Rucaparib versus standard-of-care chemotherapy in patients with relapsed ovarian cancer and a deleterious BRCA1 or BRCA2 mutation (ARIEL4): an international, open-label, randomised, phase 3 trial
Language English Country England, Great Britain Media print-electronic
Document type Clinical Trial, Phase III, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't
PubMed
35298906
DOI
10.1016/s1470-2045(22)00122-x
PII: S1470-2045(22)00122-X
Knihovny.cz E-resources
- MeSH
- Indoles MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Mutation MeSH
- Ovarian Neoplasms * drug therapy genetics pathology MeSH
- Poly(ADP-ribose) Polymerase Inhibitors * adverse effects MeSH
- Prospective Studies MeSH
- BRCA1 Protein genetics MeSH
- BRCA2 Protein genetics MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial, Phase III MeSH
- Research Support, Non-U.S. Gov't MeSH
- Randomized Controlled Trial MeSH
- Names of Substances
- BRCA1 protein, human MeSH Browser
- BRCA2 protein, human MeSH Browser
- Indoles MeSH
- Poly(ADP-ribose) Polymerase Inhibitors * MeSH
- BRCA1 Protein MeSH
- BRCA2 Protein MeSH
- rucaparib MeSH Browser
BACKGROUND: Few prospective studies have compared poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors to chemotherapy for the treatment of BRCA1-mutated or BRCA2-mutated ovarian carcinoma. We aimed to assess rucaparib versus platinum-based and non-platinum-based chemotherapy in this setting. METHODS: In this open-label, randomised, controlled, phase 3 study (ARIEL4), conducted in 64 hospitals and cancer centres across 12 countries (Brazil, Canada, Czech Republic, Hungary, Israel, Italy, Poland, Russia, Spain, Ukraine, the UK, and the USA), we recruited patients aged 18 years and older with BRCA1-mutated or BRCA2-mutated ovarian carcinoma, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and who had received two or more previous chemotherapy regimens. Eligible patients were randomly assigned (2:1), using an interactive response technology and block randomisation (block size of six) and stratified by progression-free interval after the most recent platinum-containing therapy, to oral rucaparib (600 mg twice daily) or chemotherapy (administered per institutional guidelines). Patients assigned to the chemotherapy group with platinum-resistant or partially platinum-sensitive disease were given paclitaxel (starting dose 60-80 mg/m2 on days 1, 8, and 15); those with fully platinum-sensitive disease received platinum-based chemotherapy (single-agent cisplatin or carboplatin, or platinum-doublet chemotherapy). Patients were treated in 21-day or 28-day cycles. The primary endpoint was investigator-assessed progression-free survival, assessed in the efficacy population (all randomly assigned patients with deleterious BRCA1 or BRCA2 mutations without reversion mutations), and then in the intention-to-treat population (all randomly assigned patients). Safety was assessed in all patients who received at least one dose of assigned study treatment. This study is registered with ClinicalTrials.gov, NCT02855944; enrolment is complete, and the study is ongoing. FINDINGS: Between March 1, 2017, and Sept 24, 2020, 930 patients were screened, of whom 349 eligible patients were randomly assigned to rucaparib (n=233) or chemotherapy (n=116). Median age was 58 years (IQR 52-64) and 332 (95%) patients were White. As of data cutoff (Sept 30, 2020), median follow-up was 25·0 months (IQR 13·8-32·5). In the efficacy population (220 patients in the rucaparib group; 105 in the chemotherapy group), median progression-free survival was 7·4 months (95% CI 7·3-9·1) in the rucaparib group versus 5·7 months (5·5-7·3) in the chemotherapy group (hazard ratio [HR] 0·64 [95% CI 0·49-0·84]; p=0·0010). In the intention-to-treat population (233 in the rucaparib group; 116 in the chemotherapy group), median progression-free survival was 7·4 months (95% CI 6·7-7·9) in the rucaparib group versus 5·7 months (5·5-6·7) in the chemotherapy group (HR 0·67 [95% CI 0·52-0·86]; p=0·0017). Most treatment-emergent adverse events were grade 1 or 2. The most common grade 3 or worse treatment-emergent adverse event was anaemia or decreased haemoglobin (in 52 [22%] of 232 patients in the rucaparib group vs six [5%] of 113 in the chemotherapy group). Serious treatment-emergent adverse events occurred in 62 (27%) patients in the rucaparib group versus 13 (12%) in the chemotherapy group; serious adverse events considered related to treatment by the investigator occurred in 32 (14%) patients in the rucaparib group and six (5%) in the chemotherapy group. Three deaths were considered to be potentially related to rucaparib (one due to cardiac disorder, one due to myelodysplastic syndrome, and one with an unconfirmed cause). INTERPRETATION: Results from the ARIEL4 study support rucaparib as an alternative treatment option to chemotherapy for patients with relapsed, BRCA1-mutated or BRCA2-mutated ovarian carcinoma. FUNDING: Clovis Oncology.
Bialostockie Centrum Onkologii im Marii Sklodowskiej Curie Białystok Poland
Biostatistics Clovis Oncology Boulder CO USA
Clinical Development Clovis Oncology Boulder CO USA
Clinical Operations Clovis Oncology Boulder CO USA
Clinical Research Center Instituto de Oncologia do Parana Curitiba Brazil
Department of Chemotherapy Arkhangelsk Clinical Oncological Dispensary Arkhangelsk Russia
Department of Chemotherapy Lviv Regional Oncology Dispensary Lviv Ukraine
Department of Chemotherapy N N Blokhin Russian Cancer Research Center Moscow Russia
Department of Obstetrics and Gynecology Clinical Center University of Debrecen Debrecen Hungary
Department of Oncology UCL Cancer Institute University College London London UK
Molecular Diagnostics Clovis Oncology Boulder CO USA
Omsk Region Clinical Oncologic Dispensary Omsk Russia
Oncogynecological Department Saint Petersburg City Oncological Dispensary Saint Petersburg Russia
Oncology and Medical Radiology Department Dnipropetrovsk Medical Academy Dnipro Ukraine
References provided by Crossref.org
ClinicalTrials.gov
NCT02855944
