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Ovarian Cancer Drug Rucaparib Receives ‘Breakthrough Therapy’ Designation
The FDA has granted a “breakthrough therapy” designation for the investigational agent rucaparib (Clovis Oncology) as monotherapy for advanced ovarian cancer in patients who have received at least two lines of platinum-containing therapy, with BRCA-mutated tumors, inclusive of both germline BRCA (gBRCA) and somatic BRCA (sBRCA) mutations.
Rucaparib is an oral inhibitor of poly (ADP-ribose) polymerase 1 (PARP1) and PARP2 being developed for the treatment of platinum-sensitive ovarian cancer, specifically in patients with tumors with BRCA mutations and other DNA repair deficiencies beyond BRCA, commonly referred to as “BRCA-like” or “BRCAness.”
The “breakthrough therapy” designation was granted based on interim efficacy and safety results from two ongoing phase II studies of rucaparib in patients with ovarian cancer, including a phase II trial in women with gBRCA mutations, as well as the ARIEL2 (Assessment of Rucaparib in Ovarian Cancer Trial 2) study.
Data from the ARIEL2 trial, presented at the 2015 Annual Meeting on Women’s Cancer, demonstrated that 70% (16/23) of evaluable BRCA-mutant patients achieved a Response Evaluation Criteria in Solid Tumors (RECIST) and/or cancer antigen 125 (CA-125) response, and that 65% (15/23) achieved a RECIST response. Responses were observed in both germline and somatic BRCA-mutant tumors.
The data also demonstrated that rucaparib was well-tolerated. At the recommended phase II dosage of 600 mg twice daily, the most common treatment-related adverse events (AEs) reported in all 121 patients included nausea, fatigue, transient elevations in alanine aminotransferase (ALT) or aspartate aminotransferase (AST), dysgeusia, constipation, anemia or low hemoglobin, decreased appetite, vomiting, and diarrhea.
Initiated in the fourth quarter of 2013, the ARIEL2 study has completed enrollment of 206 ovarian cancer patients with relapsed, platinum-sensitive disease. The single-arm, open-label phase II trial is designed to prospectively test molecular features that predict sensitivity to rucaparib using DNA sequencing to evaluate each patient’s tumor. ARIEL2 was recently expanded into a registration study (the ARIEL2 extension), which will include approximately 300 additional women with recurrent breast cancer after at least three prior lines of chemotherapy. Data from this study are expected to serve as the basis of a new drug application (NDA) filing for the treatment of ovarian cancer in 2016.
In addition to the ARIEL program in ovarian cancer, rucaparib is being evaluated in other solid tumor types with significant BRCA and BRCA-like populations, including breast, gastroesophageal, and pancreatic cancer.
More than 90% of ovarian cancer arises from the uncontrolled growth and replication of the epithelial cells that form the surface of the ovary. High grade serous carcinoma is a subtype of epithelial ovarian cancer, accounting for approximately 70% of cases. If detected at an early stage, ovarian cancer can usually be removed surgically, and this can be potentially curative. However, ovarian cancer often does not have clearly identifiable initial symptoms, and in approximately 90% of high-grade serous tumors, the cancer has metastasized before a person is diagnosed.
Source: Clovis Oncology; April 6, 2015.