TOPARP
Research type
Research Study
Full title
TOPARP: Phase II Trial of Olaparib in Patients with Advanced Castration Resistant Prostate Cancer.
IRAS ID
76882
Contact name
Johann De Bono
Sponsor organisation
Institute of Cancer Research
Eudract number
2011-000601-49
ISRCTN Number
n/a
Research summary
Prostate cancer is the second commonest cause of male cancer death in the UK with a third of patients developing advanced disease. This initially responds to treatment called androgen deprivation, but invariably progresses to a terminal phase, called castration-resistant. Docetaxel is the mainstay of treatment for patients with metastatic castrate-resistant prostate cancer (mCRPC) but only 40-45% of patients have a survival benefit from this treatment. Thus, effective therapeutic options that offer sustained responses and clinical benefit for mCRPC patients remain an important area of unmet medical need. Prostate cancer is a clinically and molecularly heterogeneous disease. Improved understanding of the biological and clinical significance of the molecular sub-classification of this disease could positively impact treatment outcomes by allowing doctors to target the most appropriate therapy for patients. We hypothesise that a proportion of mCRPC have defects in a form of DNA repair. The drug olaparib has shown activity in other cancer types that have this DNA repair deficit and we are testing whether mCRPC patients also will benefit from olaparib treatment. We also hope that predictive biomarkers can be identified to define this patient population. The aims and objectives of this trial are therefore:1) To evaluate the antitumour activity of olaparib in mCRPC. 2) To identify predictive biomarkers of HR repair deficiency for mCRPC. To do this, we have developed a novel trial designed to test the benefit of the drug while looking for molecular predictors of clinical response.
Lay Summary of Results
TOPARP-B was a clinical trial in advanced castration resistant prostate cancer. This study aimed to see if giving olaparib helps men with prostate cancer that has got worse, despite treatment with hormone therapy and chemotherapy drugs. The study also looked at whether some men are more likely to benefit from olaparib than others based on genetic changes within their cancer cells. The results ofTOPARP-B have now been published in The Lancet Oncology medical journal. Here we summarise these results. We have also included a link to the publication at the end of this document in case you would like to read the results in more detail. The published results describe the two groups of participants who cannot be identified personally in any of the publications. Background After a patient agreed to take part in TOPARP-B they would have joined one of two dose groups to receive either: • Higher dose:400mg of olaparib twice a day OR • Lower dose: 300mg of olaparib twice a day Trial participation 98men joined the trial between April 2015 and August 2018 from 17 NHS hospitals across the UK. 49men were in each of the two olaparib dose groups. The results: How well did Olaparib work in advanced prostate cancer? We found that olaparib did have anti-tumour effects in men with advanced prostate cancer. We could assess response to olaparib in 92 patients. Overall, 43 men (47%) showed a response to olaparib and olaparib stopped the cancer starting to grow again by an average of 5.5months. The response to olaparib was stronger for those patients who received the higher dose: • 25patients (54%) showed a response with the higher dose • 18 patients (39%) showed a response with the lower dose Did olaparib work better for some patients compared to others? The response to olaparib was different depending on the type of genetic change that was present in the patient’s cancer. The best response was seen in men with cancers that had BRCA mutations, which are genetic changes specifically within the BRCA gene that means cells are less able to protect themselves against cancer. Over 80% of men with cancer that had BRCA mutations responded to olaparib treatment. However, men who had cancers with other genetic changes also benefitted from olaparib. Did the treatments have side effects? We found that half of the study participants experienced a serious symptom or side-effect. The most common side-effect of olaparib was anaemia (low blood iron levels), which was reported by 68 patients overall: 31 patients (64%) in the lower dose group and 37 patients (76%) in the higher dose group. Anaemia was considered serious for 33 patients: 15 patients (31%) in the lower dose group and 18 patients (37%) in the higher dose group. More side-effects were reported for participants who received a higher dose of olaparib than those who received a lower dose. This led to18 patients (37%) on the higher dose of olaparib reducing their dose, mainly due to anaemia. The drug used in TOPARP-B is already used to help people with ovarian or breast cancer, and is being tested in other cancer trials. The side-effects reported in TOPARP-B were the same as those previously reported for olaparib and other similar drugs. What do these results mean? We have confirmed that olaparib is beneficial for men with advanced prostate cancer and particular genetic changes. These results support routine testing of genetic changes in advanced prostate cancer in order to identify men who are likely to respond better to olaparib. What will happen now? We hope that the results from TOPARP-B will lead to a change in the diagnosis and treatment for men with advanced prostate cancer. Results of this trial have already supported the Food and Drug Administration (FDA) and European Commission approval ofolaparib for prostate cancer patients with specific genetic changes. In the United Kingdom, the National Institute for Health and Care Excellence (NICE) are currently reviewing olaparib for this patient group. We are continuing to look at the data collected in TOPARP-B, especially around the less common genetic changes, to understand more about the response to olaparib. We would like to thank everyone involved in the TOPARP trial, especially the participants without whom this study would not have been possible. Publication in The Lancet Oncology medical journal: https://doi.org/10.1016/S1470-2045(19)30684-9
REC name
London - Surrey Borders Research Ethics Committee
REC reference
11/LO/2019
Date of REC Opinion
29 Dec 2011
REC opinion
Favourable Opinion