Rucaparib showed an overall response rate of 82% among a cohort of patients with BRCA-mutated ovarian cancer in the phase II ARIEL2 study.
Robert Coleman, MD
Rucaparib showed an overall response rate (ORR) of 82% among a cohort of patients withBRCA-mutant ovarian cancer in the phase II ARIEL2 study presented at the 2015 ASCO Annual Meeting. In aBRCA-like group of patients with homologous recombination deficiency (HRD), the ORR was 45%. The median progression-free survival (PFS) was 9.4 months in theBRCA-mutated group and 7.1 months in theBRCA-like arm. In the biomarker negative group, the median PFS was 3.7 months and the ORR was 13%.
“To see the encouraging progression-free survival rates mirror the impressive response rates in both the BRCA-mutant and BRCA-like populations represents a very exciting step forward in the treatment of advanced ovarian cancer,” study co-author Robert L. Coleman, MD, Professor & Deputy Chairman in the Department of Gynecologic Oncology and Reproductive Medicine at University of Texas MD Anderson Cancer Center in Houston, said in a statement. “The opportunity to provide a very compelling targeted therapy in an ovarian cancer population in addition to those who carry germline or somaticBRCAmutation represents a potentially practice changing advance in the treatment of this terrible disease.”
In the phase II study, 204 women with high-grade serous or endometrioid ovarian cancer were treated with rucaparib at 600 mg twice daily. Patients were stratified into three arms, based onBRCAmutation and biomarker status. Only 15 patients with known germlineBRCAmutations were enrolled. Overall, 20% of patients had aBRCAmutation (n = 41), 40% wereBRCA-like (biomarker positive; n = 82), 34% had biomarker-negative disease (n = 69), and 6% were unclassified (n = 12).
The median age of patients enrolled was 65 years and the majority had epithelial ovarian cancer (80%) with serous histology (96%). Fifty-seven percent of patients had received 1 prior therapy and 43% had received ≥2 prior regimens. The primary endpoint of the study was PFS, with ORR, safety, and pharmacokinetics as secondary outcome measures.
In comparison with the negative group, those with aBRCAmutation saw a 53% reduction in the risk of progression with rucaparib (HR = 0.47; 90%, 0.35-0.64). For those with aBRCA-like tumor, the risk of progression was reduced by 39% compared with the negative biomarker arm (HR = 0.61; 90% CI, 0.41-0.92).
There were robust responses in both the somatic and germline mutation carriers with rucaparib. In those with germline mutations inBRCA, the ORR was 81%. In patients with somaticBRCAmutations, the ORR reached 88%, which included 4 complete responses. The median duration of response was 9.3 months and remained ongoing at the analysis.
The most frequently observed adverse events with rucaparib were nausea (66%), asthenia/fatigue (61%), ALT/AST increase (40%), dysgeusia (38%), and decreased appetite (31%). The most common grade 3/4 adverse events were anemia (16%), ALT/AST increase (11%), and fatigue (6%).
“With these data presented at ASCO, we believe rucaparib has clearly emerged as a unique and best-in-class PARP inhibitor," Patrick J. Mahaffy, president and CEO of Clovis Oncology, the company developing the drug, said in a statement. "In addition, with our now clinically provenBRCA-like clinical assay, we have validated our commitment to develop rucaparib not only for the 25% of women with germline and somaticBRCAmutations, but for the additional approximately 35% of women with the prospectively identified BRCA-like signature."
In April 2015, rucaparib received a breakthrough therapy designation from the FDA as a treatment for women withBRCA-mutated advanced ovarian cancer following progression on at least two prior lines of platinum-based chemotherapy. Clovis Oncology, the company developing rucaparib, plans to submit a new drug application (NDA) to the FDA in 2016, based on the expansion cohort data.
Part 2 of the ARIEL2 study remains ongoing for patients with heavily pretreated ovarian cancer. 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.
"With the ARIEL2 extension enrolling rapidly, we look forward to submitting our NDA for rucaparib for the treatment of advanced ovarian cancer next year," Mahaffy added.
McNeish IA, Oza AM, Coleman RL, et al. Results of ARIEL2: A phase 2 trial to prospectively identify ovarian cancer patients likely to respond to rucaparib using tumor genetic analysis.J Clin Oncol