Phase 3 ARIEL4 Study Meets Primary End Point in Relapsed, BRCA-Mutant Ovarian Cancer

The phase 3 ARIEL4 trial is evaluating rucaparib (Rubraca) versus chemotherapy in patients with platinum-sensitive, partially platinum-sensitive, and platinum-resistant relapsed ovarian cancer and a BRCA mutation who have received 2 or more prior lines of chemotherapy.

Topline data from the randomized phase 3 ARIEL4 study (NCT02855944) of rucaparib (Rubraca) were announced by Clovis Oncology, revealing the study met its primary end point of improved investigator-assessed progression-free survival (PFS) compared with chemotherapy in patients whose ovarian cancer tumors harbor BRCA mutations (inclusive of germline and/or somatic) following 2 or more prior lines of chemotherapy.1

“The ARIEL4 study verified that women with relapsed, BRCA mutation­–positive advanced ovarian cancer, including those who are platinum-sensitive or -resistant, received benefit with rucaparib treatment when compared to chemotherapy,” Amit M. Oza, BSc, MD, MBBS, FRCPC, head of the division of Medical Oncology & Hematology, medical director of the Cancer Clinical Research Unit at Princess Margaret Cancer Centre, co-director of the Drug Development Program at Princess Margaret Cancer Centre, senior scientist at the Princess Margaret Cancer Centre, and professor of Medicine at the University of Toronto, as well as a coordinating investigator on the ARIEL4 study, said in a press release. “These results underscore the importance of rucaparib as a treatment option for women with BRCA-mutant advanced ovarian cancer.”

The international, multicenter, randomized phase 3 study is evaluating rucaparib at a dose of 600 mg twice daily versus chemotherapy in patients with platinum-sensitive, partially platinum-sensitive, and platinum-resistant relapsed ovarian, fallopian tube, or primary peritoneal cancers and a BRCA mutation who have received 2 or more prior lines of chemotherapy.2 Overall, 349 women were enrolled in the trial across North and South America, Europe, and Israel. Of note, the efficacy patient population (n = 325) consisted of patients with a deleterious tumor BRCA mutation and excluded those with a BRCA reversion mutation, as determined by a blood test.

The primary end point of the study is investigator-assessed PFS by RECIST 1.1. Other outcome measures include overall survival (OS), objective response rate by RECIST and by RECIST/cancer antigen 125 (CA-125) criteria, duration of response, patient-reported outcomes by European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire (QLQ-C30) and the ovarian cancer module (QLQ-OV28), and safety and tolerability of rucaparib versus chemotherapy.

For the primary end point of investigator-assessed PFS, therapy with rucaparib (n = 220) achieved statistical significance over chemotherapy (n = 105) in the efficacy population, with a hazard ratio of 0.639 (P = .001). The median PFS was 7.4 months with rucaparib compared with 5.7 months for chemotherapy alone.

Additionally, among the intention-to-treat (ITT) patient population (n = 349), the investigator-assessed PFS in the rucaparib arm (n = 233) achieved statistical significance over the chemotherapy arm (n = 116), with a hazard ratio of 0.665 (P = .0017). The medians were 7.4 months versus 5.7 months, respectively.

Minimal benefit with rucaparib therapy was noted in the 7% of patients who had a BRCA reversion mutation, based on investigator-assessed PFS results.

In an interim analysis of OS, investigators revealed a trend toward an OS advantage in the chemotherapy arm; however, this was confounded by the high rate (64%) of per-protocol crossover to rucaparib following progression on chemotherapy. In an analysis of the ITT population comparing patients who received rucaparib at any point on the trial versus those who did not, a trend toward an OS advantage was observed for the PARP inhibitor.

Regarding safety, adverse events (AEs) were found to be consistent with the known safety profiles of rucaparib and chemotherapy. The most common treatment-emergent grade 3/4 AEs occurring in more than 5% of all patients who received rucaparib (n = 232) in the ARIEL4 study were anemia/decreased hemoglobin (22%), neutropenia/decreased absolute neutrophil count (10%), asthenia/fatigue (8%), thrombocytopenia/decreased platelets (8%), and increased alanine transaminase/aspartate transaminase (8%).

“We are pleased with these topline results from the ARIEL4 trial, which confirm the clinical benefit of [rucaparib] versus chemotherapy, including platinum-based chemotherapy, as a treatment for women with BRCA mutation–positive advanced ovarian cancer, including patients who are platinum-resistant,” Patrick J. Mahaffy, president and CEO of Clovis Oncology, said in the release. “We look forward to sharing comprehensive results at an upcoming medical meeting.”


1. Clovis Oncology’s Rubraca (rucaparib) met the primary endpoint of significantly improving progression-free survival vs. chemotherapy in the ARIEL4 randomized phase 3 treatment study in later-line ovarian cancer patients with a BRCA mutation [news release]. Boulder, Colorado. Published December 21, 2020. Accessed January 5, 2021.

2. Oza AM, Lorusso D, Oaknin A, et al. ARIEL4: An international, multicenter randomized phase 3 study of the PARP inhibitor rucaparib vs chemotherapy in germline or somatic BRCA1- or BRCA2-mutated, relapsed, high-grade ovarian carcinoma. J Clin Oncol. 2017;35(suppl 15):TPS5603. doi:10.1200/JCO.2017.35.15_suppl.TPS5603

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