What is rucaparib?
Rucaparib is a PARP (poly [ADP-ribose] polymerase) inhibitor.
How does rucaparib work?
Cancer cells with harmful mutations in BRCA1 or BRCA2 lead to deficiencies in repair of DNA strand breaks, occurring in about 20 percent of ovarian cancer patients. Even with wild-type BRCA, there can be genomic loss of heterozygosity (LOH) that also leads to homologous recombination deficiency. This has led to a reliance on other DNA repair pathways such as PARP. Cancer cells with BRCA mutations or LOH are sensitive to PARP inhibitors, leading to accumulation of unrepaired damaged DNA and cell apoptosis.
What is this approved for?
Rucaparib is approved as monotherapy treatment for patients with advanced ovarian cancer harboring germline or somatic BRCA mutations, who have been treated with two or more chemotherapy regimens. The companion diagnostic test is the FoundationFocus CDxBRCATM test.
What is the basis for this approval?
The ARIEL2 Part 1 study was recently published. It was a single-arm phase II trial enrolling patients with recurrent, platinum-sensitive, high-grade ovarian cancer. The participants were stratified into three groups based on the mutations: 1) BRCA-mutant, 2) BRCA wild-type with high LOH, and 3) BRCA wild-type with low LOH [cutoff 14%]. Patients received rucaparib 600mg PO BID until disease progression or unacceptable toxicity. In the BRCA-mutant group, the median PFS was 12.8 months and response rate of 80 percent, which was significantly longer than that of the other two groups. The other two groups had a much lower PFS and response rate. The LOH biomarker cutoff of 15 percent did not seem to discern BRCA wild-type patients who might benefit from rucaparib, but a different cutoff value might be superior (Lancet Oncol 2017;18:75-87).
How do you administer this drug?
Rucaparib is given at a dose of 600 mg orally BID, administered with or without food. It is available as 200 mg and 300 mg tablets. If the rucaparib dose must be adjusted for toxicity, doses are to be reduced by 100 mg BID.
Are there any premedications needed for rucaparib?
No premedications are needed. However, some patients may require an antiemetic, as the incidence of nausea and vomiting is fairly high, but usually not severe.
What are the common side effects associated with rucaparib?
Adverse effect data reported in the prescribing data represent the experience of 377 patients. Dose reduction/interruption was needed in 62 percent and discontinuation in 10 percent of patients.
The most common grade 3 or grade 4 toxicities were anemia, increased ALT/AST, asthenia/fatigue, neutropenia, lymphopenia, thrombocytopenia, and nausea.
The most common all-grade adverse effects included increased creatinine, nausea/vomiting, asthenia/fatigue, increased ALT/AST, anemia, lymphopenia, hypercholesterolemia, constipation, dysgeusia, decreased appetite, thrombocytopenia, neutropenia, diarrhea, and abdominal pain.
Are there any important drug interactions I should be aware of?
Rucaparib may increase myelosuppressive effects of other medications. Data is lacking about drug interactions with rucaparib. It is primarily metabolized by CYP2D6, and to a lesser degree by CYP1A2 and CYP3A4. In vitro studies indicate rucaparib may inhibit some hepatic CYP enzymes.
How do I adjust the dose in the setting of renal insufficiency?
In patients with a CrCl ≥ 30mL/min, no dosage adjustment is needed. Rucaparib has not been studied in patients with CrCl < 30mL/min or in those receiving hemodialysis.
How do I adjust the dose in the setting of hepatic insufficiency?
No dosing adjustment is needed for patients with mild hepatic impairment (total bilirubin levels </=ULN and AST>ULN OR total bilirubin levels 1-1.5xULN and any AST). It has not been studied in those with moderate to severe hepatic impairment.
CBC should be drawn at baseline and monitored monthly. If significant myelosuppression occurs, CBC should be monitored weekly until normalization.
What should my patients know about rucaparib?
Rucaparib may cause photosensitivity reactions and patients should use appropriate sun protection.
What else should I know about rucaparib?
Pregnancy testing is recommended before initiation of rucaparib in women of reproductive capacity and effective contraception should be used, as rucaparib is expected to cause fetal harm. MDS/AML and AML were reported rarely in clinical trials.
What useful links are available?
Any ongoing clinical trials related to rucaparib?
Rucaparib is being studied as maintenance therapy in ovarian cancer, as well as being compared to chemotherapy in BRCA-mutated ovarian cancer. Rucaparib is also being investigated in the treatment of prostate, breast, and pancreatic cancers. More information is available at www.clinicaltrials.gov.
LISA LOHR, PHARMD, BCOP, BCPS, is Oncology Clinical Pharmacy Specialist and Oncology MTM Provider at the Oral Chemotherapy Program Pharmacy, M Health Cancer Care, University of Minnesota/Fairview, Minneapolis. Oncology Times Clinical Advisory Editor RAMASWAMY GOVINDAN, MD, Co-Director, Section of Medical Oncology, Professor of Medicine, Washington University School of Medicine, Alvin J. Siteman Cancer Center, serves as the Pharmacy Forum column physician advisor. JANELLE E. MANN, PHARMD, BCOP, is an Investigational Drug Pharmacist, Washington University School of Medicine, Alvin J. Siteman Cancer Center, St. Louis, Mo., and serves as the Pharmacy Forum column co-editor. SARA K. BUTLER, PHARMD, BCPS, BCOP, is Clinical Oncology Pharmacy Supervisor, Barnes-Jewish Hospital, St. Louis, Mo., and also serves as a Pharmacy Forum column co-editor.
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