Rucaparib does not improve overall survival (OS), when compared with chemotherapy, in patients with heavily pretreated, BRCA1/2-mutated ovarian cancer, according to updated results from the ARIEL4 trial.1
In fact, OS favored the chemotherapy arm in this trial. These results are what prompted Clovis Oncology to withdraw the approval for rucaparib as a treatment for BRCA-mutated ovarian cancer after 2 or more lines of chemotherapy.2,3 This withdrawal took effect in June for the United States and in August for Europe.
The updated trial results were presented at ESMO Congress 2022 by Amit M. Oza, MD, MBBS, of the Princess Margaret Cancer Centre in Canada.
The ARIEL4 trial (ClinicalTrials.gov Identifier: NCT02855944) enrolled patients with relapsed, high-grade, heavily pretreated, BRCA1/2-mutated ovarian cancer. Patients were randomly assigned 2:1 to receive rucaparib (n=233) or chemotherapy (n=116), and they were stratified by platinum sensitivity.
Patients with a progression-free interval (PFI) from last platinum therapy of 1 month to less than 6 months were deemed platinum-resistant, those with a PFI of 6 months to less than 12 months were partially platinum-sensitive, and those with a PFI of 12 months or more were considered fully platinum-sensitive.
In the platinum-resistant cohort, 120 patients were assigned to rucaparib and 59 to chemotherapy. In the partially platinum-sensitive cohort, 65 patients were assigned to rucaparib and 31 to chemotherapy. In the fully platinum-sensitive cohort, 48 patients were assigned to rucaparib and 26 to chemotherapy.
In the chemotherapy arm, patients received paclitaxel if they were platinum-resistant or partially platinum-sensitive, and they received platinum-based single or doublet chemotherapy if they were fully platinum-sensitive. Patients from the chemotherapy arm could crossover to the rucaparib arm after disease progression. Ultimately, 69% of patients (80/116) crossed over.
Results: OS, PFS2, and Safety
In the overall population, OS favored the chemotherapy arm. The median OS was 25.4 months in the chemotherapy arm and 19.4 months in the rucaparib arm (hazard ratio [HR], 1.313; 95% CI, 0.999-1.725).
This difference seems to be driven by patients with platinum-resistant disease, Dr Oza said. In the platinum-resistant group, the median OS was 22.2 months in the chemotherapy arm and 14.2 months in the rucaparib arm (HR, 1.511; 95% CI, 1.053-2.170).
In patients with partially platinum-sensitive disease, the median OS was 21.1 months in the rucaparib arm and 23.2 months in the chemotherapy arm (HR, 0.972; 95% CI, 0.583-1.621). In the fully platinum-sensitive cohort, the median OS was 36.3 months and 47.2 months, respectively (HR, 1.243; 95% CI, 0.619-2.498).
Dr Oza noted that OS was confounded by the high rate of crossover from the chemotherapy arm to the rucaparib arm. When patients who crossed over were excluded, the median OS was significantly longer in the rucaparib arm than in the chemotherapy arm — 19.4 months and 9.1 months, respectively (HR, 0.423; 95% CI, 0.276-0.650).
When data were censored at crossover, the median OS was 19.4 months in the rucaparib arm and 26.2 months in the chemotherapy arm (HR, 1.059; 95% CI, 0.688-1.630).
Second progression-free survival (PFS2) was largely similar between the arms. In the platinum-resistant cohort, the median PFS2 was 11.8 months in the rucaparib arm and 11.5 months in the chemotherapy arm (HR, 0.968; 95% CI, 0.697-1.344).
In the partially platinum-sensitive cohort, the median PFS2 was 16.5 months in the rucaparib arm and 13.3 months in the chemotherapy arm (HR, 0.650; 95% CI, 0.410-1.030). In the fully platinum-sensitive cohort, the median PFS2 was 26.9 months and 24.4 months, respectively (HR, 0.886; 95% CI, 0.492-1.596).
Grade 3 or higher treatment-emergent adverse events (TEAEs) were more common with rucaparib than with chemotherapy — 63.4% and 39.8%, respectively. The most common grade 3 or higher TEAEs were anemia, neutropenia, thrombocytopenia, and asthenia/fatigue.
Myelodysplastic syndrome or acute myeloid leukemia was reported in 3.0% of patients in the rucaparib arm and none of the patients in the chemotherapy arm.
Disclosures: This study was supported by Clovis Oncology, Inc. Some of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.
1. Oza AM, Lisyanskaya AS, Fedenko AA, et al. Overall survival results from ARIEL4: A phase III study assessing rucaparib vs chemotherapy in patients with advanced, relapsed ovarian carcinoma and a deleterious BRCA1/2 mutation. Presented at ESMO 2022; September 9-13, 2022. Abstract 518O.
2. Liu A. Amid death risk fears, Clovis pulls Rubraca in 3rd-line ovarian cancer as PARP player plugs away at earlier setting. Fierce Pharma. Published June 17, 2022. Accessed September 9, 2022.
3. Rubraca (rucaparib): Restriction of indication. European Medicines. Agency. Updated August 8, 2022. Accessed September 9, 2022.