The US Food and Drug Administration (FDA) today granted accelerated approval to the oral therapy rucaparib (Rubraca, Clovis Oncology) for the treatment of women with advanced ovarian cancer who have received two or more prior chemotherapies and whose tumors have a BRCA gene mutation.
The BRCA mutations must be identified by the FoundationFocus CDxBRCA companion diagnostic test (Foundation Medicine), which was also approved by FDA today for use in this setting. Approximately 15% to 20% of ovarian cancers have a BRCAgene mutation, according to the agency.
Rucaparib is a poly-adenosine diphosphate-ribose polymerase (PARP) inhibitor that blocks an enzyme that would otherwise help repair damaged DNA in cancer cells, and thus the drug may slow or stop tumor growth.
"Today's approval is another example of the trend we are seeing in developing targeted agents to treat cancers caused by specific mutations in a patient's genes," said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research.
There is already another similar drug on the market — the PARP inhibitor olaparib (Lynparza, AstraZeneca), which was approved in 2014 for use in heavily pretreated women with advanced ovarian cancer with BRCA mutations, as detected by an FDA-approved test. At the time, Dr Pazdur described olaparib as "the first of a new class of drug for treating ovarian cancer."
Results From Two Clinical Trials
Rucaparib becomes another drug approved by the FDA under its accelerated approval program and with the use of a surrogate endpoint (response rate).
The approval of rucaparib is based on results from two single-arm clinical trials involving 106 women with advanced ovarian cancer who had been treated with two or more chemotherapy regimens and had their BRCA-mutations confirmed by the companion diagnostic test.
In the trials, known as Study 10 and ARIEL2 (Assessment of Rucaparib In Ovarian CancEr TriaL2) Parts 1 and 2, there was an overall response rate of 54% (complete, 9%; partial, 45%) and a median duration of response of 9.2 months, according to the FDA press materials.
The drug's prescribing information contains these same figures but also indicates that the overall response rate as assessed by an independent radiology review was 42%, with a median duration of response of 6.7 months, while the investigator-assessed response rate was 66%.
For all assessments, the overall response rate was similar for patients with a BRCA1 gene mutation or BRCA2 gene mutation.
The median age of the patients was 59 years (range, 33 to 84 years), most were white (78%), and 100% had an Eastern Cooperative Oncology Group performance status of 0 or 1. All patients had received at least two prior platinum-based chemotherapies, and 43% had received 3 or more prior lines of chemotherapy.
The recommended dose of rucaparib is 600 mg (two 300-mg tablets) taken orally twice daily with or without food. Treatment is to be continued until disease progression or unacceptable toxicity.
In terms of safety, patients receiving rucaparib commonly (≥20%) experienced nausea, fatigue, vomiting, anemia, abdominal pain, dysgeusia, constipation, decreased appetite, diarrhea, and dyspnea. Most common laboratory abnormalities (≥35%) were increase in creatinine, increase in alanine aminotransferase, increase in aspartate aminotransferase, decrease in hemoglobin, decrease in lymphocytes, increase in cholesterol, decrease in platelets, and decrease in absolute neutrophil count.
The FDA advises monitoring patients for hematologic toxicity at baseline and monthly thereafter. The drug also has potential for serious risks, including myelodysplastic syndrome, acute myeloid leukemia, and fetal harm.
Myelodysplastic syndrome/acute myeloid leukemia (AML) was reported in 2 of 377 (0.5%) patients with ovarian cancer treated with rucaparib. Both patients had received prior treatment with platinum and other DNA-damaging agents.
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More data on rucaparib will eventually come from other trials. The ARIEL3 maintenance confirmatory study has completed enrollment and has results expected in mid-2017. ARIEL3 is a phase 3 trial designed to evaluate the effect of rucaparib as maintenance treatment following platinum-based therapy in women with platinum-sensitive, relapsed, high-grade serous or endometrioid ovarian, fallopian tube, or primary peritoneal cancer.
Also, ARIEL4 is open for enrollment. The phase 3 trial is for women with relapsed, high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer who have a BRCA mutation.
Rucaparib received the FDA's orphan drug designation, which provides incentives such as tax credits, user fee waivers, and eligibility for exclusivity to assist and encourage the development of drugs intended to treat rare diseases.