TRITON2: A Multicenter, Open-label Phase 2 Study of Rucaparib in mCRPC
Research type
Research Study
Full title
TRITON2: A Multicenter, Open-label Phase 2 Study of Rucaparib in Patients with Metastatic Castration-resistant Prostate Cancer Associated with Homologous Recombination Deficiency
IRAS ID
219516
Contact name
Elias Pintus
Contact email
Sponsor organisation
Clovis Oncology, Inc.
Eudract number
2016-003162-13
Clinicaltrials.gov Identifier
Clinicaltrials.gov Identifier
129,840, IND
Duration of Study in the UK
3 years, 4 months, 30 days
Research summary
Summary of Research
The purpose of this study is to find out if a drug called rucaparib is safe and effective in treating patients with prostate cancer who have a mutation in one of their DNA repair genes.Cells continuously need to repair their DNA to carry on living. Cells with a DNA repair gene mutation, including cancer cells, can still repair their DNA via alternatives routes but if these routes are also blocked, the cell dies. Rucaparib belongs to a class of drugs which may block this alternative route of repair, thereby causing the cancer cell to die.
The study will look at how patients respond to treatment through review of tumour scans, prostate-specific antigen (PSA) blood levels and any side effects that occur. Researchers will also look at the effect of treatment on patients’ quality of life, degree of pain and the time it takes before another cancer treatment is needed.
Study patients will come to clinic for study visits every 2 weeks for the first 2 months and every 4 weeks thereafter, and scans will occur every 8 weeks for the first 6 months and every 12 weeks thereafter. Patients will receive rucaparib orally on a daily basis.
Summary of Results
This study, “TRITON2: A multicenter, open-label Phase 2 study of rucaparib in patients with metastatic castration-resistant prostate cancer associated with homologous recombination deficiency,” was sponsored and funded by Clovis Oncology, Inc.PARP (or, poly ADP-ribose polymerase) is a protein inside cells that helps repair damage to DNA, which is the genetic material that carries the instructions for your body’s growth and development and allows cells to continue on living. Cancer can result when there are changes in a person’s genetic material (sometimes called DNA mutations) that can cause cells to grow out of control. Research has shown that PARP inhibitors can be used as a cancer treatment as they stop the PARP proteins from doing their repair work specifically in cancer cells with a little to no effect on healthy cells. Cancer cells that are not able to repair themselves will sometimes stop growing and eventually die.
Rucaparib, a type of PARP inhibitor, is approved for the treatment of ovarian cancer in the US, UK, European Union (EU), and Israel, and for maintenance treatment of ovarian cancer in the US, EU, UK, Israel, and Switzerland.
Our goal in this study was to determine whether rucaparib is a good treatment option also in metastatic Castration-Resistant Prostate Cancer patients with BRCA, and non-BRCA DNA-repair gene mutations, shown to be associated with potential sensitivity to similar treatments. We wanted to know about side-effects, how the drug is used in the body, and how well it could control prostate cancer.
We enrolled 277 patients in Australia, Belgium, Canada, Denmark, France, Germany, Ireland, Israel, Italy, Spain, the United Kingdom (UK), and the United States (US) between February 2017 and July 2021. Our study patients were male with an average age of 71 years old (range, 49-88 years). Most patients were white (198) and recruited from North America (120) and Europe (125), and we enrolled 32 patients from other geographic regions. All patients received 600 mg rucaparib orally twice a day until the end of treatment.
All enrolled patients with metastatic Castration-Resistant Prostate Cancer presenting mutations in BRCA, or non-BRCA DNA-repair genes were evaluated in a 3rd line treatment setting following their disease progression. Clinically, almost all patients respond and then progress after 1st and 2nd line standard of care treatments. Third- and later-line therapies are available, but these therapies have low response rates with significant side effects. We wanted to know if rucaparib was better or worse than these treatments.
Our study showed that 37 out of 81 patients with a BRCA gene mutation had shrinkage in their cancer whereas 7 out of 52 patients with a non-BRCA gene mutation had cancer shrinkage, when we measured by scanning. We also looked at patients’ Prostate-Specific Antigen (PSA) levels in the blood. PSA is a protein produced by both healthy and cancerous prostate cells, but its high level can sometimes be a sign of prostate cancer. In this study, 92 out of 172 patients with a BRCA gene mutation had at least a 50% decrease in their PSA values while 13 out of 105 patients with a non-BRCA gene mutation showed the same level of decrease in their PSA.
In patients with a BRCA gene mutation, 15 out of 30 with soft tissue disease such as in lungs or liver, and 22 out of 51 with only lymph node disease, had a confirmed radiographic response, meaning their cancer had reduced in size overall by scanning.
Our study also showed that patients with a BRCA gene mutation that had shrinkage in their cancer with rucaparib treatment had a median of 15.5 months radiologically confirmed durability when checked by independent reviewers, which indicates the length of time patients had without their cancer growing or spreading. The median was 6.6 months if the patients’ doctors assessed this themselves. Median means in the middle – half of the patients did worse, and the other half did better. If we also counted patients that did not have shrinkage of their tumours all together in one group, they had a median of 10.7 months before their cancer became worse when checked by scanning.
The median time for PSA to get worse for all patients with a BRCA gene mutation after they responded by PSA in the blood, was 4.7 months.
To confirm the correct dose of rucaparib, we looked at rucaparib concentrations in the blood and showed that they were consistent over time on treatment, and also the type of DNA-repair gene mutations did not make a difference.
When we finished the study most patients had stopped treatment because their disease had started to get worse (189 pts). Some patients stopped treatment because of side effects (30 pts), and some patients decided not to continue (18 pts). Some (23) patients stayed on treatment after the study finished.
Rucaparib was generally well tolerated with manageable side-effects such as weakness & fatigue, nausea, decreased haemoglobin in the blood (or anaemia) in about half of all patients (up to 59 out of 100) taking rucaparib. We saw more serious (called Grade 3) side effects in patients including: decreased haemoglobin in the blood (or anaemia) in 29 of 100 patients, weakness & fatigue in 11 of 100 patients, and decreased platelets in the blood (which help prevent bleeding) in 8 of 100 patients. About 12 in 100 patients stopped taking rucaparib due to side effects. 8 patients died whilst on our clinical study, with 2 deaths considered caused by rucaparib.
Overall, the side effects of rucaparib in patients with metastatic Castration-Resistant Prostate Cancer was very similar with that seen in other patients with cancers where rucaparib was approved by health authorities for use in patients.
The results of this study were shared with the US health authority, Food and Drug Administration (FDA) and we received approval to use rucaparib for metastatic Castration-Resistant Prostate Cancer patients. The results will also support more research in prostate cancer which may allow approval of rucaparib in other countries.
REC name
London - London Bridge Research Ethics Committee
REC reference
16/LO/2195
Date of REC Opinion
10 Feb 2017
REC opinion
Further Information Favourable Opinion