Phase III ARIEL4 Confirms Rucaparib’s Benefit in BRCA-Mutated Relapsed Ovarian Cancer

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In patients with BRCA-mutated, advanced, relapsed ovarian cancer, treatment with the PARP (poly [ADP-ribose] polymerase) inhibitor rucaparib led to a significant improvement in progression-free survival compared with standard-of-care chemotherapy, according to results of the international phase III ARIEL4 trial presented at 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 vs chemotherapy,” said Rebecca Kristeleit, MD, of the University College London and UCL Cancer Institute.

Rebecca Kristeleit, MD

Rebecca Kristeleit, MD

The same benefit—a reduction of approximately 35% in the risk of disease progression or death—was shown for both the overall efficacy population and intent-to-treat population by investigator assessment. Rucaparib was not effective, however, in a small subset of patients with BRCA reversion mutations, she added. 

Based on previous data from phase I/II trials, rucaparib was approved as monotherapy for patients with BRCA-mutated, relapsed ovarian cancer who have received two or more prior lines of platinum-based chemotherapy. ARIEL4 is the phase III confirmatory trial of this agent in this treatment setting.

About ARIEL4

ARIEL4 trial enrolled 349 patients with high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer and a BRCA1/2 germline mutation (84%) or somatic mutation (16%) who had received two or more prior chemotherapy regimens but not a PARP inhibitor. By progression-free interval, 51% were classified as platinum-resistant (between 1 and 6 months), 28% were partially platinum-sensitive (between 6 and 12 months), and 21% were fully platinum-sensitive (more than 12 months).

A total of 23 patients (6.6%) were found to have BRCA reversion mutations. The acquisition of BRCA reversion mutations, which restore protein function, is believed to convey resistance to platinum-based chemotherapies and PARP inhibitors in BRCA-mutant cancers.

Patients were randomly assigned to rucaparib or standard-of-care chemotherapy in the following treatment arms: (1) rucaparib at 600 mg twice daily; and (2) weekly paclitaxel at 60 to 80 mg/m2 for patients with platinum-resistant or partially platinum-sensitive disease.

Investigator’s choice of platinum-based chemotherapy ­(single-agent carboplatin or cisplatin, or platinum doublet [carboplatin plus paclitaxel, carboplatin plus gemcitabine, or cisplatin plus gemcitabine]) was for patients with fully platinum-sensitive disease.The primary endpoint was investigator-assessed progression-free survival. Hierarchical testing was performed for progression-free survival. Overall survival was a stand-alone efficacy endpoint outside of the step-down analysis; these data are not mature.

In both the efficacy and intent-to-treat populations, median progression-free survival was significantly longer with rucaparib than with chemotherapy, reported Dr. Kristeleit. Investigator-assessed progression-free survival in the efficacy population was 7.4 months with rucaparib and 5.7 months with chemotherapy (hazard ratio [HR] = 0.64; P = .001). This was mirrored in the intent-to-treat population, where median progression-free survival was 7.4 months and 5.7 months as well (HR = 0.67; P = .002). In an exploratory analysis of the 23 patients with BRCA reversion mutations, the median progression-free survival was shorter with rucaparib than with chemotherapy: 2.9 months vs 5.5 months (HR = 2.77).

The objective response rate in the efficacy population was similar between the treatment arms: 40.3% in the rucaparib arm and 32.3% in the chemotherapy arm (P = .13). However, the median duration of response was longer with rucaparib: 9.4 months vs 7.2 months (HR = 0.59). Measures of global health status up to cycle 7 were not significantly changed from baseline in either group.

Adverse events were consistent with the known safety profiles of all the drugs, with no new safety signals emerging. 

DISCLOSURE: Dr. Kristeleit has received honoraria from AstraZeneca, Clovis Oncology, Merck Sharp & Dohme, Roche/Genentech, and Tesaro; has served as a consultant or advisor to Basilea, Cerulean Pharma, Clovis Oncology, Roche/­Genentech, and Sotio; and has been reimbursed for travel, accommodations, or other expenses by Basilea, Clovis Oncology, and ValiRx.


1. Kristeleit R, Lisyanskaya A, Fedenko A, et al: Rucaparib vs chemotherapy in patients with advanced, relapsed ovarian cancer and a deleterious BRCA mutation. Society of Gynecologic Oncology 2021 Virtual Annual Meeting on Women’s Cancer. Abstract 1. Presented March 19, 2021.


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