New trial updates for rucaparib for advanced ovarian cancer

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data analysis_oncology news australia_800x500New data from parts 1 and 2 of the ongoing ARIEL2 phase II trial was presented in oral sessions at the 2017 Society of Gynecologic Oncology (SGO) Annual Meeting on Women’s Cancer in National Harbor, MD.

New data from these presentations include analyses of patient subsets from the ARIEL2 trial, including an integrated summary of data in patients from ARIEL2 parts 1 and 2 with a germline or somatic BRCA1 or BRCA2 (BRCA) mutation.

ARIEL2 enrolled 493 patients with relapsed ovarian cancer to identify those patients most likely to respond to treatment with rucaparib: part 1 enrolled 206 patients who received one or more prior therapies, had platinum as their last treatment, and were platinum-sensitive; part 2 enrolled 287 patients treated with three or four prior therapies who were either platinum-sensitive, -resistant or -refractory at time of enrollment.

“These results demonstrate the impressive activity of rucaparib, especially in earlier line, platinum-sensitive patients,” said Dr. Konecny MD, associate professor of Medicine, Department of Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA. “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.”

Dr. Konecny’s presentation analysed objective response rate (ORR) and progression-free survival (PFS) in the 134 ovarian cancer patients with a germline or somatic BRCA mutation enrolled in ARIEL2, as well as the effect of platinum sensitivity status and prior lines of therapy on these endpoints.

These data demonstrate that the objective response rate (ORR), disease control rate (DCR) and median progression-free survival (PFS) in patients with a BRCA mutation were greatest in platinum-sensitive patients, followed in descending order by those who were platinum-resistant, and those who were platinum-refractory.

All responses were assessed and confirmed according to RECIST.

DCR in ARIEL2 was defined as the percentage of patients who had achieved either a complete response, partial response or stable disease that was maintained for greater than 12 weeks.

Patients with disease progression occurring at least 6 months after last platinum were considered platinum-sensitive; patients with disease progression occurring less than 6 months after last platinum with best response other than progressive disease (PD) were considered platinum-resistant; and patients with best response of PD on last platinum which occurred during or up to 2 months after treatment were considered platinum-refractory.

The data analysis cutoff date was January 4, 2017 and this analysis was limited to patients with BRCA-mutated ovarian cancer enrolled in the ARIEL2 study.

In 57 platinum-sensitive patients whose immediate prior therapy was platinum-based, the investigator-assessed ORR was 70% (95% CI: 57-72) for the overall population, with 83% (95% CI: 59-96), 86% (95% CI: 57-98) and 52% (95% CI: 31-72) ORR observed in patients treated with one, two, or three or more prior lines, respectively.

The DCR in the same population was 81% (95% CI: 68-90) for the overall population, with 94% (95% CI: 73-100), 86% (95% CI: 57-98) and 68% (95% CI: 47-85) in patients treated with one, two, or three or more prior lines, respectively.

The median PFS in the overall platinum-sensitive population whose immediate prior therapy was platinum-based was 12.7 months (95% CI: 9.0-14.7; 30% censoring).

In addition, PFS and ORR were assessed by BRCA mutation type in platinum-sensitive patients whose immediate prior treatment was platinum.

Dr. Konecny’s presentation also discussed the potential role of secondary somatic mutations restoring BRCA function as a mechanism of platinum resistance in patients with platinum-resistant or -refractory disease.

Published data have shown that secondary mutations in BRCA are more frequently observed in platinum-resistant patients than platinum-sensitive patients.

Data presented show that the presence of secondary somatic BRCA mutations may be a better predictor of rucaparib efficacy than prior responsiveness to platinum-based chemotherapy in patients with platinum-resistant or -refractory disease.

In 55 evaluable patients with platinum-resistant or -refractory disease, those without a secondary somatic BRCA mutation (n=47) achieved a median PFS of 7.3 months (95% CI: 5.4-9.0; 26% censoring); conversely, eight patients with a secondary somatic mutation demonstrated a median PFS of only 1.7 months (95% CI: 1.6-3.2; 0% censoring).

These secondary mutations were identified by sequencing of screening tumour biopsy and/or circulating tumour DNA (ctDNA) analysis.

The most common treatment-emergent adverse events observed in ARIEL2 included nausea (78%), asthenia/fatigue (78%), and vomiting (49%).

The most common treatment-emergent grade 3/4 adverse events observed in ARIEL2 included anaemia/decreased haemoglobin (29%), ALT/AST increased (10%), and asthenia/fatigue (10%).

Treatment-emergent adverse events led to dose reductions in 49% of patients, and treatment discontinuation in 13% of patients.

In the second presentation today, Dr. Elizabeth Swisher MD, University of Washington Medical Center, Seattle, WA discussed an analysis of BRCA1 and RAD51C hypermethylation among archival and pretreatment biopsies from part 1 of the ARIEL2 study.

The analysis demonstrated that, among ovarian cancer patients, methylation of BRCA1 and RAD51C is associated with high loss of heterozygosity (LOH), consistent with the HRD phenotype.

Further, methylation of BRCA1 and RAD51C appear to confer sensitivity to rucaparib, as do mutations of CDK12.

These data suggest that methylation is more reliably assessed in pretreatment than archival tumour samples.

Dr. Swisher concludes that routine sequencing of high-grade ovarian cancer tumour tissue biopsies would identify at least 10-15% of women with a somatic mutation and 20% of women with a germline mutation whose tumours might be sensitive to rucaparib.

“We are pleased to present these additional data from the ARIEL2 trial and are encouraged that these findings continue to reinforce rucaparib’s activity and safety profile in the treatment of patients with advanced ovarian cancer,” said Patrick J. Mahaffy, CEO and president of Clovis Oncology, developers of rucaparib. “The data presented today demonstrate our continued commitment to investing in and conducting the rigorous scientific research that will help us and physicians better understand the patients who can benefit most significantly from treatment with rucaparib.”
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