SERD Combinations to Treat Cancer

Abstract

The present disclosure relates to a method of treating a patient with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), breast cancer, comprising administering to a patient in need of treatment an oral selective estrogen receptor degrader (SERD) in combination with an AKT inhibitor or an mTOR inhibitor and / or a cyclin-dependent kinase 4 / 6 inhibitor (CDK4 / 6i).

Description

[Technical Field]

[0001] The present specification relates to the use of oral SERDs in combination with AKT inhibitors or mTOR inhibitors, and / or CDK4 / 6 inhibitors to treat cancer, for example, breast cancer. [Background technology]

[0002] Next-generation oral selective estrogen receptor degraders (ngSERDs) aim to become the backbone endocrine therapy (ET) for patients with estrogen receptor (ER)-positive breast cancer by blocking estrogen receptor (ER) signaling to a greater extent than current therapies and addressing key mechanisms of resistance. Camizestrant (AZD9833), an ngSERD for treating ER+ breast cancer, has demonstrated selective ERα degradation, pure ER antagonism, and significant antitumor activity in ESR1 wild-type (ESR1wt) and mutant (ESR1m) tumors, and is showing increasing clinical activity in early-stage clinical trials.

[0003] ER+ breast cancer responds to therapies targeting ERα and CDK4 / 6 signaling as adjuvant and metastatic settings. To explore the potential of SERD as a backbone ET therapy, we combined camizestrant with either palbociclib or abemaciclib in CDK4 / 6 inhibitor-naive and -resistant in vitro and in vivo models, mirroring the SERENA-1 and SERENA-4 clinical trials. In vitro benefit of the combination was observed in three parental ER+ breast cancer cell lines. Furthermore, camizestrant plus abemaciclib demonstrated activity in palbociclib-resistant cell lines, including those lacking CCNE1amp and RB1. In vivo, the combination of camizestrant with palbociclib or abemaciclib was well tolerated, and the combination promoted improved efficacy in ESR1wt and ESR1m PDX ("patient-derived xenograft") tumor models compared with the camizestrant and CDK4 / 6 inhibitor monotherapy arms in this study.

[0004] ER+-positive breast cancers have a high rate of altered PI3K / AKT / PTEN pathways, providing an opportunity for treatment with PI3K / AKT pathway inhibitors. In CTC-174, ESR1m, and PI3KCAm tumor models (i.e., models with both estrogen receptor and PI3KCA mutations), the ngSERD camizestrant demonstrated enhanced efficacy when combined with the mTOR inhibitor everolimus and the AKT inhibitor capivasertib. Additionally, the combination with the AKT inhibitor capivasertib was more effective than monotherapy at clinically relevant doses and schedules in both wild-type and mutant PI3K pathways in PDX models. These data demonstrate the interplay between PI3K pathway inhibition and camizestrant's mechanism of action. Notably, the combination of camizestrant and capivasertib proved significantly more active than optimal doses of fulvestrant and capivasertib in both ESR1m and ESR1wt PDX models, suggesting that clinical benefit may be derived from the use of camizestrant rather than combining fulvestrant with an AKT inhibitor.

[0005] Finally, this specification also discloses the use of a triple combination of camizestrant, capivasertib, and palbociclib in palbociclib-resistant models representing PI3KCA / AKT wild-type and mutant tumors. This strategy resulted in robust efficacy across these models compared with monotherapy and the two-drug combination. The triple combination of camizestrant, capivasertib, and palbociclib resulted in long-lasting regressions at clinically achievable doses of all compounds, regardless of genetic background. These preclinical data demonstrate the potential of SERDs like camizestrant as backbone ETs with high in vivo combinatorial potential with CDK4 / 6, mTOR, and AKT inhibitors. The activity profile of these combinations highlights opportunities to impact the care of patients with early and metastatic ER+ breast cancer by providing benefit across a broad patient population, including those with ESR1wt or ESR1m tumors, independent of PI3K pathway mutation status, and in both CDK4 / 6i-naive and -refractory patients. Summary of the Invention

[0006] The present specification provides a means for enhancing the antiproliferative effects of SERD treatment in cancer (e.g., breast cancer) by utilizing a SERD (e.g., ngSERD) in combination with an mTOR, AKT, and / or CDK4 / 6 inhibitor.

[0007] In embodiments, a SERD is provided for use in the treatment of cancer, wherein the SERD is administered in combination with an AKT inhibitor or an mTOR inhibitor, and / or a CDK4 / 6 inhibitor.

[0008] In an embodiment, there is provided a SERD for use in the treatment of cancer, comprising: -AKT inhibitors or mTOR inhibitors CDK4 / 6 inhibitors, or - A SERD is provided that is administered in combination with an AKT inhibitor or an mTOR inhibitor and a CDK4 / 6 inhibitor.

[0009] 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 "treatment of cancer" includes both in vitro 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 proliferation (including reversal of cancer growth); promotion of cancer cell death (e.g., by promoting apoptosis or another cell death mechanism); improvement of symptoms; duration of 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.

[0010] The phrase "in combination with" and similar terms encompasses the administration of two or more active pharmaceutical ingredients to a subject, including simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition where two or more active pharmaceutical ingredients are present. For triple combinations, hybrid administration in which two drugs are administered simultaneously and one drug is administered separately or sequentially from the other drug is encompassed by the foregoing definition.

[0011] In embodiments, the SERD and each inhibitor are administered separately, sequentially, or simultaneously.

[0012] In an embodiment, the SERD and each inhibitor are administered separately.

[0013] In embodiments, the SERD and each inhibitor are administered sequentially.

[0014] In embodiments, the SERD and each inhibitor are administered simultaneously.

[0015] In a further aspect, there is provided the use of a SERD in the manufacture of a medicament for treating cancer, wherein the SERD is administered in combination with an AKT inhibitor or an mTOR inhibitor, and / or a CDK4 / 6 inhibitor.

[0016] In a further aspect, a method of treating cancer in an animal patient in need of such treatment is provided, comprising administering to the animal patient a therapeutically effective amount of a SERD, wherein the SERD is administered in combination with a therapeutically effective amount of an AKT inhibitor or an mTOR inhibitor, and / or a CDK4 / 6 inhibitor.

[0017] The term "therapeutically effective amount" refers to an amount of a compound or combination of compounds described herein sufficient to effect the intended application, including, but not limited to, disease treatment. A therapeutically effective amount may vary depending on the intended application (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 specific response in target cells (e.g., the amount of apoptosis). The specific dose will vary depending on the particular compound selected, the dosing regimen to be followed, whether the compound is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system by which the compound is delivered.

[0018] In a further aspect, a method of treating cancer in an animal patient in need of such treatment is provided, comprising administering to the animal patient a SERD, wherein the SERD is administered in combination with an AKT inhibitor or an mTOR inhibitor, and a CDK4 / 6 inhibitor.

[0019] In a further aspect, a method of treating cancer in an animal patient in need of such treatment is provided, comprising administering to the animal patient a first amount of a SERD, a second amount of an AKT inhibitor or an mTOR inhibitor, and a third amount of a CDK4 / 6 inhibitor, wherein the first amount, second amount, and third amount together comprise a therapeutically effective amount.

[0020] In a further aspect, a pharmaceutical composition is provided comprising a SERD in combination with an AKT inhibitor or an mTOR inhibitor, and / or a CDK4 / 6 inhibitor, and a pharmaceutically acceptable excipient.

[0021] The term "pharmaceutically acceptable" is used to specify that an object (e.g., a salt, a dosage form (tablet or capsule), or an excipient (such as a diluent or carrier) is suitable for use in patients. An exemplary list of pharmaceutically acceptable salts can 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.

[0022] Pharmaceutically acceptable acid addition salts can be formed using inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Pharmaceutically acceptable base addition salts can be formed using inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins. Examples include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. [Brief explanation of the drawings]

[0023] [Figure 1] Mouse patient-derived xenograft (PDX) assay. Co-dosing of 10 mg / kg AZD9833 and 5 mg / kg everolimus via oral administration (PO) once daily for 28 days in a volume of 0.1 mL per 10 g of mouse enhances efficacy compared to monotherapy in D538G ESR1mt / PI3KCA N345K PDX CTC174. Statistical analysis was performed by a one-tailed unequal variance t-test versus log(change in tumor volume) compared to vehicle control on the last day of treatment. ****, p<0.0001. [Figure 2] Mouse patient-derived xenograft assay. Co-dosing of AZD9833 and capivasertib at 10 mg / kg and 85 mg / kg, respectively, via oral administration (PO) for 28 days (camizestrant was dosed continuously, capivasertib was dosed on a 4-day on, 3-day off schedule) enhances efficacy compared to AZD9833 or capivasertib monotherapy in D538G ESR1mt / PI3KCA N345K PDX CTC174. Statistical analysis was performed by a one-tailed unequal variance t-test versus log(change in tumor volume) compared to vehicle control on the last day of treatment. ****, p<0.0001. [Figure 3] Mouse patient-derived xenograft assay. AZD9833 at 10 mg / kg, palbociclib at 50 mg / kg, or the same doses of both agents were administered in combination once daily by oral gavage throughout the study. Combining the CDK4 / 6 inhibitor palbociclib with AZD9833 enhances efficacy compared to monotherapy in D538G ESR1mt / PI3KCA N345K PDX CTC174. Statistical analysis was performed by a one-tailed unequal variance t-test versus log(change in tumor volume) compared to vehicle control on the last day of treatment. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. [Figure 4]Characterization of palbociclib-resistant cell lines. Genetic alterations were assessed by whole exosome sequencing (WES) for the cell lines indicated in the table. Combination matrix plots showing 7-day cell viability assays for combination treatment with camizestrant and palbociclib or abemaciclib in MCF7 parental and palbociclib-resistant cell lines (PC1, PC6, PC8) were measured using Cell Titer Glo (CTG, Promega). Cells were seeded in 60 μL of medium one day prior to treatment. Compound was added to assay plates the following day (day 0), and read on day 7. Untreated plates were read on day 0. These results were obtained by reading luminescence after the addition of 30 μL of CTG and a 30-minute incubation at ambient temperature. Data were normalized to the initial seeding day 0 and maximum day 7 growth (DMSO alone). [Figure 5] Mouse patient-derived xenograft assay. Combining AZD9833 with CDK4 / 6 and / or mTOR / AKT inhibitors promotes robust activity in PDX models. In vivo, camizestrant was co-administered at 10 mg / kg daily with palbociclib at 50 mg / kg daily, abemaciclib at 50 mg / kg daily, and capivasertib at 130 mg / kg daily in PDX ST1799 for 40 days (gray area). Note: Due to the large number of treatment groups, the graph was subdivided into two subgraphs; the vehicle and palbociclib groups are the same in the two plotted subgraphs. Statistical analysis was performed using a one-sided unequal variance t-test versus log(change in tumor volume) on the last day of treatment compared to vehicle control. Statistical analysis was performed using a one-sided unequal variance t-test versus log(change in tumor volume) on the last day of treatment compared to vehicle control. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. [Figure 6]Mouse patient-derived xenografts in the ST3632 and ESR1wt models. The combination of AZD9833 with a CDK4 / 6 inhibitor promoted robust activity in ER+ PDX models derived from primary tumors representative of early-stage disease and insensitive to palbociclib monotherapy. AZD9833 was administered orally at 10 mg / kg daily along with palbociclib at 50 mg / kg daily and abemaciclib at 50 mg / kg daily. Statistical analysis was performed using a one-sided unequal variance t-test versus log(change in tumor volume) compared to vehicle control on the last day of treatment. Statistical analysis was performed using a one-sided unequal variance t-test versus log(change in tumor volume) compared to vehicle control on the last day of treatment. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. [Figure 7] Combination efficacy of the triple combination of AZ9833, palbociclib, and capivasertib compared with the combination of fulvestrant and palbociclib. Patient-derived xenograft preclinical models were treated with palbociclib and fulvestrant, and with the triple combination of camizestrant, capivasertib, and palbociclib in PDX tumor models. Triple treatment with combined ER, CDK4 / 6, and AKT inhibition was superior to the palbociclib / fulvestrant combination and was broadly effective in both PI3K pathway-mutant and wild-type PDX models. AZ9833 at 10 mg / kg daily was administered with palbociclib at 50 mg / kg daily and capivasertib at 130 mg / kg daily for 4 days, followed by a 3-day washout period. Statistical analysis was performed using a one-sided unequal variance t-test versus log(change in tumor volume) compared to vehicle control on the last day of treatment. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. [Figure 8]Model characterization and combination efficacy summary of the triple combination of AZ9833, palbociclib, and capivasertib. Model features of patient-derived xenograft preclinical models are summarized in a heatmap. Triple combination activity of AZ9833, capivasertib, and palbociclib was compared to monotherapy and a doublet triplet. Triple treatment with combined ER, CDK4 / 6, and AKT inhibition was superior to the palbociclib / fulvestrant combination and was broadly effective in both PI3K pathway-mutant and wild-type PDX models. Statistical analysis was performed using a one-sided unequal variance t-test versus log(change in tumor volume) compared to vehicle control on the last day of treatment. Statistical analysis was performed using a one-sided unequal variance t-test versus log(change in tumor volume) compared to vehicle control on the last day of treatment. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. [Figure 9] Combination efficacy of AZD9833 with capivasertib and / or palbociclib in the ST1799 model (ESR1 wt, PI3KCAm E542K) as doublet and triplet combinations. Using a patient-derived xenograft preclinical model, the triplet combination of AZD9833, capivasertib, and palbociclib was compared to various corresponding monotherapies and doublet combinations (fulvestrant + palbociclib, fulvestrant + capivasertib, camizestrant + palbociclib, and camizestrant + capivasertib). Figure 9 shows tumor volume plots for ER+ breast cancer PDXs in a 28-day efficacy study, showing all treatment groups. Dosage: Oral palbociclib 50 mg / kg once daily, subcutaneous fulvestrant 5 mg / kg once weekly, oral camizestrant 10 mg / kg once daily, and capivasertib 130 mg / kg twice daily, with a 4-day on, 3-day off schedule. The triple combination was superior to both the doublet combination and monotherapy. The combination of camizestrant and capivasertib was also superior to the combination of fulvestrant and capivasertib. [Figure 10]Combination efficacy of AZD9833 with capivasertib and / or palbociclib in the ST3632 model (ESR1 wt, AKT1m E17K) as doublet and triplet combinations. Using a patient-derived xenograft preclinical model, the triplet combination of AZD9833, capivasertib, and palbociclib was compared to various corresponding monotherapies and doublet combinations (fulvestrant + palbociclib, fulvestrant + capivasertib, camizestrant + palbociclib, and camizestrant + capivasertib). Figure 10 shows tumor volume plots for ER+ breast cancer PDXs in a 28-day efficacy study, showing all treatment groups. Dosage: Oral palbociclib 50 mg / kg once daily, subcutaneous fulvestrant 5 mg / kg once weekly, oral camizestrant 10 mg / kg once daily, and capivasertib 130 mg / kg twice daily, with a 4-day on, 3-day off schedule. The triple combination was superior to both the doublet combination and monotherapy. The combination of camizestrant and capivasertib was also superior to the combination of fulvestrant and capivasertib. [Figure 11] Combination efficacy of AZD9833 with capivasertib and / or palbociclib in the ST941 model (ESR1m Y537S) as doublet and triplet combinations. Using a patient-derived xenograft preclinical model, the triplet combination of AZD9833, capivasertib, and palbociclib was compared to various corresponding monotherapies and doublet combinations (fulvestrant + palbociclib, fulvestrant + capivasertib, camizestrant + palbociclib, and camizestrant + capivasertib). Figure 11 shows tumor volume plots for ER+ breast cancer PDXs in a 28-day efficacy study, showing all treatment groups. Dosage: Oral palbociclib 50 mg / kg once daily, subcutaneous fulvestrant 5 mg / kg once weekly, oral camizestrant 10 mg / kg once daily, and capivasertib 130 mg / kg twice daily, with a 4-day on, 3-day off schedule. The triple combination was superior to both the doublet combination and monotherapy. The combination of camizestrant and capivasertib was also superior to the combination of fulvestrant and capivasertib. [Figure 12]Combination efficacy of AZD9833 with capivasertib and / or palbociclib in the CTC174 model (altered PI3KCA / AKT or PTEN ER+; ESR1m D538G, PI3KCAm N345K) as doublet and triplet combinations. Using a xenograft preclinical model, the triplet combination of AZD9833, capivasertib, and palbociclib was compared with various corresponding monotherapies and doublet combinations (fulvestrant + palbociclib, fulvestrant + capivasertib, camizestrant + palbociclib, and camizestrant + capivasertib). Figure 12 shows tumor volume plots for ER+ breast cancer PDXs in a 28-day efficacy study, showing all treatment groups. Dosage: Oral palbociclib 50 mg / kg once daily, subcutaneous fulvestrant 5 mg / kg once weekly, oral camizestrant 10 mg / kg once daily, capivasertib 130 mg / kg twice daily, 4 days on, 3 days off. The triple combination and the combination of camizestrant and capivasertib proved superior to other doublet combinations and monotherapy groups. [Figure 13] Combination efficacy of the AZD9833 / S capivasertib dual combination compared to the fulvestrant / capivasertib dual combination and monotherapy in the ST1799 model (ESR1 wt, PI3KCAm E542K). Patient-derived xenograft preclinical models were used to compare the indicated combinations and monotherapies. Figure 13 shows tumor volume plots for ER+ breast cancer PDXs in a 28-day efficacy study, with all treatment groups shown. Dosing: Subcutaneous fulvestrant 5 mg / kg weekly, oral camizestrant 10 mg / kg once daily, capivasertib 130 mg / kg twice daily, 4 days on, 3 days off dosing schedule. Fulvestrant and camizestrant monotherapy similarly inhibited tumor growth in this model. The combination of camizestrant and capivasertib was superior to the combination of fulvestrant and capivasertib and to the monotherapy arms of the study. [Figure 14]Combination efficacy of the AZD 9833 / S capivasertib dual combination compared to the fulvestrant / capivasertib dual combination and monotherapy in the ST3632 model (ESR1 wt, AKT1m E17K). Patient-derived xenograft preclinical models were used to compare the indicated combinations and monotherapies. Figure 14 shows tumor volume plots for ER+ breast cancer PDXs in a 28-day efficacy study, with all treatment groups shown. Dosing: Subcutaneous fulvestrant 5 mg / kg once weekly, oral camizestrant 10 mg / kg once daily, capivasertib 130 mg / kg twice daily, with a 4-day on, 3-day off dosing schedule. The camizestrant and capivasertib combination was superior to the fulvestrant and capivasertib combination and the monotherapy arms of the study. [Figure 15] Combination efficacy of the AZD 9833 / S capivasertib dual combination compared to the fulvestrant / capivasertib dual combination and monotherapy in the ST941 model (ESR1m Y537S). Patient-derived xenograft preclinical models were used to compare the indicated combinations and monotherapies. Figure 15 shows tumor volume plots for ER+ breast cancer PDXs in a 28-day efficacy study, with all treatment groups shown. Dosing: Subcutaneous fulvestrant 5 mg / kg once weekly, oral camizestrant 10 mg / kg once daily, capivasertib 130 mg / kg twice daily, with a 4-day on, 3-day off dosing schedule. The camizestrant and capivasertib combination was superior to the fulvestrant and capivasertib combination. [Figure 16]Combination efficacy of the AZD 9833 / S capivasertib dual combination compared to the fulvestrant / capivasertib dual combination and monotherapy in the CTC174 model (altered PI3KCA / AKT or PTEN ER+: ESR1m D538G, PI3KCAm N345K). A xenograft preclinical model was used to compare the indicated combinations and monotherapies. Figure 16 shows tumor volume plots for ER+ breast cancer PDXs in a 28-day efficacy study, with all treatment groups shown. Dosing: Subcutaneous fulvestrant 5 mg / kg once weekly, oral camizestrant 10 mg / kg once daily, capivasertib 130 mg / kg twice daily, with a 4-day on, 3-day off dosing schedule. The camizestrant and capivasertib combination was superior to the fulvestrant and capivasertib combination and the monotherapy arms of the study. DETAILED DESCRIPTION OF THE INVENTION

[0024] Cancer treatment In an embodiment, the treatment of cancer is the treatment of an animal cancer (eg, a mammalian cancer, such as a human cancer).

[0025] In embodiments, the cancer is a hormone-sensitive cancer (e.g., an estrogen- or androgen-sensitive cancer). "Estrogen- or androgen-sensitive" means that the growth of the cancer is driven, at least in part, by the respective hormone pathway, such that blocking the hormone attenuates growth and has a therapeutic effect.

[0026] In embodiments, the cancer is breast cancer (eg, early stage, advanced stage, or metastatic breast cancer).

[0027] In an embodiment, the cancer is early stage breast cancer.

[0028] In an embodiment, the cancer is advanced breast cancer.

[0029] In an embodiment, the cancer is metastatic breast cancer.

[0030] In an embodiment, the cancer is hormone-sensitive breast cancer.

[0031] In an embodiment, the cancer is estrogen-sensitive breast cancer.

[0032] In an embodiment, the cancer is ovarian cancer.

[0033] In an embodiment, the cancer is estrogen-sensitive ovarian cancer.

[0034] In an embodiment, the cancer is endometrial cancer.

[0035] In an embodiment, the cancer is estrogen-sensitive endometrial cancer.

[0036] In an embodiment, the cancer is prostate cancer.

[0037] In an embodiment, the cancer is androgen-sensitive prostate cancer.

[0038] Patient Selection and Diagnostic Methods In an embodiment, the cancer is estrogen receptor positive (ER+) breast cancer.

[0039] An "estrogen receptor positive" cancer includes tumors that have estrogen receptors (e.g., in at least 1%, at least 10%, at least 20%, or at least 50% of tumor cells) and can metabolize estrogen to grow. ER+ status can be determined by methods known in the art, such as immunohistochemistry (IHC) testing.

[0040] In an embodiment, the cancer is estrogen receptor positive breast cancer.

[0041] In an embodiment, the cancer is a breast cancer that contains only wild-type estrogen receptors. Such cancers do not contain mutant estrogen receptors, but only receptors found in their normal state.

[0042] In one embodiment, cancer is breast cancer that contains mutant estrogen receptor.Mutant estrogen receptor is synthesized by cancer that has mutation in its gene structure (for example, ESR1 gene).The mutation in estrogen receptor can be determined by methods known in the art, for example, by next-generation sequencing.

[0043] In an embodiment, the cancer does not comprise an ESR1 mutation.

[0044] In an embodiment, the cancer does not involve an ESR1 fusion.

[0045] In an embodiment, the cancer does not contain an ESR1 mutation or fusion.

[0046] In embodiments, the cancer comprises a mutation in ESR1 selected from an E380Q mutation, a Y537S mutation, and a D538G mutation.

[0047] In an embodiment, the cancer comprises an ESR1-CCDC170 fusion.

[0048] In embodiments, the cancer comprises a mutation in ESR1 selected from an E380Q mutation, a Y537S mutation, and a D538G mutation, and / or an ESR1-CCDC170 fusion.

[0049] In embodiments, the cancer comprises a mutation in ESR1 selected from an E380Q mutation, a Y537S mutation, and a D538G mutation, and / or an ESR1-CCDC170 fusion.

[0050] In embodiments, the cancer is PTEN-deficient (e.g., comprises cancerous cells (e.g., a population of cancerous cells, such as a majority of cancerous cells) that have a reduced normal amount or function of the PTEN tumor suppressor protein (e.g., compared to non-cancerous cells of the same patient). PTEN status can be determined by methods known in the art.

[0051] In embodiments, the cancer comprises an AKT1 mutation (e.g., a gain-of-function mutation, or a deletion, substitution, or insertion mutation such as the E17K mutation). AKT1 mutation status can be determined by methods known in the art.

[0052] In embodiments, the cancer is characterized by a PI3KCA mutation (e.g., a gain-of-function mutation, or a deletion, substitution, or insertion mutation, e.g., PI3KCA E542K , PI3KCA E545K , PI3KCA Q546R , PI3KCA 1047L , or PI3KCA H1047R PI3KCA mutation status can be determined by methods known in the art.

[0053] In embodiments, the PI3KCA mutation is selected from R88Q, C420R, E542K, E545A, E545D, E545Q, E545K, E545G, Q546E, Q546K, Q546R, Q546P, M1043V, M1043I, N345K, H1047Y, H1047R, H1047L, and G1049R.

[0054] In embodiments, the PI3KCA mutation is selected from R88Q, E542K, E545K, and N354K.

[0055] In an embodiment, the PI3KCA mutation is selected from E545K and N345K.

[0056] In one embodiment, a SERD is provided for use in treating cancer, wherein the SERD is administered in combination with an AKT inhibitor, and the cancer is PTEN-deficient, contains an AKT1 mutation (e.g., an E17K AKT1 mutation), and / or contains a PI3KCA mutation (e.g., a PI3KCA mutation selected from an E545K mutation and an N345K mutation).

[0057] In one embodiment, a SERD is provided for use in treating cancer, wherein the SERD is administered in combination with an AKT inhibitor, and the cancer is PTEN-deficient, AKT1-mutated, or PI3KCA-mutated.

[0058] In one embodiment, a SERD is provided for use in treating cancer, wherein the SERD is administered in combination with an AKT inhibitor, and the cancer is PTEN-deficient, contains an AKT1 mutation, or contains a PI3KCA mutation.

[0059] In one embodiment, a SERD is provided for use in treating cancer, wherein the SERD is administered in combination with an AKT inhibitor and the cancer is PTEN-deficient.

[0060] In one embodiment, a SERD is provided for use in treating cancer, wherein the SERD is administered in combination with an AKT inhibitor, and the cancer comprises an AKT1 mutation and / or comprises a PI3KCA mutation.

[0061] In one embodiment, a SERD is provided for use in treating cancer, wherein the SERD is administered in combination with an AKT inhibitor and the cancer comprises an AKT1 mutation and a PI3KCA mutation.

[0062] In one embodiment, a SERD is provided for use in treating cancer, wherein the SERD is administered in combination with an AKT inhibitor and the cancer comprises an AKT1 mutation and a PI3KCA mutation.

[0063] In embodiments, the cancer is estrogen receptor-positive (ER+) breast cancer that contains a mutation in ESR1 (e.g., a mutation in ESR1 selected from E380Q, Y537S, and D538G mutations); and / or an ESR1-CCDC170 fusion; and is PTEN-deficient, contains an AKT1 mutation (e.g., E17K mutation), and / or contains a PI3KCA mutation (e.g., a PI3KCA mutation selected from E542K and N345K mutations).

[0064] In embodiments, the cancer is estrogen receptor positive (ER+) breast cancer that does not contain an ESR1 mutation or fusion, but does contain an E542K PI3KCA mutation.

[0065] In embodiments, the cancer is estrogen receptor positive (ER+) breast cancer that does not contain an ESR1 mutation or fusion, but does contain an E17K AKT1 mutation.

[0066] In an embodiment, the cancer is estrogen receptor positive (ER+) breast cancer containing the Y537S ESR1 mutation.

[0067] In embodiments, the cancer is estrogen receptor positive (ER+) breast cancer that is PTEN deficient and contains the R88Q PI3KCA mutation.

[0068] In an embodiment, the cancer is estrogen receptor positive (ER+) breast cancer, which comprises an E380Q ESR1 mutation and an N345K PI3KCA mutation.

[0069] In an embodiment, the cancer is estrogen receptor positive (ER+) breast cancer containing a D538G ESR1 mutation and an E545K PI3KCA mutation.

[0070] In embodiments, the cancer is characterized by any of the biomarker profiles (e.g., genetic marker profiles) mentioned in the experimental section (e.g., the cell line-associated biomarkers listed in Table 2 and corresponding portions of the figures and legends [e.g., Figure 8, etc.], alone or in combination).

[0071] In embodiments, the cancer contains a PIK3CA mutation and is characterized by an ATM deletion, a BCL2 deletion, and / or an MCL1 amplification.

[0072] In embodiments, the cancer overexpresses Cdc6, cyclin D1, and / or cyclin E.

[0073] In embodiments, the cancer is characterized by overexpression of Cdc6 and / or loss of Rb.

[0074] In embodiments, the cancer overexpresses CDK6 and / or CCNE1.

[0075] In an embodiment, the treatment of cancer is in a postmenopausal or premenopausal woman.

[0076] A female is an adult human female whose sex is designed to produce large gametes (eggs).

[0077] In an embodiment, the treatment of cancer is in a postmenopausal woman.

[0078] In an embodiment, the treatment of cancer is in a premenopausal woman.

[0079] In embodiments, the cancer has previously been treated with a selective estrogen receptor degrader, a selective estrogen receptor modulator, or an aromatase inhibitor.

[0080] In embodiments, the human patient's cancer has reached a stage of maximal response (minimal residual disease) during or after treatment with a selective estrogen receptor degrader, selective estrogen receptor modulator, or aromatase inhibitor.

[0081] In embodiments, the cancer is resistant to treatment with a selective estrogen receptor degrader, a selective estrogen receptor modulator, or an aromatase inhibitor.

[0082] In embodiments, the cancer has progressed during or after prior treatment with a selective estrogen receptor degrader, a selective estrogen receptor modulator, and / or an aromatase inhibitor. When cancer growth has "progressed," its growth is no longer adequately controlled by the subject's treatment.

[0083] In an embodiment, the human patient's cancer has reached a stage of maximal response (minimal residual disease) during or after treatment with fulvestrant or a pharmaceutical salt thereof.

[0084] In an embodiment, the cancer is resistant to treatment with fulvestrant or a pharmaceutical salt thereof.

[0085] In an embodiment, the cancer has progressed during or after previous treatment with fulvestrant or a pharmaceutical salt thereof.

[0086] In an embodiment, the cancer has previously been treated with a CDK4 / 6 inhibitor.

[0087] In an embodiment, the cancer has reached the stage of maximal response (minimal residual disease) during or after treatment with a CDK4 / 6 inhibitor.

[0088] In an embodiment, the cancer is resistant to treatment with a CDK4 / 6 inhibitor.

[0089] In embodiments, the human patient's cancer reaches a stage of maximal response (minimal residual disease) during or after treatment with palbociclib or a pharmaceutical salt thereof.

[0090] In an embodiment, the cancer is resistant to treatment with palbociclib or a pharmaceutical salt thereof.

[0091] In an embodiment, the cancer has progressed during or after prior treatment with palbociclib or a pharmaceutical salt thereof.

[0092] In embodiments, the cancer is CCNE1 amplified (i.e., expresses greater than normal amounts of CCNE1 compared to normal healthy cells of the same type), RB1 deficient (i.e., expresses less than normal amounts of RB1 compared to normal healthy cells of the same type), overexpresses CDC6 (i.e., expresses greater than normal amounts of CDC6 compared to normal healthy cells of the same type), and / or overexpresses CDK6 (i.e., expresses greater than normal amounts of CDK6 compared to normal healthy cells of the same type).

[0093] In embodiments, the cancer is CCNE1 amplified and / or RB1 deficient.

[0094] In embodiments, the cancer is resistant to treatment with a CDK4 / 6 inhibitor, is CCNE1 amplified, is RB1 deficient, overexpresses CDC6, and / or overexpresses CDK6.

[0095] In embodiments, the cancer is resistant to treatment with a CDK4 / 6 inhibitor and is CCNE1 amplified or RB1 deficient.

[0096] In an embodiment, the cancer has progressed during or after previous treatment with a CDK4 / 6 inhibitor.

[0097] In an embodiment, the cancer has not previously been treated with a CDK4 / 6 inhibitor.

[0098] In embodiments, the cancer has the characteristics (e.g., biomarker characteristics) of any of the cell lines used in the experimental section (e.g., the cell lines and biomarker characteristics shown in Table 2).

[0099] Selective estrogen degraders "Selective estrogen degraders" (SERDs) downregulate estrogen receptors by binding to them and degrading them.

[0100] In an embodiment, the selective estrogen degrader is a next generation selective estrogen degrader ("ngSERD"), e.g., gildedestrant or a pharmaceutically acceptable salt thereof, elacestrant or a pharmaceutically acceptable salt thereof, imrunestrant or a pharmaceutically acceptable salt thereof, or camizestrant or a pharmaceutically acceptable salt thereof.

[0101] In embodiments, the selective estrogen receptor degrader is selected from fulvestrant or a pharmaceutically acceptable salt thereof, gildestrant or a pharmaceutically acceptable salt thereof, elastrant or a pharmaceutically acceptable salt thereof, imrunestrant or a pharmaceutically acceptable salt thereof, and camizestrant or a pharmaceutically acceptable salt thereof.

[0102] In embodiments, the selective estrogen receptor degrader is selected from fulvestrant or a pharmaceutically acceptable salt thereof, gildestrant or a pharmaceutically acceptable salt thereof, and elastrant or a pharmaceutically acceptable salt thereof.

[0103] In embodiments, the selective estrogen receptor degrader is selected from giledestrant or a pharmaceutically acceptable salt thereof, elastrant or a pharmaceutically acceptable salt thereof, imrunestrant or a pharmaceutically acceptable salt thereof, and camizestrant or a pharmaceutically acceptable salt thereof.

[0104] In embodiments, the selective estrogen receptor degrader is selected from giledestrant or a pharmaceutically acceptable salt thereof and elastrant or a pharmaceutically acceptable salt thereof.

[0105] In an embodiment, the selective estrogen receptor degrader is camizestrant or a pharmaceutically acceptable salt thereof.

[0106] In an embodiment, the selective estrogen receptor degrader is fulvestrant or a pharmaceutically acceptable salt thereof.

[0107] In an embodiment, the selective estrogen receptor degrader is gildestrant or a pharmaceutically acceptable salt thereof.

[0108] In an embodiment, the selective estrogen receptor degrader is imrunestrant or a pharmaceutically acceptable salt thereof.

[0109] In an embodiment, the selective estrogen receptor degrader is camizestrant or a pharmaceutically acceptable salt thereof.

[0110] In an embodiment, the selective estrogen receptor degrader is a PROTAC (proteolysis targeting chimera).

[0111] In an embodiment, the selective estrogen receptor degrader is ARV-471 or a pharmaceutically acceptable salt thereof.

[0112] Camizestrant (AZD9833) has the following chemical structure:

[0113] [ka]

[0114] 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).

[0115] Imulnestrand (LY-3484356) has the following chemical structure:

[0116] [ka]

[0117] 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.

[0118] Giledestrant (GDC-9545) has the following chemical structure:

[0119] [ka]

[0120] 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).

[0121] ARV-471 has the following chemical structure:

[0122] [ka] ARV-471 is disclosed in WO2018102725.

[0123] AKT inhibitors In one embodiment, there is provided a SERD for use in the treatment of cancer, administered in combination with an AKT inhibitor.

[0124] In one embodiment, there is provided an AKT inhibitor for use in the treatment of cancer, administered in combination with a SERD.

[0125] In embodiments, an AKT inhibitor is any molecule or compound that binds to and inhibits the activity of one or more AKT isoforms (e.g., a pIC of >4.5, >5, >6, >7, >8, or >9 for the isoform(s) of interest). 50 (having).

[0126] In embodiments, the AKT inhibitor is a proteolysis targeting chimera (PROTAC).

[0127] In embodiments, the AKT inhibitor is milansertib (ARQ-092) or a pharmaceutically acceptable salt thereof, BAY1125976 or a pharmaceutically acceptable salt thereof, volsertib or a pharmaceutically acceptable salt thereof, AT7867 or a pharmaceutically acceptable salt thereof, CCT128930 or a pharmaceutically acceptable salt thereof, A-674563 or a pharmaceutically acceptable salt thereof, PHT-427 or a pharmaceutically acceptable salt thereof, Akti-1 / 2 or a pharmaceutically acceptable salt thereof, AT13148 or a pharmaceutically acceptable salt thereof, SC79 or a pharmaceutically acceptable salt thereof, capivasertib or a pharmaceutically acceptable salt thereof, miltefosine or or a pharmaceutically acceptable salt thereof, perifosine or a pharmaceutically acceptable salt thereof, MK-2206 or a pharmaceutically acceptable salt thereof, RX-0201 or a pharmaceutically acceptable salt thereof, erucylphosphocholine or a pharmaceutically acceptable salt thereof, PBI-05204 or a pharmaceutically acceptable salt thereof, GSK690693 or a pharmaceutically acceptable salt thereof, afuresertib (GSK2110183) or a pharmaceutically acceptable salt thereof, uprosertib (GSK2141795) or a pharmaceutically acceptable salt thereof, XL-418 or a pharmaceutically acceptable salt thereof, and ipatasertib (GDC-0068) or a pharmaceutically acceptable salt thereof.

[0128] In embodiments, the AKT inhibitor is selected from capivasertib or a pharmaceutically acceptable salt thereof, perifosine or a pharmaceutically acceptable salt thereof, MK-2206 or a pharmaceutically acceptable salt thereof, RX-0201 or a pharmaceutically acceptable salt thereof, erucylphosphocholine or a pharmaceutically acceptable salt thereof, PBI-05204 or a pharmaceutically acceptable salt thereof, GSK690693 or a pharmaceutically acceptable salt thereof, uprosertib (GSK2141795) or a pharmaceutically acceptable salt thereof, XL-418 or a pharmaceutically acceptable salt thereof, and ipatasertib or a pharmaceutically acceptable salt thereof.

[0129] In embodiments, the AKT inhibitor is selected from capivasertib or a pharmaceutically acceptable salt thereof, perifosine or a pharmaceutically acceptable salt thereof, MK-2206 or a pharmaceutically acceptable salt thereof, GSK690693 or a pharmaceutically acceptable salt thereof, afuresertib (GSK2110183) or a pharmaceutically acceptable salt thereof, uprosertib (GSK2141795) or a pharmaceutically acceptable salt thereof, and ipatasertib (GDC-0068) or a pharmaceutically acceptable salt thereof.

[0130] In an embodiment, the AKT inhibitor is capivasertib or a pharmaceutically acceptable salt thereof.

[0131] Capivasertib has the following chemical structure:

[0132] [ka]

[0133] The free base of capivasertib is known by the chemical name (S)-4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide). Capivasertib is disclosed in WO 2009 / 047563, which discloses capivasertib (Example 9) and describes its synthesis.

[0134] Perifosine has the following chemical structure:

[0135] [ka]

[0136] Perifosine is known by the chemical name 1,1-dimethylpiperidinium-4-yl octadecyl phosphate. Perifosine is disclosed in U.S. Patent No. 8,383,607.

[0137] MK-2206 has the following chemical structure:

[0138] [ka]

[0139] The free base of MK-2206 is known by the chemical name 8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl[1,2,4]triazolo[3,4-f][1,6]naphthyridin-3(2H)-one. MK-2206 is disclosed in WO 2008070016.

[0140] GSK690693 has the following chemical structure:

[0141] [ka]

[0142] The free base of GSK690693 is known by the chemical name 4-(2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(3S)-3-piperidinylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol. GSK690693 is disclosed in WO2007058850.

[0143] Afuresertib (GSK2110183) has the following chemical structure:

[0144] [ka]

[0145] The free base of afuresertib is known by the chemical name N-[(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl]-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide. Afuresertib is disclosed in WO2008098104.

[0146] Uprosertib (GSK2141795) has the following chemical structure:

[0147] [ka]

[0148] The free base of uprosertib is known by the chemical name N-[(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl]-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide. Uprosertib is disclosed in WO 2008098104.

[0149] Ipatasertib has the following chemical structure:

[0150] [ka]

[0151] The free base of ipatasertib is known by the chemical name 2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one. Ipatasertib is disclosed in WO2008006040.

[0152] mTOR inhibitors In one embodiment, there is provided a SERD for use in the treatment of cancer, administered in combination with an mTOR inhibitor.

[0153] In one embodiment, there is provided an mTOR inhibitor for use in the treatment of cancer, administered in combination with a SERD.

[0154] In embodiments, an mTOR inhibitor is any molecule or compound that binds to mTOR and inhibits its activity (e.g., a pIC for mTOR of >4.5, >5, >6, >7, >8, or >9). 50 (having).

[0155] In an embodiment, the mTOR inhibitor is an mTORC1 inhibitor.

[0156] In embodiments, the mTOR inhibitor is an mTORC1-selective inhibitor. An mTORC1-selective inhibitor has greater activity against mTORC1 (e.g., >10-fold, >100-fold, or >1000-fold activity) than against any other mTOR complex.

[0157] In embodiments, the mTOR inhibitor is selected from everolimus (e.g., Afinitor®) or a pharmaceutically acceptable salt thereof and temsirolimus (e.g., Torisel®) or a pharmaceutically acceptable salt thereof.

[0158] In an embodiment, the mTOR inhibitor is everolimus or a pharmaceutically acceptable salt thereof.

[0159] In an embodiment, the mTOR inhibitor is temsirolimus or a pharmaceutically acceptable salt thereof.

[0160] CDK4 / 6 inhibitors In one embodiment, a SERD is provided for use in the treatment of cancer, wherein the SERD is administered in combination with a CDK4 / 6 inhibitor.

[0161] In one embodiment, there is provided a CDK4 / 6 inhibitor for use in the treatment of cancer, administered in combination with a SERD.

[0162] In one embodiment, there is provided an ngSERD (e.g., giledestrant or a pharmaceutically acceptable salt thereof, elacestrant or a pharmaceutically acceptable salt thereof, imrunestrant or a pharmaceutically acceptable salt thereof, or camizestrant or a pharmaceutically acceptable salt thereof) for use in the treatment of cancer, administered in combination with a CDK4 / 6 inhibitor.

[0163] In one embodiment, there is provided a CDK4 / 6 inhibitor for use in the treatment of cancer, administered in combination with an ngSERD.

[0164] In embodiments, a CDK4 / 6 inhibitor is any molecule or compound that binds to and inhibits the activity of CDK4 and CDK6 (e.g., a pIC of >4.5, >5, >6, >7, >8, or >9 for CDK4 and CDK6). 50 (having).

[0165] In embodiments, the CDK4 / 6 inhibitor is selected from palbociclib (e.g., Ibrance®) or a pharmaceutically acceptable salt thereof, ribociclib (e.g., Kisqali®) or a pharmaceutically acceptable salt thereof, and abemaciclib (e.g., Verzenios®) or a pharmaceutically acceptable salt thereof.

[0166] In an embodiment, the CDK4 / 6 inhibitor is palbociclib or a pharmaceutically acceptable salt thereof.

[0167] In an embodiment, the CDK4 / 6 inhibitor is ribociclib or a pharmaceutically acceptable salt thereof.

[0168] In an embodiment, the CDK4 / 6 inhibitor is abemaciclib or a pharmaceutically acceptable salt thereof.

[0169] Other endocrine therapies "Selective estrogen modulators" (SERMs) are compounds that agonize or antagonize estrogen receptors, often depending on the tissue they act on. In embodiments, selective estrogen modulators have anti-estrogenic effects on cancer. In embodiments, the selective estrogen receptor modulator is selected from tamoxifen (e.g., Nolvadex®) or a pharmaceutically acceptable salt thereof, toremifene (e.g., Fareston®) or a pharmaceutically acceptable salt thereof, and raloxifene (e.g., Evista®) or a pharmaceutically acceptable salt thereof.

[0170] In an embodiment, the SERM is tamoxifen or a pharmaceutically acceptable salt thereof.

[0171] In an embodiment, the SERM is toremifene or a pharmaceutically acceptable salt thereof.

[0172] In an embodiment, the SERM is raloxifene or a pharmaceutically acceptable salt thereof.

[0173] An "aromatase inhibitor" is a compound that blocks the biosynthesis of estrogen. In embodiments, the aromatase inhibitor is selected from anastrozole (e.g., Arimidex®) or a pharmaceutically acceptable salt thereof, letrozole (e.g., Femara®) or a pharmaceutically acceptable salt thereof, and exemestane (e.g., Aromasin®) or a pharmaceutically acceptable salt thereof.

[0174] In an embodiment, the aromatase inhibitor is anastrozole or a pharmaceutically acceptable salt thereof.

[0175] In an embodiment, the aromatase inhibitor is letrozole or a pharmaceutically acceptable salt thereof.

[0176] In an embodiment, the aromatase inhibitor is exemestane or a pharmaceutically acceptable salt thereof.

[0177] Triple drug combination In one embodiment, there is provided a SERD for use in the treatment of cancer, administered in combination with an AKT inhibitor or an mTOR inhibitor, and a CDK4 / 6 inhibitor.

[0178] In one embodiment, there is provided an AKT inhibitor or an mTOR inhibitor for use in the treatment of cancer, administered in combination with a SERD and CDK4 / 6 inhibitor.

[0179] In one embodiment, there is provided an AKT inhibitor for use in the treatment of cancer, administered in combination with a SERD and CDK4 / 6 inhibitor.

[0180] In one embodiment, there is provided an mTOR inhibitor for use in the treatment of cancer, administered in combination with a SERD and CDK4 / 6 inhibitor.

[0181] In one embodiment, there is provided a CDK4 / 6 inhibitor for use in the treatment of cancer, administered in combination with a SERD and AKT inhibitor or an mTOR inhibitor.

[0182] In embodiments, the SERD and each inhibitor are administered separately, sequentially, or simultaneously.

[0183] In an embodiment, the SERD and each inhibitor are administered separately.

[0184] In embodiments, the SERD and each inhibitor are administered sequentially.

[0185] In embodiments, the SERD and each inhibitor are administered simultaneously.

[0186] Specific combination use In one embodiment, there is provided an AKT inhibitor or an mTOR inhibitor for use in the treatment of cancer, administered in combination with a SERD and optionally a CDK4 / 6 inhibitor.

[0187] In one embodiment, the SERD for use in the treatment of cancer comprises milansertib or a pharmaceutically acceptable salt thereof, BAY1125976 or a pharmaceutically acceptable salt thereof, volsertib or a pharmaceutically acceptable salt thereof, AT7867 or a pharmaceutically acceptable salt thereof, CCT128930 or a pharmaceutically acceptable salt thereof, A-674563 or a pharmaceutically acceptable salt thereof, PHT-427 or a pharmaceutically acceptable salt thereof, Akti-1 / 2 or a pharmaceutically acceptable salt thereof, AT13148 or a pharmaceutically acceptable salt thereof, SC79 or a pharmaceutically acceptable salt thereof, capivasertib or a pharmaceutically acceptable salt thereof, miltefosine or a pharmaceutically acceptable salt thereof, perifosine or a pharmaceutically acceptable salt thereof, MK-2206 or a pharmaceutically acceptable salt thereof, RX-0201 or or a pharmaceutically acceptable salt thereof, erucylphosphocholine or a pharmaceutically acceptable salt thereof, PBI-05204 or a pharmaceutically acceptable salt thereof, GSK690693 or a pharmaceutically acceptable salt thereof, afuresertib or a pharmaceutically acceptable salt thereof, uprosertib or a pharmaceutically acceptable salt thereof, XL-418 or a pharmaceutically acceptable salt thereof, and ipatasertib or a pharmaceutically acceptable salt thereof, or an mTOR inhibitor selected from everolimus or a pharmaceutically acceptable salt thereof and temsirolimus or a pharmaceutically acceptable salt thereof, and / or a CDK4 / 6 inhibitor selected from palbociclib or a pharmaceutically acceptable salt thereof, ribociclib or a pharmaceutically acceptable salt thereof, and abemaciclib or a pharmaceutically acceptable salt thereof.

[0188] As can be seen from the data presented herein, combination therapy with camizestrant and capivasertib results in superior activity compared to therapy with fulvestrant and capivasertib in ESR1wt and ESR1m patient-derived xenograft (PDX) models. Camizestrant and capivasertib appear to act synergistically. This surprisingly advantageous combination generally results in greater responses than observed with monotherapy using either agent across all ESR1wt and ESR1m PDX models. Furthermore, the combination of camizestrant and capivasertib resulted in deeper responses than those obtained with optimal doses of fulvestrant combined with capivasertib. Thus, for the first time, the clinical potential of combination therapy with camizestrant and capivasertib has been demonstrated—an important finding given the results of the phase 3 CAPitello-291 trial, in which the combination of capivasertib and fulvestrant demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) versus placebo plus Faslodex in patients with hormone receptor (HR)-positive, HER2-low or -negative, locally advanced or metastatic breast cancer following recurrence or progression during or after endocrine therapy (with or without a CDK4 / 6 inhibitor).

[0189] Triple combinations including camizestrant and capivasertib in combination with CDK4 / 6 inhibitors are observed to provide superior synergistic activity across a broad range of PDX models, for example, those with clinically relevant mutations to ESR1 in the AKT / PI3K pathway, or PDX models that are CCNE1 amplified or RB1 deficient or that overexpress CDC6 and / or overexpress CDK6.

[0190] In embodiments, camizestrant or a pharmaceutically acceptable salt thereof for use in the treatment of cancer is provided, wherein the camizestrant or a pharmaceutically acceptable salt thereof is administered in combination with capivasertib or a pharmaceutically acceptable salt thereof, and optionally the use further comprises administration of a CDK4 / 6 inhibitor. In such embodiments, the camizestrant or a pharmaceutically acceptable salt thereof may be administered once daily at a dose of 75 mg or 150 mg.

[0191] In embodiments, there is provided capivasertib for use in the treatment of cancer, wherein capivasertib or a pharmaceutically acceptable salt thereof is administered in combination with camizestrant or a pharmaceutically acceptable salt thereof, and optionally, the use further comprises administration of a CDK4 / 6 inhibitor. In such embodiments, capivasertib or a pharmaceutically acceptable salt thereof may be administered at a dose of 400 mg twice daily under an intermittent dosing schedule.

[0192] In embodiments, there is provided camizestrant or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, wherein the camizestrant or a pharmaceutically acceptable salt thereof is administered in combination with capivasertib or a pharmaceutically acceptable salt thereof.

[0193] In embodiments, there is provided capivasertib or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, wherein capivasertib or a pharmaceutically acceptable salt thereof is administered in combination with camizestrant or a pharmaceutically acceptable salt thereof.

[0194] In embodiments, there is provided camizestrant or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, wherein the camizestrant or a pharmaceutically acceptable salt thereof is administered in combination with capivasertib or a pharmaceutically acceptable salt thereof and a CDK4 / 6 inhibitor. In embodiments, there is provided capivasertib or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, wherein the capivasertib or a pharmaceutically acceptable salt thereof is administered in combination with camizestrant or a pharmaceutically acceptable salt thereof and a CDK4 / 6 inhibitor.

[0195] In an embodiment, there is provided camizestrant or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, wherein the camizestrant or a pharmaceutically acceptable salt thereof is administered in combination with capivasertib or a pharmaceutically acceptable salt thereof, optionally wherein the use further comprises administration of a CDK4 / 6 inhibitor, and wherein the cancer is estrogen receptor-positive (ER+) breast cancer that does not contain an ESR1 mutation or fusion.

[0196] In an embodiment, there is provided camizestrant or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, wherein the camizestrant or a pharmaceutically acceptable salt thereof is administered in combination with capivasertib or a pharmaceutically acceptable salt thereof, optionally wherein the use further comprises administration of a CDK4 / 6 inhibitor, and wherein the cancer is estrogen receptor-positive (ER+) breast cancer comprising a mutation in ESR1, and optionally wherein the mutation in ESR1 is selected from an E380Q mutation, a Y537S mutation, and a D538G mutation, and / or an ESR1-CCDC170 fusion.

[0197] In an embodiment, there is provided camizestrant or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, wherein the camizestrant or a pharmaceutically acceptable salt thereof is administered in combination with capivasertib or a pharmaceutically acceptable salt thereof, optionally wherein the use further comprises administration of a CDK4 / 6 inhibitor, and wherein the cancer is estrogen receptor-positive (ER+) breast cancer comprising a mutation in ESR1, and optionally wherein the mutation in ESR1 is selected from a Y537S mutation and a D538G mutation.

[0198] In an embodiment, there is provided camizestrant or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, wherein the camizestrant or a pharmaceutically acceptable salt thereof is administered in combination with capivasertib or a pharmaceutically acceptable salt thereof, optionally wherein the use further comprises administration of a CDK4 / 6 inhibitor, and the cancer is PTEN-deficient, contains an AKT1 mutation (e.g., an E17K mutation), and / or contains a PI3KCA mutation (e.g., a PI3KCA mutation selected from an E542K mutation and an N345K mutation).

[0199] In an embodiment, there is provided camizestrant or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, wherein the camizestrant or a pharmaceutically acceptable salt thereof is administered in combination with capivasertib or a pharmaceutically acceptable salt thereof, optionally wherein the use further comprises administration of a CDK4 / 6 inhibitor, wherein the cancer is estrogen receptor-positive (ER+) breast cancer comprising a mutation in ESR1, optionally wherein the mutation in ESR1 is selected from an E380Q mutation, a Y537S mutation, and a D538G mutation, and / or an ESR1-CCDC170 fusion, and wherein the cancer is PTEN-deficient, comprises an AKT1 mutation (e.g., an E17K mutation), and / or comprises a PI3KCA mutation (e.g., a PI3KCA mutation selected from an E542K mutation and an N345K mutation).

[0200] In an embodiment, there is provided camizestrant or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, wherein the camizestrant or a pharmaceutically acceptable salt thereof is administered in combination with capivasertib or a pharmaceutically acceptable salt thereof, optionally wherein the use further comprises administration of a CDK4 / 6 inhibitor, and wherein the cancer is estrogen receptor-positive (ER+) breast cancer comprising a mutation in ESR1, optionally wherein the mutation in ESR1 is selected from a Y537S mutation and a D538G mutation, and wherein the cancer comprises an E17K AKT1 mutation and / or a PI3KCA mutation selected from an E542K and an N345K mutation.

[0201] In an embodiment, there is provided capivasertib or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, wherein capivasertib or a pharmaceutically acceptable salt thereof is administered in combination with camizestrant or a pharmaceutically acceptable salt thereof, optionally wherein the use further comprises administration of a CDK4 / 6 inhibitor, and wherein the cancer is estrogen receptor positive (ER+) breast cancer that does not contain an ESR1 mutation or fusion.

[0202] In an embodiment, there is provided capivasertib or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, wherein the capivasertib or a pharmaceutically acceptable salt thereof is administered in combination with camizestrant or a pharmaceutically acceptable salt thereof, optionally wherein the use further comprises administration of a CDK4 / 6 inhibitor, and wherein the cancer is estrogen receptor positive (ER+) breast cancer comprising a mutation in ESR1, and optionally wherein the mutation in ESR1 is selected from an E380Q mutation, a Y537S mutation, and a D538G mutation, and / or an ESR1-CCDC170 fusion.

[0203] In an embodiment, there is provided capivasertib or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, wherein the capivasertib or a pharmaceutically acceptable salt thereof is administered in combination with camizestrant or a pharmaceutically acceptable salt thereof, optionally wherein the use further comprises administration of a CDK4 / 6 inhibitor, and wherein the cancer is estrogen receptor positive (ER+) breast cancer comprising a mutation in ESR1, and optionally wherein the mutation in ESR1 is selected from a Y537S mutation and a D538G mutation.

[0204] In an embodiment, there is provided capivasertib or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, wherein the capivasertib or a pharmaceutically acceptable salt thereof is administered in combination with camizestrant or a pharmaceutically acceptable salt thereof, optionally wherein the use further comprises administration of a CDK4 / 6 inhibitor, and the cancer is PTEN-deficient, contains an AKT1 mutation (e.g., an E17K mutation), and / or contains a PI3KCA mutation (e.g., a PI3KCA mutation selected from an E542K mutation and an N345K mutation).

[0205] In an embodiment, there is provided capivasertib or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, wherein the capivasertib or a pharmaceutically acceptable salt thereof is administered in combination with camizestrant or a pharmaceutically acceptable salt thereof, optionally wherein the use further comprises administration of a CDK4 / 6 inhibitor, and the cancer is estrogen receptor positive (ER+) breast cancer comprising a mutation in ESR1, optionally wherein the mutation in ESR1 is selected from an E380Q mutation, a Y537S mutation, and a D538G mutation, and / or an ESR1-CCDC170 fusion, and the cancer is PTEN-deficient, comprises an AKT1 mutation (e.g., an E17K mutation), and / or comprises a PI3KCA mutation (e.g., a PI3KCA mutation selected from an E542K mutation and an N345K mutation).

[0206] In an embodiment, there is provided capivasertib or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, wherein the capivasertib or a pharmaceutically acceptable salt thereof is administered in combination with camizestrant or a pharmaceutically acceptable salt thereof, optionally wherein the use further comprises administration of a CDK4 / 6 inhibitor, and wherein the cancer is estrogen receptor positive (ER+) breast cancer comprising a mutation in ESR1 selected from a Y537S mutation and a D538G mutation, and the cancer comprises an E17K AKT1 mutation and / or a PI3KCA mutation selected from an E542K and an N345K mutation.

[0207] In one embodiment, the present invention relates to a SERD for use in the treatment of cancer, comprising: milansertib or a pharmaceutically acceptable salt thereof, BAY1125976 or a pharmaceutically acceptable salt thereof, volsertib or a pharmaceutically acceptable salt thereof, AT7867 or a pharmaceutically acceptable salt thereof, CCT128930 or a pharmaceutically acceptable salt thereof, A-674563 or a pharmaceutically acceptable salt thereof, PHT-427 or a pharmaceutically acceptable salt thereof, Akti-1 / 2 or a pharmaceutically acceptable salt thereof, AT13148 or a pharmaceutically acceptable salt thereof, SC79 or a pharmaceutically acceptable salt thereof, capivasertib or a pharmaceutically acceptable salt thereof, miltefosine or a pharmaceutically acceptable salt thereof, perifosine or a pharmaceutically acceptable salt thereof, MK and / or a CDK4 / 6 inhibitor selected from palbociclib or a pharmaceutically acceptable salt thereof, ribociclib or a pharmaceutically acceptable salt thereof, and abemaciclib or a pharmaceutically acceptable salt thereof.

[0208] In one embodiment, there is provided a SERD for use in the treatment of cancer, wherein the SERD is administered in combination with an mTOR inhibitor selected from everolimus or a pharmaceutically acceptable salt thereof and temsirolimus or a pharmaceutically acceptable salt thereof, and / or a CDK4 / 6 inhibitor selected from palbociclib or a pharmaceutically acceptable salt thereof, ribociclib or a pharmaceutically acceptable salt thereof, and abemaciclib or a pharmaceutically acceptable salt thereof.

[0209] In one embodiment, the SERD for use in the treatment of cancer comprises milansertib or a pharmaceutically acceptable salt thereof, BAY1125976 or a pharmaceutically acceptable salt thereof, volsertib or a pharmaceutically acceptable salt thereof, AT7867 or a pharmaceutically acceptable salt thereof, CCT128930 or a pharmaceutically acceptable salt thereof, A-674563 or a pharmaceutically acceptable salt thereof, PHT-427 or a pharmaceutically acceptable salt thereof, Akti-1 / 2 or a pharmaceutically acceptable salt thereof, AT13148 or a pharmaceutically acceptable salt thereof, SC79 or a pharmaceutically acceptable salt thereof, capivasertib or a pharmaceutically acceptable salt thereof, miltefosine or a pharmaceutically acceptable salt thereof, perifosine or a pharmaceutically acceptable salt thereof, MK-2206 or a pharmaceutically acceptable salt thereof, RX-0201 or or a pharmaceutically acceptable salt thereof, erucylphosphocholine or a pharmaceutically acceptable salt thereof, PBI-05204 or a pharmaceutically acceptable salt thereof, GSK690693 or a pharmaceutically acceptable salt thereof, afuresertib or a pharmaceutically acceptable salt thereof, uprosertib or a pharmaceutically acceptable salt thereof, XL-418 or a pharmaceutically acceptable salt thereof, and ipatasertib or a pharmaceutically acceptable salt thereof, or an mTOR inhibitor selected from everolimus or a pharmaceutically acceptable salt thereof and temsirolimus or a pharmaceutically acceptable salt thereof, and a CDK4 / 6 inhibitor selected from palbociclib or a pharmaceutically acceptable salt thereof, ribociclib or a pharmaceutically acceptable salt thereof, and abemaciclib or a pharmaceutically acceptable salt thereof.

[0210] In one embodiment, a SERD for use in the treatment of cancer comprising milansertib or a pharmaceutically acceptable salt thereof, BAY1125976 or a pharmaceutically acceptable salt thereof, volsertib or a pharmaceutically acceptable salt thereof, AT7867 or a pharmaceutically acceptable salt thereof, CCT128930 or a pharmaceutically acceptable salt thereof, A-674563 or a pharmaceutically acceptable salt thereof, PHT-427 or a pharmaceutically acceptable salt thereof, Akti-1 / 2 or a pharmaceutically acceptable salt thereof, AT13148 or a pharmaceutically acceptable salt thereof, SC79 or a pharmaceutically acceptable salt thereof, capivasertib or a pharmaceutically acceptable salt thereof, miltefosine or a pharmaceutically acceptable salt thereof, perifosine or a pharmaceutically acceptable salt thereof, MK and a CDK4 / 6 inhibitor selected from palbociclib or a pharmaceutically acceptable salt thereof, ribociclib or a pharmaceutically acceptable salt thereof, and abemaciclib or a pharmaceutically acceptable salt thereof.

[0211] In one embodiment, there is provided a SERD for use in the treatment of cancer, wherein the SERD is administered in combination with an mTOR inhibitor selected from everolimus or a pharmaceutically acceptable salt thereof and temsirolimus or a pharmaceutically acceptable salt thereof, and a CDK4 / 6 inhibitor selected from palbociclib or a pharmaceutically acceptable salt thereof, ribociclib or a pharmaceutically acceptable salt thereof, and abemaciclib or a pharmaceutically acceptable salt thereof.

[0212] In one embodiment, there is provided a SERD for use in the treatment of cancer, the SERD being camizestrant or a pharmaceutically acceptable salt thereof administered in combination with abemaciclib, wherein the cancer is resistant to treatment with palbociclib.

[0213] Pharmaceutical Compositions and Dosage Forms In one embodiment, a pharmaceutical composition is provided comprising a SERD in combination with an AKT inhibitor or an mTOR inhibitor, and / or a CDK4 / 6 inhibitor, and a pharmaceutically acceptable excipient.

[0214] "Pharmaceutically acceptable excipients" include diluents, disintegrants, or lubricants. In further embodiments, the pharmaceutical composition comprises one or more pharmaceutical diluents (e.g., mannitol and microcrystalline cellulose), one or more pharmaceutical disintegrants (e.g., low-substituted hydroxypropyl cellulose), or one or more pharmaceutical lubricants (e.g., sodium stearyl fumarate).

[0215] In one embodiment, a pharmaceutical composition is provided comprising a SERD in combination with an AKT inhibitor or an mTOR inhibitor and a pharmaceutically acceptable excipient.

[0216] In one embodiment, a pharmaceutical composition is provided comprising a SERD in combination with a CDK4 / 6 inhibitor and a pharmaceutically acceptable excipient.

[0217] In one embodiment, a pharmaceutical composition is provided comprising a SERD in combination with an AKT inhibitor or an mTOR inhibitor, a CDK4 / 6 inhibitor, and a pharmaceutically acceptable excipient.

[0218] In an embodiment, the composition is in an oral dosage form.

[0219] In an embodiment, the composition is in the form of a tablet or capsule.

[0220] In embodiments, camizestrant or a pharmaceutically acceptable salt thereof is administered to a subject at a daily dosage of 75 mg or 150 mg.

[0221] In the compositions disclosed herein, capivasertib or a pharmaceutically acceptable salt thereof is generally administered to a subject in a daily dosage of about 100 mg to about 1600 mg.

[0222] In one embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered in a daily dosage of about 150 mg to about 1500 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered in a daily dosage of about 200 mg to about 1400 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered in a daily dosage of about 300 mg to about 1300 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered in a daily dosage of about 400 mg to about 1200 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered in a daily dosage of about 500 mg to about 1100 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered in a daily dosage of about 600 mg to about 1000 mg. In embodiments, capivasertib or a pharmaceutically acceptable salt thereof is administered to a subject once daily (QD).

[0223] In an embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered once daily at a dosage of about 100 mg to about 1000 mg.

[0224] In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered once daily at a dosage of about 150 mg to about 900 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered once daily at a dosage of about 200 mg to about 850 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered once daily at a dosage of about 250 mg to about 800 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered once daily at a dosage of about 300 mg to about 750 mg.

[0225] In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered once daily at a dosage of about 350 mg to about 700 mg, hi another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered once daily at a dosage of about 400 mg to about 650 mg.

[0226] In an embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered to a subject twice daily (BID). In one embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily at a dosage of about 50 mg to about 900 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily at a dosage of about 100 mg to about 875 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily at a dosage of about 200 mg to about 850 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily at a dosage of about 250 mg to about 825 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily at a dosage of about 150 mg to about 250 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily at a dosage of about 250 mg to about 350 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily at a dosage of about 350 mg to about 450 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily at a dosage of about 450 mg to about 550 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily at a dosage of about 550 mg to about 650 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily at a dosage of about 650 mg to about 750 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered at a dosage of about 750 mg to about 850 mg twice daily. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered at a dosage of about 160 mg twice daily. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered at a dosage of about 200 mg twice daily. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered at a dosage of about 240 mg twice daily. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered at a dosage of about 280 mg twice daily.In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered at a dosage of about 320 mg twice daily. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered at a dosage of about 360 mg twice daily. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered at a dosage of about 400 mg twice daily. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered at a dosage of about 440 mg twice daily. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered at a dosage of about 480 mg twice daily. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered at a dosage of about 520 mg twice daily. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered at a dosage of about 560 mg twice daily. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered at a dosage of about 600 mg twice daily. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered at a dosage of about 640 mg twice daily. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered at a dosage of about 680 mg twice daily. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered at a dosage of about 720 mg twice daily. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered at a dosage of about 760 mg twice daily. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered at a dosage of about 800 mg twice daily.

[0227] In embodiments, capivasertib or a pharmaceutically acceptable salt thereof is administered under a continuous dosing schedule. In one embodiment, for example, capivasertib or a pharmaceutically acceptable salt thereof is administered for 1, 2, 3, 4, 5, 6, 7, 14, 21, 28, 35, 42, 49, or more than 56 days. In another embodiment, the dosing cycle is 28 days. Administration of capivasertib or a pharmaceutically acceptable salt thereof, and repetition of the dosing cycle, can continue as long as is tolerated and beneficial to the subject.

[0228] In one embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered once daily (QD) on a continuous dosing schedule. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered once daily on a continuous dosing schedule at a dosage of about 100 mg to about 900 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered once daily on a continuous dosing schedule at a dosage of about 150 mg to about 875 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered once daily on a continuous dosing schedule at a dosage of about 175 mg to about 850 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered once daily on a continuous dosing schedule at a dosage of about 200 mg to about 825 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered once daily on a continuous dosing schedule at a dosage of about 225 mg to about 800 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered once daily on a continuous dosing schedule at a dosage of about 250 mg to about 750 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered once daily on a continuous dosing schedule at a dosage of about 275 mg to about 700 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered once daily on a continuous dosing schedule at a dosage of about 300 mg to about 650 mg. In an embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily (BID) on a continuous dosing schedule. In one embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily on a continuous dosing schedule at a dosage of about 100 mg to about 800 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily on a continuous dosing schedule at a dosage of about 150 mg to about 750 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily on a continuous dosing schedule at a dosage of about 200 mg to about 700 mg.In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily on a continuous dosing schedule at a dosage of about 225 mg to about 650 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily on a continuous dosing schedule at a dosage of about 250 mg to about 650 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily on a continuous dosing schedule at a dosage of about 300 mg to about 600 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily on a continuous dosing schedule at a dosage of about 200 mg to about 300 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily on a continuous dosing schedule at a dosage of about 300 mg to about 400 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily on a continuous dosing schedule at a dosage of about 400 mg to about 500 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily on a continuous dosing schedule at a dosage of about 500 mg to about 600 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily on a continuous dosing schedule at a dosage of about 600 mg to about 700 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily on a continuous dosing schedule at a dosage of about 700 mg to about 800 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily on a continuous dosing schedule at a dosage of about 160 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily on a continuous dosing schedule at a dosage of about 200 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily on a continuous dosing schedule at a dosage of about 240 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily on a continuous dosing schedule at a dosage of about 280 mg.In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily on a continuous dosing schedule at a dosage of about 320 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily on a continuous dosing schedule at a dosage of about 360 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily on a continuous dosing schedule at a dosage of about 400 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily on a continuous dosing schedule at a dosage of about 440 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily on a continuous dosing schedule at a dosage of about 480 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily on a continuous dosing schedule at a dosage of about 520 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily on a continuous dosing schedule at a dosage of about 580 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily on a continuous dosing schedule at a dosage of about 600 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily on a continuous dosing schedule at a dosage of about 640 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily on a continuous dosing schedule at a dosage of about 680 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily on a continuous dosing schedule at a dosage of about 720 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily on a continuous dosing schedule at a dosage of about 760 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily on a continuous dosing schedule at a dosage of about 800 mg. In an embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered to a subject on an intermittent dosing schedule.Administering capivasertib or a pharmaceutically acceptable salt thereof on an intermittent dosing schedule may have greater efficacy and / or tolerability than, for example, a continuous dosing schedule. In one embodiment, capivasertib or a pharmaceutically acceptable salt thereof is intermittently administered on a 1 day on / 6 days off schedule (i.e., capivasertib or a pharmaceutically acceptable salt thereof is administered for 1 day, followed by 6 days off). In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is intermittently administered on a 2 days on / 5 days off schedule (i.e., capivasertib or a pharmaceutically acceptable salt thereof is administered for 2 days, followed by 5 days off). In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is dosed intermittently on a 3-day on / 4-day off schedule (i.e., capivasertib or a pharmaceutically acceptable salt thereof is administered for 3 days followed by 4 days off). In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is dosed intermittently on a 4-day on / 3-day off schedule (i.e., capivasertib or a pharmaceutically acceptable salt thereof is administered for 4 days followed by 3 days off). In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is dosed intermittently on a 5-day on / 2-day off schedule (i.e., capivasertib or a pharmaceutically acceptable salt thereof is administered for 5 days followed by 2 days off). In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered intermittently on a 6-day on / 1-day off schedule (i.e., capivasertib or a pharmaceutically acceptable salt thereof is administered for 6 days, followed by 1 day off). The dosing cycle of such an embodiment is then repeated as long as tolerated and beneficial to the subject. In an embodiment, the dosing cycle is 7 days. In an embodiment, the dosing cycle is 14 days. In another embodiment, the dosing cycle is 21 days. In another embodiment, the dosing cycle is 28 days. In another embodiment, the dosing cycle is 2 months. In another embodiment, the dosing cycle is 6 months. In another embodiment, the dosing cycle is 1 year.

[0229] In embodiments, the dosing cycle is 28 days, but capivasertib or a pharmaceutically acceptable salt thereof is not co-administered to the subject during week 4 of the dosing cycle (i.e., there is a capivasertib or a pharmaceutically acceptable salt thereof holiday during the final week of the dosing cycle).

[0230] In one embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered once daily (QD) on an intermittent dosing schedule. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered once daily on an intermittent dosing schedule at a dosage of about 100 mg to about 900 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered once daily on an intermittent dosing schedule at a dosage of about 150 mg to about 850 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered once daily on an intermittent dosing schedule at a dosage of about 175 mg to about 800 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered once daily on an intermittent dosing schedule at a dosage of about 200 mg to about 750 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered once daily on an intermittent dosing schedule at a dosage of about 225 mg to about 725 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered once daily on an intermittent dosing schedule at a dosage of about 250 mg to about 700 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered once daily on an intermittent dosing schedule at a dosage of about 275 mg to about 675 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered once daily on an intermittent dosing schedule at a dosage of about 300 mg to about 650 mg. In an embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily (BID) on an intermittent dosing schedule. In one embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily on an intermittent dosing schedule at a dosage of about 100 mg to about 800 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily on an intermittent dosing schedule at a dosage of about 150 mg to about 750 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily on an intermittent dosing schedule at a dosage of about 200 mg to about 700 mg.In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily on an intermittent dosing schedule at a dosage of about 225 mg to about 675 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily on an intermittent dosing schedule at a dosage of about 250 mg to about 650 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily on an intermittent dosing schedule at a dosage of about 300 mg to about 625 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily on an intermittent dosing schedule at a dosage of about 200 mg to about 300 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily on an intermittent dosing schedule at a dosage of about 300 mg to about 400 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily on an intermittent dosing schedule at a dosage of about 400 mg to about 500 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily on an intermittent dosing schedule at a dosage of about 500 mg to about 600 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily on an intermittent dosing schedule at a dosage of about 600 mg to about 700 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily on an intermittent dosing schedule at a dosage of about 700 mg to about 800 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily on an intermittent dosing schedule at a dosage of about 160 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily on an intermittent dosing schedule at a dosage of about 200 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily on an intermittent dosing schedule at a dosage of about 240 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily on an intermittent dosing schedule at a dosage of about 280 mg.In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily on an intermittent dosing schedule at a dosage of about 320 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily on an intermittent dosing schedule at a dosage of about 360 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily on an intermittent dosing schedule at a dosage of about 400 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily on an intermittent dosing schedule at a dosage of about 440 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily on an intermittent dosing schedule at a dosage of about 480 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily on an intermittent dosing schedule at a dosage of about 520 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily on an intermittent dosing schedule at a dosage of about 580 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily on an intermittent dosing schedule at a dosage of about 600 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily on an intermittent dosing schedule at a dosage of about 640 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily on an intermittent dosing schedule at a dosage of about 680 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily on an intermittent dosing schedule at a dosage of about 720 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily on an intermittent dosing schedule at a dosage of about 760 mg. In another embodiment, capivasertib or a pharmaceutically acceptable salt thereof is administered twice daily on an intermittent dosing schedule at a dosage of about 800 mg.

[0231] In embodiments, a kit is provided that includes a pharmaceutical composition comprising camizestrant and instructions for its use in the treatment of ER+ breast cancer, the use in combination with capivasertib, and optionally, the use in further combination with a CDK4 / 6 inhibitor. In such embodiments, the instructions may indicate that the pharmaceutical composition is for use based on the presence of a mutation in PI3KCA or AKT1, or the cancer identified as PTEN-deficient.

[0232] In embodiments, a kit is provided that includes a pharmaceutical composition comprising capivasertib and instructions for its use in the treatment of ER+ breast cancer, the use in combination with camizestrant, and optionally, the use in further combination with a CDK4 / 6 inhibitor. In such embodiments, the instructions may indicate that the pharmaceutical composition is for use based on the presence of a mutation in PI3KCA or AKT1, or the cancer identified as PTEN-deficient.

[0233] In any embodiment referring to a marketed or approved drug, the marketed or approved drug may be administered according to its label (e.g., as approved by the U.S. FDA or any other similar regulatory agency).

[0234] In any embodiment referring to a drug being tested in a human clinical trial, the drug may be administered according to the dosing regimen described in any of its published clinical trial protocols (e.g., as described on clinicaltrials.gov or the like). [Example]

[0235] The following specific examples, which refer to the accompanying drawings, are provided for illustrative purposes only and are not to be construed as limiting the teachings herein.

[0236] The text accompanying the figure explains how the experiment was performed. The cells used in the experiment are discussed below.

[0237] MCF7 is a cell line derived from pleural fluid / effusion obtained from a human patient with ductal carcinoma of the breast. The cell line was derived from ATCC HTB-22 and harbors an activating mutation in PIK3CA E545K. MCF7 cells were routinely cultured in RPMI (Gibco #11835-063) + 5% FCS + 1% L-glutamine and incubated at 37°C, 5% CO2.

[0238] The MCF7 PC1 cell line was generated from MCF-7 cells cultured in increasing concentrations of palbociclib over a period of 4 to 9 months until they were able to grow in 1000 nM palbociclib under the same cell culture conditions described above for the parental MCF7.

[0239] The MCF7 PC6 cell line was generated from MCF-7 cells cultured in increasing concentrations of palbociclib over a period of 4 to 9 months until they were able to grow in 1000 nM palbociclib under the same cell culture conditions described above for the parental MCF7.

[0240] The MCF7 PC8 cell line was generated from MCF-7 cells cultured in increasing concentrations of palbociclib over a period of 4 to 9 months until they were able to grow in 1000 nM palbociclib under the same cell culture conditions described above for the parental MCF7.

[0241] The MCF7 PC10 cell line was generated from MCF-7 cells cultured in increasing concentrations of palbociclib over a period of 4 to 9 months until they were able to grow in 1000 nM palbociclib under the same cell culture conditions described above for the parental MCF7.

[0242] All cell lines were generated from the parental ATCC HTB-133 stock, which had been exposed to fulvestrant and palbociclib for extended periods. Before treatment began, cell stocks were cultured in T175 flasks. The medium was removed from the flasks, and the cells were washed with 10 mL of DPBS and detached by adding 2 mL of trypsin. Once detached, the cells were resuspended in 10 mL of growth medium, and 10 μL of each was mixed with 10 μL of trypan blue and counted using a ThermoFisher Invitrogen Countess. The 10 mL was then distributed to three T25 flasks containing 2.0 × 10 cells. 4 Two flasks were spiked with 30 nM fulvestrant and 300 nM palbociclib to generate a resistant pool, while one flask received an equal percentage of DMSO as a control. The cells were transferred to an incubator and allowed to adhere overnight. Once the cells began to proliferate, they were initially spiked with 30 nM fulvestrant and 300 nM palbociclib, expanding to 100 nM fulvestrant and 1 μM palbociclib. The medium in the flask was removed and replaced with 10 mL of fulvestrant and palbociclib-containing medium (fulvestrant: 2.2 μL of 300 μM fulvestrant stock was added to 22 mL of growth medium and diluted 1:10,000 to obtain a 30 nM final; palbociclib: 2.2 μL of 3 mM stock was added to 22 mL of growth medium and diluted 1:10,000 to obtain a 300 nM final). Cells were re-fed twice weekly and maintained for 6 months as they slowly expanded from a small viable fraction. Cells were expanded into T75 flasks and the dose was increased to 100 nM fulvestrant + 1 μM palbociclib. Cells were then expanded for 40 days to generate cryopreservation stocks.

[0243] CTC-174 is a patient-derived xenograft representing metastatic breast cancer harboring ESR1 D538G and PI3KCA N345K mutations (Ladd et al. Oncotarget, 7(34):54120-54136, 2016).

[0244] ST1799 / HI / PBR is an ER+ breast cancer patient-derived xenograft tumor model derived from a primary tumor sample harboring the PI3KCA_E542K mutation (provided by XenoSTART).

[0245] ST3632 is an AKT1 mutated ER+ breast cancer patient-derived xenograft tumor model (donated by XenoSTART).

[0246] ST3932 is an ER+ breast cancer patient-derived xenograft tumor model derived from a primary patient sample harboring the PI3KCA_R88Q mutation (donated by XenoSTART).

[0247] CTG2432 is an ER+ breast cancer patient-derived xenograft tumor model derived from a primary patient sample harboring ESR1 E380Q and PI3KCA N345K (provided by Champions Oncology).

[0248] ST3164B / PBR is an ER+ breast cancer patient-derived xenograft tumor model derived from a metastatic patient sample harboring the ESR1_CCDC170 fusion (provided by XenoSTART).

[0249] ST941 / HI / PBR is an ER+ breast cancer patient-derived xenograft tumor model derived from a metastatic patient sample harboring the ESR1 Y537S activating mutation (donated by XenoSTART).

[0250] CTG1211 is an ER+ breast cancer patient-derived xenograft tumor model derived from a primary patient sample harboring the ESR1 D538G activating mutation (donated by Champions Oncology).

[0251] Example 1: Combination experiments with palbociclib-resistant cell lines The Highest Single Agent (HSA) model calculates a synergy score matrix for blocking drug combinations. Scores were determined for MCF7 and T47D parental cell lines and palbociclib-resistant mutants exposed to a combination of camizestrant and AZD5363 or everolimus, abemaciclib, and palbociclib for 7 days according to the method described in Figure 4, and the results are shown in Table 1 below. Table 2 summarizes the genetic characteristics of the tested cell lines.

[0252] [Table 1]

[0253] [Table 2]

[0254] Example 2: Xenograft experiments Patient-derived xenograft models were generated from patient biopsies from either metastases or primary tumors. Samples were implanted into immunocompromised mice for growth and drug treatment using standard techniques well known in the art. The results of various combination treatments of the xenografts are shown in Figures 1-3 and 5-16 and are also described in the list of figures.

[0255] Example 3: Clinical Data for the Combination of Camizestrant and Capivasertib Example 3: Clinical Data for the Combination of Camizestrant and Capivasertib Parts I and J of the SERENA-1 trial (NCT03616587, see https: / / classic.clinicaltrials.gov / ct2 / show / NCT03616587 ), a first-in-human, open-label, Phase I study of camizestrant in women with endocrine-resistant ER+, HER2- breast cancer that cannot be treated with curative intent, evaluated the therapeutic combination of camizestrant and capivasertib.

[0256] In the camizestrant and capivasertib combination portion of the SERENA-1 study, a once-daily oral dose of 75 mg camizestrant (tablet) was combined with capivasertib 400 mg (tablet form) administered twice daily (BID; intermittent; 4 days on, 3 days off). In other words, over the course of each week of treatment, capivasertib was administered at a dose of 400 mg twice daily on days 1, 2, 3, and 4, but not on days 5, 6, and 7. Meanwhile, camizestrant was administered once daily at a dose of 75 mg each day of the week.

[0257] Demographic data for study participants receiving camizestrant and capivasertib are shown in Table 3. Interim results of the ongoing SERENA-1 study, available on September 14, 2023, are shown in Table 4.

[0258] [Table 3]

[0259] The primary objective was to determine the safety and tolerability of camizestrant 75 mg once daily (QD) in combination with capivasertib 400 mg twice daily (BID, intermittent; 4 days on, 3 days off). Secondary objectives included investigating antitumor response and pharmacokinetics (PK). Participants were women of any menopausal status (premenopausal women received the combination in conjunction with ongoing ovarian suppression). Two or fewer lines of prior chemotherapy were permitted in advanced disease. Prior endocrine therapy (ET) was required in advanced disease, with no limit on the number of lines. Prior treatment with CDK4 / 6 inhibitors (CDK4 / 6i) and fulvestrant was permitted.

[0260] result: As of September 14, 2023, 29 patients in Parts I and J of the SERENA-1 study were receiving camizestrant in combination with capivasertib. As one skilled in the art will appreciate, as is typically the case with Phase 1 clinical trials, this Phase 1 study was not powered to provide definitive evidence of clinical efficacy or to conclusively demonstrate superiority of one arm over another. Nevertheless, the results from this study support the idea that the promising preclinical activity of combinations comprising an ngSERD, such as camizestrant, and an AKT inhibitor, such as capivasertib, described above, can be successfully translated into the clinical setting.

[0261] The safety and tolerability profile of the combination of camizestrant and capivasertib was broadly consistent with that observed with each drug individually, with no apparent worsening of the known tolerability profiles of either agent. This represents first-in-human data on the combination that are sufficient for future clinical use from a safety and tolerability perspective.

[0262] Among heavily pretreated patients receiving camizestrant plus capivasertib in the SERENA-1 trial (48% prior chemotherapy, 90% prior CDK4 / 6i, 55% prior fulvestrant; all in the advanced disease setting), 72% had visceral metastases. Furthermore, 17 patients had detectable ESR1m (mutations in the gene encoding the estrogen receptor) and evaluable C2D1 results at baseline. Of these, ESR1m was reduced by >50% at C2D1 in 11 cases (91.7%), and ESR1m was eliminated at C2D1 in 8 cases (66.7%). As can be seen in Table 4, the objective response rate (ORR) observed in the camizestrant / capivasertib combination was 37.0% (10 / 29), the clinical benefit rate at 24 weeks (CBR24) was 51.7% (15 / 29), and the median progression-free survival (PFS) was 8.5 months (15 / 29, 95% Cl). In patients with a detectable ESR1m at baseline, the median PFS was 13.8 months.

[0263] PK and safety data from Parts I and J of SERENA-1 demonstrated no clinically relevant drug-drug interactions affecting either camizestrant or capivasertib.

[0264] Thus, the preclinical promise of the combination comprising camizestrant and capivasertib as a novel treatment for ER+ HER2- breast cancer is supported by favorable results obtained in a heavily pretreated patient cohort, including patients whose tumors had progressed after treatment with the CDK4 / 6 inhibitor, fulvestrant, and patients whose tumors had detectable ESR1m.

[0265] [Table 4] Maturity is the proportion of patients with uncensored PFS out of the total number evaluated. §The once-daily oral dose of camizestrant and the dose and dosing schedule of capivasertib are as described above. * The number of patients with CR or PR, n, within the number of patients, m, in the relevant patient population. ** The number of patients with confirmed response or SD for 23 weeks or more after treatment, n, among the number of patients with at least (DCO) day - date of first dose), post-treatment scan ≥ 24 weeks or ≥ 23 weeks.

Claims

1. A SERD for use in the treatment of cancer, wherein the SERD is administered in combination with an AKT inhibitor or an mTOR inhibitor, and / or a CDK4 / 6 inhibitor.

2. A SERD for use as described in claim 1 selected from fulvestrant or a pharmaceutically acceptable salt thereof, gildestrant or a pharmaceutically acceptable salt thereof, elastrant or a pharmaceutically acceptable salt thereof, imrunestrant or a pharmaceutically acceptable salt thereof, and camizestrant or a pharmaceutically acceptable salt thereof.

3. A SERD for use as described in claim 1, selected from gildedestrant or a pharmaceutically acceptable salt thereof, elastrant or a pharmaceutically acceptable salt thereof, imrunestrant or a pharmaceutically acceptable salt thereof, and camizestrant or a pharmaceutically acceptable salt thereof.

4. 4. A SERD for use as claimed in claim 3 which is camizestrant or a pharmaceutically acceptable salt thereof.

5. A SERD for use as claimed in any one of claims 1 to 4, administered in combination with an AKT inhibitor or an mTOR inhibitor.

6. A SERD for use as claimed in any one of claims 1 to 5, administered in combination with an AKT inhibitor.

7. The AKT inhibitor is selected from the group consisting of milansertib or a pharmaceutically acceptable salt thereof, BAY1125976 or a pharmaceutically acceptable salt thereof, volsertib or a pharmaceutically acceptable salt thereof, AT7867 or a pharmaceutically acceptable salt thereof, CCT128930 or a pharmaceutically acceptable salt thereof, A-674563 or a pharmaceutically acceptable salt thereof, PHT-427 or a pharmaceutically acceptable salt thereof, Akti-1 / 2 or a pharmaceutically acceptable salt thereof, AT13148 or a pharmaceutically acceptable salt thereof, SC79 or a pharmaceutically acceptable salt thereof, capivasertib or a pharmaceutically acceptable salt thereof, miltefosine or a pharmaceutically acceptable salt thereof 7. A SERD for use as claimed in any one of claims 1 to 6, selected from erucylphosphocholine or a pharmaceutically acceptable salt thereof, perifosine or a pharmaceutically acceptable salt thereof, MK-2206 or a pharmaceutically acceptable salt thereof, RX-0201 or a pharmaceutically acceptable salt thereof, erucylphosphocholine or a pharmaceutically acceptable salt thereof, PBI-05204 or a pharmaceutically acceptable salt thereof, GSK690693 or a pharmaceutically acceptable salt thereof, afuresertib or a pharmaceutically acceptable salt thereof, uprosertib or a pharmaceutically acceptable salt thereof, XL-418 or a pharmaceutically acceptable salt thereof, and ipatasertib or a pharmaceutically acceptable salt thereof.

8. A SERD for use as claimed in any one of claims 1 to 7, wherein said AKT inhibitor is capivasertib or a pharmaceutically acceptable salt thereof.

9. A SERD for use as claimed in any one of claims 1 to 5, administered in combination with an mTOR inhibitor.

10. A SERD for use as claimed in any one of claims 1 to 9, wherein said mTOR inhibitor is an mTORC1 inhibitor.

11. A SERD for use as claimed in any one of claims 1 to 10, wherein said mTOR inhibitor is an mTORC1 selective inhibitor.

12. A SERD for use as claimed in any one of claims 1 to 11, wherein the mTOR inhibitor is selected from everolimus or a pharmaceutically acceptable salt thereof and temsirolimus or a pharmaceutically acceptable salt thereof.

13. A SERD for use in the treatment of cancer as claimed in any one of claims 1 to 3, administered in combination with a CDK4 / 6 inhibitor.

14. 14. A SERD for use in the treatment of cancer as claimed in claim 13, wherein said CDK4 / 6 inhibitor is selected from palbociclib or a pharmaceutically acceptable salt thereof, ribociclib or a pharmaceutically acceptable salt thereof, and abemaciclib or a pharmaceutically acceptable salt thereof.

15. A SERD for use as claimed in any one of claims 1 to 4, administered in combination with an AKT inhibitor or an mTOR inhibitor and a CDK4 / 6 inhibitor.

16. A SERD for use as claimed in any one of claims 1 to 15, wherein the SERD and each inhibitor are administered separately, sequentially or simultaneously.

17. A SERD for use as claimed in any one of claims 1 to 16, wherein said cancer is breast cancer.

18. 18. A SERD for use as claimed in claim 17, wherein said cancer is advanced or metastatic breast cancer.

19. 19. A SERD for use as claimed in claim 17 or claim 18, wherein said breast cancer is estrogen receptor positive breast cancer.

20. 20. A SERD for use as claimed in claim 19, wherein said breast cancer contains only wild-type estrogen receptors.

21. 20. A SERD for use as claimed in claim 19, wherein said breast cancer comprises a mutant estrogen receptor.

22. A SERD for use as claimed in any of claims 18 to 20, wherein said cancer does not contain an ESR1 mutation or fusion.

23. 22. A SERD for use as claimed in any of claims 18, 19 or 21, wherein the cancer comprises a mutation in ESR1 selected from the E380Q mutation, the Y537S mutation, and the D538G mutation, and / or an ESR1-CCDC170 fusion.

24. A SERD for use as claimed in any one of claims 17 to 23, wherein the breast cancer is resistant to treatment with a SERD, a SERM, or an aromatase inhibitor.

25. A SERD for use as claimed in any of claims 17 to 23, wherein the breast cancer has progressed during or after previous treatment with a SERD, a SERM, and / or an aromatase inhibitor.

26. 26. A SERD for use as claimed in claim 24 or claim 25, wherein the SERM is selected from tamoxifen or a pharmaceutically acceptable salt thereof, toremifene or a pharmaceutically acceptable salt thereof, and raloxifene or a pharmaceutically acceptable salt thereof.

27. 26. A SERD for use as claimed in claim 24 or claim 25, wherein the aromatase inhibitor is selected from anastrozole or a pharmaceutically acceptable salt thereof, letrozole or a pharmaceutically acceptable salt thereof, and exemestane or a pharmaceutically acceptable salt thereof.

28. A SERD for use as claimed in any one of claims 1 to 27, wherein said patient is a postmenopausal or premenopausal woman.

29. A SERD for use as claimed in any one of claims 1 to 28, wherein said cancer is PTEN deficient.

30. A SERD for use as claimed in any one of claims 1 to 29, wherein said cancer comprises an AKT1 mutation.

31. 31. A SERD for use as claimed in claim 30, wherein said AKT1 mutation is an E17K mutation.

32. A SERD for use as claimed in any one of claims 1 to 31, wherein said cancer comprises a PI3KCA mutation.

33. 33. A SERD for use as described in claim 32, wherein the PI3KCA mutation is selected from R88Q, N345K, C420R, E542K, E545A, E545D, E545Q, E545K, E545G, Q546E, Q546K, Q546R, Q546P, M1043V, M1043I, H1047Y, H1047R, H1047L, and G1049R.

34. 34. A SERD for use as claimed in any one of claims 29 to 33, wherein the SERD is administered in combination with an AKT inhibitor and the cancer is PTEN-deficient, AKT1-mutated, and / or PI3KCA-mutated.

35. A SERD for use as claimed in any one of claims 1 to 34, wherein the breast cancer is resistant to treatment with a CDK4 / 6 inhibitor.

36. 36. A SERD for use as claimed in claim 35, wherein the breast cancer is CCNE1 amplified, RB1 deficient, CDC6 overexpressing, and / or CDK6 overexpressing.

37. A SERD for use as claimed in any one of claims 1 to 36, wherein the cancer has progressed during or after previous treatment with a CDK4 / 6 inhibitor.

38. A SERD for use as claimed in any one of claims 1 to 37, wherein said cancer has not previously been treated with a CDK4 / 6 inhibitor.

39. milansertib or a pharmaceutically acceptable salt thereof, BAY1125976 or a pharmaceutically acceptable salt thereof, vorsertib or a pharmaceutically acceptable salt thereof, AT7867 or a pharmaceutically acceptable salt thereof, CCT128930 or a pharmaceutically acceptable salt thereof, A-674563 or a pharmaceutically acceptable salt thereof, PHT-427 or a pharmaceutically acceptable salt thereof, Akti-1 / 2 or a pharmaceutically acceptable salt thereof, AT13148 or a pharmaceutically acceptable salt thereof, SC79 or a pharmaceutically acceptable salt thereof, capivasertib or a pharmaceutically acceptable salt thereof, miltefosine or a pharmaceutically acceptable salt thereof, perifosine or a pharmaceutically acceptable salt thereof, MK-2206 or a pharmaceutically acceptable salt thereof, RX-0201 or a pharmaceutically acceptable salt thereof, erucylphosphocholine 2. A SERD for use as claimed in claim 1, wherein the SERD is administered in combination with an AKT inhibitor selected from pembrolizumab or a pharmaceutically acceptable salt thereof, PBI-05204 or a pharmaceutically acceptable salt thereof, GSK690693 or a pharmaceutically acceptable salt thereof, afuresertib or a pharmaceutically acceptable salt thereof, uprosertib or a pharmaceutically acceptable salt thereof, XL-418 or a pharmaceutically acceptable salt thereof, and ipatasertib or a pharmaceutically acceptable salt thereof, or an mTOR inhibitor selected from everolimus or a pharmaceutically acceptable salt thereof and temsirolimus or a pharmaceutically acceptable salt thereof, and / or a CDK4 / 6 inhibitor selected from palbociclib or a pharmaceutically acceptable salt thereof, ribociclib or a pharmaceutically acceptable salt thereof, and abemaciclib or a pharmaceutically acceptable salt thereof.

40. 2. The SERD for use as claimed in claim 1, wherein the SERD is camizestrant or a pharmaceutically acceptable salt thereof administered in combination with abemaciclib, and the cancer is resistant to treatment with palbociclib.

41. 10. Use of a SERD in the manufacture of a medicament for treating cancer, wherein the SERD is administered in combination with an AKT inhibitor or an mTOR inhibitor, and / or a CDK4 / 6 inhibitor.

42. A method for treating cancer in an animal patient in need of such treatment, comprising administering to the animal patient a therapeutically effective amount of a SERD, wherein the SERD is administered in combination with an AKT inhibitor or an mTOR inhibitor, and a CDK4 / 6 inhibitor.

43. 43. The method of treating cancer of claim 42, wherein the SERD is administered in combination with an AKT inhibitor or an mTOR inhibitor, and a CDK4 / 6 inhibitor.

44. A method for treating cancer in an animal patient in need of such treatment, comprising administering to the animal patient a first amount of a SERD, a second amount of an AKT inhibitor or an mTOR inhibitor, and a third amount of a CDK4 / 6 inhibitor, wherein the first amount, the second amount, and the third amount together constitute a therapeutically effective amount.

45. A pharmaceutical composition comprising a SERD in combination with an AKT inhibitor or an mTOR inhibitor, and / or a CDK4 / 6 inhibitor, and a pharmaceutically acceptable excipient.

46. 46. ​​The pharmaceutical composition of claim 45, comprising a SERD in combination with an AKT inhibitor or an mTOR inhibitor, and a pharmaceutically acceptable excipient.

47. 47. The pharmaceutical composition of claim 46, comprising a SERD in combination with a CDK4 / 6 inhibitor and a pharmaceutically acceptable excipient.

48. 48. The pharmaceutical composition of any one of claims 45 to 47, comprising a SERD in combination with an AKT inhibitor, an mTOR inhibitor, or a CDK4 / 6 inhibitor, and a pharmaceutically acceptable excipient.

49. A kit comprising a pharmaceutical composition comprising camizestrant and instructions for its use in the treatment of ER+ breast cancer, said use in combination with capivasertib, and optionally said use in further combination with a CDK4 / 6 inhibitor.

50. A kit comprising a pharmaceutical composition comprising capivasertib and instructions for its use in the treatment of ER+ breast cancer, said use in combination with camizestrant, and optionally said use in further combination with a CDK4 / 6 inhibitor.

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