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
Mené sur 349 patientes atteintes d'un cancer de l'ovaire récidivant et présentant des mutations BRCA (âge médian : 58 ans), cet essai de phase III compare l'efficacité, du point de vue de la survie sans progression, et la toxicité du rucaparib par rapport à une chimiothérapie avec ou sans sels de platine
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 andnon-platinum-based chemotherapy in this setting.
Methods : In this open-label, randomised, controlled, phase 3 study (ARIEL4), conducted in 64hospitals and cancer centres across 12 countries (Brazil, Canada, Czech Republic,Hungary, Israel, Italy, Poland, Russia, Spain, Ukraine, the UK, and the USA), we recruitedpatients aged 18 years and older with BRCA1-mutated or BRCA2-mutated ovarian carcinoma, with an Eastern Cooperative Oncology Group performancestatus 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 technologyand block randomisation (block size of six) and stratified by progression-free intervalafter the most recent platinum-containing therapy, to oral rucaparib (600 mg twicedaily) or chemotherapy (administered per institutional guidelines). Patients assignedto the chemotherapy group with platinum-resistant or partially platinum-sensitivedisease were given paclitaxel (starting dose 60–80 mg/m2 on days 1, 8, and 15); those with fully platinum-sensitive disease received platinum-basedchemotherapy (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 assignedpatients 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 receivedat 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 datacutoff (Sept 30, 2020), median follow-up was 25·0 months (IQR 13·8–32·5). In the efficacypopulation (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 versus5·7 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 inthe 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 1or 2. The most common grade 3 or worse treatment-emergent adverse event was anaemiaor 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 eventsoccurred in 62 (27%) patients in the rucaparib group versus 13 (12%) in the chemotherapygroup; serious adverse events considered related to treatment by the investigatoroccurred in 32 (14%) patients in the rucaparib group and six (5%) in the chemotherapygroup. Three deaths were considered to be potentially related to rucaparib (one dueto cardiac disorder, one due to myelodysplastic syndrome, and one with an unconfirmedcause).
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.
The Lancet Oncology , résumé, 2021