The purpose of this study is to find out whether the new drug PX-866 will slow the growth of your prostate cancer. The investigators will also watch you carefully for any side effects that PX-866 might cause.

PX 866 is a new type of drug that inhibits a molecule related to cancer cell growth. While this molecule is also found in normal cells, it is much more active in some cancer cells, so inhibiting the molecule with PX-866 is hoped to slow the growth of cancer cells. Laboratory tests show that it may help slow the growth of prostate cancer in animals, but it is not known whether it will have the same effects in humans. PX-866 has been studied in some cancer patients to find out safe doses that can be given but it has not undergone study in prostate cancer. This study will be the first study of PX-866 in prostate cancer.

Health Canada has not approved the sale or use of PX-866 to treat prostate cancer, although they have approved its use in this clinical trial.

Inclusion Criteria:

• Patients must have a histological or cytological diagnosis of adenocarcinoma of the prostate.
• All patients must have formalin fixed paraffin embedded tissue (from their primary or metastatic tumour) available for translational studies.
• Presence of clinically and/or radiologically documented disease (measureable or non-measurable). All radiology studies must be performed within 28 days prior to registration (within 35 days if negative).
• Androgen ablation must include either medical or surgical castration. If the patient is receiving medical androgen ablation, a castrate level of testosterone (< 1.7 nmol/L) must be present.
• Patients must have metastatic or locally recurrent disease, for which no curative therapy exists and for which systemic therapy is indicated.
• No prior chemotherapy regimens for recurrent disease

For Part A, patients must have progression defined as:

PSA Progression: A rising PSA, while receiving androgen ablative therapy, with 2 subsequent rises over a reference value (not necessarily consecutively), measured a minimum of one week apart. The PSA that confirms progression must have a value of ≥ 5 ng/ml and must be performed no longer than 7 days prior to trial registration.

OR Radiological Progression: defined as the development of new metastatic lesions with a stable or rising PSA.

Patients entered to Part B of the study (after 2nd stage of accrual completed) must have a rise in their PSA while on abiraterone/prednisone continuing at time of registration (≥ 25% higher from baseline or nadir, whichever is lowest).

• The PSA must be ≥5 ng/ml at the time of study entry.
• ECOG performance of 0, 1 or 2.
• Age ≥ 18 years of age.

Previous therapy:

Surgery:

Previous major surgery is permitted provided that it has been at least 14 days prior to patient registration and that wound healing has occurred.

Hormonal Therapy:

Prior hormone therapy is required. Patients must be hormone refractory and have discontinued anti-androgens for at least 4 weeks prior to study entry (at least 6 weeks for bicalutamide). Therapy with LHRH agonist must continue for those prostate cancer patients already receiving this treatment at the time of enrollment. If the patient has discontinued the LHRH agonist, this must be restarted (if not surgically castrated) and the castrate level of testosterone must be present. Prior therapy with CYP17 inhibitors (e.g. abiraterone, ketoconazole) or novel anti-androgens (e.g. MDV3100) is permitted.

Part B: Patients must be hormone refractory and have discontinued anti-androgens for at least 4 weeks prior to study entry (at least 6 weeks for bicalutamide). Therapy with LHRH agonist must continue for those prostate cancer patients already receiving this treatment at the time of enrollment. If the patient has discontinued the LHRH agonist, this must be restarted (if not surgically castrated) and the castrate level of testosterone must be present. All patients must currently be receiving abiraterone.

Radiation:

Prior external beam radiation is permitted provided a minimum of 2 weeks has elapsed between the last dose and enrollment to the trial. Exceptions may be made for low dose, non-myelosuppressive radiotherapy after consultation with NCIC CTG. Prior strontium is not permitted.

- Laboratory Requirements (must be done within 7 days prior to registration)

Hematology:

Granulocytes (AGC) ≥ 1.5 x 10^9/L Platelets ≥ 100 x 10^9/L

Biochemistry:

Serum creatinine ≤ 1.5 x UNL Total bilirubin ≤ 1.5 x UNL ALT and AST ≤ 1.5 x UNL Glucose ≤ 8.9 mmol/L (≤ Grade 1) PSA ≥ 5ng/mL

-Patient consent must be appropriately obtained in accordance with applicable local and regulatory requirements. Each patient must sign a consent form prior to enrollment in the trial to document their willingness to participate.

Patients who cannot give informed consent (i.e. mentally incompetent patients, or those physically incapacitated such as comatose patients) are not to be recruited into the study. Patients competent but physically unable to sign the consent form may have the document signed by their nearest relative or legal guardian. Each patient will be provided with a full explanation of the study before consent is requested.

• Patients must be accessible for treatment and follow-up. Patients registered on this trial must be treated and followed at the participating centre. This implies there must be reasonable geographical limits (for example: 2 hour's driving distance) placed on patients being considered for this trial. Investigators must assure themselves that the patients registered on this trial will be available for complete documentation of the treatment, adverse events, response assessment and follow-up.
• In accordance with NCIC CTG policy, protocol treatment is to begin within 5 working days of patient registration.

Exclusion Criteria:

• Patients with a history of other malignancies, except for adequately treated non-melanoma skin cancer or solid tumours curatively treated with no evidence of disease for >=3 years.
• Known HIV-positive patients.
• Uncontrolled diabetes mellitus.
• Patients with upper gastrointestinal or other conditions that would preclude compliance or absorption of oral medication are not eligible.
• Patients with active or uncontrolled infections, or with serious illnesses or medical conditions which would not permit the patient to be managed according to the protocol.
• Patients are not eligible if they have a known hypersensitivity to the study drug(s) or their components.
• Patients with history of central nervous system metastases or untreated spinal cord compression.
• Patients who have had prior treatment with a PI3 kinase inhibitor.
• Men who are not sterile unless they use an adequate method of birth control.
• Patients enrolled to Part B must be suitable for continued therapy with abiraterone/prednisone.

All patients enrolled in this study

6 months