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Encouraging Results Reported for Ovarian Cancer Drug Rucaparib

Seventy percent response rate observed in ongoing phase II study

Initial mid-stage results have been announced from the ARIEL2 (Assessment of Rucaparib In Ovarian CancEr TriaL 2) study.

Rucaparib (Clovis Oncology) is an investigational oral, small-molecule inhibitor of PARP1 and PARP2 that is being developed for the treatment of platinum-sensitive ovarian cancer, specifically in patients with tumors with BRCA gene mutations and other DNA repair deficiencies beyond BRCA, commonly referred to as “BRCA-like” or “BRCA-ness.” BRCA mutations have been linked to the development of breast and ovarian cancers.

The data were presented November 19 at the 26th European Organization for Research and Treatment of Cancer (EORTC)–National Cancer Institute (NCI)–American Association for Cancer Research (AACR) Symposium on Molecular Targets and Cancer Therapeutics, held in Barcelona, Spain.

The global ARIEL2 trial involved 121 patients with platinum-sensitive ovarian cancer. The study’s objectives included determining rucaparib sensitivity in prospectively defined molecular subgroups through the assessment of progression-free survival (PFS) in patients with tumors with BRCA mutations or BRCA-like mutations (DNA repair deficiencies but normal BRCA genes), and in biomarker-negative patients, as well as the objective response rate (ORR), safety, and pharmacokinetics.

To date, patients in the study have received a median of one prior treatment regimen and one prior platinum-based therapy regimen. The patients were treated with rucaparib at the recommended phase II dosage of 600 mg twice daily. Few progression events have occurred to date; therefore, ORR data were reported in the interim analysis.

Target-lesion reduction was observed in 77% of patients with screening biopsy results (n = 61) and a first staging scan; the most robust clinical activity was observed in patients with tumor BRCA mutations. Seventy percent (16/23) of BRCA-mutant patients achieved a RECIST and/or CA-125 response, and 61% (14/23) achieved a RECIST response. Responses were observed in both germline and somatic BRCA-mutant tumors.

In addition, in patients with normal BRCA genes, rucaparib activity was different between patients with a prospectively defined BRCA-like signature and biomarker-negative patients. Forty percent (10/25) of patients with normal BRCA and the BRCA-like signature achieved a RECIST and/or CA-125 response, and 32% (8/25) achieved a RECIST response. Few responses were observed in biomarker-negative patients: 8% (1/13) of patients achieved a RECIST and/or CA-125 response.

At a dosage of 600 mg twice daily, the most common treatment-related adverse events (AEs) associated with rucaparib included nausea, fatigue, transient alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevations, dysgeusia, decreased appetite, anemia or low hemoglobin, constipation, and vomiting. No patient has discontinued rucaparib because of a treatment-related AE.

The ARIEL2 trial is currently enrolling approximately 180 ovarian cancer patients with relapsed, platinum-sensitive disease. The single-arm, open-label study is designed to prospectively test molecular features that predict sensitivity to rucaparib using DNA sequencing to evaluate each patient’s tumor. The efficacy of rucaparib is being assessed and correlated with the genotype of each patient’s tumor, and these data will inform the final definition of “BRCA-ness” for an upcoming pivotal study (ARIEL3).

Source: Clovis Oncology; November 19, 2014.


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