Study: Rucaparib May Improve Progression-Free Survival in Patients With Later-line Ovarian Cancer With a BRCA mutation

Topline data from the phase 3 ARIEL4 study (NCT02855944) of rucaparib (Rubraca; Clovis Oncology) met its primary endpoint of improved progression-free survival (InvPFS) compared to chemotherapy in patients with relapsed ovarian cancer with a tumor mutation of BRCA. These patients received 2 or more prior lines of chemotherapy.¹

Rucaparib is an oral, small molecule inhibitor of PARP1, PARP2 and PARP3 being developed in multiple tumor types, including ovarian and metastatic castration-resistant prostate cancers, as monotherapy, and in combination with other anticancer agents. Exploratory studies in other tumor types are also underway.

According to Dr Amit Oza, head of the Division of Medical Oncology & Hematology, medical director of the Cancer Clinical Research Unit, co-director of the Drug Development Program, and senior scientist at the Princess Margaret Cancer Centre; and professor of medicine at University of Toronto in Canada, results of the ARIEL4 study have 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.

“These results underscore the importance of rucaparib as a treatment option for women with BRCA-mutant advanced ovarian cancer,” said Oza, in a prepared statement.

Ovarian cancer ranks fifth in cancer deaths among women in the United States and the European Union (EU). Although there are a growing number of therapies to treat ovarian cancer, after initial therapy, 70%-90% of US women with advanced disease will recur. In the EU, approximately 70% of patients experience a relapse within 3 years following initial therapy.

Rucaparib is indicated for the maintenance treatment of adult women with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy; and for the treatment of adult women with a deleterious BRCA mutation (germline and/or somatic)-associated epithelial ovarian, fallopian tube, or primary peritoneal cancer who have been treated with 2 or more chemotherapies.

The multicenter, randomized ARIEL4 study evaluates rucaparib versus chemotherapy in platinum-sensitive, partially platinum-sensitive, and platinum-resistant patients with relapsed ovarian cancer and a BRCA mutation who have received 2 or more prior lines of chemotherapy. The primary endpoint of the study is InvPFS, with a step down analysis from the efficacy population (if significant) to the ITT population. The efficacy population comprised the group of patients with a deleterious tumor BRCA mutation and excluded those with a BRCA reversion mutation as determined by a blood test. Development of reversion mutations that restore BRCA protein function are associated with resistance to platinum-based chemotherapies and PARP inhibitors in BRCA-mutant cancers, and these occur more frequently in platinum-resistant vs platinum-sensitive patients (13% and 2% respectively in the ARIEL2 study).

According to Clovis Oncology, 349 women in North and South America, Europe, and Israel were enrolled in the ARIEL4 study. The efficacy population (n=325) comprised the group of patients with a deleterious tumor BRCA mutation and excluded those with a BRCA reversion mutation. The rucaparib arm (n=220) successfully achieved statistical significance over the chemotherapy arm (n=105) for the primary endpoint of InvPFS with a hazard ratio of 0.639 (p=0.0010). The median PFS for the patients in the efficacy population treated with rucaparib was 7.4 months vs. 5.7 months among those who received chemotherapy.

Additionally, in the ITT population (n=349), the rucaparib arm (n=233) successfully achieved statistical significance over the chemotherapy arm (n=116) for the primary endpoint of InvPFS with a hazard ratio of 0.665 (p=0.0017). The median PFS for the patients in the ITT population treated with rucaparib was 7.4 months vs. 5.7 months among those who received chemotherapy.

An interim analysis of overall survival, a secondary endpoint in the study in which 51% of events have occurred in the ITT population, showed a trend toward an overall survival (OS) advantage in the chemotherapy arm, but was confounded by the high rate (64%) of per-protocol crossover to rucaparib following progression on chemotherapy. According to Clovis Oncology, an analysis of the ITT population of patients showed a trend toward an OS advantage for those patients who received rucaparib at any point in the trial versus those who did not.

The most common (>5%) treatment-emergent grade 3/4 AEs among all patients treated with rucaparib (n=232) in the ARIEL4 study were anemia (22%), neutropenia (10%), fatigue (8%), thrombocytopenia (8%), and increased ALT/AST (8%).

In a prepared statement, Dr. Rebecca Kristeleit, co-chief investigator of ARIEL4 and consultant medical oncologist in London, United Kingdom, noted that there are limited treatment options for relapsed ovarian cancer, which remains a deadly gynecologic cancer.

“There is a need for therapies that can extend time to progression. The ARIEL4 data confirm the clinical relevance of BRCA reversion mutations and advance our understanding of how best to manage the treatment of women with advanced ovarian cancer,” Kristeleit added.

Clovis Oncology plans to provide an expanded description of the ARIEL4 results at a medical meeting in 2021, according to the company.

REFERENCE

• 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, CO; December 21, 2020: Clovis Oncology. Accessed December 21, 2020. https://ir.clovisoncology.com/investors-and-news/news-releases/press-release-details/2020/Clovis-Oncologys-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/default.aspx