Combination comprising capivasertib and abiraterone for treating PTEN-deficient metastatic hormone-sensitive prostate cancer (MHSPC)

Abstract

The present disclosure relates to methods of treating PTEN-deficient metastatic hormone- sensitive prostate cancer (mHSPC) in patients in need thereof, the methods comprising administering to the patients a combination comprising capivasertib or a pharmaceutically acceptable salt thereof; and abiraterone or an ester prodrug thereof, or a pharmaceutically acceptable salt thereof.

Description

METHODS OF TREATING PROSTATE CANCERCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 723,780, filed November 22, 2024, and U.S. Provisional Patent Application No. 63 / 876,229, filed September 5, 2025, the disclosures of which are incorporated by reference herein.FIELD

[0002] The present disclosure relates to methods of treating phosphatase and tensin homolog deficient (PTEN-deficient) metastatic hormone-sensitive prostate cancer (mHSPC) using therapeutic combinations comprising capivasertib or a pharmaceutically acceptable salt thereof; and abiraterone or an ester prodrug thereof, or a pharmaceutically acceptable salt thereof (such as a combination comprising capivasertib and abiraterone acetate).BACKGROUND

[0003] Prostate cancer is the most prevalent form of cancer in men and is associated with considerable morbidity and mortality. An estimated 1.3 million men worldwide were diagnosed with prostate cancer in 2018, accounting for 13% of the cancers diagnosed in men. With an estimated 358,989 deaths in 2018, prostate cancer is the fifth leading cause of death from cancer in men (6.7% of the total deaths from cancer in men) (International Agency for Research on Cancer. GLOBOCAN database (September 2018). Available at URL: http: / / gco.iarc.fr / ).

[0004] For patients with metastatic hormone-sensitive prostate cancer (mHSPC, also known as metastatic castration-sensitive prostate cancer or metastatic hormone naive prostate cancer), androgen deprivation therapy (ADT) with either orchiectomy or medical castration with gonadotropin-releasing hormone (GnRH) analogues is highly effective in shrinking tumour burden, decreasing prostate-specific antigen (PSA) levels, and enhancing quality of life. Recent studies demonstrated the benefits (including improved survival) in patients with mHSPC of adding the androgen biosynthesis inhibitor abiraterone (Fizazi et al. Lancet Oncol. 2019, 20, 686-700; James et al. N Engl J Med. 2017, 377, 338-51; Mottet et al. Eur Urol. 2018, 73, 316-21) to ADT. Unfortunately, despite the benefits of such combination therapy, mHSPC inevitably progresses to a castration-resistant phenotype, which is not yet curable, with 90% of overallmortality attributable to the underlying malignant disease (Scher et al. PLoS One. 2015, 10, e0139440).

[0005] Patients with de novo mHSPC are at higher risk of progressing to a castration-resistant disease state than those with prostate cancer that has progressed to metastasis after treatment for what was initially localised or locally advanced disease (referred to as ‘recurrent mHSPC’), as demonstrated by shorter median overall survival (OS) and time to castration resistance (Francini et al. Prostate. 2018, 78, 889-95; Francini et al. Prostate Cancer Prostatic Dis. 2019, 22, 420-7; Gravis et al. Eur Urol. 2015, 68, 196-204).

[0006] The phosphatase and tensin homolog (PTEN) gene is a tumour suppressor gene and encodes the PTEN tumour suppression protein. Loss of PTEN gene expression in prostate cancer is associated with features of more aggressive disease and poor prognosis; patients with PTEN loss at diagnosis have increased risk of recurrence and poorer survival (Ahearn et al. J Natl Cancer Inst. 2015, 108, pii:djv346; Chaux et al. Mod Pathol. 2012, 25, 1543-49; Cuzick et al. Br J Cancer. 2013, 108, 2582-9; Lotan et al. Eur Urol Focus. 2016, 2, 180-88; Reid et al. Br J Cancer. 2010, 102, 678-84; Thapa, Annals of Oncology 2024, 35 (suppl_2): S962-S1003). Thus, there is an important unmet medical need for treatments in the de novo mHSPC setting that are able to delay cancer progression and ultimately, death, particularly in patients whose tumours are characterised by PTEN deficiency.

[0007] The need for treatments for PTEN-deficient mHSPC led to the design and initiation of the phase 3 CAPItello-281 trial (ClinicalTrials.gov ID NCT04493853). The CAPItello-281 trial, results from which are disclosed herein, investigated whether the combination of capivasertib plus abiraterone acetate is superior to placebo plus abiraterone acetate in participants with mHSPC characterised by PTEN deficiency with respect to radiographic progression-free survival (rPFS).SUMMARY

[0008] Provided herein is a method of treating PTEN-deficient metastatic hormone-sensitive prostate cancer (mHSPC) in a patient in need thereof, the method comprising administering to the patient a combination comprising capivasertib or a pharmaceutically acceptable salt thereof; and abiraterone or an ester prodrug thereof, or a pharmaceutically acceptable salt thereof.

[0009] Also provided are methods of extending (a) radiographic progression-free survival (rPFS), (b) overall survival (OS), (c) time to first subsequent therapy (TFST), (d) PFS2, (e) time to PSA progression, (f) symptomatic skeletal event-free survival (SSE-FS), (g) time to castration resistance (TTCR), and / or (h) time to pain progression (TTPP) in a patient with PTEN-deficient metastatic hormone-sensitive prostate cancer (mHSPC), the methods comprising administering to the patient a combination comprising capivasertib or a pharmaceutically acceptable salt thereof; and abiraterone or an ester prodrug thereof, or a pharmaceutically acceptable salt thereof.

[0010] In any of the methods described herein, the capivasertib or a pharmaceutically acceptable salt thereof may be capivasertib.[OH] In any of the methods described herein, the abiraterone or an ester prodrug thereof, or a pharmaceutically acceptable salt thereof, may be abiraterone acetate.

[0012] In any of the methods described herein, the methods may further comprise administration of a glucocorticoid (such as prednisone or prednisolone) and / or androgen deprivation therapy (ADT).

[0013] In any of the methods described herein, the PTEN-deficient mHSPC may be PTEN- deficient de novo mHSPC.

[0014] Also provided is capivasertib or a pharmaceutically acceptable salt thereof for use in any of the methods described herein.

[0015] Also provided is the use of capivasertib or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in any of the methods described herein.

[0016] Also provided is a kit comprising: (a) capivasertib or a pharmaceutically acceptable salt thereof, and (b) instructions for use of the capivasertib or a pharmaceutically acceptable salt thereof in any of the methods described herein.

[0017] Further aspects of the disclosure will be apparent to one skilled in the art from reading this specification.BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1: Study design for the Phase 3 clinical trial described in Example 1 (A Phase III Double-Blind, Randomised, Placebo-Controlled Study Assessing the Efficacy and Safety of Capivasertib + Abiraterone Versus Placebo + Abiraterone as Treatment for Patients with DeNovo Metastatic Hormone-Sensitive Prostate Cancer (mHSPC) Characterised by PTEN deficiency (CAPItello-281) (ClinicalTrials.gov ID NCT04493853).

[0019] Figure 2: Screening process for the Phase 3 clinical trial described in Example 1.

[0020] Figure 3: Kaplan-Meier curve for results of primary analysis from Example 1 : Radiographic Progression-free Survival, Investigator Assessment.

[0021] Figure 4: Kaplan-Meier curve for Radiographic Progression-free Survival, BICR results from Example 1.

[0022] Figures 5 to 9: Subgroup forest plots of Radiographic Progression-free Survival by Investigator Assessment from Example 1.

[0023] Figure 10: Kaplan-Meier curve for interim Overall Survival results from Example 1.

[0024] Figure 11: Kaplan-Meier curve for Time to Castration Resistance (TTCR) results from Example 1.DETAILED DESCRIPTION OF THE EMBODIMENTS

[0025] The disclosure may be more fully appreciated by reference to the following description, including the following definitions and examples.

[0026] It is to be appreciated that certain features of the invention which are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. That is, unless obviously incompatible or excluded, each individual embodiment is deemed to be combinable with any other embodiment(s) and such a combination is considered to be another embodiment. Conversely, various features of the invention that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any sub-combination. It is further noted that the claims may be drafted to exclude an optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “only” and the like in connection with the recitation of claim elements, or use of a “negative” limitation.

[0027] All documents cited herein are each entirely incorporated by reference herein, including all data, tables, figures, and text presented in the cited documents.Definitions

[0028] Unless otherwise defined herein, scientific and technical terms used in the present disclosure shall have the meanings that are commonly understood by one of ordinary skill in the art. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.

[0029] The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0030] The use of the term "or" in the claims is used to mean "and / or," unless explicitly indicated to refer only to alternatives or the alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and "and / or."

[0031] As used herein, the terms "comprising" (and any variant or form of comprising, such as "comprise" and "comprises"), "having" (and any variant or form of having, such as "have" and "has"), "including" (and any variant or form of including, such as "includes" and "include") or "containing" (and any variant or form of containing, such as "contains" and "contain") are inclusive or open-ended and do not exclude additional, unrecited, elements or method steps.

[0032] The use of the term "for example" and its corresponding abbreviation "e.g." means that the specific terms recited are representative examples and embodiments of the disclosure that are not intended to be limited to the specific examples referenced or cited unless explicitly stated otherwise.

[0033] As used herein, "between" is a range inclusive of the ends of the range. For example, a number between x and y explicitly includes the numbers x and y and any numbers that fall within x and y.

[0034] When a value is expressed as an approximation by use of the descriptor “about” it will be understood that the particular value forms another embodiment. In general, use of the term “about” indicates approximations that can vary depending on the desired properties sought to be obtained by the disclosed subject matter and is to be interpreted in the specific context in which it is used, based on its function. The person skilled in the art will be able to interpret this as a matter of routine. In some cases, the number of significant figures used for a particular value may be one non-limiting method of determining the extent of the word “about.” In other cases, the gradations used in a series of values may be used to determine the intended range available tothe term “about” for each value. Where present, all ranges are inclusive and combinable. That is, references to values stated in ranges include every value within that range.

[0035] The term “effective amount” or “therapeutically effective amount” refers to that amount of a compound or combination of compounds as described herein that is sufficient to affect the intended application including, but not limited to, disease treatment. A therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo), or the patient and disease condition being treated (e.g., the weight, age and gender of the patient), the severity of the disease condition, the manner of administration, etc. which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that will induce a particular response in target cells (e.g., the reduction of platelet adhesion and / or cell migration). The specific dose will vary depending on the particular compounds chosen, the dosing regimen to be followed, whether the compound is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which the compound is carried.

[0036] The terms “administer,” “administering,” “administration,” and the like, as used herein, refer to methods that may be used to enable delivery of a drug, e.g., capivasertib or abiraterone acetate, to a patient, as described herein.

[0037] A “therapeutic effect” as that term is used herein, encompasses a therapeutic benefit and / or a prophylactic benefit. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0038] The terms “treat,” “treating,” and “treatment” refer to at least partially alleviating, inhibiting, and / or ameliorating a condition, disorder, or disease, such as PTEN-deficient mHSPC. The effectiveness of treatment of PTEN-deficient mHSPC can be assessed in a variety of ways, including but not limited to: inhibiting cancer cell proliferation (including the reversal of cancer growth); promoting cancer cell death (e.g., by promoting apoptosis or another cell death mechanism); improvement in symptoms; duration of response to the treatment; delay in progression of disease; prolonging progression free survival (PFS), such as radiographic progression free survival (rPFS); or prolonging overall survival (OS).

[0039] The term “combination therapy” can refer to simultaneous, separate, or sequential administration of two or more therapeutic agents. In some embodiments, “combination” can refer to simultaneous administration (e.g., administration of both agents in a single dosage form). In another embodiment, “combination” refers to separate administration (e.g., administration of both agents in separate dosage forms, but at substantially the same time). In a further embodiment, “combination” refers to separate and sequential administration (e.g., where a first therapeutic agent is administered, followed by a delay, followed by administration of a second or further therapeutic agent). The two therapeutic agents (capivasertib and abiraterone acetate) may each be administered multiple times within a pre-defined treatment cycle. Where the administration is sequential or separate, the delay in administering the later component should be neither too long nor too short, so as not to lose the benefit of the combination. The combination may also include further therapies, such as administration of a glucocorticoid or administration of androgen deprivation therapy (ADT) which may be administered simultaneously, separately, or sequentially to the other therapeutic agents in the combination.

[0040] The terms “co-administration,” “in combination with,” “simultaneous,” and “concurrent,” as used herein, encompass administration of two or more active pharmaceutical ingredients to a patient and include simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which two or more active pharmaceutical ingredients are present.

[0041] The term “pharmaceutically acceptable” is used to specify that a salt is suitable for use in patients. An example list of pharmaceutically acceptable salts can be found in the Handbook of Pharmaceutical Salts: Properties, Selection and Use, P. H. Stahl and C. G. Wermuth, editors, Weinheim / Zurich:Wiley-VCH / VHCA, 2002.

[0042] In the context of a clinical trial study, the term “radiographic progression free survival (rPFS)” is defined as the time (usually measured in months) from randomization to 1) the first documented radiographic progression confirmed by RECIST version 1.1 criteria (see Eisenhauer et al., European Journal of Cancer (2009) 45:228-247) for soft tissue and / or PCWG3 criteria (Scher et al. J Clin Oncol 2016, 34, 1402-18) for bone, or 2) death from any cause. In a real- world clinical (non-trial) setting, rPFS can be defined as the time from first administration of the monotherapy or combination therapy to 1) the first documented radiographic progression confirmed by RECIST version 1.1 criteria for soft tissue and / or PCWG3 criteria for bone, or 2)death from any cause. In other words, rPFS can also be defined as the time from start of treatment to 1) the first documented radiographic progression confirmed by RECIST version 1.1 criteria for soft tissue and / or PCWG3 criteria for bone, or 2) death from any cause.

[0043] In the context of a clinical trial study, the term “progression-free survival after next-line treatment (PFS2)” is defined as the time (usually measured in months) from randomization until progression on next-line treatment (i.e. the line of treatment following the first progression in the study), as clinical progression, PSA progression, or radiographic progression determined by RECIST version 1.1 (soft tissue) and / or PCWG3 criteria (bone), or death due to any cause. In a real-world clinical (non-trial) setting, PFS2 can be defined as the time from first administration of the monotherapy or combination therapy until progression on next-line treatment, as clinical progression, PSA progression, or radiographic progression determined by RECIST version 1.1 (soft tissue) and / or PCWG3 criteria (bone) as assessed by a clinician, or death due to any cause. In other words, PFS2 can also be defined as the time from start of treatment until progression on next-line treatment, as clinical progression, PSA progression, or radiographic progression determined by RECIST version 1.1 (soft tissue) and / or PCWG3 criteria (bone) as assessed by a clinician, or death due to any cause.

[0044] In the context of a clinical trial study, the term “overall survival (OS)” is defined as the time from randomization to death due to any cause. In a real-world clinical (non-trial) setting, OS can be defined as the time from first administration of the monotherapy or combination therapy until death due to any cause. In other words, OS can also be defined as the time from start of treatment until death due to any cause.

[0045] In the context of a clinical trial study, the term “time to PSA progression” is defined as the time from randomisation to PSA progression, as determined by PCWG3 criteria. In a real- world clinical (non-trial) setting, time to PSA progression can be defined as the time from first administration of the monotherapy or combination therapy to PSA progression, as determined by PCWG3 criteria. In other words, time to PSA progression can also be defined as the time from start of treatment to PSA progression, as determined by PCWG3 criteria.

[0046] In the context of a clinical trial study, the term “Time to First Subsequent Therapy (TFST)” is defined as the time from randomisation to the earlier of start date of the first subsequent anticancer therapy after discontinuation of randomised treatment, or death due to any cause. In a real-world clinical (non-trial) setting, TFST can be defined as the time from firstadministration of the monotherapy or combination therapy to the earlier of start date of the first subsequent anticancer therapy after discontinuation of randomised treatment, or death due to any cause. In other words, TFST can also be defined as the time from start of treatment to the earlier of start date of the first subsequent anticancer therapy after discontinuation of randomised treatment, or death due to any cause.

[0047] In the context of a clinical trial study, the term “Symptomatic skeletal event-free survival (SSE-FS)” is defined as the time from randomisation to death due to any cause or any of the following: 1) Use of radiation therapy to prevent or relieve skeletal symptoms; 2) Occurrence of new symptomatic pathological vertebral or non-vertebral bone fractures, confirmed by radiology, and wherein the pathological fracture is associated with low or no trauma and deemed to have occurred at a site of bone metastasis, as assessed by a clinician; 3) Occurrence of spinal cord compression, confirmed by radiology; and 4) Orthopaedic surgical intervention for bone metastasis. In a real-world clinical (non-trial) setting, SSE-FS can be defined as the time from first administration of the monotherapy or combination therapy to death due to any cause or any of the following: 1) Use of radiation therapy to prevent or relieve skeletal symptoms; 2) Occurrence of new symptomatic pathological vertebral or non-vertebral bone fractures, confirmed by radiology, and wherein the pathological fracture is associated with low or no trauma and deemed to have occurred at a site of bone metastasis, as assessed by a clinician; 3) Occurrence of spinal cord compression, confirmed by radiology; and 4) Orthopaedic surgical intervention for bone metastasis.

[0048] In the context of a clinical trial study, the term “Time to castration resistance (TTCR)” is defined as the time from randomisation to the first castration-resistant event, whichever occurs first, at castrate levels of testosterone (below 50 ng / dL), wherein the castration-resistant event is selected from 1) radiographic disease progression determined by RECIST version 1.1 (soft tissue) and / or PCWG3 criteria (bone) as assessed by the investigator; 2) PSA progression, as determined by PCWG3 criteria, and 3) a symptomatic skeletal event (SSE) selected from i) Use of radiation therapy to prevent or relieve skeletal symptoms; ii) Occurrence of new symptomatic pathological vertebral or non-vertebral bone fractures, confirmed by radiology, and wherein the pathological fracture is associated with low or no trauma and deemed to have occurred at a site of bone metastasis, as assessed by a clinician; iii) Occurrence of spinal cord compression, confirmed by radiology; and iv) Orthopaedic surgical intervention for bone metastasis. In a real-world clinical (non-trial) setting, TTCR can be defined as the time from first administration of the monotherapy or combination therapy to the first castration-resistant event, whichever occurs first, at castrate levels of testosterone (below 50 ng / dL), wherein the castration-resistant event is as defined above. In other words, TTCR can also be defined as the time from start of treatment to the first castration-resistant event, whichever occurs first, at castrate levels of testosterone (below 50 ng / dL), wherein the castration-resistant event is as defined above.

[0049] In the context of a clinical trial study, the term “Time to Pain Progression (TTPP)” is defined as the time from randomisation to the time point at which clinically meaningful pain progression is observed based on the Brief Pain Inventory-Short Form (BPLSF) Item 3 ‘worst pain in 24 hours’ score (Cleeland and Ryan, Ann Acad Med Singapore. 1994, 23, 129-38), wherein the clinically meaningful pain progression is 1) for an asymptomatic patient at baseline with average BPLSF Item 3 score of 0 and not taking opioids, i) increase of 2 or more points in the average BPLSF Item 3 score from baseline observed at 2 consecutive time points separated by 3 to 4 weeks, or ii) initiation of opioid use for pain; or 2) for a symptomatic patient at baseline with average BPLSF Item 3 score > 0 and / or taking opioids, i) increase of 2 or more points in the average BPLSF Item 3 score from baseline observed at 2 consecutive time points separated by 3 to 4 weeks and an average BPLSF Item 3 score > 4, and no decrease in average opioid use measured as 1 or more points decrease on the analgesic quantification algorithm (AQA) score (Chung et al. Pain Med. 2014, 15, 225-32) from a starting value of 2 or higher; or ii) increase in the average opioid use measured as 1 or more points increase (or at least 2 points increase if the starting value is 0) in the AQA score from baseline observed at 2 consecutive time points separated by 3 to 4 weeks. In a real-world clinical (non-trial) setting, TTPP can be defined as the time from first administration of the monotherapy or combination therapy to the time point at which clinically meaningful pain progression is observed, wherein the clinically meaningful pain progression is as defined above. In other words, TTPP can also be defined as the time from start of treatment to the time point at which clinically meaningful pain progression is observed, wherein the clinically meaningful pain progression is as defined above.Methods

[0050] In one embodiment, there is provided a method of treating PTEN-deficient metastatic hormone-sensitive prostate cancer (mHSPC) in a patient in need thereof, the method comprisingadministering to the patient a combination comprising capivasertib or a pharmaceutically acceptable salt thereof; and abiraterone or an ester prodrug thereof, or a pharmaceutically acceptable salt thereof (such as a combination comprising capivasertib and abiraterone acetate). In some embodiments, the PTEN-defi cient mHSPC is PTEN-deficient de novo mHSPC.

[0051] In one embodiment, there is provided a method of extending radiographic progression- free survival (rPFS) in a patient with PTEN-deficient metastatic hormone-sensitive prostate cancer (mHSPC), the method comprising administering to the patient a combination comprising capivasertib or a pharmaceutically acceptable salt thereof; and abiraterone or an ester prodrug thereof, or a pharmaceutically acceptable salt thereof (such as a combination comprising capivasertib and abiraterone acetate). In some embodiments, the PTEN-deficient mHSPC is PTEN-deficient de novo mHSPC.

[0052] In one embodiment, there is provided a method of extending overall survival (OS) in a patient with PTEN-deficient metastatic hormone-sensitive prostate cancer (mHSPC), the method comprising administering to the patient a combination comprising capivasertib or a pharmaceutically acceptable salt thereof; and abiraterone or an ester prodrug thereof, or a pharmaceutically acceptable salt thereof (such as a combination comprising capivasertib and abiraterone acetate). In some embodiments, the PTEN-deficient mHSPC is PTEN-deficient de novo mHSPC.

[0053] In one embodiment, there is provided a method of extending time to first subsequent therapy (TFST) in a patient with PTEN-deficient metastatic hormone-sensitive prostate cancer (mHSPC), the method comprising administering to the patient a combination comprising capivasertib or a pharmaceutically acceptable salt thereof; and abiraterone or an ester prodrug thereof, or a pharmaceutically acceptable salt thereof (such as a combination comprising capivasertib and abiraterone acetate). In some embodiments, the PTEN-deficient mHSPC is PTEN-deficient de novo mHSPC.

[0054] In one embodiment, there is provided a method of extending PFS2 in a patient with PTEN-deficient metastatic hormone-sensitive prostate cancer (mHSPC), the method comprising administering to the patient a combination comprising capivasertib or a pharmaceutically acceptable salt thereof; and abiraterone or an ester prodrug thereof, or a pharmaceutically acceptable salt thereof (such as a combination comprising capivasertib and abiraterone acetate). In some embodiments, the PTEN-deficient mHSPC is PTEN-deficient de novo mHSPC.

[0055] In one embodiment, there is provided a method of extending time to PSA progression in a patient with PTEN-deficient metastatic hormone-sensitive prostate cancer (mHSPC), the method comprising administering to the patient a combination comprising capivasertib or a pharmaceutically acceptable salt thereof; and abiraterone or an ester prodrug thereof, or a pharmaceutically acceptable salt thereof (such as a combination comprising capivasertib and abiraterone acetate). In some embodiments, the PTEN-deficient mHSPC is PTEN-deficient de novo mHSPC.

[0056] In one embodiment, there is provided a method of extending symptomatic skeletal event- free survival (SSE-FS) in a patient with PTEN-deficient metastatic hormone-sensitive prostate cancer (mHSPC), the method comprising administering to the patient a combination comprising capivasertib or a pharmaceutically acceptable salt thereof; and abiraterone or an ester prodrug thereof, or a pharmaceutically acceptable salt thereof (such as a combination comprising capivasertib and abiraterone acetate). In some embodiments, the PTEN-deficient mHSPC is PTEN-deficient de novo mHSPC.

[0057] In one embodiment, there is provided a method of extending time to castration resistance (TTCR) in a patient with PTEN-deficient metastatic hormone-sensitive prostate cancer (mHSPC), the method comprising administering to the patient a combination comprising capivasertib or a pharmaceutically acceptable salt thereof; and abiraterone or an ester prodrug thereof, or a pharmaceutically acceptable salt thereof (such as a combination comprising capivasertib and abiraterone acetate). In some embodiments, the PTEN-deficient mHSPC is PTEN-deficient de novo mHSPC.

[0058] In one embodiment, there is provided a method of extending time to pain progression (TTPP) in a patient with PTEN-deficient metastatic hormone-sensitive prostate cancer (mHSPC), the method comprising administering to the patient a combination comprising capivasertib or a pharmaceutically acceptable salt thereof; and abiraterone or an ester prodrug thereof, or a pharmaceutically acceptable salt thereof (such as a combination comprising capivasertib and abiraterone acetate). In some embodiments, the PTEN-deficient mHSPC is PTEN-deficient de novo mHSPC.PTEN-deficient mHSPC

[0059] In the methods of the present invention, the mHSPC is characterized by phosphatase and tensin homolog (PTEN) deficiency (“PTEN-deficient mHSPC”). The PTEN status (such as PTEN-deficient) of mHSPC may be determined by methods known in the art, for example by immunohistochemistry (IHC) testing or next-generation sequencing (NGS) of tumour samples.

[0060] In some embodiments, the PTEN status (such as PTEN-deficient) of the mHSPC is determined by a test approved by a regulatory authority of a sample of tumour tissue. In some embodiments, the PTEN status (such as PTEN-deficient) of the mHSPC is determined by an FDA-approved test of a sample of tumour tissue. In some embodiments, the PTEN status (such as PTEN-deficient) of the mHSPC is determined by an IHC test of a sample of tumour tissue.

[0061] The tissue sample obtained from the patient may be any sample type that contains tumour material suitable for the test to determine PTEN status. In some embodiments, the sample of tumour tissue is from a primary or metastatic site. In some embodiments, the tumour sample is not from a bone metastasis. In some embodiments, the tumour sample is not a fine needle aspirate (FNA) sample.

[0062] In some embodiments, a sample of PTEN-deficient mHSPC tumour tissue has >50%, for example >55%, >60%, >65%, >70%, >75%, >80%, >85%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98% or >99%, such as >90%, of viable malignant cells with a reduction in the normal amount (for example compared to a non-cancerous cell of the same patient) or function of the PTEN tumour suppression protein. In some embodiments, a sample of PTEN- deficient mHSPC tumour tissue has >95% of viable malignant cells with a reduction in the normal amount (for example compared to a non-cancerous cell of the same patient) or function of the PTEN tumour suppression protein. In some embodiments, a sample of PTEN-deficient mHSPC tumour tissue has >99% of viable malignant cells with a reduction in the normal amount (for example compared to a non-cancerous cell of the same patient) or function of the PTEN tumour suppression protein.

[0063] In some embodiments, a sample of PTEN-deficient mHSPC tumour tissue has >50%, for example >55%, >60%, >65%, >70%, >75%, >80%, >85%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98% or >99% of viable malignant cells with no specific cytoplasmic PTEN staining in a PTEN IHC test. In some embodiments, a sample of PTEN-deficient mHSPC tumour tissue has >90% of viable malignant cells with no specific cytoplasmic PTEN staining in a PTEN IHC test. In some embodiments, a sample of PTEN-deficient mHSPC tumour tissue has>95% of viable malignant cells with no specific cytoplasmic PTEN staining in a PTEN IHC test. In some embodiments, a sample of PTEN -deficient mHSPC tumour tissue has >99% of viable malignant cells with no specific cytoplasmic PTEN staining in a PTEN IHC test.

[0064] In some embodiments, the IHC test may be conducted using a PTEN rabbit monoclonal antibody. In some embodiments, the IHC test may be conducted using a PTEN rabbit SP218 monoclonal antibody. In some embodiments, the IHC test may be conducted using the VENTANA PTEN (SP218) IHC assay (available from ROCHE DIAGNOSTICS, USA).

[0065] In some embodiments, the PTEN-deficient mHSPC is PTEN-deficient de novo mHSPC. “De novo mHSPC” is a type of mHSPC in which a patient is diagnosed with mHSPC at their initial diagnosis of prostate cancer. Patients with de novo mHSPC are at higher risk of progressing to a castration-resistant disease state than those with hormone-sensitive prostate cancer that has progressed to metastasis after treatment for what was initially localised or locally advanced disease (referred to as “recurrent mHSPC”).

[0066] In some embodiments, the patient has not received treatment with abiraterone or an ester prodrug thereof, or a pharmaceutically acceptable salt thereof (such as abiraterone acetate) prior to first administration of the combination described herein. In some embodiments, the patient has received treatment with abiraterone or an ester prodrug thereof, or a pharmaceutically acceptable salt thereof (such as abiraterone acetate) prior to first administration of the combination described herein. In some embodiments, the patient has received treatment with abiraterone or an ester prodrug thereof, or a pharmaceutically acceptable salt thereof (such as abiraterone acetate) for a maximum of 93 days prior to first administration of the combination described herein.

[0067] In some embodiments, the patient is receiving ongoing treatment with androgen deprivation therapy (ADT), wherein the ADT is administration of a LHRH agonist or a LHRH antagonist, or bilateral orchiectomy. In some embodiments, the patient has received treatment with ADT for a maximum of 93 days prior to first administration of the combination described herein.

[0068] In some embodiments, the PTEN-deficient mHSPC is PTEN-deficient metastatic hormone-sensitive prostate adenocarcinoma. In some embodiments, the PTEN-deficient mHSPC is de novo PTEN-deficient metastatic hormone-sensitive prostate adenocarcinoma. In some embodiments, the patient does not have small cell prostate cancer.

[0069] In some embodiments, the patient has not had prior radical prostatectomy. In some embodiments, the patient has not had definitive radiotherapy with therapeutic intent for prostate cancer.

[0070] In some embodiments, the patient does not have brain metastases. In some embodiments, the patient does not have spinal cord compression.

[0071] In some embodiments, the patient has metastatic disease with > 1 bone lesion (defined as 1 lesion with positive uptake on bone scan) and / or > 1 soft tissue lesion at baseline. In some embodiments, local lymph node involvement is not considered metastatic disease.

[0072] In some embodiments, the patient has metastatic disease with > 1 soft tissue lesion at baseline. In some embodiments, the metastatic disease has only soft tissue lesions at baseline.

[0073] In some embodiments, the patient has metastatic disease with no bone lesions at baseline. In some embodiments, the patient has metastatic disease with 1-3 bone lesions at baseline. In some embodiments, the patient has metastatic disease with 4-9 bone lesions at baseline. In some embodiments, the patient has metastatic disease with 10-30 bone lesions at baseline. In some embodiments, the patient has metastatic disease with > 30 bone lesions at baseline.

[0074] In some embodiments, the patient has a high volume of disease. High volume disease is defined as the presence of visceral metastases or > 4 bone lesions with > 1 beyond the vertebral bodies and pelvis. In some embodiments, the patient has a low volume of disease. Low volume disease is a volume of disease that does not meet the criteria for high volume disease.

[0075] In some embodiments, the patient has a high volume of disease with visceral metastases. In some embodiments, the patient has a high volume of disease without visceral metastases. In some embodiments, the patient has a low volume of disease.

[0076] In some embodiments, the patient is at high disease risk. In some embodiments, high disease risk requires the patient to have at least 2 of the following: Gleason score of > 8, > 3 bone metastases, or the presence of visceral metastases. In some embodiments, the patient is at low disease risk. In some embodiments, low disease risk is a disease risk that does not meet the criteria for high disease risk. The Gleason score is a grading system used to describe prostate cancer (Gleason DF. Cancer Chem other Rep. 1966, 50(3), 125-8).

[0077] In some embodiments, the patient has liver and / or lung metastases. In some embodiments, the patient does not have liver or lung metastases.

[0078] In some embodiments, the patient has a Gleason score <8. In some embodiments, the patient has a Gleason score >8.

[0079] In some embodiments, the patient has an Eastern Cooperative Oncology Group (ECOG) / World Health Organization (WHO) performance status of 0 or 1. The ECOG / WHO performance status scale is described in Oken et al. Am J Clin Oncol. 1982, 5, 649-55. In some embodiments, the patient has an ECOG / WHO performance status of 0. In some embodiments, the patient has an ECOG / WHO performance status of 1.

[0080] In some embodiments, the patient has a baseline prostate-specific antigen (PSA) level below or equal to median at baseline. In some embodiments, the patient has a baseline PSA level above median at baseline.

[0081] In some embodiments, the patient is an adult. In some embodiments, the patient has an age > 18 years. In some embodiments, the patient has an age < 65 years. In some embodiments, the patient has an age > 65 years.Capivasertib

[0082] As used herein, capivasertib refers to the compound with chemical name 4-amino-A- [(lS)-l-(4-chlorophenyl)-3-hydroxypropyl]-l-(7J / -pyrrolo[2,3- ]pyrimidin-4-yl)-4- piperidinecarboxamide. The molecular formula for capivasertib is C21H25CIN6O2 and the molecular weight is 428.92 g / mol. Capivasertib is a white to off-white powder with pH- dependent solubility. It is freely soluble in water at pH values below 1.2 and practically insoluble at pH values above 6.8. Capivasertib has the following chemical structure:

[0083] Capivasertib is described in Example 9 of W02009 / 047563, which also describes its synthesis.

[0084] Capivasertib is an inhibitor of all 3 isoforms of serine / threonine kinase AKT (AKT1, AKT2 and AKT3) and inhibits phosphorylation of downstream AKT substrates. AKT activation in tumours is a result of activation of upstream signaling pathways, mutations in AKT loss of phosphatase and tensin homolog (PTEN) function and mutations in the catalytic subunit alpha of phosphatidylinositol 3 -kinase (PIK3CA).

[0085] In some embodiments, capivasertib may be administered orally in the form of film-coated tablets with 160 mg or 200 mg capivasertib. In some embodiments, the tablets also contain croscarmellose sodium, dibasic calcium phosphate, magnesium stearate, and microcrystalline cellulose. In some embodiments, the film coat contains the following inactive ingredients: copovidone, hypromellose, iron oxide black, iron oxide red, iron oxide yellow, medium chain triglycerides, polydextrose, polyethylene glycol 3350, and titanium dioxide.

[0086] In some embodiments, capivasertib is orally administered at a dose of 400 mg twice daily on an intermittent weekly schedule of 4 days on followed by 3 days off. For example, in a two week period, capivasertib would be administered on days 1, 2, 3, 4, 8, 9, 10 and 11, but not on days 5, 6, 7, 12, 13 and 14. In some embodiments, the two daily doses are spaced approximately 12 hours apart. In some embodiments, capivasertib is administered with or without food.

[0087] In some embodiments, the dose of capivasertib may be reduced if the patient exhibits an adverse reaction. In some embodiments, capivasertib is orally administered at a dose of 320 mg twice daily on an intermittent weekly schedule of 4 days on followed by 3 days off. In some embodiments, capivasertib is orally administered at a dose of 200 mg twice daily on an intermittent weekly schedule of 4 days on followed by 3 days off. In some embodiments, the two daily doses are spaced approximately 12 hours apart. In some embodiments, capivasertib is administered with or without food.

[0088] In some embodiments, the capivasertib utilized in the methods described herein may be administered as a pharmaceutically acceptable salt of capivasertib. The amount of the pharmaceutically acceptable salt of capivasertib administered is chosen such that it provides the required amount of capivasertib in its free form.Abiraterone

[0089] Abiraterone is an androgen biosynthesis inhibitor that inhibits CYP17 (17a- hydroxylase / C17,20-lyase). Abiraterone has the following chemical structure:

[0090] Abiraterone may be prepared according to the procedures described in WO 1993 / 20097.

[0091] The methods described herein utilize abiraterone or an ester prodrug thereof, or a pharmaceutically acceptable salt thereof. Ester prodrugs of abiraterone (such as abiraterone acetate) may be prepared from abiraterone using esterification conditions and reagents that are well-known to the skilled person.

[0092] In some embodiments, an ester prodrug of abiraterone may be a compound where a Ci- ealkanoyl group is attached to the hydroxyl group of abiraterone. In some embodiments, an ester prodrug of abiraterone may be a compound where a Ci-salkanoyl group is attached to the hydroxyl group of abiraterone. In some embodiments, an ester prodrug of abiraterone may be a compound where a C2alkaloyl group is attached to the hydroxyl group of abiraterone (i.e. abiraterone acetate). In some embodiments, the ester prodrug of abiraterone is abiraterone acetate.

[0093] Abiraterone acetate, the active ingredient of the approved drug product ZYTIGA, has the chemical name (3P)-17-(3-pyridinyl)androsta-5,16-dien-3-yl acetate and its chemical structure is:

[0094] Abiraterone acetate is converted in vivo to abiraterone.

[0095] In some embodiments, abiraterone acetate may be administered orally in the form of tablets with 250 mg or 500 mg abiraterone acetate. In some embodiments, the tablets also contain lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, povidone, sodium lauryl sulfate, magnesium stearate, and colloidal silicon dioxide.

[0096] In some embodiments, abiraterone acetate is orally administered at a dose of 1000 mg once daily. In some embodiments, abiraterone acetate is administered without food. In some embodiments, the patient should not consume food for at least two hours prior to administration of abiraterone acetate and for at least one hour after administration of abiraterone acetate.

[0097] In some embodiments, the dose of abiraterone acetate may be reduced if the patient has hepatic impairment or exhibits hepatotoxicity. In some embodiments, abiraterone acetate is orally administered at a dose of 250 mg once daily. In some embodiments, abiraterone acetate is orally administered at a dose of 500 mg once daily. In some embodiments, abiraterone acetate is orally administered at a dose of 750 mg once daily.

[0098] In some embodiments, the abiraterone or an ester prodrug thereof utilized in the methods described herein may be administered as a pharmaceutically acceptable salt, for example a pharmaceutically acceptable salt of abiraterone, or a pharmaceutically acceptable salt of an ester prodrug of abiraterone (such as a pharmaceutically acceptable salt of abiraterone acetate). The amount of the pharmaceutically acceptable salt of abiraterone acetate administered is chosen such that it provides the required amount of abiraterone acetate in its free form.

[0099] In some embodiments, the patient has not received abiraterone or an ester prodrug thereof, or a pharmaceutically acceptable salt thereof, prior to first administration of the combination described herein. In some embodiments, the patient has not received abiraterone or abiraterone acetate prior to first administration of the combination described herein. In some embodiments, the patient has not received abiraterone acetate prior to first administration of the combination described herein.Glucocorticoids

[0100] In some embodiments, the methods described herein further comprise administration of a glucocorticoid to the patient. Administration of a glucocorticoid may be desired to manage adverse events related to mineralocorticoid excess which can occur as a result of CYP17 inhibition by abiraterone (Auchus et al. Oncologist. 2014, 19, 1231-1240).

[0101] In some embodiments, the glucocorticoid is selected from dexamethasone, dexamethasone sodium phosphate, prednisone, prednisolone, prednisolone acetate and prednisolone sodium phosphate. In some embodiments, the glucocorticoid is selected from prednisone and prednisolone. In some embodiments, the glucocorticoid is prednisone. In some embodiments, the glucocorticoid is prednisolone.

[0102] The chemical name for prednisone is 17,21-dihydroxypregna-l,4-diene-3, 11,20-trione, and the structural formula is:

[0103] In some embodiments, prednisone is orally administered at a dose of 5 mg once daily.

[0104] The chemical name for prednisolone is 113,17,21 -trihydroxypregna-l,4-diene-3, 20- dione, and the structural formula is:

[0105] In some embodiments, prednisolone is orally administered at a dose of 5 mg once daily.

[0106] In some embodiments, prednisolone is administered in the form of a prodrug, such as prednisolone acetate or prednisolone sodium phosphate. In some embodiments, prednisolone acetate is orally administered at a dose of 5.6 mg once daily. 5.6 mg is the amount of prednisolone acetate required to provide a dose of 5 mg prednisolone. In some embodiments, prednisolone sodium phosphate is orally administered at a dose of 6.7 mg once daily. 6.7 mg is the amount of prednisolone sodium phosphate required to provide a dose of 5 mg prednisolone.Androgen deprivation therapy

[0107] In some embodiments, the methods described herein further comprise administration of androgen deprivation therapy (ADT) to the patient. In some embodiments the ADT comprises performing bilateral orchiectomy on the patient or administration of a luteinizing hormone- releasing hormone (LHRH) agonist or a luteinizing horm one-releasing hormone (LHRH) antagonist.

[0108] In some embodiments, the patient has received a bilateral orchiectomy. In such circumstances, the patient may not require treatment with further ADT.

[0109] In some embodiments the method comprises administration of androgen deprivation therapy (ADT) selected from administration of a LHRH agonist or a LHRH antagonist. In some embodiments, the patient has not received a bilateral orchiectomy, and the method comprises administration of androgen deprivation therapy (ADT) selected from administration of a LHRH agonist or a LHRH antagonist.

[0110] LHRH agonists (also known as gonadotropin-releasing hormone (GnRH) receptor agonists) useful for ADT are well known in the art and include, for example, leuprorelin, goserelin, triptorelin, histrelin, buserelin and nafarelin. In some embodiments, the LHRH agonist is selected from leuprorelin, goserelin, triptorelin, histrelin, buserelin and nafarelin.[OHl] LHRH antagonists (also known as gonadotropin-releasing hormone (GnRH) receptor antagonists) useful for ADT are well known in the art and include, for example, degarelix, relugolix, abarelix, cetrorelix, ganirelix, elagolix and linzagolix. In some embodiments, the LHRH antagonist is selected from degarelix, relugolix, abarelix, cetrorelix, ganirelix, elagolix and linzagolix.

[0112] The appropriate dosing regimen of the LHRH agonist or LHRH antagonist required to provide the desired therapeutic effect of ADT may be readily determined by the skilled person in conjunction with approved prescription guidance.

[0113] In some embodiments, the patient has received ADT (such as bilateral orchiectomy or administration of a LHRH agonist or a LHRH antagonist) prior to first administration of the combinations described herein.Outcomes

[0114] In some embodiments, the methods described herein extend radiographic progression- free survival (rPFS) in the patient. In some embodiments, the methods described herein extend rPFS in the patient relative to administration of abiraterone alone. In some embodiments, the methods described herein extend rPFS by at least 6 months, such as at least 6.5 months or at least 7 months, in the patient relative to administration of abiraterone alone. In some embodiments, the methods described herein extend rPFS by about 7.5 months in the patient relative to administration of abiraterone alone. In some embodiments, the methods described herein extend rPFS in the patient relative to administration of abiraterone alone with hazard ratio (HR) <1, such as <0.9, <0.85 or <0.82. In some embodiments, the hazard ratio is <1 and the entirety of the 95% confidence interval (CI) of the hazard ratio is <1. In some embodiments, the hazard ratio is <0.9 and the entirety of the 95% confidence interval (CI) of the hazard ratio is <1. In some embodiments, the hazard ratio is <0.85 and the entirety of the 95% confidence interval (CI) of the hazard ratio is <1. In some embodiments, the hazard ratio is <0.82 and the entirety of the 95% confidence interval (CI) of the hazard ratio is <1. In some embodiments, the HR is about 0.81. In some embodiments, the HR is about 0.81 with a 95% confidence interval (CI) of from 0.66 to 0.98. In some embodiments, the hazard ratio is from 0.66 to 0.98.

[0115] In some embodiments, a sample of PTEN-deficient mHSPC tumour tissue has >95% of viable malignant cells with no specific cytoplasmic PTEN staining in a PTEN IHC test, and (a) the methods described herein extend rPFS by at least 10 months in the patient relative to administration of abiraterone alone; (b) the methods described herein extend rPFS by about 10.5 months in the patient relative to administration of abiraterone alone; (c) the methods described herein extend rPFS in the patient relative to administration of abiraterone alone with hazard ratio <0.8, such as about 0.75; (d) the methods described herein extend rPFS in the patient relative to administration of abiraterone alone with hazard ratio <0.8 and the entirety of the 95% confidence interval (CI) of the hazard ratio is <1, such as <0.95; (e) the methods described herein extend rPFS in the patient relative to administration of abiraterone alone with hazard ratio of about 0.75 with a 95% confidence interval (CI) of from 0.60 to 0.94; and / or (f) the methods described herein extend rPFS in the patient relative to administration of abiraterone alone with hazard ratio of from 0.60 to 0.94.

[0116] In some embodiments, a sample of PTEN-deficient mHSPC tumour tissue has >99% of viable malignant cells with no specific cytoplasmic PTEN staining in a PTEN IHC test, and (a)the methods described herein extend rPFS by at least 10 months, such as by at least 11 months, in the patient relative to administration of abiraterone alone; (b) the methods described herein extend rPFS by about 12 months in the patient relative to administration of abiraterone alone; (c) the methods described herein extend rPFS in the patient relative to administration of abiraterone alone with hazard ratio <0.8, such as <0.75, such as about 0.71; (d) the methods described herein extend rPFS in the patient relative to administration of abiraterone alone with hazard ratio <0.8, such as <0.75, and the entirety of the 95% confidence interval (CI) of the hazard ratio is <1; (e) the methods described herein extend rPFS in the patient relative to administration of abiraterone alone with hazard ratio of about 0.71 with a 95% confidence interval (CI) of from 0.52 to 0.97; and / or (f) the methods described herein extend rPFS in the patient relative to administration of abiraterone alone with hazard ratio of from 0.52 to 0.97.

[0117] In some embodiments, the rPFS is investigator-assessed rPFS. In some embodiments, the rPFS is rPFS assessed by blinded independent central review (BICR).

[0118] In some embodiments, the methods described herein extend overall survival (OS) in the patient. In some embodiments, the methods described herein extend OS in the patient relative to administration of abiraterone alone. In some embodiments, the methods described herein extend OS in the patient relative to administration of abiraterone alone with hazard ratio (HR) <1, such as <0.95, <0.9, <0.85 or <0.8. In some embodiments, the HR is about 0.9. In some embodiments, the HR is about 0.9 with a 95% confidence interval (CI) of from 0.71 to 1.15.

[0119] In some embodiments, a sample of PTEN-deficient mHSPC tumour tissue has >95% of viable malignant cells with no specific cytoplasmic PTEN staining in a PTEN IHC test, and the methods described herein extend OS in the patient relative to administration of abiraterone alone with hazard ratio <0.90, such as <0.85, such as about 0.80.

[0120] In some embodiments, a sample of PTEN-deficient mHSPC tumour tissue has >99% of viable malignant cells with no specific cytoplasmic PTEN staining in a PTEN IHC test, and the methods described herein extend OS in the patient relative to administration of abiraterone alone with hazard ratio <0.90, such as <0.85 or <0.80, such as about 0.77.

[0121] In some embodiments, the methods described herein extend time to first subsequent therapy (TFST) in the patient. In some embodiments, the methods described herein extend TFST in the patient relative to administration of abiraterone alone. In some embodiments, the methods described herein extend TFST by at least 5 months, such as at least 5.5 months, at least 6 months,or at least 6.5 months, in the patient relative to administration of abiraterone alone. In some embodiments, the methods described herein extend TFST by about 6.1 months in the patient relative to administration of abiraterone alone. In some embodiments, the methods described herein extend TFST in the patient relative to administration of abiraterone alone with hazard ratio (HR) <1, such as <0.95. In some embodiments, the HR is about 0.92. In some embodiments, the HR is about 0.92 with a 95% confidence interval (CI) of from 0.75 to 1.1.

[0122] In some embodiments, a sample of PTEN-deficient mHSPC tumour tissue has >95% of viable malignant cells with no specific cytoplasmic PTEN staining in a PTEN IHC test, and the methods described herein extend TFST in the patient relative to administration of abiraterone alone with hazard ratio <0.90, such as <0.85, such as about 0.83.

[0123] In some embodiments, a sample of PTEN-deficient mHSPC tumour tissue has >99% of viable malignant cells with no specific cytoplasmic PTEN staining in a PTEN IHC test, and the methods described herein extend TFST in the patient relative to administration of abiraterone alone with hazard ratio <0.90, such as <0.85, such as about 0.82.

[0124] In some embodiments, the methods described herein extend PFS2 in the patient. In some embodiments, the methods described herein extend PFS2 in the patient relative to administration of abiraterone alone. In some embodiments, the methods described herein extend PFS2 by at least 5 months, such as at least 5.5 months, in the patient relative to administration of abiraterone alone. In some embodiments, the methods described herein extend PFS2 in the patient relative to administration of abiraterone alone with hazard ratio (HR) <1, such as <0.95. In some embodiments, the HR is about 0.9. In some embodiments, the HR is about 0.9 with a 95% confidence interval (CI) of from 0.71 to 1.13.

[0125] In some embodiments, a sample of PTEN-deficient mHSPC tumour tissue has >95% of viable malignant cells with no specific cytoplasmic PTEN staining in a PTEN IHC test, and the methods described herein extend PFS2 in the patient relative to administration of abiraterone alone with hazard ratio <0.90, such as <0.85, such as about 0.80.

[0126] In some embodiments, a sample of PTEN-deficient mHSPC tumour tissue has >99% of viable malignant cells with no specific cytoplasmic PTEN staining in a PTEN IHC test, and the methods described herein extend PFS2 in the patient relative to administration of abiraterone alone with hazard ratio <0.90, such as <0.85, such as about 0.82.

[0127] In some embodiments, the methods described herein extend time to PSA progression in the patient. In some embodiments, the methods described herein extend time to PSA progression in the patient relative to administration of abiraterone alone. In some embodiments, the methods described herein extend time to PSA progression in the patient relative to administration of abiraterone alone with hazard ratio (HR) <1 such as <0.8. In some embodiments, the HR is about 0.73. In some embodiments, the HR is about 0.73 with a 95% confidence interval (CI) of from 0.52 to 1.01.

[0128] In some embodiments, a sample of PTEN-deficient mHSPC tumour tissue has >95% of viable malignant cells with no specific cytoplasmic PTEN staining in a PTEN IHC test, and the methods described herein extend time to PSA progression in the patient relative to administration of abiraterone alone with hazard ratio <0.80, such as <0.75, such as about 0.70.

[0129] In some embodiments, a sample of PTEN-deficient mHSPC tumour tissue has >99% of viable malignant cells with no specific cytoplasmic PTEN staining in a PTEN IHC test, and the methods described herein extend time to PSA progression in the patient relative to administration of abiraterone alone with hazard ratio <0.70, such as <0.65, <0.60 or <0.55, such as about 0.53.

[0130] In some embodiments, the methods described herein extend symptomatic skeletal event- free survival (SSE-FS) in the patient. In some embodiments, the methods described herein extend SSE-FS in the patient relative to administration of abiraterone alone. In some embodiments, the methods described herein extend SSE-FS by at least 4 months, such as at least 4.5 months or at least 5 months, in the patient relative to administration of abiraterone alone. In some embodiments, the methods described herein extend SSE-FS by about 5.2 months in the patient relative to administration of abiraterone alone. In some embodiments, the methods described herein extend SSE-FS in the patient relative to administration of abiraterone alone with hazard ratio (HR) <1, such as <0.9 or <0.85. In some embodiments, the HR is about 0.82. In some embodiments, the HR is about 0.82 with a 95% confidence interval (CI) of from 0.66 to 1.02.

[0131] In some embodiments, a sample of PTEN-deficient mHSPC tumour tissue has >95% of viable malignant cells with no specific cytoplasmic PTEN staining in a PTEN IHC test, and the methods described herein extend SSE-FS in the patient relative to administration of abiraterone alone with hazard ratio <0.80, such as <0.75, such as about 0.72.

[0132] In some embodiments, a sample of PTEN-deficient mHSPC tumour tissue has >99% of viable malignant cells with no specific cytoplasmic PTEN staining in a PTEN IHC test, and the methods described herein extend SSE-FS in the patient relative to administration of abiraterone alone with hazard ratio <0.85, such as <0.80, such as about 0.75.

[0133] In some embodiments, the methods described herein extend time to castration resistance (TTCR) in the patient. In some embodiments, the methods described herein extend TTCR in the patient relative to administration of abiraterone alone. In some embodiments, the methods described herein extend TTCR by at least 6 months, such as at least 6.5 months or at least 7 months, in the patient relative to administration of abiraterone alone. In some embodiments, the methods described herein extend TTCR by about 7.5 months in the patient relative to administration of abiraterone alone. In some embodiments, the methods described herein extend TTCR in the patient relative to administration of abiraterone alone with hazard ratio (HR) <1, such as <0.9, <0.85 or <0.8. In some embodiments, the hazard ratio is <1 and the entirety of the 95% confidence interval (CI) of the hazard ratio is <1. In some embodiments, the hazard ratio is <0.9 and the entirety of the 95% confidence interval (CI) of the hazard ratio is <1. In some embodiments, the hazard ratio is <0.85 and the entirety of the 95% confidence interval (CI) of the hazard ratio is <1. In some embodiments, the hazard ratio is <0.8 and the entirety of the 95% confidence interval (CI) of the hazard ratio is <1. In some embodiments, the HR is about 0.77. In some embodiments, the HR is about 0.77 with a 95% confidence interval (CI) of from 0.64 to 0.94. In some embodiments, the hazard ratio is from 0.64 to 0.94.

[0134] In some embodiments, a sample of PTEN-deficient mHSPC tumour tissue has >95% of viable malignant cells with no specific cytoplasmic PTEN staining in a PTEN IHC test, and the methods described herein extend TTCR in the patient relative to administration of abiraterone alone with hazard ratio <0.80, such as <0.75, such as about 0.71.

[0135] In some embodiments, a sample of PTEN-deficient mHSPC tumour tissue has >99% of viable malignant cells with no specific cytoplasmic PTEN staining in a PTEN IHC test, and the methods described herein extend TTCR in the patient relative to administration of abiraterone alone with hazard ratio <0.80, such as <0.75 or <0.70, such as about 0.66.

[0136] In some embodiments, the methods described herein extend time to pain progression (TTPP) in the patient. In some embodiments, the methods described herein extend TTPP in the patient relative to administration of abiraterone alone. In some embodiments, the methodsdescribed herein extend TTPP in the patient relative to administration of abiraterone alone with hazard ratio (HR) <1.

[0137] In some embodiments described herein, a comparison is made “relative to abiraterone alone.” In one embodiment, the comparison is made relative to abiraterone acetate alone. Such a comparison may also include additional therapies, such as a glucocorticoid or ADT. For example, a method using a therapeutic combination comprising capivasertib, abiraterone acetate, prednisone and ADT would be compared to the same therapeutic combination without capivasertib, i.e. the combination of abiraterone acetate, prednisone and ADT.Certain Combinations

[0138] In some embodiments, a combination comprising capivasertib or a pharmaceutically acceptable salt thereof, and abiraterone acetate, or a pharmaceutically acceptable salt thereof, is administered to the patient. In some embodiments, a combination comprising capivasertib or a pharmaceutically acceptable salt thereof, and abiraterone acetate is administered to the patient. In some embodiments, a combination comprising capivasertib and abiraterone acetate is administered to the patient.

[0139] In some embodiments, a combination comprising capivasertib or a pharmaceutically acceptable salt thereof, abiraterone acetate, or a pharmaceutically acceptable salt thereof, and a glucocorticoid is administered to the patient. In some embodiments, a combination comprising capivasertib or a pharmaceutically acceptable salt thereof, abiraterone acetate and a glucocorticoid is administered to the patient. In some embodiments, a combination comprising capivasertib, abiraterone acetate and a glucocorticoid is administered to the patient. In some embodiments, a combination comprising capivasertib, abiraterone acetate and prednisone or prednisolone is administered to the patient.

[0140] In some embodiments, a combination comprising capivasertib or a pharmaceutically acceptable salt thereof, abiraterone acetate, or a pharmaceutically acceptable salt thereof, a glucocorticoid, and androgen deprivation therapy (ADT) is administered to the patient. In some embodiments, a combination comprising capivasertib or a pharmaceutically acceptable salt thereof, abiraterone acetate, a glucocorticoid and ADT is administered to the patient. In some embodiments, a combination comprising capivasertib, abiraterone acetate, a glucocorticoid and ADT is administered to the patient. In some embodiments, a combination comprisingcapivasertib, abiraterone acetate, prednisone or prednisolone, and ADT is administered to the patient. In some embodiments the ADT comprises administration of a LHRH agonist or a LHRH antagonist.

[0141] In some embodiments, the amount of capivasertib or a pharmaceutically acceptable salt thereof and the amount of abiraterone or an ester prodrug thereof, or a pharmaceutically acceptable salt thereof utilized in the methods described herein together comprise a therapeutically effective amount.

[0142] In some embodiments, capivasertib or a pharmaceutically acceptable salt thereof is orally administered at a dose of 400 mg twice daily on an intermittent weekly schedule of 4 days on followed by 3 days off, and abiraterone acetate, or a pharmaceutically acceptable salt thereof, is orally administered at a dose of 1000 mg once daily.

[0143] In some embodiments, capivasertib or a pharmaceutically acceptable salt thereof is orally administered at a dose of 400 mg twice daily on an intermittent weekly schedule of 4 days on followed by 3 days off, abiraterone acetate, or a pharmaceutically acceptable salt thereof, is orally administered at a dose of 1000 mg once daily, and prednisone or prednisolone is orally administered at a dose of 5 mg once daily.

[0144] In some embodiments, capivasertib or a pharmaceutically acceptable salt thereof is orally administered at a dose of 400 mg twice daily on an intermittent weekly schedule of 4 days on followed by 3 days off, abiraterone acetate, or a pharmaceutically acceptable salt thereof, is orally administered at a dose of 1000 mg once daily, prednisone or prednisolone is orally administered at a dose of 5 mg once daily, and ADT (such as a LHRH agonist or a LHRH antagonist) is administered to the patient.

[0145] In some embodiments, capivasertib is orally administered at a dose of 400 mg twice daily on an intermittent weekly schedule of 4 days on followed by 3 days off, abiraterone acetate is orally administered at a dose of 1000 mg once daily, prednisone or prednisolone is orally administered at a dose of 5 mg once daily, and ADT (such as a LHRH agonist or a LHRH antagonist) is administered to the patient.Compounds for use in the methods described herein

[0146] In some embodiments, there is provided capivasertib or a pharmaceutically acceptable salt thereof for use in any of the methods described herein. In some embodiments, there is provided capivasertib for use in any of the methods described herein.

[0147] In some embodiments, there is provided the use of capivasertib or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in any of the methods described herein. In some embodiments, there is provided the use of capivasertib in the manufacture of a medicament for use in any of the methods described herein.

[0148] In some embodiments, there is provided a kit comprising: (a) capivasertib or a pharmaceutically acceptable salt thereof, and (b) instructions for use of the capivasertib or a pharmaceutically acceptable salt thereof in any of the methods described herein. In some embodiments, there is provided a kit comprising: (a) capivasertib, and (b) instructions for use of the capivasertib in any of the methods described herein.Further embodiments of the invention:Embodiment Al . Capivasertib or a pharmaceutically acceptable salt thereof for use in the treatment of PTEN-deficient metastatic hormone-sensitive prostate cancer (mHSPC) in a patient, wherein capivasertib or a pharmaceutically acceptable salt thereof is administered to the patient in combination with abiraterone or an ester prodrug thereof, or a pharmaceutically acceptable salt thereof.Embodiment A2. Capivasertib or a pharmaceutically acceptable salt thereof for use of embodiment Al, wherein the treatment extends radiographic progression-free survival (rPFS) in the patient.Embodiment A3. Capivasertib or a pharmaceutically acceptable salt thereof for use of embodiment A2, wherein the rPFS is extended by at least 6 months relative to administration of abiraterone alone.Embodiment A4. Capivasertib or a pharmaceutically acceptable salt thereof for use of embodiment A2, wherein the rPFS is extended relative to administration of abiraterone alone with a hazard ratio of <0.82.Embodiment A5. Capivasertib or a pharmaceutically acceptable salt thereof for use of any one of embodiments Al to A4, wherein the treatment extends overall survival (OS) in the patient.Embodiment A6. Capivasertib or a pharmaceutically acceptable salt thereof for use of embodiment A5, wherein the OS is extended relative to administration of abiraterone alone.Embodiment A7. Capivasertib or a pharmaceutically acceptable salt thereof for use of embodiment A5, wherein the OS is extended relative to administration of abiraterone alone with a hazard ratio of <1, such as <0.95.Embodiment A8. Capivasertib or a pharmaceutically acceptable salt thereof for use of any one of embodiments Al to A7, wherein the treatment extends (a) time to first subsequent therapy (TFST), (b) PFS2, (c) time to PSA progression, (d) symptomatic skeletal event-free survival (SSE-FS), (e) time to castration resistance (TTCR), and / or (f) time to pain progression (TTPP) in the patient.Embodiment A9. Capivasertib or a pharmaceutically acceptable salt thereof for use of any one of embodiments Al to A8, wherein the PTEN-deficient mHSPC is PTEN-deficient de novo mHSPC.Embodiment A10. Capivasertib or a pharmaceutically acceptable salt thereof for use of any one of embodiments Al to A9, wherein a sample of the PTEN-deficient mHSPC tumour tissue has >90% of viable malignant cells with no specific cytoplasmic PTEN staining in a PTEN IHC test.Embodiment Al 1. Capivasertib or a pharmaceutically acceptable salt thereof for use of any one of embodiments Al to A9, wherein a sample of the PTEN-deficient mHSPC tumour tissue has >95%, such as >99%, of viable malignant cells with no specific cytoplasmic PTEN staining in a PTEN IHC test.Embodiment A12. Capivasertib or a pharmaceutically acceptable salt thereof for use of any one of embodiments Al to All, wherein capivasertib or a pharmaceutically acceptable salt thereof is orally administered at a dose of 400 mg twice daily on an intermittent weekly schedule of 4 days on followed by 3 days off.Embodiment Al 3. Capivasertib or a pharmaceutically acceptable salt thereof for use of any one of embodiments Al to All, wherein capivasertib or a pharmaceutically acceptable salt thereof is orally administered at a dose of 320 mg twice daily on an intermittent weekly schedule of 4 days on followed by 3 days off, or 200 mg twice daily on an intermittent weekly schedule of 4 days on followed by 3 days off.Embodiment A14. Capivasertib or a pharmaceutically acceptable salt thereof for use of any one of embodiments Al to A13, wherein the capivasertib or a pharmaceutically acceptable salt thereof is capivasertib.Embodiment Al 5. Capivasertib or a pharmaceutically acceptable salt thereof for use of any one of embodiments Al to A14, wherein the abiraterone or an ester prodrug thereof, or a pharmaceutically acceptable salt thereof is abiraterone acetate.Embodiment Al 6. Capivasertib or a pharmaceutically acceptable salt thereof for use of any one of the embodiments Al to A15, comprising oral administration of 1000 mg abiraterone acetate once daily.Embodiment Al 7. Capivasertib or a pharmaceutically acceptable salt thereof for use of any one of embodiments Al to Al 5, comprising oral administration of 250 mg, 500 mg or 750 mg abiraterone acetate once daily.Embodiment Al 8. Capivasertib or a pharmaceutically acceptable salt thereof for use of any one of embodiments Al to Al 7, wherein the combination further comprises administration of a glucocorticoid to the patient.Embodiment Al 9. Capivasertib or a pharmaceutically acceptable salt thereof for use of embodiment Al 8, wherein the glucocorticoid is selected from prednisone and prednisolone.Embodiment A20. Capivasertib or a pharmaceutically acceptable salt thereof for use of embodiment Al 9, wherein the prednisone or prednisolone is orally administered at a dose of 5 mg once daily.Embodiment A21. Capivasertib or a pharmaceutically acceptable salt thereof for use of any one of embodiments Al to All, comprising oral administration of capivasertib at a dose of 400 mg twice daily on an intermittent weekly schedule of 4 days on followed by 3 days off,oral administration of abiraterone acetate at a dose of 1000 mg once daily, and oral administration of prednisone or prednisolone at a dose of 5 mg once daily.Embodiment A22. Capivasertib or a pharmaceutically acceptable salt thereof for use of any one of embodiments Al to A21, wherein the combination further comprises administering androgen deprivation therapy (ADT) to the patient.Embodiment A23. Capivasertib or a pharmaceutically acceptable salt thereof for use of embodiment A22, wherein the ADT comprises performing bilateral orchiectomy on the patient or administration of a luteinizing hormone-releasing hormone (LHRH) agonist or a luteinizing hormone-releasing hormone (LHRH) antagonist.Embodiment A24. Capivasertib or a pharmaceutically acceptable salt thereof for use of embodiment A22, wherein the ADT is selected from administration of a LHRH agonist or a LHRH antagonist.Abbreviations used hereinEXAMPLES:

[0149] The following examples are non-limiting examples.

[0150] In the example below, reference is made to “abiraterone”. It will be understood that references to abiraterone in the example refer to administration of abiraterone acetate to the patient, which is converted in vivo to abiraterone.Example 1: A Phase III Double-Blind, Randomised, Placebo-Controlled Study Assessing the Efficacy and Safety of Capivasertib + Abiraterone Versus Placebo + Abiraterone as Treatment for Patients with De Novo Metastatic Hormone-Sensitive Prostate Cancer (mHSPC) Characterised by PTEN deficiency (CAPItello-281) (ClinicalTrials.gov ID NCT04493853)Study Design:

[0151] This Phase III, double-blind, randomised, placebo-controlled, parallel-group, global study is designed to compare the efficacy and safety of capivasertib versus placebo when added to abiraterone (+ prednisone / prednisolone) on a background of ADT in patients with de novo (newly diagnosed, previously untreated) mHSPC characterised by PTEN deficiency. The Study Design is illustrated in Figure 1.

[0152] Approximately 5500 participants will be enrolled and screened to achieve a total of approximately 1000 randomised in a 1 :1 ratio to the 2 treatment arms.

[0153] Screening will be conducted in a 2-part process (see Figure 2), which must be completed within a 93-day period between the participant starting ADT and being randomised to study treatment. In the 93-day period between screening Part 1 and randomisation, participants may be receiving abiraterone as well as ADT. Part 1 will include those eligibility criteria marked with an asterisk (*) in the Inclusion and Exclusion criteria below, and testing for PTEN status. In Part 2, all remaining screening assessments will be performed, and must be completed within 28 days before randomisation.

[0154] Eligible participants will have histologically confirmed metastatic hormone-sensitive prostate adenocarcinoma, without small-cell features. PTEN status is confirmed by IHC via central testing of tumour tissue using an Investigational Use Only (IUO) assay (VENTANAPTEN (SP218) IHC assay (available from ROCHE DIAGNOSTICS, USA)). For screening Part 1, patients are required to provide a formalin-fixed paraffin-embedded (FFPE) tumour sample, collected as part of routine clinical practice, for central testing. This should preferably be a tissue block that contains sufficient tissue to generate at least 6 slides, or if not possible to provide a block, at least 6 freshly-cut, unstained, serial tumour slides from the same block. For screening Part 2, eligible participants (ie, participants for whom PTEN deficiency was detected in tumour sample provided for screening Part 1) will be required to provide an additional tumour sample FFPE block (preferred) or 20 (minimum 15) freshly-cut unstained serial tumour tissue sections. A patient cannot be randomised until a valid, central laboratory tested PTEN IHC result indicates PTEN deficiency.

[0155] Approximately 1000 participants will be randomised (1 : 1 ratio) to receive either capivasertib or placebo, in combination with abiraterone on a background of ADT. It is expected that approximately 5500 potential participants will be screened. The screen failure rate is estimated on the following assumptions: PTEN deficiency prevalence of 21% (screen failure rate of 79%), as well as a further 15% screen failure for other reasons (eg, informed consent / eligibility criteria / PTEN IHC test failure rate). Participants will receive oral treatment with capivasertib or placebo BD (4 days on and 3 days off) until investigator-assessed disease progression by RECIST 1.1 or PCWG3 bone progression criteria, unacceptable toxicity, or the participant requests to stop the treatment. Participants will also receive the approved oral dose of abiraterone (1000 mg once daily) with 5 mg prednisone or 5 mg prednisolone daily. All participants should also receive continuous ADT using either a LHRH agonist, a LHRH antagonist, or bilateral orchiectomy.

[0156] The randomisation scheme will be stratified on the following factors:• Combination of volume of disease according to CHAARTED criteria and presence of visceral metastases (ie, high volume disease with visceral metastases / high volume disease without visceral metastases / low volume disease)• Geographic location: North America, Western Europe, and Australia, Latin America and Eastern Europe, and Asia.

[0157] High volume disease is defined as the presence of either visceral metastases or > 4 bone metastases with > 1 beyond the vertebral bodies and pelvis (Sweeney et al. N Engl J Med. 2015, 373, 737-46).Study Population:

[0158] Following written informed consent, all participants will undergo central PTEN status assessment using the IHC assay. Where possible, investigators should ensure eligibility criteria marked with an asterisk (*) in the Inclusion criteria and Exclusion criteria below, are met prior to the PTEN status assessment.

[0159] Documented PTEN deficiency of tumour tissue is required for selection of participants onto the study. All participants must provide FFPE tumour tissue (block or slides) from primary or metastatic sites (excluding bone metastases or FNA samples) for IHC -based determination of PTEN deficiency.

[0160] Deficiency was defined as >90% of viable malignant cells with no specific cytoplasmic PTEN staining using the VENTANA PTEN (SP218) IHC assay.

[0161] Inclusion Criteria. Participants are eligible to be included in the study only if all of the following criteria apply:1 *Participant must be > 18 years of age and of local age of consent at the time of signing the informed consent.2 *Histologically-confirmed prostate adenocarcinoma that is de novo (ie, prostate cancer diagnosed within 180 days of randomisation, date of diagnosis based on pathology report documented within the electronic study database) and is of hormone-sensitive status. Note: adenocarcinoma must be the primary histological pattern and patients with small cell tumours are not eligible.3 *Consent to provide a FFPE tissue block (preferred) or slides. Cytologic or FNA samples are not acceptable. Tumour tissue from bone metastases is not acceptable.4 A valid PTEN IHC result indicating PTEN deficiency (centralised testing).5 Metastatic disease documented prior to randomisation by clear evidence of > 1 bone lesion (defined as 1 lesion with positive uptake on bone scan) and / or > 1 soft tissue lesion (measurable and / or non-measurable) that can be accurately assessed at baseline and is suitable for repeated assessment with CT and / or MRI. Patients with metastatic disease identified by PSMAPET only, will not be eligible. Local lymph node involvement is not considered metastatic disease.6 Asymptomatic or mildly symptomatic form of prostate cancer based on the investigator’s clinical evaluation.7 *Candidate for abiraterone and steroid therapy. Previous treatment with abiraterone and / or a steroid for de novo disease is allowed up to a maximum of 93 days prior to randomisation (prior treatment with chemotherapy or other NHAs is not allowed).8 Ongoing ADT with GnRH analogue (combination with first generation androgen receptor antagonists, eg, bicalutamide is allowed), or LHRH antagonist, or bilateral orchiectomy. Duration of ongoing ADT (regardless of method) is from 0 days to a maximum of 93 days prior to randomisation.9 ECOG / WHO performance status 0 to 1 with no deterioration over the previous 2 weeks and minimum life expectancy of 12 weeks.10 *Able and willing to swallow and retain oral medication.11 Participants must complete the 7-day BPI-SF and BFI questionnaires and the analgesic diary during screening (only after PTEN deficiency is confirmed), prior to randomisation. Note: participants must complete a minimum of 4 successful assessments within a 7-day period prior to randomisation. If the minimum of 4 assessments is not completed during the 7-day period, participants must be re-screened, a new 7 days of questionnaire / diary entries completed, and any screening tests which are consequently outside of the applicable 28 days prior to randomisation must also be repeated.12 *Participants will be male.13 Agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm:- Sterilisation (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate).- Participants should use barrier contraception (ie, condoms) from the time of screening until 16 weeks after discontinuation of study drug. It is not known whether the pre clinical changes seen in the male animal reproductive organs, after treatment with capivasertib, will be fully reversible or will permanently affect the ability to produce healthy sperm following treatment. Therefore, if participants wish to father children, they should be advised to arrange for collection of sperm samples prior to the start of study treatment.14 *Capable of giving signed informed consent

[0162] Exclusion Criteria. Participants are excluded from the study if any of the following criteria apply:Prior radical prostatectomy or definitive radiotherapy with therapeutic intent for prostate cancer. Palliative radiotherapy is allowed providing any wide field radiation therapy (eg, more than one-third of the skeleton) is completed more than 4 weeks before the start of study treatment (capivasertib / placebo). Major surgery (excluding placement of vascular access, transurethral resection of prostate, bilateral orchiectomy, or internal stents) within 4 weeks of the start of study treatment. Brain metastases, or spinal cord compression (unless spinal cord compression is asymptomatic, treated and stable and not requiring steroids for at least 4 weeks prior to start of study treatment). *Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease. Any of the following cardiac criteria:- Mean resting corrected QT interval (QTc) > 470 msec obtained from triplicate ECGs performed at screening.- History of QT prolongation associated with other medications that required discontinuation of that medication.- Family history of long QT syndrome, or unexplained sudden death under 40 years of age in first-degree relatives.- Medical history significant for arrhythmia (eg, multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia), which is symptomatic or requires treatment (CTCAE Grade 3), symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Participants with atrial fibrillation controlled by medication or arrhythmias controlled by pacemakers may be permitted to enter the study based on the Investigator judgement with cardiologist consultation recommended.- Any clinically important abnormalities in conduction or morphology of resting ECG (eg, complete left bundle branch block, third-degree heart block).- Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as hypokalaemia of Grade > 1, potential for Torsades de Pointes, or congenital long QT syndrome, or any concomitant medication (within 5 half-lives of the first dose of studytreatment) known to significantly prolong the QT interval and associated with Torsade de Pointes.- Experience of any of the following procedures or conditions in the preceding 3 months: coronary artery bypass graft, angioplasty, myocardial infarction, or unstable angina pectoris.- Congestive heart failure New York Heart Association (NYHA) Grade > 2.- Symptomatic hypotension - systolic blood pressure (SBP) < 90 mmHg and / or diastolic blood pressure (DBP) < 50 mmHg with clinical symptoms of haemodynamic instability.- Uncontrolled hypertension (SBP > 160 mmHg or DBP > 95 mmHg). *Clinically significant abnormalities of glucose metabolism as defined by any of the following:- Diabetes mellitus type I or diabetes mellitus type II requiring insulin treatment.- HbAlc > 8.0% (63.9 mmol / mol). Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values:- Absolute neutrophil count < 1.5x 109 / L.- Platelet count < lOOx 109 / L.- Haemoglobin < 9 g / dL (< 5.59 mmol / L). [Note: any blood transfusion must be > 7 days prior to the determination of a haemoglobin > 9 g / dL (> 5.59 mmol / L)].- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) > 2.5x upper limit of normal (ULN) if no demonstrable liver metastases or > 5x ULN in the presence of liver metastases. Elevated alkaline phosphatase (ALP) is not exclusionary if due to the presence of bone metastases and liver function is otherwise considered adequate in the investigator’s judgement.- Total bilirubin > 1.5x ULN (participants with confirmed Gilbert’s syndrome may be included in the study with a higher value)- Creatinine clearance (CrCL) < 50 mL / min, measured (timed urine collection) or calculated by Cockcroft and Gault equation):Cockcroft and Gault equation for measuring CrCL in mL / min:= (140 - age) x weight (kg) / 72 x serum creatinine (mg / dL)OR= (140 - age) x weight (kg) / 0.814 x plasma creatinine (pmol / L)* As judged by the investigator, any evidence of severe or uncontrolled systemic diseases, including active bleeding diatheses, or known active infection including hepatitis B and hepatitis C. Diagnosis with HIV with a CD4+ T-cell count < 350 cells / pL or a history of an acquired immunodeficiency syndrome (AIDS)-defining opportunistic infection within the past 12 months. Screening for chronic conditions is not required. Participants who are unevaluable for both bone and soft tissue progression as defined by meeting both of the following criteria:- A bone scan referred to as a superscan showing an intense symmetric activity in the bones and no or limited technetium excretion by the kidneys, and- No soft tissue lesion (measurable or non-measurable) that can be assessed by RECIST criteria. *Refractory nausea and vomiting, malabsorption syndrome, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection, or other condition that would preclude adequate absorption of capivasertib. *Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that, in the investigator’s opinion, gives reasonable suspicion of a disease or condition that contra-indicates the use of an investigational drug, may affect the interpretation of the results, render the patient at high risk from treatment complications or interferes with obtaining informed consent. *Evidence of dementia, altered mental status, or any psychiatric condition that would prohibit understanding or rendering of informed consent. *Previous allogeneic bone marrow transplant or solid organ transplant. * History of another primary malignancy except for malignancy treated with curative intent with no known active disease > 2 years before the first dose of study intervention and of low potential risk for recurrence. Exceptions include adequately resected non melanoma skin cancer and curatively treated in situ disease. Treatment with any of the following:- Nitrosourea or mitomycin C within 6 weeks of the first dose of study treatment.- Any investigational agents or study drugs from a previous clinical study within 30 days or 5 half-lives (whichever is longer) of the first dose of study treatment.- Any other chemotherapy, immunotherapy, immunosuppressant medication (other thancorticosteroids) or anticancer agents within 3 weeks of the first dose of study treatment. A longer washout may be required for drugs with a long half-life (eg, biologies) as agreed by the sponsor.- Strong inhibitors or strong inducers of CYP3 A4 within 2 weeks before the start of study treatment (3 weeks for St John’s wort). Note that adequate washout or dose reduction may be required for some CYP3 A substrates prior to initiating capivasertib dosing.- Drugs known to significantly prolong the QT interval and associated with Torsades de Pointes within 5 half-lives of the first dose of study treatment.16 Participation in another clinical study with an investigational product administered in the last 30 days or 5 half-lives, whichever is longer.17 *History of hypersensitivity to active or inactive excipients of capivasertib, abiraterone, or drugs with a similar chemical structure or class.18 *Involvement in the planning and / or conduct of the study.19 * Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements.

[0163] The rationale for the inclusion of participants with mHSPC without high-risk features in this study is based on the analyses from the STAMPEDE study, which demonstrated that abiraterone achieved positive efficacy outcomes for both rPFS and OS in the target patient population, regardless of risk status (James et al. N Engl J Med. 2017, 377, 338-51). In addition, as noted above, classifying patients with prostate cancer for treatment based on risk status is not distinguished within treatment guidelines, and is not routinely done in the clinic.

[0164] Only adenocarcinomas without small-cell histology are allowed; this is consistent with the LATITUDE study (Fizazi et al. N Engl J Med. 2017, 377, 352-60), which was the primary basis for the approval of abiraterone in mHSPC.

[0165] The presence of metastatic disease will be confirmed using standard imaging techniques that are widely used in the staging of prostate cancer in routine clinical practice, with RECIST 1.1 and PCWG3 principles adopted for assessment of metastatic lesions.

[0166] Only patients with ECOG performance status 0 or 1 are eligible, in line with guidelines recommending that abiraterone should be offered only to patients with ECOG status 0 or 1.

[0167] The use of mild opioid analgesics for cancer-related pain, bisphosphonates and denosumab for management of bone-related metastases, LHRH analogues (ie, ADT) to maintaintestosterone < 50 ng / dL, conventional multivitamins and selenium, prednisone dose increases and eplerenone to manage refractory mineralocorticoid-related toxicities, transfusions and haematopoietic growth factors will all be permitted during the study. However, where possible, these will be kept at a stable dose to allow accurate characterisation of the capivasertib treatment effect.

[0168] The Eastern Cooperative Oncology Group (ECOG) / World Health Organization (WHO) performance status scale is presented below (Oken et al. Am J Clin Oncol. 1982, 5, 649-55):Study Intervention:

[0169] Abiraterone (dosed in the form of abiraterone acetate) is indicated for use in combination with ADT, and it is also recommended that abiraterone is used with prednisone or prednisolone. In this study, ADT (either surgical or chemical) is given as a standard care for prostate cancer, and prednisone / prednisolone are to be administered in line with practice for participants treated with abiraterone. Androgen deprivation therapy, prednisone, and prednisolone should be prescribed in accordance with local guidelines, where applicable and indicated.

[0170] Study Intervention(s) Administered. Details of the Investigational Products are provided below:a Prednisone / prednisolone are to be administered in line with practice for participants treated with abiraterone.AxMP Auxiliary medicinal product; BD Twice daily; IMP Investigational medicinal product; NIMP Non investigational medicinal product; QD Once daily.

[0171] Where possible, all doses of capivasertib / placebo should be taken at approximately the same time each day, 12 hours apart, with or without food. Fasting restrictions apply on days where fasting glucose is to be tested. If vomiting occurs, a replacement dose should not be taken, and the participant should take their allotted dose at the next scheduled time.

[0172] Should a participant miss a scheduled dose, the participant will be allowed to take the dose up to a maximum of 2 hours after the scheduled dose time. If greater than 2 hours after the scheduled dose time, the missed dose should not be taken, and the participant should take their allotted dose at the next scheduled time. If a participant needs to take the dose earlier, the participant can take the dose up to 2 hours earlier than the scheduled dose time. The participant should make every reasonable effort to take the capivasertib / placebo tablet(s) on time.

[0173] Any regular medication required by the participant, including abiraterone and prednisone / prednisolone, can be taken at the same time as capivasertib / placebo, provided that this does not contravene the dosing instructions in the prescribing information for that medication.

[0174] Abiraterone should be taken under fasting conditions (only water to drink) from at least 2 hours prior to dosing to at least 1 hour post-dose. The tablets should be swallowed whole with water and not crushed or chewed.

[0175] Recommended Concomitant Therapy. The following therapies are recommended during study participation, as applicable:- Corticosteroids: In the treatment of patients with mHSPC, abiraterone is indicated for use with corticosteroid in the form of 5 mg prednisone or 5 mg prednisolone daily in line with the locally approved abiraterone package insert. Doses of the corticosteroid may be adjusted as clinically indicated (eg, during and after an acute illness or a stressful situation). Participants will receive the treating investigator’s choice of commercially available prednisone or prednisolone.- Androgen deprivation therapy (ADT): Abiraterone is indicated for use in combination with ADT; therefore, participants must be receiving the treating investigator’s choice of commercially available LHRH analogues or have received surgical castration.- Anti-diarrhoeal therapy for symptomatic treatment of diarrhoea.- Antidiabetic therapy for management of hyperglycaemia.

[0176] Restricted Concomitant Therapy. The following concomitant therapies are restricted during study treatment:- Other anticancer agents, other investigational agents and radiotherapy, although radiation for palliation at focal sites is permitted (as long as the radiation field covers less than 30% of the marrow and does not include whole pelvis or spine; disease progression in the bones has to be excluded by appropriate imaging investigations).- Drugs or herbal supplements that are known to be potent inhibitors / inducers of CYP3 A4, as they may increase / decrease the exposure and thus, affect the toxicity / efficacy of capivasertib.- Drugs known to be sensitive to inhibition of CYP3 A4 metabolism with a narrow therapeutic window and / or MATE1 or OCT2 transport may require dose adjustment.- The concomitant administration of drugs known to significantly prolong the QT interval and associated with Torsades de Pointes is restricted unless considered essential due to participant management, in which case, participants should be closely monitored. Information regardingdrugs known to prolong the QT interval can be found at URL: https: / / crediblemeds.org.- Avoid concomitant strong CYP3 A4 inducers and CYP2D6 substrates with abiraterone; for more details on restrictions and cautions required when administering concomitant medications with abiraterone, please refer to abiraterone local prescribing information.

[0177] Dose Modification for capivasertib. Dose reductions or holds are allowed as clinically indicated by the treating physician and in line with the table below. For each participant, a maximum of 2 dose reductions will be allowed for capivasertib / placebo. Dose re-escalations are not allowed for either capivasertib / placebo.

[0178] Dose reductions for capivasertib / placebo should be carried out as described in the table below. The dose of capivasertib / placebo can be reduced twice (initially, reduction to dose reduction level 1; subsequently, in case of occurrence of further toxicity, further reduction to dose reduction level 2).Dose Levels for Capivasertib / Placebo

[0179] Dose Modification for Abiraterone. In case dose reductions are necessary for abiraterone, the investigator should refer to abiraterone local prescribing information (eg, SmPC for Europe, Product Monograph for Canada) for further details.Objectives and Endpoints:BFI Brief Fatigue Inventory; BPI-SF Brief Pain Inventory-Short Form; FACT-G Functional Assessment of Cancer Therapy General; FACT-P Functional Assessment of Cancer Therapy - Prostate; FAPSI-6 Functional Assessment of Cancer Therapy Advanced Prostate Symptom Index-6; PCWG3 Prostate Cancer Working Group 3; PK Pharmacokinetics; PSA Prostate Specific Antigen; PTEN Phosphatase and tensin homolog; RECIST Response Evaluation Criteria in Solid Tumours; rPFS Radiographic progression free survival; SSE-FS Symptomatic skeletal event-free survival; TFST Time to start of the first subsequent anticancer therapy or death; TOI Trial outcome index; TTPP Time to pain progression.AE Adverse event; CTCAE Common Terminology Criteria for Adverse Events; ECG Electrocardiogram; PTEN Phosphatase and Tensin Homolog; SAE Serious adverse event.Efficacy Assessments:

[0180] Tumour assessments. Tumour assessments will be performed using a CT or MRI scan for soft tissue of chest, abdomen, and pelvis, and a bone scan for whole body. Any other areas of disease involvement should be additionally imaged based on the signs and symptoms of individual participants. Baseline assessments should be performed no more than 28 days before randomisation, and ideally, should be performed as close as possible to randomisation. Followup assessments will be performed every 16 weeks (± 14 days) relative to the date of randomisation until objective disease progression as defined by RECIST 1.1 (soft tissue) and / or PCWG3 criteria (bone), regardless of discontinuation of study treatment (eg, discontinuation due to toxicity or clinical progression) or initiation of subsequent anticancer therapy.Evaluation of Disease Progression

[0181] Radiographic PFS. Radiographic PFS is defined as the time from randomisation to: 1) radiographic progression, as assessed by the investigator per RECIST version 1.1 (soft tissue) (Eisenhauer et al. Eur J Cancer 2009, 45,228-47) and / or PCWG3 criteria (bone) (Scher et al. J Clin Oncol 2016, 34, 1402-18), or 2) death due to any cause regardless of whether the participant withdraws from randomised treatment or receives another anticancer therapy prior to progression.

[0182] Radiographic PFS will be measured by investigator assessment, and a sensitivity analysis of rPFS assessed by BICR will also be conducted.

[0183] Participants who have not progressed (defined as CR, PR, NED, NE, or SD by RECIST 1.1 for soft tissue, and Non-PD or NE for PCWG3 for bone) or died at the time of analysis will be censored at the time of the earliest date of their last evaluable RECIST 1.1 assessment (taking the latest target lesion, non-target lesion, or new lesion scan date) or PCWG3 assessment that showed Non-PD; else, the latest of the previous RECIST 1.1 assessment and bone scan if done at the same visit.

[0184] However, if the participant progresses or dies immediately after 2 or more consecutive missed visits for either soft tissue or bone assessments, the participant will be censored at the earliest of the previous RECIST 1.1 assessment (taking the latest target lesion, non-target lesion, or new lesion scan date) or previous bone scan assessment prior to the 2 consecutive missed visits (if RECIST and bone scan done at different visits); else, the latest of the previous RECIST 1.1 assessment and bone scan if done at the same visit.

[0185] Evaluation of Soft Tissue Lesions. The criteria for objective tumour response on soft tissue lesions will be based on RECIST 1.1 : CR (complete response), PR (partial response), SD (stable disease), PD (progressive disease), NE (not evaluable), and NED (no evidence of disease).

[0186] For participants with measurable lesion at baseline, target lesion progression will be calculated in reference to the smallest tumour burden on study (ie, the smallest sum of diameters previously recorded on study). In the absence of progression, target lesion response will be calculated using as reference the baseline tumour measurements obtained before starting treatment. For these participants, the objective tumour response assessment options are CR, PR, SD, PD, and NE.

[0187] For participants with non-measurable soft tissue lesions only at baseline, the objective tumour response assessment options are CR, PD, Non CR / Non PD, and NE.

[0188] For participants with bone lesions only and no soft tissue disease at baseline, the objective tumour response assessment options will be NED, PD (if a new soft tissue lesion appears), or NE (if the scan is not performed).

[0189] If the investigator is in doubt as to whether disease progression has occurred, particularly with regard to non-target lesions or the appearance of a new lesion, it is advisable to continue treatment and reassess the tumour burden at the next scheduled assessment or sooner if clinically indicated. If repeat scans confirm progression, then the date of the initial scan should be declared as the date of progression. New bone lesions should not be counted in the RECIST assessment.

[0190] To achieve ‘unequivocal progression’ on the basis of non-target lesions, there must be an overall level of substantial worsening in non-target disease such that, even in presence of SD or PR in target lesions, the overall tumour burden has increased sufficiently to merit discontinuation of therapy. A modest ‘increase’ in the size of 1 or more non-target lesions is usually not sufficient to qualify for unequivocal progression status.

[0191] Evaluation of Bone Lesions. Progression on a bone scan is identified using PCWG3 criteria, by having 2 or more new metastatic bone lesions.

[0192] For participants without progression at the first visit after baseline, the scan from this first visit after baseline now serves as new reference for all subsequent scans, ie, assuming all visits are acquired according to schedule, all bone scans after Week 16 are compared to the Week 16 scan.

[0193] The requirements for determination of radiographic progression by either bone scan (bone progression) or CT / MRI (soft tissue progression) are summarised in the table below:

[0194] Central Reading of Scans. A BICR of the scans will be conducted and the results used in a sensitivity analysis of rPFS. Images, including unscheduled visit scans, will be collected on an ongoing basis and sent for BICR.

[0195] PFS2. PFS2 is defined as the time from randomisation until progression on next-line treatment (ie, the line of treatment following the first progression in the study), as clinical progression, PSA progression, or radiographic progression determined by RECIST version 1.1 (soft tissue) and / or PCWG3 criteria (bone) as assessed by the investigator, or death due to any cause.

[0196] A participant will enter the PFS2 follow-up period once that participant has discontinued study treatment due to progressive disease by RECIST 1.1 for soft tissue lesions and / or PCWG3 criteria for bone lesions. The participant’s status at first progression will be used as the reference for assessment of PFS2.

[0197] Overall Survival. Overall survival is the length of time from randomisation until the date of death due to any cause. In the survival follow-up period, all subsequent cancer therapies and vital status will be documented at least every 12 weeks until death, lost to follow-up, or withdrawal of consent, whichever comes first.

[0198] Any participant not known to have died at the time of analysis will be censored based on the last recorded date on which the participant was known to be alive.

[0199] Time to PSA progression. Time to PSA progression is defined as the time from randomisation to PSA progression, as determined by PCWG3 criteria: PSA progression is the date that an increase of 25% or more and absolute increase of 2 ng / mL or more from the nadir are documented, which is confirmed by a second value obtained 3 or more weeks later.

[0200] Time to First Subsequent Therapy. Time to First Subsequent Therapy (TFST) is defined as time from randomisation to the earlier of start date of the first subsequent anticancer therapy after discontinuation of randomised treatment, or death due to any cause.

[0201] SSE-FS. Symptomatic skeletal event-free survival (SSE-FS) is defined as the time from randomisation until any of the following (or death due to any cause):- Use of radiation therapy to prevent or relieve skeletal symptoms.- Occurrence of new symptomatic pathological bone fractures (vertebral or non-vertebral). Radiologic documentation is required. A pathological fracture, as determined by investigator, is defined as associated with low or no trauma and deemed to have occurred at a site of bone metastasis.- Occurrence of spinal cord compression. Radiologic documentation is required.- Orthopaedic surgical intervention for bone metastasis.

[0202] Participants who have not experienced any of the above conditions will be censored at the time of the last SSE assessment.

[0203] Time to Castration Resistance. Time to castration resistance (TTCR) is defined as the time from randomisation to the first castration-resistant event (radiographic disease progression, PSA progression, or SSE), whichever occurs first, at castrate levels of testosterone (below 50 ng / dL).

[0204] Patient-reported Outcomes. The following PROs will be administered in this study: BPI-SF (Cleeland and Ryan, Ann Acad Med Singapore. 1994, 23, 129-38), BFI (Mendoza et al. Cancer. 1999, 85, 1186-96), FACT-P (Esper et al. Urology. 1997, 50, 920-8), PGI-S, EQ-5D-5L (EuroQol Group. Health Policy. 1990, 16, 199-208), and selected questions from the National Cancer Institute (NCI) PRO-CTCAE items library.

[0205] BPI -SF. The BPI-SF is a validated, 15-item domain-specific instrument designed to primarily assess the severity of pain and the impact / interference of pain on daily functions (Cleeland and Ryan, Ann Acad Med Singapore. 1994, 23, 129-38).

[0206] Time to Pain Progression. The key secondary endpoint of TTPP is defined as the time from randomisation to the time point at which clinically meaningful pain progression is observed, based on a 2-point increase from baseline in the BPI-SF Item 3 ‘worst pain in 24 hours’ score and / or initiation of / increase in opiate analgesic use. A minimum of 4 out of 7 days of data is required. The criteria for pain progression depend on whether a participant is asymptomatic or symptomatic at baseline:

[0207] Asymptomatic participants at baseline (average BPI-SF Item 3 score of 0 and not taking opioids):- Increase of 2 or more points in the average (ie, average of 7-day assessments) ‘worst pain in 24 hours’ (BPI-SF Item 3) from baseline observed at 2 consecutive follow-up assessments / visits (separated by 3 to 4 weeks)OR- Initiation of opioid use for pain

[0208] Symptomatic participants at baseline (average BPI-SF Item 3 score > 0 and / or currently taking opioids):- Increase of 2 or more points in the average (ie, average of 7-day assessments) ‘worst pain in 24 hours’ (BPI-SF Item 3) from baseline observed at 2 consecutive follow-up assessments / visits (separated by 3 to 4 weeks) and an average worst pain score > 4, and no decrease in average (ie, average of 7-day assessments) opioid use measured as 1 or more points decrease in AQA score from a starting value of 2 or higherOR- Increase in the average (ie, average of 7-day assessments) opioid use measured as 1 or more points increase (or at least 2 points increase if the starting value is 0) in the AQA score from baseline observed at 2 consecutive follow-up assessments / visits (separated by 3 to 4 weeks).

[0209] The analgesic quantification algorithm (AQA) (Chung et al. Pain Med. 2014, 15, 225-32) will be used to quantify and score analgesic use in the study.

[0210] Participants satisfying one or more of the criteria above will be considered to have pain progression. Participants who do not satisfy any of the criteria above will be censored at the time of the last known assessment that showed an absence of pain progression.

[0211] Censoring. A number of situations will lead to a participant’s time to pain progression being censored; these are as follows:- If a participant meets the criteria for pain progression after 2 or more missed visits (visits which showed < 4 days of BPI-SF worst pain [Item 3] assessments and the average AQA score does not meet the progression criteria), then the participant will be censored at the time of the latest evaluable average BPI-SF ‘worst pain’ assessment (the earliest date of the assessments contributing to the average will be used).- Participants who have not met the criteria for pain progression at the time of analysis:- The censoring date will be the date of the latest evaluable average BPI-SF ‘worst pain’ assessment (the earliest date of the assessments contributing to the average will be used).- Participants with no evaluable baseline or post-baseline data will be censored at Day 1.- For participants who receive subsequent anticancer therapy:- The censoring date will be the date of the latest evaluable average BPI-SF ‘worst pain’ assessment prior to the start date of subsequent anticancer therapy (the earliest date of the assessments contributing to the average will be used).- Participants with no evaluable baseline or post-baseline data will be censored at Day 1.Results

[0212] Efficacy was analyzed for the intention-to-treat population and safety was analyzed for all participants who received any amount of capivasertib, abiraterone or placebo.

[0213] The results described herein are from the final planned analysis of the primary endpoint of rPFS by investigator assessment. The final analysis was planned to occur after 386 progression or death events (38.6% maturity) to provide 94% power to show a statistically significant difference in rPFS by investigator assessment at the two-sided 5% level.

[0214] The smallest treatment difference that would be statistically significant with 386 events is an rPFS by investigator assessment hazard ratio of 0.819.

[0215] Final OS analysis is planned at a fourth data cutoff, once 522 deaths (52.2% maturity) have been observed.Patient Demographics and Characteristics

[0216] Patient demographics and characteristics are shown in the table below. Baseline characteristics were generally balanced between arms.Patient DispositionEfficacy

[0217] A statistically significant improvement in the primary endpoint, rPFS by investigator assessment was observed for capivasertib + abiraterone vs placebo + abiraterone (HR=0.81, p 0.034). The median rPFS is a clinically meaningful 7.5 months longer in the capivasertib + abiraterone arm, over the placebo + abiraterone arm of 25.7 months. Figure 3 shows the Kaplan- Meier curve for rPFS by investigator assessment. Therefore, capivasertib + abiraterone represents a potential first-in-class treatment for patients with PTEN deficient de novo mHSPC.

[0218] The control arm median rPFS was shorter in comparison with the non-biomarker selective LATITUDE study with abiraterone in mHSPC, demonstrating the marked impact of PTEN deficiency on prognosis and highlighting the unmet need in this patient population.

[0219] A reduced effect was observed in rPFS by BICR data (HR=0.86, nominal p>0.05). rPFS by BICR data had lower maturity than rPFS by investigator assessment. Figure 4 shows the Kaplan-Meier curve for rPFS by BICR.

[0220] Broadly consistent rPFS results were observed across clinically relevant subgroups.

[0221] The rPFS data is presented in the tables below, and Figures 5 to 9 show subgroup forest plots for rPFS by investigator assessment:Radiographic progression-free survival (rPFS):Radiographic Progression Free Survival, Investigator Assessment Subgroup Analyses (Patients with unknown subgroup status are not included in the table):Capi = capivasertib; abi = abirateroneSensitivity analyses of rPFS by Investigator

[0222] rPFS sensitivity analyses shown in the table below appear consistent with primary rPFS analysis:[a] Analysis was performed using mid-point between time of progression and previous evaluable assessment (RECIST 1.1 or PCWG3). For patients whose death was used as the rPFS event, the date of death is used.[b] Analysis was performed using the actual rPFS event times, rather than the censored times, for patients who progressed or died (in the absence of progression) following 2 or more missed visits. In addition, patients who take subsequent therapy prior to progression or death are censored at their last evaluable assessment prior to taking subsequent therapy.[c] Patients with confirmed / suspected COVID-19 deaths are censored at their last evaluable assessment prior to death.Overall Survival and Secondary Endpoints

[0223] At interim analysis, overall survival data is relatively immature (approximately 27% maturity), but showed overall survival was numerically greater for the capivasertib + abiraterone arm compared with the placebo + abiraterone arm (HR=0.90, p=0.401). A Kaplan-Meier curve showing interim Overall Survival data is shown in Figure 10.

[0224] Other secondary endpoints are relatively immature with numerically consistent treatment effects:Capi = capivasertib; abi = abirateroneExposure and Safety

[0225] Based on the high-level results, the overall safety profile of capivasertib appears broadly consistent with its known profile (based on data in breast cancer population in combination with fulvestrant), and show capivasertib + abiraterone has a manageable safety profile.

[0226] Treatment durations were similar overall between arms but there were increased discontinuations of capi due to adverse events (Actual treatment duration capivasertib vs placebo, median 12.06 vs 14.65 months, median percentage intended dose (PID) 96.5 vs 100%).

[0227] Grade >3 AEs more common with capivasertib (67.0% vs 40.4%). Grade 5 AEs were 7.2% vs 5.2%, no potential signal. Discontinuations of capivasertib due to any AE frequency was <20% (18.3 vs 4.8%).

[0228] No marked impact on abiraterone safety profile was observed (actual treatment duration abiraterone, median 14.46 vs 14.72 months, median PID 99.8 vs 100%; AE leading to discontinuation of abiraterone 9.5% vs 5.4%).

[0229] Adverse events in any category:PTEN cut-off exploratory analyses

[0230] An exploratory analysis was performed to investigate rPFS and OS using different PTEN deficiency cut-offs. Deficiency is the specified % of viable malignant cells with no specific cytoplasmic PTEN staining using the VENTANA PTEN (SP218) IHC assay. The results for the rPFS and OS endpoints are shown in the following table:Capi = capivasertib; abi = abiraterone; Pbo = placebo

[0231] The safety profile was similar across different PTEN cut-off subgroups. rPFS maturity was consistent across the overall trial (39%) and different PTEN cut-off subgroups (40-41%).

[0232] Further analysis of the TFST, SSE-FS, TTCR, PFS2 and time to PSA progression endpoints using different PTEN deficiency cut-offs was conducted. Deficiency is the specified % of viable malignant cells with no specific cytoplasmic PTEN staining using the VENTANAPTEN (SP218) IHC assay. The results are shown in the following tables:Capi = capivasertib; abi = abiraterone; Pbo = placebo

[0233] The results show a trend of increased treatment benefit with capivasertib + abiraterone in higher PTEN cut-off subgroups, and increasingly poorer outcomes for patients receiving placebo + abiraterone.

Claims

CLAIMS1. A method of treating PTEN-deficient metastatic hormone-sensitive prostate cancer (mHSPC) in a patient in need thereof, the method comprising administering to the patient a combination comprising capivasertib or a pharmaceutically acceptable salt thereof; and abiraterone or an ester prodrug thereof, or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the method extends radiographic progression-free survival (rPFS) in the patient.

3. The method of claim 1 or claim 2, wherein the method extends overall survival (OS) in the patient.

4. The method of any one of the preceding claims, wherein the method extends (a) time to first subsequent therapy (TFST), (b) PFS2, (c) time to PSA progression, (d) symptomatic skeletal event-free survival (SSE-FS), (e) time to castration resistance (TTCR), and / or (f) time to pain progression (TTPP) in the patient.

5. A method of extending radiographic progress! on -free survival (rPFS) in a patient with PTEN-deficient metastatic hormone-sensitive prostate cancer (mHSPC), the method comprising administering to the patient a combination comprising capivasertib or a pharmaceutically acceptable salt thereof; and abiraterone or an ester prodrug thereof, or a pharmaceutically acceptable salt thereof.

6. The method of claim 2 or claim 5, wherein the rPFS is extended by at least 6 months relative to administration of abiraterone alone.

7. The method of claim 2 or claim 5, wherein the rPFS is extended relative to administration of abiraterone alone with a hazard ratio of <0.82.

8. A method of extending overall survival (OS) in a patient with PTEN-deficient metastatic hormone-sensitive prostate cancer (mHSPC), the method comprising administering to the patient a combination comprising capivasertib or a pharmaceutically acceptable salt thereof; and abiraterone or an ester prodrug thereof, or a pharmaceutically acceptable salt thereof.

9. The method of claim 3 or claim 8, wherein the OS is extended relative to administration of abiraterone alone.

10. The method of claim 3 or claim 8, wherein the OS is extended relative to administration of abiraterone alone with a hazard ratio of <1, such as <0.95.

11. A method of extending (a) time to first subsequent therapy (TFST), (b) PFS2, (c) time to PSA progression, (d) symptomatic skeletal event-free survival (SSE-FS), (e) time to castration resistance (TTCR), and / or (f) time to pain progression (TTPP) in a patient with PTEN-deficient metastatic hormone-sensitive prostate cancer (mHSPC), the method comprising administering to the patient capivasertib or a pharmaceutically acceptable salt thereof; and abiraterone or an ester prodrug thereof, or a pharmaceutically acceptable salt thereof.

12. The method of any one of the preceding claims, wherein the PTEN-deficient mHSPC is PTEN-deficient de novo mHSPC.

13. The method of any one of the preceding claims, wherein a sample of the PTEN-deficient mHSPC tumour tissue has >90% of viable malignant cells with no specific cytoplasmic PTEN staining in a PTEN IHC test.

14. The method of any one of claims 1 to 12, wherein a sample of the PTEN-deficient mHSPC tumour tissue has >95%, such as >99%, of viable malignant cells with no specific cytoplasmic PTEN staining in a PTEN IHC test.

15. The method of any one of the preceding claims, wherein capivasertib or a pharmaceutically acceptable salt thereof is orally administered at a dose of 400 mg twice daily on an intermittent weekly schedule of 4 days on followed by 3 days off.

16. The method of any one of claims 1 to 14, wherein capivasertib or a pharmaceutically acceptable salt thereof is orally administered at a dose of 320 mg twice daily on an intermittent weekly schedule of 4 days on followed by 3 days off, or 200 mg twice daily on an intermittent weekly schedule of 4 days on followed by 3 days off.

17. The method of any one of the preceding claims, wherein the capivasertib or a pharmaceutically acceptable salt thereof is capivasertib.

18. The method of any one of the preceding claims, wherein the abiraterone or an ester prodrug thereof, or a pharmaceutically acceptable salt thereof is abiraterone acetate.

19. The method of any one of the preceding claims, comprising oral administration of 1000 mg abiraterone acetate once daily.

20. The method of any one of claims 1 to 18, comprising oral administration of 250 mg, 500 mg or 750 mg abiraterone acetate once daily.

21. The method of any one of the preceding claims, further comprising administration of a glucocorticoid to the patient.

22. The method of claim 21, wherein the glucocorticoid is selected from prednisone and prednisolone.

23. The method of claim 22, wherein the prednisone or prednisolone is orally administered at a dose of 5 mg once daily.

24. The method of any one of claims 1 to 14, comprising oral administration of capivasertib at a dose of 400 mg twice daily on an intermittent weekly schedule of 4 days on followed by 3 days off, oral administration of abiraterone acetate at a dose of 1000 mg once daily, and oral administration of prednisone or prednisolone at a dose of 5 mg once daily.

25. The method of any one of the preceding claims, further comprising administration of androgen deprivation therapy (ADT) to the patient.

26. The method of claim 25, wherein the ADT comprises performing bilateral orchiectomy on the patient or administration of a luteinizing hormone-releasing hormone (LHRH) agonist or a luteinizing hormone-releasing hormone (LHRH) antagonist.

27. The method of claim 25, wherein the ADT is selected from administration of a LHRH agonist or a LHRH antagonist.

28. Capivasertib or a pharmaceutically acceptable salt thereof for use in the method of any one of the previous claims.

29. Use of capivasertib or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the method of any one of claims 1 to 27.

30. A kit comprising: (a) capivasertib or a pharmaceutically acceptable salt thereof, and (b) instructions for use of the capivasertib or a pharmaceutically acceptable salt thereof in the method of any one of claims 1 to 27.

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