Ovarian cancer patients with a BRCA mutation who responded to their last line of platinum-based chemotherapy are more likely to benefit from Rubraca (rucaparib) than those resistant or refractory to platinum treatment, according to new data from the Phase 2 ARIEL2 study.
Results were recently presented at the 2017 Society of Gynecologic Oncology (SGO) Annual Meeting on Women’s Cancer in National Harbor, Maryland, in two oral plenary sessions.
The first presentation, titled “Rucaparib in patients with relapsed, primary platinum-sensitive high-grade ovarian carcinoma with germline or somatic BRCA mutations: Integrated summary of efficacy and safety from the phase II study ARIEL2” was given by Gottfried E. Konecny, MD, associate professor of Medicine, Department of Medicine, David Geffen School of Medicine, UCLA, Los Angeles.
The second abstract, “BRCA1 and RAD51C promoter hypermethylation confer sensitivity to the PARP inhibitor rucaparib in patients with relapsed, platinum-sensitive ovarian carcinoma in ARIEL2 Part 1,” was presented by Elizabeth M. Swisher, MD, University of Washington Medical Center, Seattle.
The ARIEL2 study (NCT01891344) is a two-part, open-label trial designed to identify which ovarian cancer patients are more likely to respond to treatment with Rubraca (by Clovis Oncology). Part 2 enrolled 287 patients who had received three or four prior therapies and were either platinum-sensitive, platinum-resistant or platinum-refractory.
Platinum-sensitive patients are those who achieve a response to initial platinum-based treatment and have been off therapy for an extended period of time. Platinum-resistant patients respond to treatment with a complete response, partial response, or demonstrated stable disease, but with disease progression less than six months after platinum therapy. Platinum-refractory patients did not respond to treatment and had disease progression during or up to two months after platinum treatment.
The new results showed that the number of prior lines of therapy influences the response rates of platinum-sensitive patients whose immediate prior therapy was platinum-based. For the overall population, the objective response rate (ORR), defined as having either a complete or partial response, was 70%. Patients treated with one, two, or three or more prior lines of therapy had an ORR of 83%, 86% and 52%, respectively.
The median progression-free survival for the overall population was 12.7 months.
In platinum-sensitive patients whose immediate prior treatment was platinum-based, results also revealed that having an inherited or acquired BRCA mutation led to similar ORRs (75% vs. 74%) and progression-free survival (PFS; 12.8 months vs. 12.7 months).
These results were better than those found in the overall population of patients with inherited or acquired BRCA mutations, which had ORRs of 71% and 70%, and PFSs of 12.8 months and 11.2 months, respectively.
All evaluable platinum-resistant and platinum-refractory patients had received three or more lines of therapy. In the 49 evaluable platinum-resistant patients, the ORR was 25% and PFS was 7.3 months, while in the 14 platinum-refractory patients, the ORR was 0% (no responders) and PFS was 5.0 months.
While patients with BRCA mutations are more likely to benefit from platinum-based chemotherapy, certain patients may develop resistance by acquiring a second mutation in BRCA that restores its normal function.
The new data suggest that the presence of such secondary BRCA mutations may help predict which patients will respond to platinum-based chemotherapy. In 55
evaluable patients who were resistant or refractory to platinum treatment, those without a secondary mutation had PFS of 7.3 months, while those with a secondary mutation had PFS of only 1.7 months.
In the second presentation, researchers revealed that methylation of the BRCA1 and RAD51C genes (in which methyl groups are placed in the DNA to affect gene expression) is associated with increased sensitivity to Rubraca.
“These results demonstrate the impressive activity of rucaparib, especially in earlier line, platinum-sensitive patients,” Konecny said in a press release. “We also gain insight into important biomarker analyses that may help us predict which patients with far more advanced disease are most likely to benefit from rucaparib.”
Rubraca was approved by the U.S. Food and Drug Administration in December 2016 as a monotherapy for women with BRCA-mutated advanced ovarian cancer. The approval was based on data from Study 10 and ARIEL2.
Rubraca is also being developed as maintenance therapy for ovarian cancer in the ARIEL3 trial (ongoing but not recruiting) for patients with tumors with BRCA mutations and other DNA repair deficiencies beyond BRCA, as well as biomarker-negative patients.
ARIEL4 is a Phase 3 trial for women with relapsed, high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer who have a BRCA1 or BRCA2 mutation. This study is designed to evaluate Rubraca against standard-of-care chemotherapy in women who have had at least two prior chemotherapy regimens, and is currently recruiting patients.
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