This phase I trial is evaluating the drug GSK525762 in combination with androgen deprivation therapy and three other drugs (abiraterone, enzalutamide and prednisone) for the treatment of castrate-resistant prostate cancer (CRPC)A Phase IB Open-label, Dose Escalation and Expansion Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics and Clinical Activity of GSK525762 in Combination With Androgen Deprivation Therapy and Other Agents in Subjects With Castrate-resistant Prostate Cancer (CRPC)

Inclusion

• Written informed consent provided.
• Males >=18 years of age (at the time written consent is obtained for screening).
• Histologically confirmed adenocarcinoma of the prostate: screening and on-treatment biopsy is mandatory. If adequate number of paired biopsy samples are collected (>=20 paired samples for each dose level in each Arm, unless an Arm is closed early), then further biopsy sampling will be considered based on available data; screening biopsy can be waived if participant had a recent biopsy after failure of the most recent therapy (within 30 days) and the biopsy sample is secured to be sent as screening biopsy for this study.
• Surgically or medically castrated, with testosterone levels of less than or equal to (<=)50 nanograms per deciliter (ng/dL) (<2.0 nanometer [nM]). If the participant is being treated with luteinizing hormone-releasing hormone (LHRH) agonists/antagonists (participant who have not undergone orchiectomy) this therapy must have been initiated at least 4 weeks prior to Week 1 Day 1 and must be continued throughout the study.

• Participants must have failed prior therapy with abiraterone, enzalutamide, or both:

  1. Has completed at least 12 weeks of prior continuous therapy with abiraterone or enzalutamide in any prior line.
  2. Lead-in dosing period for enzalutamide only will be required under the following circumstance:

  (i) If the participant has enzalutamide discontinuation for >7 days prior to dosing start with GSK525762 plus enzalutamide on trial, then a enzalutamide only lead-in dosing of 28 days is required.

(ii) If the participant has enzalutamide discontinuation for <=7 days prior to dosing start with GSK525762 plus enzalutamide on trial, then an enzalutamide only lead-in dosing of 14 days is required.

(iii) If the participant is on continuous dosing with enzalutamide prior to dosing start with GSK525762 plus enzalutamide on trial, then participant can start on combined dosing at end of screening period.

(c) Lead-in dosing period for abiraterone only will be required: if the participant has abiraterone discontinuation for more than 3 days prior to dosing start with GSK525762 plus abiraterone on trial, then abiraterone only lead-in dosing of 7 days is required.

• One to two line(s) of prior taxane-based chemotherapy allowed. If docetaxel chemotherapy is used more than once, this will be considered as one regimen. Participants who have not received prior chemotherapy in any setting will qualify for study if they are ineligible for or refuse chemotherapy.

• Documented prostate cancer progression as assessed by the investigator with one of the following:

  1. PSA progression defined by a minimum of 3 rising PSA levels with an interval of >=1 week between each determination. The PSA value at screening must be >=5 microgram (µg)/Liter (L) (5 ng/mL) if PSA is the only indication of progression; participants on systemic glucocorticoids for control of symptoms must have documented PSA progression by PCWG3 while on systemic glucocorticoids prior to commencing Week 1 Day 1 treatment.
  2. Radiographic progression of soft tissue disease by PCWG3-modified RECIST 1.1 criteria or bone metastasis with 2 or more documented new bone lesions on a bone scan with or without PSA progression.
• ECOG performance status of 0 or 1.
• Life expectancy >12 weeks.
• Able to swallow and retain orally administered medication.
• Must have adequate organ function.
• Male participants are eligible to participate if they agree to use contraceptive methods.