Phase II investigation of a PARP inhibitor (olaparib) in castration resistant prostate cancer (CRPC) which incorporates the possibility that treatment effect may be restricted to biomarker defined subgroups

Abstract

The objective was to undertake a phase II trial (TO-PARP) to identify the best CRPC patient group(s) to be studied for sensitivity to olaparib in a phase III trial. A multistage phase II design has been adopted which has a non-randomised component with response as the primary endpoint followed by a randomised component with overall survival as the primary endpoint. Non-randomised component : This allows early progression to a randomised comparison if there is evidence of a high response rate (50% or more) in unselected patients. Biomarker defined groups are investigated for treatment sensitivity if the response rate is weaker than this. The first stage involves entry of 30 patients. If 50% or more respond then no more patients will be entered and the randomised component will be undertaken in unselected patients. If 2 (7%) or less respond then olaparib will be rejected. If between 3-14 (10%-47%) patients respond then a further 15 patients will be entered. Should 23 (51%) or more respond overall then the randomised component will be undertaken in unselected patients but if 5 (11%) or fewer respond then olaparib will be rejected. Otherwise with 6-22 responders (13%-49%), biomarker analysis of tissue collected from all 45 patients will be undertaken with the aim of identifying a sensitive subgroup, with a response rate which is compatible with a 50% response rate. If such a subgroup is found, a confirmatory single stage 44 patient trial will be undertaken in this group; this will also yield experience of prospective biomarker testing in a multi-centre clinical trial setting. Randomised component : a phase II assessment of the results generated in the non-randomised part, offering more secure evidence before proceeding to phase III. 180 patients will be randomised 2:1 to olaparib or an appropriate standard of care (? 1-sided 10%, power 80%).