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
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.
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.
Perspectives on ARIEL4 were provided for The ASCO Post by the invited discussant Ursula Matulonis, MD, Professor of Medicine, Harvard Medical School, and Chief of Gynecologic Oncology and the Brock Wilson Family Chair at Dana-Farber Cancer Institute, Boston, and by Konstantin Zakashansky, MD,...