FDA Accepts New Drug Application, Grants Priority Review of Rucaparib for the Treatment of Advanced BRCA-Mutant Ovarian Cancer


The U.S. Food and Drug Administration (FDA) has accepted Clovis Oncology’s New Drug Application (NDA) for accelerated approval of rucaparib and granted Priority Review status to the application with a Prescription Drug User Fee Act date of February 23, 2017. Rucaparib is an oral, small-molecule inhibitor of PARP1, PARP2, and PARP3 being developed for advanced ovarian cancer.

In late June 2016, Clovis completed its NDA submission of rucaparib to the FDA for the treatment of advanced ovarian cancer in patients with deleterious BRCA-mutated tumors inclusive of both germline and somatic BRCA mutations (as detected by an FDA-approved test) who have been treated with two or more chemotherapies. Rucaparib was granted Breakthrough Therapy designation for the proposed indication by the FDA in April 2015.

“The acceptance of the rucaparib NDA submission represents an important milestone for rucaparib, and for Clovis,” said Patrick J. Mahaffy, MA, President and CEO of Clovis Oncology. “There is tremendous need for additional therapeutic options for patients with advanced mutant BRCA ovarian cancer, and we look forward to cooperating with FDA on the rucaparib NDA review.”

“Recurrent ovarian cancer remains a very difficult disease to treat, even among women who carry or whose tumors have a mutation in the BRCA genes. Despite the available treatment options, few effective therapies are at our disposal. Thus, the opportunity to treat women with germline or somatic BRCA mutations with rucaparib after two prior lines of platinum-based therapy represents a meaningful step forward for our patients,” said Robert L. Coleman, MD, Professor and Deputy Chairman, Vice Chair of Clinical Research, and Ann Rife Cox Chair in Gynecology in the Department of Gynecologic Oncology and Reproductive Medicine at The University of Texas MD Anderson Cancer Center and one of the principal investigators in the ARIEL clinical trial program.

Efficacy Assessment

The efficacy of rucaparib was assessed in 106 patients from two multicenter, single-arm, open-label clinical trials, Study 1 (Study 10, NCT01482715) and Study 2 (ARIEL2 Parts 1 and 2, NCT01891344), in patients with advanced BRCA-mutant ovarian cancer and disease progression after two or more prior chemotherapies. Median age was 59 years, and median number of prior chemotherapy regimens was three.

Study 1 was limited to platinum-sensitive patients. Study 2 included platinum-sensitive, platinum-resistant, and platinum-refractory patients.

All 106 patients received the starting dose of rucaparib at 600 mg twice daily. The major efficacy outcome measure of both trials was objective response rate and duration of response, as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. All responses were confirmed.

Efficacy results from Study 1 and Study 2 in all patients treated are summarized below:

Overall Response and Duration of Response

Study 1 (N =42)

  • Objective response rate = 60% (95% confidence interval [CI]) = 43%—74%)
  • Complete response rate = 10%
  • Partial response rate = 50%
  • Median duration of response = 7.8 months (95% CI = 5.6—10.5 months)

Study 2 (N = 64)

  • Objective response rate = 50% (95% CI = 37%—63%)
  • Complete response rate = 8%
  • Partial response rate = 42%
  • Median duration of response = 11.6 months (95% CI = 5.5—18.2 months)

Overall (N = 106)

  • Objective response rate = 54% (95% CI = 44%—64%)
  • Complete response rate: 9%
  • Partial response rate: 45%
  • Median duration of response = 9.2 months (95% CI = 6.6—11.6 months)

Nine (9%) of the 106 patients overall had progressive disease as best response. The overall response rate was similar for patients with germline BRCA-mutant ovarian cancer or somatic BRCA-mutant ovarian cancer and for patients with a BRCA1/2 gene mutation.

Safety Assessment

The safety population comprises the 377 ovarian cancer patients treated with a starting dose of rucaparib at 600 mg twice daily in Study 1 and Study 2.

The grade 3/4 treatment emergent adverse events reported in ≥ 10% of patients were anemia/decreased or low hemoglobin (25%); fatigue/asthenia (11%); and increased alanine transaminase (ALT)/aspartate transaminase (AST) (11%). The observed increases in aminotransferase levels were asymptomatic, reversible, and rarely associated with increases in bilirubin. The elevations normalized over time with continued rucaparib treatment.

The discontinuation rate for ovarian cancer patients due to rucaparib-related adverse events was 8%.

Myelodysplastic syndrome was reported in 1 of 377 (0.3%) patients with ovarian cancer.

In addition, in the ongoing ARIEL3 maintenance trial, a blinded, randomized trial evaluating rucaparib vs placebo, acute myeloid leukemia (AML) was reported in 2 (<0.5%) patients with ovarian cancer. One case of AML was fatal. Both of these patients had received prior treatment with platinum and other DNA-damaging agents.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.