Phase III ARIEL4 Trial Confirms Benefit of Rucaparib 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. These results from the international phase III ARIEL4 trial were presented by Rebecca Kristeleit, MD, PhD, in the first scientific Plenary Session of the Society of Gynecologic Oncology (SGO) 2021 Virtual Annual Meeting on Women’s Cancer (Abstract ID 11479).

“Patients with BRCA-mutated, advanced, relapsed ovarian cancer who received rucaparib had a significant improvement in progression-free survival vs chemotherapy,” said Dr. Kristeleit, of the University College London and UCL Cancer Institute.

The same benefit—a reduction of approximately 35% in risk of disease progression or death—was shown for the efficacy and intent-to-treat populations by investigator assessment.

Patients with BRCA-mutated, advanced, relapsed ovarian cancer who received rucaparib had a significant improvement in progression-free survival vs chemotherapy.
— Rebecca Kristeleit, MD, PhD

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Rucaparib was not effective, however, in a small subset of patients with BRCA reversion mutations, she added, noting, “This is the first prospective report from a randomized trial demonstrating that the presence of a BRCA reversion mutation predicts for primary resistance to rucaparib.”

Based on previous data from phase I/II trials, rucaparib became 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

The ARIEL4 trial enrolled 349 patients with high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer and a germline BRCA1/2 mutation (84%) or somatic mutation (16%) who had received two or more prior chemotherapy regimens, but not a prior PARP inhibitor. The vast majority of patients had epithelial ovarian cancer and serous histology.

By progression-free interval, 51% of patients were classified as platinum-resistant (≥ 1 to < 6 months), 28% were partially platinum-sensitive (≥ 6 to < 12 months), and 21% were fully platinum-sensitive (≥ 12 months).

There were 23 (6.6%) patients who 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. An exploratory analysis determined the efficacy of rucaparib in these patients.

Patients were randomly assigned to receive rucaparib or standard-of-care chemotherapy in the following treatment arms:

  • Rucaparib at 600 mg twice daily
  • 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]) 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.

Rucaparib Superior in Two Analyses

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 also 7.4 months vs 5.7 months (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). 

Secondary Endpoints

The objective response rate was similar between the treatment arms: 40.3% in the rucaparib arm and 32.3% in the chemotherapy arm (P = .13). However, median duration of response was longer with rucaparib: 9.4 months vs 7.2 months (HR = 0.59). Global health status measures 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 served on advisory boards for Clovis Oncology, Roche, and Tesaro.


The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.