Rebecca Kristeleit, BSc, PhD
The majority of heavily pretreated patients with high-grade ovarian cancer (HGOV) and germline or somatic BRCA
mutations showed a durable response to rucaparib, according to findings from an analysis of two phase II trials presented at the 2016 ESMO Congress.
In the efficacy cohort of 106 patients, progression-free survival was a median of 10 months (range: 0 to 22.1) with the PARP inhibitor. In this cohort, 50 patients did not show disease progression nor were there any deaths at data cutoff. Additionally, 32 of the 50 patients remain on rucaparib, and 18 discontinued due to reasons other than disease progression.
With rucaparib, the investigator-assessed objective response rate (ORR) by RECIST v1.1 was 53.8% (95% CI, 43.6-63.5). Complete response was confirmed in 9 patients (8.5%), partial response was seen in 48 (45.3%), and stable disease was achieved by 36 patients (34.0%). Progressive disease occurred in just 9 patients and 4 patients were not evaluable. The median duration of investigator-assessed confirmed response was 9.2 months (95% CI, 6.6-11.7 months).
Subgroup analysis revealed that the response was poorer in platinum-refractory patients, where the ORR was 0%, and in platinum-resistant patients who demonstrated an ORR of 25% compared with an ORR of 65.8% in platinum-sensitive patients.
“Approximately 14% to 18% of epithelial ovarian cancers harbor a germline BRCA 1
mutation, and an additional 5% to 7% harbor a somatic BRCA mutation,” explained lead author Rebecca Kristeleit, BSc, PhD, of the University College-London Cancer Institute. “The PARP inhibitor, rucaparib, has demonstrated clinical activity in BRCA
-mutated high- grade ovarian cancer in two phase II studies.”
Kristeleit presented findings on behalf of colleagues from an integrated efficacy and safety analysis of pooled data of 144 patients with HGOC participating in the ARIEL 2 trial and Study 10 of rucaparib. The efficacy analysis involved 64 and 42 patients participating in ARIEL 2 and STUDY 10, respectively, wherein all patients had received 2 or more prior chemotherapy regimens, including 2 or more (median 3, range 2-6) platinum-based regimens, and had a germline or somatic BRCA
The safety analysis was conducted using data from 315 patients in the ARIEL 2 study and 62 Study 10 patients with a diagnosis of ovarian cancer.
All patients received at least 1 dose of oral rucaparib at 600 mg twice daily in 21- or 28-day cycles or until disease progression or study discontinuation.
In the efficacy analysis, 62.3% of patients had BRCA 1
and 36.8% had BRCA 2
mutations which were germline in 83% of patients and somatic in 12.3%. The origin of BRCA
mutation was undefined in 4.7% of patients. The majority (85.8%) of patients in the efficacy analysis and 80.9% of patients in the safety analysis had epithelial ovarian cancer.
Treatment-related adverse events (TRAEs) occurred in 95.5% of patients and 46.9% of patients had a TRAE grade ≥3. AEs leading to treatment interruption occurred in 58.6% of patients, and 44.3% of patients had a dose reduction due to an AE. AEs leading to death occurred in 9 (2.4%) patients and 8 (2.1%) patients died due to disease progression.
The most commonly reported grade ≥3 AEs were asthenia/fatigue, reported by 10.9% of patients, anemia (24.9%), nausea (5%), vomiting (4%), and thrombocytopenia (4.5%). Laboratory anomalies from baseline of grades 3 or 4 included decreased hemoglobin in 23.5% of patients and ALT/AST was reported in 12.5% and 4.5% of patients, respectively.
“Rucaparib had an acceptable safety profile with most adverse events manageable with treatment interruption or dose modification,” said Kristeleit, who pointed out that 2 phase III confirmatory trials in patients with high-grade ovarian cancer are underway: “Ariel 3 is evaluating rucaparib in the maintenance setting, and Ariel 4 is evaluating rucaparib compared with standard chemotherapy.”
The FDA has accepted the New Drug Approval for accelerated approval of rucaparib for the treatment of advanced ovarian cancer in patients with BRCA-mutated tumors who have been treated with 2 or more chemotherapies. The agency granted it priority review status with a decision expected in February 2017, according to the drug’s manufactuer, Clovis Oncology. The European marketing authorization application for rucaparib is slated for later this year.
Kristeleit RS, Shapira-Frommer R, Oaknin A, et al. Clinical activity of the poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib in patients ( pts) with high-grade ovarian carcinoma (HGOC) and a BRCA mutation (BRCAmut): Analysis of pooled data from Study 10 ( parts 1, 2a, and 3) and ARIEL2 (parts 1 and 2). Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract 8560.
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