Study of Maintenance Rucaparib in Relapsed High-grade Ovarian Cancer
Research type
Research Study
Full title
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase 3 Study of Rucaparib as Switch Maintenance Following Platinum-Based Chemotherapy in Patients with Platinum-Sensitive, High-Grade Serous or Endometrioid Epithelial Ovarian, Primary Peritoneal or Fallopian Tube Cancer
IRAS ID
140185
Contact name
Jonathan Ledermann
Contact email
Sponsor organisation
Clovis Oncology, Inc.
Eudract number
2013-000518-39
Clinicaltrials.gov Identifier
106,289, IND Number
Duration of Study in the UK
2 years, 9 months, 31 days
Research summary
Summary of Research
Rucaparib is an anti-cancer agent known as a PARP inhibitor, being developed for treatment of ovarian cancer. PARP is a protein inside cells in the body that helps repair damage to genetic material (DNA). Cancer can result from changes in a person’s DNA and some of these changes 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. The purpose of this study is to evaluate progression-free survival (a measure of time to progression after starting treatment) in patients with relapsed high-grade serous or endometrioid ovarian cancers following a response to platinum-based chemotherapy (2 or more platinum-based therapies and radiologic relapse >6 months after last dose of penultimate regimen).
As part of this study, tumour and blood samples will be analysed looking for biomarkers (substances including DNA and proteins found in blood and tumours that might show if a cancer patient will respond or not respond to treatment). These biomarker tests include BRCA mutational analysis; if patients are BRCA+ they will be referred for counseling.
This is a placebo-controlled study of rucaparib. Approximately 540 patients will participate in this study at 90 – 100 hospitals worldwide. The study will take about 3 years to complete.
Patients will take rucaparib twice daily for continuous treatment cycles of 28-days each. During the first two treatment cycles, patients will return to hospital half-way through the cycle and at the end of the cycle. After two cycles are completed, patients will return to hospital approximately once every 4 weeks. Patients will complete a treatment discontinuation visit after they stop taking study medication and then a 28-day follow up visit and long term follow-up for overall survival tracking.
A pharmaceutical company is funding this research.Summary of Results
This study, “ARIEL3: A multicenter, randomized, double-blind, placebo-controlled phase 3 study of
rucaparib as switch maintenance following platinum-based chemotherapy in patients with platinum-sensitive, high-grade serous or endometrioid epithelial ovarian, primary peritoneal or fallopian tube 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 a chemical that tells the cells how to work and behave and it is constantly being damaged and repairing itself within our bodies. DNA double strand breaks are repaired by the process called homologous recombination. Homologous recombination deficiency (HRD) is when your body is unable to repair double strand breaks in DNA. If a tumor is positive for HRD, it means the tumor cells are not repairing DNA correctly and that treatment with a PARP inhibitor may be more effective. BRCA1 and BRCA2 mutations were the first mutations to be associated with HRD and it’s now known that HRD can result from mutations in several genes and occur in around half of women with high-grade serous ovarian cancer. These mutations can either be inherited (germline) or acquired in the tumor (somatic). Research has shown that PARP inhibitors stop the PARP protein from working, and that can sometimes cause cancer cells to stop growing. PARP inhibitors given during the time that ovarian cancer patients have stopped taking a platinum-based chemotherapy has been found to extend the time that a patient is cancer-free.The purpose of ARIEL3 was to see how long rucaparib might stop recurrent ovarian cancer from growing or spreading (also referred to as progression-free survival or PFS) after patients received a platinum-based chemotherapy treatment as compared to placebo and to understand the role genetic mutations had on the efficacy of rucaparib. Patients provided tumor tissue and blood samples which were tested for genetic mutations and other genetic abnormalities.
ARIEL3 had the following analysis populations:
• Efficacy population. The analysis of PFS occurred in a stepwise fashion beginning with the group of patients most likely to benefit from rucaparib and then advanced to the next group if benefit was shown:
1. tBRCA (BRCA1 or BRCA2 mutation) population
2. HRD (tBRCA + non-BRCA HRD [Patients without a BRCA1 or BRCA2 mutation but with another HRD mutation])
3. ITT (all randomized patients including tBRCA + non-tBRCA HRD + biomarker negative [patients without any genetic mutations])
• Safety population (all patients who received at least 1 dose of rucaparib or placebo).This was a blinded study, meaning a computer randomly assigned (randomized) the patients 2:1 to treatment with rucaparib or placebo (no treatment). The computer had 3 criteria to evaluate for each patient for evenly assigning between the two treatment options:
• HRD status – tBRCA, non-BRCA HRD or biomarker negative.
• Time from the patient’s second to last platinum treatment to disease recurrence (progression)
• Patient’s best response to their platinum treatment immediately prior to starting on this study, both by RECIST and their CA-125 results
There were 564 patients randomized into this study: 375 patients in the rucaparib group and 189 patients in the placebo group. 3 patients discontinued from the study prior to receiving any study drug resulting in 372 patients in the rucaparib group. They were enrolled across 92 sites in 11 countries, Australia, Belgium, Canada, Israel, Italy, France, Germany, New Zealand, Spain, the United Kingdom and the United States between April 2014 and July 2016. All study subjects were female with an average age of 61.0 years (range, 36-85 years). The majority of subjects were white (80.5% rucaparib; 78.8% placebo), reflective of the countries of recruitment. All subjects in the treatment group initially received 600 mg rucaparib orally twice a day. All subjects in the placebo arm received pills that looked like rucaparib and were instructed to take the same number per day as subjects taking rucaparib.The majority of patients had epithelial ovarian cancer which is cancer that started in the surface layer covering the ovary (83.2% rucaparib; 84.1% placebo), and most patients had serous histology (95.2% rucaparib; 94.7% placebo). A similar percentage of patients in the rucaparib group (37.6%) as compared to placebo (34.9%) had measurable disease at baseline as assessed by the investigator. All patients met the requirement of platinum-sensitive disease (time from last dose of the second to last platinum to disease worsening ≥ 6 months) with a median progression-free interval after the last dose of platinum of 13.8 months for the rucaparib group and 14.6 months for the placebo group.
For the primary efficacy populations, the tBRCA population was comprised of 196 patients, and the HRD population consisted of 354 patients, inclusive of the tBRCA patients. The primary endpoint was achieved with a highly statistically significant difference in investigator assessed PFS (invPFS) between rucaparib treatment compared to placebo for each of the 3 primary efficacy analysis populations (16.6 vs 5.4 months for tBRCA, 13.6 vs. 5.4 months for HRD, and 10.8 vs. 5.4 for ITT). Similar results were determined by the independent readers for assessing PFS (irrPFS) for the 3 populations treated with rucaparib or placebo, 26.8 vs 5.4 months for tBRCA , 22.9 vs. 5.5 months for HRD, and 13.7 vs. 5.4 for ITT. Following the primary analysis of invPFS, which demonstrated a highly significant clinical benefit of rucaparib over placebo, the final analysis of the long-term follow-up (LTFU) efficacy endpoints further confirmed this benefit. As expected, the most substantial improvements in PFS following rucaparib treatment were observed among the tBRCA population. The confirmed overall response rate (ORR) by investigator assessed RECIST v1.1 in the tBRCA group treated with rucaparib was 37.5% (15/40), including 17.5% (7/40) with a complete response, compared to an ORR of 8.7% (2/23) in the placebo group.
The overall survival (OS) data shows no difference between rucaparib and placebo for the 3 study populations of tBRCA, HRD, and ITT. The median OS for rucaparib vs placebo was 45.9 months vs 47.8 months for tBRCA, 40.5 months vs 47.8 months for HRD, and 36.0 months vs 43.2 months for ITT population. The median OS in both treatment arms for all analysis populations exceeds that reported in previous Phase 3 trials in ovarian cancer that were conducted before widespread availability of PARPi. This supports the hypothesis that subsequent PARPi treatment in ARIEL3 improved outcomes in patients randomized to placebo. Of the placebo patients who reported subsequent anticancer treatment, 45.8% (77/168) went on to receive a PARPi in a subsequent therapy line. In addition, the correlation between PFS and OS was lower in the placebo arm compared to rucaparib, with some patients who had short PFS in ARIEL3 experiencing prolonged overall survival in the presence of subsequent PARP inhibitor use.
Final safety data were consistent with the safety data presented in the final clinical study report, with no new safety signals observed. The most common rucaparib side effects group were nausea, asthenia/fatigue, combined abdominal pain, combined rash, anemia/hemoglobin decreased, constipation, vomiting, ALT/AST increased, and diarrhea.
The results of the study support utility of rucaparib as maintenance therapy in all women with high grade serous ovarian, fallopian tube, or primary peritoneal cancers responding to platinum for recurrent disease. In addition, assessment of tumor HRD status defined by Foundation Medicine’s next-generation sequencing test may be useful to guide health care professionals and patients when estimating possible duration of benefit before starting rucaparib.
The last patient on treatment was transitioned off study on 07 July 2022 (last patient last visit (LPLV)), and the study was officially closed as of that date.
REC name
London - Brent Research Ethics Committee
REC reference
13/LO/1682
Date of REC Opinion
8 Jan 2014
REC opinion
Further Information Favourable Opinion