Rucaparib in Platinum-Sensitive Relapsed High-Grade Ovarian Cancer
Research type
Research Study
Full title
A Phase 2, Open-Label Study of Rucaparib in Patients with Platinum-Sensitive, Relapsed, High-Grade Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer
IRAS ID
132240
Contact name
Iain McNeish
Contact email
Sponsor organisation
Clovis Oncology, Inc.
Eudract number
2013-000517-20
Clinicaltrials.gov Identifier
Research summary
Summary of Results
This study, “ARIEL2: A Phase 2, Open-label Study of Rucaparib in Subjects with Platinum-sensitive, Relapsed, High-grade Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer” was sponsored and funded by Clovis Oncology, Inc. Rucaparib belongs to a class of anti-cancer agents known as PARP (or, poly ADP-ribose polymerase) inhibitors. PARP is a protein inside cells that helps repair damage to DNA. DNA is the genetic material that carries the instructions for the body’s growth and development and allows cells to continue living. Cancer can result when there are changes in a person’s genetic material (sometimes called DNA mutations) that can cause cancer cells to grow out of control. Research has shown that PARP inhibitors stop the PARP protein from working, and that can sometimes cause cancer cells to stop growing.As part of the study, samples, tumor tissue and blood were analyzed to look for biomarkers. Biomarkers are substances such as genetic material (DNA and RNA) and proteins found in blood and tumor tissue that might show if a cancer patient is likely to respond or not respond to a treatment. One of the goals of the biomarker research was to identify which biomarkers are present most often in subjects that appear to benefit from treatment with rucaparib and to eventually develop a diagnostic test to help identify subjects with these biomarkers before treatment is started. In order to help doctors decide if rucaparib is a good treatment option, Part 1 of this study was carried out to identify biomarkers in ovarian cancer subjects with platinum-sensitive disease which means subjects’ ovarian cancer came back 6 months or more after completing their chemotherapy regimen that contained the metal platinum. The goal of Part 2 was to expand on that to determine whether rucaparib benefits subjects who had previously received 3 or 4 chemotherapy regimens. Subjects enrolled into either Part 1 or Part 2 of the study. Part 2 began once enrollment of Part 1 was completed.
The study enrolled 491 subjects (Part 1 = 204 subjects, Part 2 = 287 subjects) across 64 sites in Australia, Canada, France, Spain, the United Kingdom and the United States between October 2013 and February 2016. All study subjects were female with an average age of 64.5 years (range, 31-86 years). The majority of subjects were white (85.3%). Most subjects (66.7%) were recruited in North America, with the remaining subjects from Europe (27.0%), and Australia (6.3%). All subjects initially received 600 mg rucaparib orally twice a day.
Most of the subjects had epithelial ovarian cancer which is cancer that started in the surface layer covering the ovary (80.4% Part 1, 81.5% Part 2) and most of the subject’s tumor arose from the serous membrane, in the epithelial layer of the ovary (96.6% Part 1, 93.7% Part 2). The tumor tissue was considered “high grade” in all subjects, meaning the ovarian cancer tissue had cancers cells that are less likely to look like normal cells. In addition, subjects had other medical conditions including high blood pressure (32.8% Part 1, 37.3% Part 2) and fatigue (27.5% Part 1, 23.7% Part 2).
The study met its goal in Part 1 as it showed that subjects receiving rucaparib had a longer time before their cancer got worse when they had specific biomarkers in their tissue samples (BRCA, non-BRCA LOH+) compared to other biomarkers (non-BRCA LOH-). Rucaparib reduced the risk of the cancer progressing by 72.7%
in subjects who had BRCA, and by 39.0% for those subjects who had a non-BRCA/LOH+ biomarker.
The overall response rate (ORR) for rucaparib - which is defined as the proportion of subjects in a trial whose tumor disappeared or was significantly reduced by a drug - was high, particularly in subjects who had the BRCA biomarker (80.0% in Part 1; and 31.0% in Part 2).
These same BRCA subjects experienced sustained responses, or duration of response (DOR), meaning the length of time that the tumor continued to respond to treatment without the cancer growing or spreading - 9.2 months in Part 1 and 5.8 months in Part 2.Response to rucaparib treatment occurred rapidly, particularly in subjects in Part 1 with most responses observed within 8 weeks of being on the study. Response was observed slightly later in the more heavily pre-treated subjects in Part 2.
A gene is the basic unit of heredity passed from parent to child. There were 4 genes (BRCA1, BRCA2, RAD51C, and RAD51D) identified as genes strongly linked to a patient being more likely to respond to rucaparib treatment as compared to the other genes identified. The overall response rate (ORR) for subjects with mutations in any one of these 4 genes was 48.1%. The response was 71.4% for subjects with a RAD51C or RAD51D mutation, 55.6% for those with a BRCA2 mutation and 41.8% for those with a BRCA1 mutation.
Part 2 enrolled subjects who were heavily pre-treated with 3 to 4 rounds of prior treatment with anticancer drugs and whose disease had worsened on the most recent round of treatment. Patients who received a treatment containing platinum whose disease worsened during treatment or within 2 months are referred to as having platinum-refractory disease, those whose disease worsened within 6 months are referred to as having platinum-resistant disease and those whose disease worsened after 6 months are referred to as having platinum-sensitive disease.
The overall response rate (ORR) was greatest in subjects with platinum-sensitive disease and who had BRCA mutations (48.4% in the BRCA subgroup versus, 7.7% in the non-BRCA/LOH+, and 6.1% in the non-BRCA/LOH- subgroups) vs. subjects who had platinum-resistant disease. Subjects with refractory platinum status, those patients who had previously stopped responding to any treatment, had poor response (ORR of 0% in the BRCA and non-BRCA/LOH+ subgroup, and 5.6% in the non-BRCA/LOH- subgroup).
Rucaparib side effects could typically be managed by decreasing the dose and/or receiving supportive care. The most common side effects were nausea, fatigue, constipation, vomiting, abdominal pain, abnormal taste, and decreased appetite. Along with decreased amount of red blood cells, decreased platelet count, and decreased amount of white blood cells as well as changes in kidney and liver function blood tests.
The last patient on treatment was transitioned off study on 28 September 2021 (last patient last visit (LPLV)), and the study was officially closed as of that date.
REC name
West of Scotland REC 1
REC reference
13/WS/0172
Date of REC Opinion
26 Nov 2013
REC opinion
Further Information Favourable Opinion