FDA Approves Rucaparib for Ovarian Cancer

Richard Pazdur, MD

The FDA has granted an accelerated approval to rucaparib (Rubraca) as a treatment for patients with BRCA-positive advanced ovarian cancer who have received at least 2 prior lines of chemotherapy, according to Clovis, the manufacturer of the PARP inhibitor.

The approval is based on data from 106 patients across 2 trials, including the ARIEL2 study. In a pooled analysis of data from the studies, the objective response rate (ORR) was 54% (95% CI, 44-64) with rucaparib.

"Today's approval is another example of the trend we are seeing in developing targeted agents to treat cancers caused by specific mutations in a patient's genes," Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research and acting director of the FDA's Oncology Center of Excellence, said in a statement. "Women with these gene abnormalities who have tried at least two chemotherapy treatments for their ovarian cancer now have an additional treatment option."

In addition to rucaparib, the FDA also approved FoundationFocus CDxBRCA as a companion diagnostic to detect deleterious BRCA mutations in tumor tissue. This test is the first next-generation sequencing-based companion diagnostic to gain FDA approval, according to the agency.

The 106 patients comprised 42 patients from a phase I/II study (NCT01482715) and 64 patients from the ARIEL2 phase II study (NCT01891344). Both trials were multicenter, single-arm, open-label studies in patients with BRCA-positive ovarian cancer who had progressed on 2 or more prior chemotherapies.

The phase I/II trial included only platinum-sensitive patients, while ARIEL2 enrolled patients who were platinum sensitive, resistant, or refractory. The group of 106 patients had a median number of prior therapies of 3 and a median age of 59 years.

The starting dose of rucaparib for all patients was 600 mg twice daily. The primary outcome measures for both studies was investigator-assessed ORR and duration of response (DOR) per RECIST version 1.1.

In the pooled analysis of the 2 trials, the complete response (CR) rate was 9% and the partial response (PR) rate was 45%. The median DOR was 9.2 months (95% CI, 6.6-11.6). ORR rates were similar, regardless of whether patients had germline or somatic BRCA mutations, or mutations of the BRCA1 gene versus the BRCA2 gene. Progressive disease occurred in 9 of the 106 patients.

Among the 42 patients in the phase I/II study, the ORR was 60% (95% CI, 43-74), which included a CR rate of 10% and a PR rate of 50%. The median DOR was 7.8 months (95% CI, 5.6-10.5).

In the ARIEL2 trial, the ORR was 50% (95% CI, 37-63), comprising a CR rate of 8% and a PR rate of 42%. The median DOR was 11.6 months (95% CI, 5.5-18.2).

“Recurrent ovarian cancer remains one of the most difficult cancers to treat and for so many years, medical advances in this space have been limited,” Robert L. Coleman, MD, professor and deputy chairman, vice chair, Clinical Research, Ann Rife Cox Chair in Gynecology, Department of Gynecologic Oncology and Reproductive Medicine at University of Texas MD Anderson Cancer Center, and one of the principal investigators in the ARIEL clinical trial program, said in a statement.

“Today’s approval of Rubraca for the treatment of advanced ovarian cancer demonstrates the value of treatment with PARP inhibitors and represents an important advance for women diagnosed with either germline or somatic BRCA-mutated tumors who have been treated with two or more chemotherapies,” added Coleman.

The safety analysis for rucaparib included 377 patients from the 2 studies who received rucaparib at 600 mg twice daily. The most common grade 3/4 adverse events (AEs) were anemia/decreased or low hemoglobin (25%), fatigue/asthenia (11%), and increased ALT/AST (11%).

Eight percent of patients discontinued treatment due to AEs associated with rucaparib. There was 1 case of myelodysplastic syndrome.

Under the FDA's accelerated approval program, continued approval of rucaparib is contingent on the results of a confirmatory trial. Enrollment has been completed for the ARIEL3 confirmatory trial (NCT01968213), which is examining rucaparib as a maintenance therapy in patients with high-grade serous or endometrioid epithelial ovarian, primary peritoneal, or fallopian tube cancer.

The PARP inhibitor is also being explored in prostate, breast, and gastroesophageal cancers.

“We believe that today’s approval of Rubraca provides an important new therapy for advanced ovarian cancer patients with a germline or somatic mutation of BRCA after 2 or more chemotherapies,” Patrick J. Mahaffy, CEO and president of Clovis Oncology, said in a statement. “We look forward to launching Rubraca with the support of our established US commercial and medical affairs organizations and bringing this much-needed precision medicine to women with advanced ovarian cancer as quickly as possible.”

The ARIEL4 confirmatory study (NCT02855944), which is now open for enrollment, is comparing rucaparib with chemotherapy in patients with BRCA-positive ovarian, fallopian tube, or primary peritoneal cancer, who have received at least 2 prior platinum-based chemotherapy regimens.