MAdCaP: MDM2 inhibition and Abiraterone in Carcinoma of the Prostate

INTERVENTION: Phase I After a single dose pharmacokinetic (PK) study on day 7 of cycle 1 patients will commence combination treatment on day 1 of cycle 1 and will continue on treatment until confirmed disease progression, intolerable toxicity or withdrawal. Prednisolone will continue until the final dose of abiraterone. Prednisolone may be continued or tapered off and stopped after this, off study, at the investigator?s discretion. Phase II Patients will be randomized in a 1:1 ratio to either the control arm (Arm A) or experimental arm (Arm B). The study will be double‐blinded. Control Arm A: 1. Abiraterone (1000mg PO daily, days 1 ‐ 28) 2. Prednisolone (5mg PO twice daily, days 1‐ 28) 3. Placebo (PO twice daily, days 1 ? 5). A cycle length is 28 days. Upon confirmed radiological progression, patients will be permitted to continue abiraterone and add in open label RO5503781 (days 1 ? 5) until further progression (defined by PSA). Experimental Arm B: 1. Abiraterone (1000mg PO daily, days 1 ‐ 28) 2. Prednisolone (5mg PO twice daily, days 1‐ 28) 3. RO5503781 (PO twice daily, days 1 ? 5). A cycle length is 28 days. Patients will commence treatment on day 1 and will continue on treatment until confirmed disease progression, intolerable toxicity or withdrawal. Prednisolone will continue until the final dose of abiraterone. Prednisolone may be continued or tapered off and stopped after this, off study, at the investigator's discretion. CONDITION: Prostate cancer ; Cancer ; Malignant neoplasm of prostate PRIMARY OUTCOME: Radiological progression free survival [as per Prostate Cancer Working Group (2) (PCWG2)]; Patients will have CT and bone scans at baseline then every 8 weeks for the first 24 weeks, thereafter every 12 weeks until progression is confirmed. Progression‐free survival will be measured from the date of randomisation to the date of progression or date of death (any cause) for those who do not progress. SECONDARY OUTCOME: 1. Prostate‐specific antigen (PSA) response rate will be the proportion of patients achieving >50% drop in PSA for greater than 4 weeks. Patients will have PSA measured every 4 weeks.; 2. Radiological response rate will be as per RECIST 1.1 for those patients with measurable disease at baseline.; 3. For patients crossing over from placebo, PSA response rate will be the proportion of patients achieving >50% reduction in PSA from the point of cross over for > 4weeks; 4. Biochemical and radiological PFS will be defined as the time from randomisation until the either PSA progression or radiological progression, (both as defined in PCWG2) or death (any cause) for patients who do not progress.; 5. Pharmacokinetics (PK) of RO5503781 with and without abiraterone (phase I only); 6. Pharmacokinetics of abiraterone with and without RO5503781 (phase I only); 7. Pharmacokinetics of abiraterone in combination with RO5503781; Pharmacokinetics samples will be taken in the dose escalation phase of the study to explore the PK of both drugs alone and in combination. INCLUSION CRITERIA: 1. Histologically proven adenocarcinoma of the prostate with documented metastases (where the metastatic lesions are confined to 1 or 2 lesions on a bone scan. These must be confirmed by a second modality (e.g. CT, MRI or biopsy). 2. Availability of archival tumour samples. Where patients are willing to undergo a biopsy as part of the study, these specimens may be used as an alternative where no archival specimen is available. 3. Proven disease progression since last change in therapy defined by at least one of the following: 3.1. Prostate‐specific antigen (PSA) progression. This must be based on a series of at least three successively increasing readings each taken at least 7 days apart. The 3rd reading must be >= 2ng/ml. In the event where an intermediate reading is lower than a previous reading, then the patient will still be eligible (i.e. the three readings do not need to be consecutive). The first of the three readings must have been obtained after co