Rucaparib Receives Breakthrough Designation for BRCA-Positive Advanced Ovarian Cancer

Robert Coleman, MD

The FDA has granted a breakthrough therapy designation to the PARP1/2 inhibitor rucaparib as a treatment for women with BRCA-mutated advanced ovarian cancer who have received at least two prior lines of platinum-based chemotherapy.

The designation was based on interim findings from two ongoing phase II clinical studies that are examining single-agent rucaparib in patients with ovarian cancer. Findings from the ARIEL2 study, which were presented at the 2015 SGO Annual Meeting, demonstrated an objective response rate (ORR) with rucaparib of 65% by RECIST criteria in patients with germline BRCA mutations.

The FDA's breakthrough therapy designation will help expedite Clovis Oncology's development of rucaparib. The company plans to seek regulatory approval for the drug in 2016, based on an expansion cohort of 300 patients enrolled in the ARIEL2 trial.

“Data presented to date in mutant BRCA patients treated with rucaparib are very encouraging, as is the breakthrough therapy designation conferred by the FDA,” Robert L. Coleman, MD, professor, Department of Gynecologic Oncology and Reproductive Medicine, University of Texas MD Anderson Cancer Center, said in a statement. "Women with ovarian cancer are in need of better therapeutic options, and there is great focus on the potential of PARP inhibitors."

The first portion of the ARIEL2 trial enrolled 206 women with platinum-sensitive, measurable, high-grade serous or grade 2/3 endometrioid ovarian cancer. Rucaparib was administered at 600 mg twice daily across 3 predefined subgroups based on homologous recombination deficiency (HRD) status: BRCA mutated, BRCA wild-type/loss of heterozygosity (LOH) high, and BRCA wild-type/LOH low.

Interim data for 61 patients were presented at the SGO meeting. The median age of patients was 64, 69% had an ECOG PS of 0, and 54% were treated with ≥2 prior regimens. Mutation analysis was conducted using a next-generation sequencing-based companion diagnostic developed by Foundation Medicine. In addition to genomic alterations in BRCA1/2, the test examines molecular signatures associated with HRD.

“I am very enthusiastic about the substantive progress made by Clovis with both rucaparib and its patient selection tool that appears to be moving beyond BRCA to efficiently identify responder versus non-responder populations," Coleman said. "Continuing successful development of this drug and its companion diagnostic will be a huge advance for women with this disease."

In patients with BRCA-mutated tumors (n = 23), the ORR by RECIST was 65% and the ORR by CA-125 and/or RECIST was 70%. In patients with BRCA wild-type and LOH high tumors (n = 25), the RECIST ORR was 40% and the CA-125/RECIST ORR was 48%. In patients with BRCA wild-type/LOH low tumors (n = 13), the ORR was 8% by both indicators.

"Importantly, these data suggest that the majority of women tested might benefit from rucaparib treatment," Coleman noted.

The most common all-grade adverse events associated with rucaparib were GI related, including nausea, dysgeusia, decreased appetite, constipation, vomiting, and diarrhea. Additionally, treatment was related with fatigue decreases in hemoglobin level, absolute neutrophil count, and platelets. An increase was seen in creatinine and a transient increase was seen in ALT/AST levels, without liver dysfunction evident.

Full data from the first portion of the ARIEL2 study will be presented at the upcoming 2015 ASCO Annual Meeting. The expansion portion of the study plans to enroll 300 patients with recurrent ovarian cancer following at least 3 prior lines of chemotherapy, with data available in 2016.

In addition to the phase II study, the phase III ARIEL3 trial will randomize patients with platinum-sensitive, high-grade ovarian cancer to maintenance therapy with rucaparib or placebo. The study plans to enroll 540 patients, with enrollment expected to complete within the next year.

"We hope that the ARIEL2 extension study in around 300 women, and the randomized ARIEL3 trial in 540 women, will offer definitive support both for rucaparib and the companion diagnostic,” said Coleman, one of the principal investigators of the ARIEL3 study.

In addition to ovarian cancer, Clovis is also assessing rucaparib as a potential therapy for other solid tumors associated with BRCA or BRCA-like HRD. A phase II study is examining rucaparib in patients with pancreatic cancer with a known deleterious BRCA mutation. Additionally, a phase II study assessed rucaparib in patients with locally advanced or metastatic breast cancer or advanced ovarian cancer.