+, HER2- breast cancer, the method comprising administering to the subject a combination of capivasertib and fulvestrant wherein the administration comprises intramuscular injections of fulvestrant and oral administration of capivasertib, wherein the administration comprises intramuscular injections of 500mg fulvestrant every 28 days, wherein the administration further comprises a 500mg loading dose of fulvestrant on day 15 of cycle 1, wherein the method comprises oral administration of 200mg capivasertib twice daily on an intermittent weekly schedule of 4 days on and 3 days off, and wherein the subject has a PIK3CA / AKT1 / PTEN-altered tumor. Compounds

[0071] As used herein, capivasertib refers to a kinase inhibitor with the chemical name 4-amino-N- [(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4- piperidinecarboxamide. The molecular formula for capivasertib is C21H25ClN6O2and the molecular weight is 428.92 g / mol. Capivasertib is a white to off-white powder with pH-dependent solubility. It is freely soluble in water at pH values below 1.2 and practically insoluble at pH values above 6.8. Capivasertib has the following chemical structure:capivasertib film-coated tablets are supplied for oral administration with 160 mg or 200 mg capivasertib. The tablets also contain croscarmellose sodium, dibasic calcium phosphate, magnesium stearate, and microcrystalline cellulose. The film coat contains the following inactive ingredients: copovidone, hypromellose, iron oxide black, iron oxide red, iron oxide yellow, medium chain triglycerides, polydextrose, polyethylene glycol 3350, and titaniumdioxide. In some embodiments, the recommended dosage of TRUQAP, in combination with fulvestrant, is 400 mg orally twice daily (approximately 12 hours apart) with or without food, for 4 days followed by 3 days off.

[0073] Capivasertib is an inhibitor of all 3 isoforms of serine / threonine kinase AKT (AKT1, AKT2 and AKT3) and inhibits phosphorylation of downstream AKT substrates. AKT activation in tumors is a result of activation of upstream signaling pathways, mutations in AKT1, loss of phosphatase and tensin homolog (PTEN) function and mutations in the catalytic subunit alpha of phosphatidylinositol 3-kinase (PIK3CA). In vitro, capivasertib reduced growth of breast cancer cell lines including those with relevant PIK3CA or AKT1 mutations or PTEN alteration. In vivo, capivasertib alone and in combination with fulvestrant inhibited tumor growth of mouse xenograft models including estrogen receptor positive breast cancer models with alterations in PIK3CA, AKT1, and PTEN.

[0074] In one embodiment, the capivasertib utilized in the methods described herein may be administered as a pharmaceutically acceptable salt of capivasertib. The amount of the pharmaceutically acceptable salt of capivasertib administered is chosen such that it provides the required amount of capivasertib in its free form.

[0075] The term “pharmaceutically acceptable” is used to specify that a salt is suitable for use in patients. An example list of pharmaceutically acceptable salts can be found in the Handbook of Pharmaceutical Salts: Properties, Selection and Use, P. H. Stahl and C. G. Wermuth, editors, Weinheim / Zürich:Wiley-VCH / VHCA, 2002, which is incorporated by reference herein in its entirety.

[0076] Capivasertib, in combination with fulvestrant, is indicated for the treatment of adult subjects with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)- negative, locally advanced or metastatic breast cancer with one or more PIK3CA / AKT1 / PTEN- alteration following progression on at least one endocrine-based regimen in the metastatic setting or recurrence on or within 12 months of completing adjuvant therapy.

[0077] As used herein, fulvestrant refers to an estrogen receptor antagonist with the chemical name 7-alpha-[9-(4,4,5,5,5-pentafluoropentylsulphinyl) nonyl]estra-1,3,5-(10)-triene3,17-beta-diol. The molecular formula is C32H47F5O3S and the molecular weight is 606.77. Fulvestrant has the following chemical structure:[ ] u ves ran s a w e pow er. n some embodiments, fulvestrant is formulated for injection for intramuscular administration. The solution for injection is a clear, colorless to yellow, viscous liquid. Each injection contains as inactive ingredients: 10% w / v Alcohol, USP, 10% w / v Benzyl Alcohol, NF, and 15% w / v Benzyl Benzoate, USP, asco-solvents, and made up to 100% w / v with Castor Oil, USP as a co-solvent and release rate modifier. FASLODEX, an injection for intramuscular administration, is supplied as 5-mL single-dose prefilled syringes containing 250 mg / 5 mL fulvestrant. The names FASLODEX and fulvestrant may be used interchangeably for the purpose of this application. In some embodiments, the dose of fulvestrant is 500 mg to be administered intramuscularly into the buttocks (gluteal area) slowly (1-2 minutes per injection) as two 5 mL injections, one in each buttock, on Days 1, 15, 29, and once monthly thereafter. In some embodiments, a dose of 250 mg can be used for subjects with moderate hepatic impairment (Child- Pugh class B) to be administered intramuscularly into the buttock (gluteal area) slowly (1 -2 minutes) as one 5 mL injection on Days 1, 15, 29, and once monthly thereafter.

[0079] Many breast cancers have estrogen receptors (ER) and the growth of these tumors can be stimulated by estrogen. Fulvestrant is an estrogen receptor antagonist that binds to the estrogen receptor in a competitive manner with affinity comparable to that of estradiol and downregulates the ER protein in human breast cancer cells.

[0080] In vitro studies demonstrated that fulvestrant is a reversible inhibitor of the growth of tamoxifen-resistant, as well as estrogen-sensitive human breast cancer (MCF-7) cell lines. In in vivo tumor studies, fulvestrant delayed the establishment of tumors from xenografts of human breast cancer MCF-7 cells in nude mice. Fulvestrant inhibited the growth of established MCF-7 xenografts and of tamoxifen-resistant breast tumor xenografts.

[0081] In some embodiments, there is provided capivasertib for use in a method as described herein.

[0082] In some embodiments, there is provided capivasertib for use in a method of treating breast cancer in a subject, wherein the method increases the time to second progression or death (PFS2), the method comprises administering to the subject a combination of capivasertib and fulvestrant, and wherein the breast cancer in the subject is a HR+, HER2- breast cancer.

[0083] In some embodiments, there is provided capivasertib for use in a method of treating breast cancer in a subject, wherein the method increases TFSC, the method comprises administering to the subject a combination of capivasertib and fulvestrant, and wherein the breast cancer in the subject is a HR+, HER2- breast cancer.

[0084] In some embodiments, there is provided a kit comprising (a) capivasertib, and (b) instructions for using capivasertib in a method described herein.

[0085] Further embodiments of the invention: Embodiment 1. Capivasertib for use in a method of treating breast cancer in a subject, wherein the method increases the time to second progression or death (PFS2), the method comprises administering to the subject a combination of capivasertib and fulvestrant, and wherein the breast cancer in the subject is a HR+, HER2- breast cancer. Embodiment 2. Capivasertib for use of embodiment 1, wherein PFS2 is increased by at least 15% relative to fulvestrant monotherapy. Embodiment 3. Capivasertib for use of embodiment 1, wherein the subject has a PIK3CA / AKT1 / PTEN-altered tumor. Embodiment 4. Capivasertib for use of embodiment 3, wherein PFS2 is increased by at least 40% relative to fulvestrant monotherapy. Embodiment 5. Capivasertib for use of embodiments 1 to 4, wherein the method further comprises increasing time to first subsequent chemotherapy (TFSC) in the subject having breast cancer. Embodiment 6. Capivasertib for use of embodiment 4, wherein the TFSC is increased by at least 50% relative to fulvestrant monotherapy.Embodiment 7. Capivasertib for use of embodiments 4 or 5, wherein TFSC is increased by at least 80% relative to fulvestrant monotherapy and wherein the subject has a PIK3CA / AKT1 / PTEN-altered tumor. Embodiment 8. Capivasertib for use in a method of treating breast cancer in a subject, wherein the method increases TFSC, the method comprises administering to the subject a combination of capivasertib and fulvestrant, and wherein the breast cancer in the subject is a HR+, HER2- breast cancer. Embodiment 9. Capivasertib for use of embodiment 8, wherein TFSC is increased by at least 50% relative to fulvestrant monotherapy. Embodiment 10. Capivasertib for use of embodiment 9, wherein the subject has a PIK3CA / AKT1 / PTEN-altered tumor. Embodiment 11. Capivasertib for use of embodiment 10, wherein TFSC is increased by at least 80% relative to fulvestrant monotherapy. Embodiment 12. Capivasertib for use of any one of embodiments 8 to 11, wherein the method further comprises increasing PFS2 by at least 40% relative to fulvestrant monotherapy when the subject has a PIK3CA / AKT1 / PTEN-altered tumor. Embodiment 13. Capivasertib for use of any one of embodiments 1 to 12, wherein the breast cancer is locally advanced or metastatic breast cancer. Embodiment 14. Capivasertib for use of any one of embodiments 1 to 13, wherein the breast cancer has progressed following subject receiving at least one endocrine-based regimen in the metastatic setting, or wherein the breast cancer has recurred within 12 months of the subject receiving adjuvant therapy. Embodiment 15. Capivasertib for use of any one of embodiments 1 to 14, wherein the subject has previously received treatment with a CDK4 / 6 inhibitor. Embodiment 16. Capivasertib for use of any one of embodiments 1 to 15, wherein the administration comprises intramuscular injections of fulvestrant and oral administration of capivasertib.Embodiment 17. Capivasertib for use of any one of embodiments 1 to 16, wherein the administration comprises intramuscular injections of 500mg fulvestrant every 28 days. Embodiment 18. Capivasertib for use of embodiment 17, wherein the administration further comprises a 500mg loading dose of fulvestrant on day 15 of cycle 1. Embodiment 19. Capivasertib for use of any one of embodiments 1 to 18, comprising oral administration of 400mg capivasertib twice daily on an intermittent weekly schedule of 4 days on and 3 days off. Embodiment 20. Capivasertib for use of any one of embodiments 1 to 18, comprising oral administration of 320mg capivasertib twice daily on an intermittent weekly schedule of 4 days on and 3 days off. Embodiment 21. Capivasertib for use of any one of embodiments 1 to 18, comprising oral administration of 200mg capivasertib twice daily on an intermittent weekly schedule of 4 days on and 3 days offEXAMPLES:

[0086] The following examples are non-limiting examples. Example 1: Capivasertib in Hormone Receptor–Positive Advanced Breast Cancer Abstract:

[0087] AKT pathway activation is implicated in endocrine-therapy resistance. Data on the efficacy and safety of the AKT inhibitor capivasertib, as an addition to fulvestrant therapy, in subjects with hormone receptor–positive advanced breast cancer are limited.

[0088] In a phase 3, randomized, double-blind trial, we enrolled eligible pre-, peri-, and postmenopausal women and men with hormone receptor–positive, human epidermal growth factor receptor 2–negative advanced breast cancer who had had a relapse or disease progression during or after treatment with an aromatase inhibitor, with or without previous cyclin-dependent kinase 4 and 6 (CDK4 / 6) inhibitor therapy. Overall, 708 subjects underwent randomization; 289 subjects (40.8%) had AKT pathway alterations, and 489 (69.1%) had received a CDK4 / 6 inhibitor previously for advanced breast cancer. Subjects were randomly assigned in a 1:1 ratio to receive capivasertib plus fulvestrant or placebo plus fulvestrant. The dual primary end point was investigator-assessed progression-free survival assessed both in the overall population and among subjects with AKT pathway–altered (PIK3CA, AKT1, or PTEN) tumors. Safety was assessed. Introduction:

[0089] Approximately 70% of advanced breast cancers express the hormone receptor estrogen or progesterone (or both) and do not have human epidermal growth factor receptor 2 (HER2) overexpression. In these subjects, endocrine therapy, often an aromatase inhibitor, combined with a cyclin-dependent kinase 4 and 6 (CDK4 / 6) inhibitor is the mainstay of first-line treatment for advanced disease. Such treatment has been shown to improve progression-free and overall survival substantially as compared with aromatase inhibitor therapy alone. Nevertheless, most subjects have disease progression, and treatment of these subjects remains a clinical challenge. Appropriate endocrine-based treatment after disease progression during aromatase inhibitor therapy, with orwithout a CDK4 / 6 inhibitor, is unclear. However, options include the selective estrogen-receptor degrader fulvestrant as monotherapy or as part of combination treatment.

[0090] AKT is the key node of the phosphatidylinositol 3-kinase (PI3K)–AKT–PTEN signaling pathway. Overactivation of the pathway occurs in approximately half of hormone receptor– positive, HER2-negative breast cancers by means of activating mutations in PIK3CA and AKT1 and inactivating alterations in PTEN. Alterations may be present at the time of cancer recurrence and can also be acquired by means of previous treatment, including with CDK4 / 6 inhibitors. AKT signaling may also be activated in the absence of genetic alterations in subjects with endocrine resistance. Frogne T. et al., Endocr. Relat. Cancer, 12:599-614 (2005); Miller TW et al., J. Clin. Invest., 120-2406-2413 (2010); Ma CX et al., Nat. Rev. Cancer, 15:260-271 (2015). Inhibition of this pathway has been successful in pretreated hormone receptor–positive advanced breast cancer — results that led to regulatory approval. The PI3Kα-selective inhibitor alpelisib, combined with fulvestrant, in PIK3CA-mutant tumors in the SOLAR-1 (Clinical Studies of Alpelisib in Breast Cancer 1) trial and the mammalian target of rapamycin (mTOR) inhibitor everolimus, combined with exemestane, in the BOLERO-2 (Breast Cancer Trials of Oral Everolimus-2) trial had greater efficacy than endocrine therapy alone. Both randomized trials were conducted before the availability of CDK4 / 6 inhibitors, but in a follow-on phase 2, single-group trial (BYLieve), investigators attempted to address the need for data in this context with alpelisib plus fulvestrant.

[0091] Capivasertib is an orally bioavailable, small molecule inhibitor of all three AKT isoforms. Capivasertib inhibited AKT in preclinical models, resulting in dephosphorylation of key downstream targets; the drug also showed antiproliferative activity in breast-cancer cell lines and had synergistic antitumor activity in combination with endocrine therapy in preclinical models. Here, we present a phase 3 trial that assessed the efficacy and safety of capivasertib–fulvestrant therapy in subjects with hormone receptor–positive, HER2- negative advanced breast cancer whose disease had progressed during or after aromatase inhibitor therapy, with or without a CDK4 / 6 inhibitor.Methods: Trial Design:

[0092] In this randomized, double-blind, placebo-controlled, phase 3 trial, we randomly assigned subjects in a 1:1 ratio to receive either oral capivasertib (at a dose of 400 mg twice daily for 4 days, followed by 3 days off) plus fulvestrant (500 mg, administered intramuscularly every 14 days for the first three injections and every 28 days thereafter) or matching placebo plus fulvestrant. One cycle was defined as 4 weeks of capivasertib or placebo receipt. Premenopausal or perimenopausal women also received a luteinizing hormone– releasing hormone agonist for the duration of the trial treatment period. Randomization was stratified according to the presence or absence of liver metastases, previous use of a CDK4 / 6 inhibitor (yes or no), and geographic region.

[0093] Treatment continued until disease progression (assessed according to the Response Evaluation Criteria in Solid Tumors [RECIST], version 1.1), the occurrence of unacceptable toxic effects, withdrawal of consent, or death. Dose reduction of capivasertib or placebo was allowed from 400 mg twice daily to 320 mg twice daily, and then to 200 mg twice daily, if indicated. Dose reductions or interruptions were made for the occurrence of adverse events of grade 3 or higher that were attributed to capivasertib or placebo or for lower grades of adverse events as clinically appropriate. Reductions in the dose of fulvestrant were not allowed. Subjects who discontinued capivasertib or fulvestrant for reasons other than disease progression could continue to receive the other. No primary prophylaxis was permitted for rash and diarrhea, but investigators were advised to consider secondary prophylaxis in specific circumstances. Subjects

[0094] Premenopausal, perimenopausal, or postmenopausal women or men (≥18 years of age in most regions; ≥20 years in Japan) with hormone receptor– positive, HER2-negative locally advanced (i.e., primary inoperable) or metastatic breast cancer were eligible. Hormone receptor– positive status was defined as estrogen-receptor expression with or without progesterone-receptor expression, which, along with HER2 status, was assessed locally. HER2-negative status was defined as 0 or 1+ intensity on immunohistochemical testing, as 2+ intensity on immunohistochemical testing and no amplification on in situ hybridization, or if immunohistochemical testing was not done, as no evidence of amplification on in situ hybridization, according to the American Society of Clinical Oncology and College of AmericanPathologists guideline recommendations. Subjects must have had disease progression while they had previously been receiving an aromatase inhibitor, with or without a CDK4 / 6 inhibitor; disease progression was defined as progression during previous therapy with an aromatase inhibitor in the context of metastatic disease or as progression during treatment or within 12 months after the end of treatment with a neoadjuvant or adjuvant aromatase inhibitor. Aromatase inhibitor therapy was not required to be the most recent treatment. Subjects were allowed to have received up to two previous lines of endocrine therapy and one previous line of chemotherapy in the context of advanced disease. The trial protocol required the enrollment of a minimum of 51% of subjects with previous CDK4 / 6 inhibitor treatment. Disease progression during previous therapy was required. Subjects with previous exposure to fulvestrant or another selective estrogen-receptor degrader or to AKT, PI3K, or mTOR inhibitors were excluded, as were subjects with diabetes who were receiving insulin or had a baseline glycated hemoglobin level of at least 8.0% (63.9 mmol per mole).

[0095] Subjects were required to have measurable disease (assessed according to RECIST, version 1.1) or at least one lytic or mixed lytic–blastic bone lesion with identifiable soft-tissue components that could be assessed by means of computed tomography (CT) or magnetic resonance imaging (MRI). Subjects had an Eastern Cooperative Oncology Group performance-status score of 0 or 1 (on a scale from 0 [no disability] to 5 [death]) with no deterioration over the preceding 2 weeks. Tumor tissue for molecular analysis was required. Activating mutations in PIK3CA and AKT1 and inactivating alterations in PTEN genes were determined centrally (after randomization) by means of next-generation sequencing with the use of the FoundationOneCDx assay (Foundation Medicine) in all countries except China (OncoScreen Plus, Burning Rock Biotech). Subjects whose tumors had at least one qualifying alteration in these three genes were included in the AKT pathway–altered population. Subjects with tumors that did not have a qualifying alteration detected in any of these three genes or with an unknown test result were included in the AKT pathway– nonaltered population.

[0096] 901 subjects were enrolled and 708 subjects underwent randomization, with 355 subjects assigned to the capivasertib–fulvestrant group and 353 to the placebo–fulvestrant group (FIG.1). A total of 289 subjects (40.8%) in the overall population had tumors with AKT pathway alterations. In an analysis that excluded the 106 subjects (15.0%) with unknown alteration status (no sample available or sample did not meet the specified quality metric), 289 (48.0%) of the 602 subjects with tumor-sequencing results had AKT pathway alterations. A total of 313 subjects (44.2%) hadconfirmed AKT pathway–nonaltered tumors (Table 5). The baseline characteristics of the subjects were broadly well-balanced between the two trial groups in both populations (Table 6). The median age of the subjects was 58 years (range, 26 to 90), and 77.3% of the subjects were postmenopausal women. All the subjects had HER2-negative disease, 69.1% had previously received a CDK4 / 6 inhibitor, and 18.2% had previously received chemotherapy for advanced cancer. The demographic characteristics of the subjects were largely representative of subjects with hormone receptor- positive, HER2-negative breast cancer. Table 5 Alteration; n (%) Capivasertib- Placebo- fulvestrant (n=355) fulvestrant (n=353) Any AKT pathway alteration 155 (43.7) 134 (38.0) PIK3CA Any 116 (32.7) 103 (29.2) PIK3CA only 110 (31.0) 92 (26.1) PIK3CA and AKT1 2 (0.6) 2 (0.6) PIK3CA and PTEN 4 (1.1) 9 (2.5) AKT1 only 18 (5.1) 15 (4.2) PTEN only 21 (5.9) 16 (4.5) AKT pathway non-altered 200 (56.3) 219 (62.0) AKT pathway alteration not detected 142 (40.0) 171 (48.4) Unknown 58 (16.3) 48 (13.6) No sample available 10 (2.8) 4 (1.1) Pre-analytical failure 39 (11.0) 34 (9.6) Post-analytical failure 9 (2.5) 10 (2.8) Table 6: Characteristics of the Subjects at Baseline Overall populationPatients with AKTpathway-altered tumors Characteristic Capivasertib- Placebo- Capivasertib- Placebo- fulvestrant fulvestrant fulvestrant fulvestrant (N=355) (N=353) (N=155) (N=134) Median age (range) — yr 59 (26-84) 58 (26-90) 58 (36-84) 60 (34-90) Female sex — no. (%) 352 (99.2) 349 (98.9) 153 (98.7) 134 (100) Race — no. (%) White 201 (56.6) 206 (58.4) 75 (48.4) 76 (56.7) Asian 95 (26.8) 94 (26.6) 48 (31.0) 35 (26.1) Black 4 (1.1) 4 (1.1) 2 (1.3) 1 (0.7) Other 55 (15.5) 49 (13.9) 30 (19.4) 22 (16.4) Postmenopausal or 287 (80.8) 260 (73.7) 130 (83.9) 105 (78.4) menopausal status — no.(%) ECOG performance status score — no. (%) 0 224 (63.1) 241 (68.3) 93 (60.0) 97 (72.4) 1 131 (36.9) 111 (31.4) 62 (40.0) 36 (26.9) 2 0 1 (0.3) 0 1 (0.7) Sites of metastases — no. (%) Bone only 51 (14.4) 52 (14.7) 25 (16.1) 16 (11.9) Liver 156 (43.9) 150 (42.5) 70 (45.2) 53 (39.6) Visceral 237 (66.8) 241 (68.3) 103 (66.5) 98 (73.1) No. of previous therapies for advanced breast cancer — no. (%) 0 37 (10.4) 52 (14.7) 12 (7.7) 20 (14.9) 1 235 (66.2) 208 (58.9) 107 (69.0) 79 (59.0) 2 73 (20.6) 77 (21.8) 31 (20.0) 29 (21.6) 3 10 (2.8) 16 (4.5) 5 (3.2) 6 (4.5) Hormone receptor status — no. (%) ER-positive / PR-positive 255 (71.8) 246 (69.7) 116 (74.8) 101 (75.4) ER-positive / PR-negative 94 (26.5) 103 (29.2) 35 (22.6) 31 (23.1) ER-positive / PR unknown 5 (1.4) 4 (1.1) 4 (2.6) 2 (1.5) Endocrine status — no. (%) Primary resistance 127 (35.8) 135 (38.2) 60 (38.7) 55 (41.0) Secondary resistance 228 (64.2) 218 (61.8) 95 (61.3) 79 (59.0) No. of previous endocrine therapies for advanced breast cancer — no. (%) 0 39 (11.0) 54 (15.3) 13 (8.4) 20 (14.9) 1 287 (80.8) 252 (71.4) 131 (84.5) 96 (71.6) 2 29 (8.2) 47 (13.3) 11 (7.1) 18 (13.4) Previous CDK4 / 6 inhibitor — no. (%) As neoadjuvant or 2 (0.6) 5 (1.4) 0 2 (1.5) adjuvant therapy As therapy for advanced 245 (69.0) 244 (69.1) 113 (72.9) 91 (67.9) breast cancer Previous chemotherapy — no. (%) As neoadjuvant or 180 (50.7) 170 (48.2) 79 (51.0) 67 (50.0) adjuvant therapy As therapy for advanced 65 (18.3) 64 (18.1) 30 (19.4) 23 (17.2) breast cancerEndpoints:

[0097] The dual primary end point was investigator assessed progression-free survival (assessed according to RECIST, version 1.1) in the overall population and among subjects with AKT pathway–altered tumors. Secondary end points included overall survival, objective response, and safety. Subject-reported end points included the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life Questionnaire (QLQ-C30). The QLQ-C30 is assessed on a scale of 0 to 100, with higher scores indicating a higher quality of life. Procedures:

[0001] Tumor assessments according to RECIST, version 1.1, were performed with the use of CT or MRI scans (or both) at screening (within 4 weeks before randomization), every 8 weeks for the first 18 months, and then every 12 weeks until disease progression. Radiographic bone scans were performed at screening and repeated as clinically indicated. Subjects who discontinued capivasertib or fulvestrant for reasons other than disease progression continued to undergo scans every 8 weeks until disease progression (assessed according to RECIST, version 1.1). Biochemical and hematologic tests and vital signs were assessed on days 1 and 15 of the first two cycles and on day 1 of subsequent cycles. Fasting glucose levels were assessed on days 1 and 15 of the first cycle and then every 4 weeks until the discontinuation of capivasertib or placebo. Adverse effects were recorded continuously until 30 days after the discontinuation of capivasertib, fulvestrant, or placebo and were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Statistical analysis:

[0098] This trial was conducted to assess the effect of capivasertib therapy on progression-free survival and overall survival. A total sample of 700 subjects was planned. The primary end point was to be analyzed at approximately 77% maturity in the overall population (when 542 events of progression or death had occurred) and in the AKT pathway–altered population (when 217 events had occurred), under an assumption that 40% of the trial population would have AKT pathway– altered tumors. Assuming a true hazard ratio of 0.64 for progression or death in the analysis of progression-free survival in both populations, it was estimated that the trial would have more than 99% power to show a significant difference in favor of the capivasertib–fulvestrant group in the overall population (at a two-sided P<0.035) and 91% power to show a significant difference infavor of the capivasertib fulvestrant group in the AKT pathway–altered population (at a two sided P<0.05), with recycling of the remaining 1.5% alpha.

[0099] Overall survival assessments of no detriment (i.e., with the hazard ratio not favoring the placebo– fulvestrant group) in the overall and AKT pathway–altered populations were conducted at the time of the primary analysis of progression free survival (with the assignment of a 0.01% alpha penalty). Efficacy analyses included all the subjects who had undergone randomization. The two primary end points were tested with the use of a log-rank test, with stratification according to the presence or absence of liver metastases, previous use of a CDK4 / 6 inhibitor (yes or no), and geographic area (assessed in the overall population only). Hazard ratios and associated 95% confidence intervals were calculated from a stratified Cox proportional-hazards model fitted with the use of the PROC PHREG procedure in SAS, version 9.4, software (SAS Institute) with the Efron method to control for ties. Subgroup analyses were performed according to various factors (e.g., AKT pathway–altered status and previous use of a CDK4 / 6 inhibitor) and are presented as forest plots. The percentage of subjects with an objective response was analyzed with the use of a logistic-regression model with adjustment for the randomization stratification factors in both populations. Safety analyses included all the subjects who received at least one dose of capivasertib, fulvestrant, or placebo. Treatment:

[0001] At the primary analysis (, 63 subjects (17.7%) were continuing to receive treatment with capivasertib and 43 (12.3%) were continuing to receive placebo. The median duration of treatment with capivasertib was 5.4 months. Subjects in the placebo–fulvestrant group received placebo for a median of 3.6 months. The median duration of treatment with fulvestrant was 5.8 months in the capivasertib–fulvestrant group and 3.7 months in the placebo–fulvestrant group. Capivasertib was discontinued in 292 subjects (82.3%), and placebo was discontinued in 307 (87.7%). The main reason for discontinuation of capivasertib or placebo was disease progression, which occurred in 209 subjects (58.9%) receiving capivasertib–fulvestrant and in 273 (78.0%) receiving placebo– fulvestrant. Example 2: Capivasertib and fulvestrant for subjects with aromatase inhibitor-resistant HR+ / HER2– advanced breast cancer: second progression-free survival (PFS2) and time to first subsequent chemotherapy (TFSC) in the Phase 3 trial.Background:

[0100] In the Phase 3 trial, the addition of capivasertib (a potent, selective pan-AKT inhibitor) to fulvestrant (F) in pts with AI-resistant, HR+ / HER2– ABC, significantly improved PFS compared with placebo + F (hazard ratio [HR] 0.60; 95% confidence interval [CI] 0.51–0.71; p<0.001), including in subjects with PIK3CA / AKT1 / PTEN-altered tumors (HR 0.50; 95% CI 0.38–0.65; p<0.001). We report outcomes after study therapy (data cut-off 15 Aug 2022). Methods:

[0101] Details of subsequent anti-cancer treatments were recorded after the progression of disease on study therapy. PFS2 was a secondary endpoint, defined as the time from randomization to second progression (the earliest progression event following treatment start after PFS or death). Time from randomization to the start of subsequent chemotherapy after discontinuation of study treatment or death (TFSC) was an exploratory endpoint. Progression free survival 2 (PFS2)

[0102] In the clinical trial setting, “time from randomization to second progression or death (PFS2)” is defined as the time from date of randomization to the earliest of the progression event (following the initial progression) subsequent to the first subsequent therapy or death.

[0103] Following discontinuation of study treatment due to disease progression, as determined by investigator-based by RECIST v1.1 assessment, subjects who started on subsequent cancer therapy post progression were continued to be followed at the 30-day follow-up visit, every 8 weeks (±7 days) for the first 2 years, and every 12 weeks (±7 days) thereafter for documentation of progression on second-line therapy. Determination of PD for PFS2 was by institutional call

[0104] Subjects alive and for whom a second disease progression had not been observed were censored at the date last known alive and without a second disease progression (i.e., censored at the PFS or PFS2 assessment date, whichever was later, if the subject had not had a second progression or death). Analysis of PFS2

[0105] Time from randomization to second progression or death in the Overall Population and Altered Populations were analyzed using a stratified log rank test, using the same methodology as described for the primary PFS endpoint for the Overall Population. The PFS2 analysis in the Overall Population was stratified by the stratification factors. The effect of treatment was estimatedby the HR together with its corresponding 95% CI. Kaplan-Meier plots were presented by treatment group.

[0106] The sensitivity analysis outlined for PFS was not repeated for PFS2 with the exception of a Kaplan-Meier plot of the time to censoring where the censoring indicator of the PFS2 event was reversed (what was originally a censored event in the analysis became an actual event and what originally was a PFS2 event became a censored event).

[0107] The number and percentage of subjects experiencing a PFS2 event and the type of progression were also summarized by treatment arm. Time from randomization to second progression was summarized by treatment arm. Time to first subsequent chemotherapy or death (TFSC)

[0108] In the clinical trial setting, TFSC is defined as the time from the date of randomization to the earlier of start date of the first subsequent chemotherapy after discontinuation of randomised treatment, or death (i.e., date of first subsequent chemotherapy / death or censoring – date of randomization + 1). Subjects alive and not known to have had a first subsequent chemotherapy were censored at the earliest of: date of study termination, date last known alive, DCO, or the last date that the subject was known not to have received a first subsequent chemotherapy. Analysis of TFSC

[0109] Time to first subsequent chemotherapy or death was analyzed using the same methodology and model as that used for the analysis of PFS. The hazard ratio for the treatment effect together with its 95% CI and p-value was presented. In addition, medians and a Kaplan-Meier plot of the time to the start of subsequent chemotherapy were presented by treatment arm and the time between progression and starting subsequent therapy was assessed. This was summarized per treatment arm, but no formal comparisons were made. No multiplicity adjustment was applied as this was viewed as a supportive endpoint.Results:

[0110] 708 pts were randomised to capivasertib + F (n=355) or placebo + F (n=353): 289 pts (40.8%) had PIK3CA / AKT1 / PTEN-altered tumors (289 / 602, 48.0% of pts with known tumor sequencing results) (FIG.1).

[0111] At the time of this analysis, 238 (67.0%) pts in the capivasertib + F arm and 264 (74.8%) pts in the placebo + F arm had received subsequent anti-cancer therapy; most commonly cytotoxic chemotherapy (56.1% vs 61.2%), hormonal therapy (27.6% vs 30.3%) and targeted therapy (18.9% vs 25.8%).

[0112] FIG.2A and FIG.2B present all post study treatment-discontinuation therapies; subsequent therapies were broadly balanced between treatment arms. Only cytotoxic chemotherapies with a frequency ≥5% in at least one subject population (overall or PIK3CA / AKT1 / PTEN pathway- altered) are shown in FIG.2A and FIG.2B. In FIG.2A and FIG.2B, Cytotoxic chemotherapy included ADCs, which were used in 3.4% of subjects in the capivasertib-fulvestrant arm and 3.1% of subjects in the placebo-fulvestrant arm in the overall population and 3.9% and 3.7% of subjects in the PIK3CA / AKT1 / PTEN pathway-altered population, respectively. In FIG.2A and FIG.2B, ’Other’ anticancer therapies included immunotherapy, biologic therapy, PARP inhibitor, experimental therapy and any other therapies.

[0113] FIG.3A and FIG.3B present first subsequent therapy post-discontinuation of study treatment. Subjects may have received more than one first subsequent anticancer therapy. Only cytotoxic chemotherapies with a frequency ≥5% in at least one subject population (overall or PIK3CA / AKT1 / PTEN pathway-altered) are shown in FIG.3A and FIG.3B. Cytotoxic chemotherapy included ADCs, which were used as first subsequent therapy in 1.4% of subjects in the capivasertib-fulvestrant arm and 2.0% of subjects in the placebo-fulvestrant arm in the overall population and 1.9% and 2.2% of subjects in the PIK3CA / AKT1 / PTEN pathway-altered population, respectively. In FIG.3A and FIG.3B, ’Other’ anticancer therapies included immunotherapy, biologic therapy, PARP inhibitor, experimental therapy and any other therapies.

[0114] PFS2 and TFSC favoured capivasertib + F over placebo + F in the overall and PIK3CA / AKT1 / PTEN-altered populations (Table 7).

[0115] In the overall population, median PFS2 was 14.7 months for the Capivasertib + F treatment group and 12.5 months for the Placebo + F treatment group (17.6% increase) (Table 7, FIG.4B).In the PIK3CA / AKT1 / PTEN-altered population, median PFS2 was 15.5 months for the Capivasertib + F treatment group and 10.8 months for the Placebo + F treatment group (43.5% increase) (Table 7, FIG.4A).

[0116] In the overall population, median TFSC was 11.0 months for the Capivasertib + F treatment group and 6.8 months for the Placebo + F treatment group (61.7% increase) (Table 7, FIG.5B). In the PIK3CA / AKT1 / PTEN-altered population, median PFS2 was 11.0 months for the Capivasertib + F treatment group and 6.0 months for the Placebo + F treatment group (83.3% increase) (Table 7, FIG.5A). Table 7 Overall population PIK3CA / AKT1 / PTEN-altered population Capivasertib + Placebo + F Capivasertib + Placebo + F F (n=355) (n=353) F (n=155) (n=134) Events; n (%) 176 (49.6) 207 (58.6) 79 (51.0) 87 (64.9) Median; PFS2 months 14.7 12.5 15.5 10.8 HR (95% CI) 0.70 (0.57–0.86) HR 0.52 (0.38–0.71) Events; n (%) 217 (61.1) 248 (70.3) 103 (66.5) 100 (74.6) Median; TFSC months 11.0 6.8 11.0 6.0 HR (95% CI) 0.63 (0.52–0.75) 0.56 (0.42–0.74)

Claims

CLAIMS 1. A method of increasing the time to second progression or death (PFS2) in a subject having breast cancer, the method comprising administering to the subject a combination of capivasertib and fulvestrant wherein the breast cancer in the subject is a HR+, HER2- breast cancer.

2. The method of claim 1, wherein PFS2 is increased by at least 15% relative to fulvestrant monotherapy.

3. The method of claim 1, wherein the subject has a PIK3CA / AKT1 / PTEN-altered tumor.

4. The method of claim 3, wherein PFS2 is increased by at least 40% relative to fulvestrant monotherapy.

5. The method of any one of claims 1 to 4, wherein the method further comprises increasing time to first subsequent chemotherapy (TFSC) in the subject having breast cancer.

6. The method of claim 4, wherein the TFSC is increased by at least 50% relative to fulvestrant monotherapy.

7. The method of claim 4 or 5, wherein TFSC is increased by at least 80% relative to fulvestrant monotherapy and wherein the subject has a PIK3CA / AKT1 / PTEN-altered tumor.

8. A method of increasing TFSC in a subject in a subject having breast cancer, the method comprising administering to the subject a combination of capivasertib and fulvestrant, wherein the breast cancer in the subject is a HR+, HER2- breast cancer.

9. The method of claim 8, wherein TFSC is increased by at least 50% relative to fulvestrant monotherapy.

10. The method of claim 9, wherein the subject has a PIK3CA / AKT1 / PTEN-altered tumor.

11. The method of claim 10, wherein TFSC is increased by at least 80% relative to fulvestrant monotherapy.

12. The method of any one of claims 8 to 11, wherein the method further comprises increasing PFS2 by at least 40% relative to fulvestrant monotherapy when the subject has a PIK3CA / AKT1 / PTEN-altered tumor.

13. The method of any one of claims 1 to 12, wherein the breast cancer is locally advanced or metastatic breast cancer.

14. The method of any one of claims 1 to 13, wherein the breast cancer has progressed following subject receiving at least one endocrine-based regimen in the metastatic setting, or wherein the breast cancer has recurred within 12 months of the subject receiving adjuvant therapy.

15. The method of any one of claims 1 to 14, wherein the subject has previously received treatment with a CDK4 / 6 inhibitor.

16. The method of any one of claims 1 to 15, wherein the administration comprises intramuscular injections of fulvestrant and oral administration of capivasertib.

17. The method of any one of claims 1 to 16, wherein the administration comprises intramuscular injections of 500mg fulvestrant every 28 days.

18. The method of claim 17, wherein the administration further comprises a 500mg loading dose of fulvestrant on day 15 of cycle 1.

19. The method of any one of claims 1 to 18, comprising oral administration of 400mg capivasertib twice daily on an intermittent weekly schedule of 4 days on and 3 days off.

20. The method of any one of claims 1 to 18, comprising oral administration of 320mg capivasertib twice daily on an intermittent weekly schedule of 4 days on and 3 days off.

21. The method of any one of claims 1 to 18, comprising oral administration of 200mg capivasertib twice daily on an intermittent weekly schedule of 4 days on and 3 days off.

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