Volume 12 Supplement 1

Clinical Trials Methodology Conference 2011

Open Access

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

  • Roger A’Hern1,
  • Johann DeBono2,
  • Shahneen Sandhu2,
  • Eletheria Kalaitzaki1,
  • Martine Usdin1 and
  • Emma E Hall1
Trials201112(Suppl 1):A88

https://doi.org/10.1186/1745-6215-12-S1-A88

Published: 13 December 2011

Objective

To undertake a phase II trial to identify the best CRPC patient group(s) to be studied for sensitivity to olaparib in a randomised, controlled phase III trial.

Methods

The TO-PARP trial has a multistage phase II design consisting of 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 part of the trial design allows rapid progression to a randomised comparison if there is evidence of a high response rate (50% or more) in unselected patients. If the evidence for a high response rate in unselected patients is weak, biomarker defined groups will be investigated for their sensitivity to olaparib.

The first stage will include 30 CRPC patients. If 15 (50%) or more respond then no more patients will be entered and the randomised component will be undertaken in unselected patients. Should 2 (7%) or fewer 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 and 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. This will aim to identify a sensitive subgroup, with a response rate which is compatible with a 50% response rate, warranting further assessment in the randomised component. If such a subgroup is found, a confirmatory single stage 44 patient trial will be undertaken in this subgroup; this will also serve to pilot prospective biomarker testing in a multi-centre clinical trial setting.

Randomised component : This is a phase II controlled, definitive endpoint assessment of the results generated in the non-randomised part, offering a more secure foundation for efficacy before proceeding to phase III. 180 patients will be randomised 2:1 to olaparib or an appropriate standard of care (α 1-sided 10%, power 80%).

Conclusions

Randomised phase II trials are the gold standard to establish a basis for treatment efficacy but only a subset of patients may be sensitive to a new therapy. This possibility was incorporated into the design of the TO-PARP trial by introducing a non-randomised initial component with the potential to identify a sensitive subgroup.

Authors’ Affiliations

(1)
Clinical Trials and Statistics Unit, Institute of Cancer Research
(2)
Department of Experimental Cancer Medicine, Institute of Cancer Research

Copyright

© A’Hern et al; licensee BioMed Central Ltd. 2011

This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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