ARIEL4 Trial Confirms PFS Benefit of Rucaparib in BRCA+ Relapsed Ovarian Cancer


An update from the phase 3 ARIEL4 trial presented at the Society of Gynecologic Oncology 2021 Virtual Annual Meeting on Women’s Cancer supports the continued use of rucaparib in patients with BRCA-mutant relapsed advanced ovarian cancer, based on progression-free survival and response data.

Improvements in both progression-free survival (PFS) and response duration were noted in patients with BRCA-mutant advanced, relapsed ovarian cancer who were treated with the PARP inhibitor rucaparib (Rubraca) versus standard-of-care chemotherapy, according to results of the phase 3 ARIEL4 trial (NCT02855944) that were presented during the Society of Gynecologic Oncology (SGO) 2021 Virtual Annual Meeting on Women’s Cancer.1

“Patients with BRCA-mutated advanced, relapsed ovarian cancer who received rucaparib had a significant improvement in progression-free survival versus standard-of-care chemotherapy,” Rebecca Kristeleit, BSc, MBChB, MRCP, PhD, said during a presentation of the findings.

In December 2016, rucaparib was first approved by the FDA for the treatment of patients with advanced ovarian cancer who have a deleterious BRCA mutation and have been treated with 2 or more chemotherapies.2 The indication received an accelerated approval based on 2 multicenter, single-arm phase 1/2 clinical trials.

The ARIEL4 trial was designed to be the confirmatory phase 3 trial to further prove the benefit of rucaparib for this indication and was created in consultation with the FDA and the European Medicines Agency.1

Patients with relapsed, high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer were enrolled in the study if they had received at least 2 prior chemotherapy regimens, with at least 1 of which being platinum based; had a deleterious germline or somatic BRCA mutation; and had not received prior PARP inhibition or single-agent paclitaxel.

For the sake of the trial, platinum status was defined as platinum resistant for those who relapsed within 6 months of treatment, partially sensitive for those who relapsed between 6 and 12 months, and as platinum fully sensitive for those who relapsed after more than a year. This served as a stratification factor for randomization.

Treatment with rucaparib was administered at 600 mg twice daily in the investigational arm (n = 233), and in the control arm (n = 116), weekly paclitaxel was given for those who were platinum resistant or partially sensitive and platinum-based chemotherapy monotherapy or doublet regimen was given to those who were fully sensitive to platinum. Treatment was continued until radiologically confirmed disease progression, unacceptable toxicity, death, or study termination. Those in the chemotherapy arm who progressed (n = 74; 64%) were able to cross over to the rucaparib arm.

The intention-to-treat (ITT) population encompassed all randomized patients (n = 349), but 24 patients were excluded from the efficacy analysis population for either not having a BRCA mutation (n = 1) or having a BRCA reversion (n = 23; 13 from rucaparib arm, 10 from chemotherapy arm). At the time of data cutoff in September 2020, 44 patients in the rucaparib arm were still receiving treatment compared with 5 in the chemotherapy arm. In both populations, investigator-assessed PFS was the primary end point.

At baseline, patients had a median age of 58.0 years (range, 38-85) and a median of 43 months (range, 13-185) since their cancer diagnosis. Almost all of the patients (94.8%) had epithelial ovarian cancer, 2.9% had fallopian tube cancer, and 2.3% had primary peritoneal cancer. Serous histology was most common in 89.7% of patients. The majority of patients also had a germline BRCA mutation (84.0%).

In terms of prior treatment, 57.9% had received 2 prior chemotherapy regimens, 37.8% had received 3 to 5, and 4.3% had received at least 6. These included 2 platinum-based regimens for 65.9% and at least 3 for 28.9%. Immediately before randomization, 22.3% of patients received a nonplatinum treatment. Platinum status included resistant disease in 51.3%, partially sensitive in 27.5%, and fully sensitive in 21.2%.

The median treatment duration was 7.3 months (range, <1-41) with rucaparib and 3.6 months (range, <1-25) with chemotherapy.

The investigator-assessed median PFS in the efficacy population was 7.4 months (95% CI, 7.3-9.1) with rucaparib in comparison with 5.7 months (95% CI, 5.5-7.3) with chemotherapy (HR, 0.64; 95% CI, 0.49-0.84; P = .001). In the ITT population, the median PFS was the same at 7.4 months (95% CI, 6.7-7.9) and 5.7 months (95% CI, 5.5-6.7) in the rucaparib and chemotherapy arms, respectively, but showed a hazard ratio of 0.67 (95% CI, 0.52-0.86; P = .002).

Among the 23 patients with a BRCA reversion mutation, the median PFS in the rucaparib group was 2.9 months (95% CI, 1.8-4.2) as compared with 5.5 months (95% CI, 1.9-6.6) with chemotherapy (HR, 2.77; 95% CI, 0.99-7.76).

“This is the first prospective report from a randomized study demonstrating that the presence of a BRCA reversion mutation may predict for primary resistance to rucaparib,” said Kristeleit, of the Department of Oncology at the Guy’s and St. Thomas’ NHS Foundation Trust in London, United Kingdom. However, she noted that the number of patients in this group was small.

Objective response rate by RECIST criteria in the efficacy population was 40.3% (95% CI, 33.6-47.2%) with rucaparib treatment compared with 32.3% (95% CI, 23.1%-42.6%) with chemotherapy. However, this did not reach statistical significance (P = .13). RECIST response and/or CA-125 response was observed in 50.7% (95% CI, 43.8%-57.5%) of patients treated with rucaparib versus in 43.6% (95% CI, 33.7%-53.8%) of those treated with chemotherapy.

Duration of response in the efficacy population was a median of 9.4 months (95% CI, 7.5-11.1) with rucaparib and 7.2 months (95% CI, 4.0-11.4) with chemotherapy (HR, 0.59; 95% CI, 0.36-0.98).

These rates were similar in the ITT population.

Overall survival data are expected to be analyzed when data are mature after approximately 51% of death events have occurred.

Global health status did not differ significantly between the 2 treatment arms over time in either population group through cycle 7 of treatment.

The most common (≥20%) treatment-emergent adverse events (TEAEs) of any grade were anemia/decreased hemoglobin (53.9% with rucaparib vs 31.9% with chemotherapy), nausea (53.4% vs 31.9%, respectively), asthenia/fatigue (49.6% vs 44.2%), alanine/aspartate aminotransferase increase (34.5% vs 11.5%), vomiting (34.1% vs 16.8%), abdominal pain (23.3% vs 15.9%), thrombocytopenia/platelet count decrease (23.3% vs 11.5%), neutropenia/neutrophil count decrease (22.4% vs 28.3%), and diarrhea (20.3% vs 21.2%). Anemia/decreased hemoglobin was the most common grade ≥3 TEAE at 22.4% in the rucaparib arm versus 5.3% in the chemotherapy arm followed by neutropenia/neutrophil count decrease at 10.3% and 15.0% in the rucaparib and chemotherapy arms, respectively.

Kristeleit noted that there were no emerging toxicities observed for either treatment arm.

In the rucaparib group, 8.2% of patients discontinued treatment due to a TEAE versus 12.4% of patients in the chemotherapy arm.

Four cases of myelodysplastic syndrome/acute myeloid leukemia were reported in the rucaparib arm—1 arose during treatment and 3 during long-term follow-up.


1. Kristeleit R, Lisyanskaya A, Fedenko A, et al. Rucaparib versus chemotherapy in patients with advanced, relapsed ovarian cancer and a deleterious BRCA mutation: efficacy and safety from ARIEL4, a randomized phase 3 study. Presented at: Society of Gynecologic Oncology 2021 Virtual Annual Meeting on Women’s Cancer; March 19-25, 2021; Virtual. Abstract 11479.

2. FDA grants accelerated approval to new treatment for advanced ovarian cancer. News release. FDA. December 19, 2016. Accessed March 19, 2021.

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