A Single-Arm Phase II Study of Neoadjuvant Intensified Androgen Deprivation (Leuprolide and Abiraterone Acetate) in Combination With AKT Inhibition (Capivasertib) for High-Risk Localized Prostate Cancer With PTEN Loss

Inclusion Criteria:

1. Informed Consent: provision of signed informed consent, which includes compliancewith the requirements and restrictions listed in the informed consent form (ICF) andin this protocol.

2. Age greater than or equal to 18 years. Members of all races and ethnic groups willbe included.

3. Participants must have histologically confirmed non-metastatic adenocarcinoma of theprostate

4. (a) Any one of the following three high risk features:

• Gleason sum >7 (ISUP Grade Group >3)

• Clinical stage T3 (resectable), per AJCC Cancer Staging Manual, 8th ed.

• PSA > 20 ng/ml oSubjects who meet high risk criteria solely by PSA (i.e., stage <T3 AND Gleason sum less than or equal to 7) must have a progression-freeprobability after radical prostatectomy that is less than or equal to 50% at 5years as estimated by the Memorial Sloan Kettering (MSK) pre-radicalprostatectomy nomogram: https://www.mskcc.org/nomograms/prostate/pre_op (b)Subjects not meeting high risk criteria that have the following combination maybe screened for inclusion:

• Gleason score 4+3=7 (ISUP Grade Group 3) AND

• Estimated progression-free probability after radical prostatectomy that is lessthan or equal to 50% at 5 years by MSK nomogram

5. No definitive evidence of metastasis on nuclear bone scan (required on all subjects)

6. No evidence of lymph nodes > 2 cm in diameter on pelvic CT scan (scan only requiredin patients with a PSA > 20 ng/ml)

7. Prostatectomy with extended lymph node dissection planned as primary therapy.

• The subject had a discussion with a clinician about other options, such asradiotherapy, and elected to undergo surgical treatment.

• The subject has been offered consultation with radiation oncology and declinedconsultation or radiation treatment, or determined it was not in best medicalinterest

8. Be willing to provide tissue from a diagnostic biopsy core or excisional biopsy of atumor lesion obtained up to 6 months/180 days prior to initiation of treatment onDay 1. Subjects for whom samples cannot be provided (e.g., inaccessible or subjectsafety concern) may submit an older archived specimen only upon agreement from theSponsor-Investigator.

9. Tumor tissue must be provided for biomarker analysis. PTEN IHC staining must be lessthan or equal to 10% as determined by the central lab. If insufficient tumor tissuecontent is provided for analysis, acquisition of additional archived tumor tissue (block and /or slides) for the biomarker analysis is required.

10. Have a performance status of 0 or 1 on the ECOG Performance Scale with nodeterioration over the previous 2 weeks prior to baseline or day of first dosing.

11. Life expectancy of greater than 10 years per the treating physician.

12. Minimum body weight of 45 kg with minimum Body Mass Index (BMI) of 18.5

13. Non-sterile men who are not totally sexually abstinent (i.e., refraining fromheterosexual intercourse during the entire period of risk associated with studyinterventions) and intend to be sexually active with a women of childbearingpotential partner must use a condom upon entering the study and until 16 weeks afterthe last dose of capivasertib. Contraception should be considered in females'partners of men taking capivasertib who are of childbearing potential

14. Able and willing to swallow and retain oral medication

15. Demonstrate adequate organ function as defined by laboratory parameters includingANC, platelets, hemoglobin, transaminases, albumin, hemoglobin A1C, CrCl or eGFR,PTT and INR (unless anticoagulated, then therapeutic range is acceptable). Allscreening labs should be performed within 30 days of treatment initiation

Exclusion Criteria:

1. As judged by the investigator, any evidence of diseases (such as severe oruncontrolled systemic diseases, including uncontrolled hypertension, renaltransplant and active bleeding diseases, uncontrolled pulmonary, renal, or hepaticdysfunction, uncontrolled infection, cardiac disease) which, in the investigator'sopinion, makes it undesirable for the participant to participate in the study orthat would jeopardize compliance with the protocol.

2. Any other disease, physical examination finding, or clinical laboratory findingthat, in the investigator's opinion, gives reasonable suspicion of a disease orcondition that contraindicates the use of an investigational drug, may affect theinterpretation of the results, render the patient at high risk from treatmentcomplications or interferes with obtaining informed consent.

3. Known to have active hepatitis infection, positive hepatitis C antibody, hepatitis Bvirus surface antigen or hepatitis B virus core antibody, at screening. Known tohave human immunodeficiency virus (HIV) with a CD4+ T-cell count < 350 cells/uL or ahistory of an acquired immunodeficiency syndrome (AIDS)-defining opportunisticinfection within the past 12 months. Known to have active tuberculosis infection (clinical evaluation that may include clinical history, physical examination andradiographic findings, or tuberculosis testing in line with local practice). Known history of drug or alcohol abuse within 6 months of screening.

4. Prior prostate cancer treatment including:

• Anti-androgen therapy including orchiectomy, LHRH therapy, abiraterone,ketoconazole, estrogen therapy (Short-term ADT allowed, less than or equal to 2months)

• Radiation (external beam or brachytherapy)

• Cytotoxic chemotherapy

• Focal or ablative therapy

• Any experimental therapy for treatment of prostate cancer.

5. History of another primary malignancy except for malignancy treated with curativeintent with no known active disease greater than or equal to 5 years before thefirst dose of study intervention and of low potential risk for recurrence.Exceptions include basal cell carcinoma of the skin and squamous cell carcinoma ofthe skin that has undergone potentially curative therapy

6. Any of the following cardiac criteria:

• Mean resting corrected QT interval (QTc) > 470 msec obtained from 3 consecutiveECGs

• Any clinically important abnormalities in rhythm, conduction or morphology ofresting ECG (e.g., complete left bundle branch block, third-degree heart block)

• Medical history significant for arrhythmia (e.g., multifocal prematureventricular contractions, bigeminy, trigeminy, ventricular tachycardia), whichis symptomatic or requires treatment (CTCAE Grade 3), symptomatic oruncontrolled atrial fibrillation despite treatment, or asymptomatic sustainedventricular tachycardia. Participants with atrial fibrillation controlled bymedication or arrhythmias controlled by pacemakers may be permitted to enterthe study

• Any factors that increase the risk of QTc prolongation or risk of arrhythmicevents such as heart failure, hypokalemia, potential for torsades de pointes,congenital long QT syndrome, family history of long QT syndrome or unexplainedsudden death under 40 years of age, or any concomitant medication known toprolong the QT interval

• Clinically significant heart disease as evidenced by myocardial infarction, orarterial thrombotic events in the past 6 months, severe or unstable angina, orNYHA or Class II to IV heart failure or cardiac ejection fraction measurementof < 50%

• Experience of any of the following procedures or conditions in the preceding 6months: coronary artery bypass graft, angioplasty, vascular stent, myocardialinfarction, angina pectoris, congestive heart failure NYHA Grade less than orequal to 2

• Uncontrolled hypotension - systolic blood pressure (SBP) <90 mmHg and/ordiastolic blood pressure (DBP) <50 mmHg

• Uncontrolled hypertension (SBP greater than or equal to 160 mmHg or DBP greaterthan or equal to 95 mmHg).

• Cardiac ejection fraction outside institutional range of normal or <50% (whichever is higher) as measured by echocardiogram (or multiple-gatedacquisition [MUGA] scan if an echocardiogram cannot be performed or isinconclusive).

7. Clinically significant abnormalities of glucose metabolism as defined by any of thefollowing:

• Patients with diabetes mellitus type 1 or diabetes mellitus type 2 requiringinsulin treatment

• HbA1c greater than or equal to 8.0% (63.9 mmol/mol)

8. Refractory nausea and vomiting, chronic gastrointestinal disease, inability toswallow the formulated product, or previous significant bowel resection that wouldpreclude adequate absorption, distribution, metabolism, or excretion of capivasertiband abiraterone.

9. Has known psychiatric or substance abuse disorders that would interfere withcooperation with the requirements of the trial.

10. Previous allogeneic bone marrow transplant or solid organ transplant

11. Received major surgery within 6 weeks prior to screening, or significant traumaticinjury within 4 weeks of the first dose of study intervention or an anticipated needfor major surgery during the study except for prostatectomy; they must haverecovered adequately from the toxicity and/or complications from the interventionprior to starting therapy.

12. Is currently participating and receiving study therapy, or has participated in astudy of an investigational agent or study drugs within 30 days or 5 half-lives (whichever is longer) of the first dose of study treatment

13. Has had a prior anti-cancer monoclonal antibody (mAb) within 30 days prior to studyDay 1 or who has not recovered (i.e., less than or equal to Grade 1 or at baseline)from adverse events due to agents administered more than 30 days earlier.

14. Has had prior chemotherapy, immunotherapy, targeted small molecule therapy,immunosuppressant medication (other than corticosteroids), or radiation therapywithin 30 days prior to study Day 1, or who has not recovered (i.e., less than orequal to Grade 1 or at baseline) from adverse events due to a previouslyadministered agent. Note: Subjects with less than or equal to Grade 2 neuropathy are an exception tothis criterion and may qualify for the study if ECOG 0-1. Note: A longer washout may be required for drugs with a long half-life (e.g., 30days or 5 half-lives, whichever is longer)

15. Treatment with any of the following:

• Nitrosourea or mitomycin C within 6 weeks of the first dose of study treatment

• Potent inhibitors or inducers of CYP3A4 within 2 weeks before the start ofstudy treatment (3 weeks for St John's wort), or sensitive substrates ofCYP3A4, CYP2C9 and/or CYP2D6 with a narrow therapeutic window within 1 weekbefore the start of study treatment

• Drugs known to prolong the QT interval within 5 half-lives of the first dose ofstudy treatment

• Any concomitant medication that may interfere with abiraterone safety andefficacy based on the prescribing information of abiraterone and local clinicalguidelines

16. History of hypersensitivity to active or inactive excipients of capivasertib,abiraterone, or drugs with a similar chemical structure or class.

17. Any restriction or contraindication based on the local prescribing information thatwould prohibit the use of abiraterone and leuprolide.

18. Is unable to undergo research related biopsy as this is necessary to completetranslational study objectives.

19. Judgment by the investigator that the participant should not participate in thestudy if the participant is unlikely to comply with study procedures, restrictionsand requirements.