Title: CRUK/11/029: TO-PARP: Trial of Olaparib in Patients with Advanced Castration Resistant Prostate Cancer
Funder: Cancer Research UK

Abstract: Background: Prostate cancer is the second commonest cause of male cancer-mortality in the UK_x000D_ with a third of patients developing advanced disease. This initially responds to androgen deprivation,_x000D_ but invariably progresses to a terminal, castration-resistant phase. Docetaxel is the mainstay of_x000D_ treatment for patients with metastatic castrate-resistant prostate cancer (mCRPC) but only 40-45%_x000D_ of patients have taxane sensitive disease and the survival benefit from this treatment is modest._x000D_ Recently, cabazitaxel also demonstrated a survival advantage in the post-docetaxel setting [1]._x000D_ Nevertheless, effective therapeutic options that offer sustained responses and clinical benefit for_x000D_ mCRPC patients remain an important area of unmet medical need._x000D_ _x000D_ Prostate cancer is a clinically and molecularly heterogeneous disease. Improved understanding of_x000D_ the biological and clinical significance of the molecular sub-classification of this disease could_x000D_ positively impact treatment outcomes through molecular stratification in clinical trials. Such_x000D_ stratification may prevent costly Phase III trial failure. One such classification could be based on loss_x000D_ of PTEN. PTEN is a tumour suppressor gene implicated in DNA repair by homologous_x000D_ recombination (HR). More than 50% of mCRPC patients present with a loss of PTEN function._x000D_ Recent studies indicate that many prostate cancers with PTEN loss also have BRCA1 loss [2]._x000D_ PTEN loss is associated with more advanced and higher grade tumours and a worse outcome. If_x000D_ PTEN deficient mCRPC harbours an HR DNA repair defect, it may be treatable by poly(ADP)-ribose_x000D_ polymerase inhibitors (PARPi). Olaparib is a potent inhibitor of PARP in clinical development._x000D_ _x000D_ Aims and objectives: We hypothesise that a proportion of mCRPC have defects in HR DNA repair_x000D_ and will benefit from olaparib treatment, and that predictive biomarkers can be identified to define_x000D_ this patient population. The aims and objectives of this trial are therefore:_x000D_ 1) To evaluate the antitumour activity of olaparib in mCRPC._x000D_ 2) To identify predictive biomarkers of HR repair deficiency for mCRPC._x000D_ _x000D_ Methods: Parts A is a single-arm, two-stage phase II trial to evaluate the anti-tumour activity of_x000D_ olaparib in unselected CRPC patients and allow the development of predictive biomarkers of_x000D_ response. Part B is a single-arm, single-stage evaluation of olaparib in patients preselected on the_x000D_ basis of putative biomarkers of HR deficiency identified in Part A. The primary endpoint in both parts_x000D_ is response rate (PSA decline of > 50% according to PSAWG II criteria and/or partial or complete_x000D_ response according to RECIST)._x000D_ _x000D_ Use of Results: Results will inform a subsequent mCRPC randomised-controlled trial of olaparib_x000D_ versus standard of care with overall survival as the primary endpoint, undertaken in either an_x000D_ unselected or pre-selected mCRPC population based on the findings of this study.


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS