IN APRIL 2018, the poly (ADP-ribose) polymerase (PARP) inhibitor rucaparib (Rubraca) was granted approval for maintenance treatment of patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy.1,2 The U.S. Food and Drug Administration (FDA) concurrently approved the complementary diagnostic test FoundationFocus CDx BRCA LOH to determine homologous recombination deficiency (HRD) status.
Supporting Efficacy Data
APPROVAL WAS BASED on the findings of the phase III double-blind ARIEL3 trial.2,3 In the trial, 561 patients with recurrent disease who had received at least 2 prior treatments of platinum-based chemotherapy and were in complete or partial response to the most recent platinum-based chemotherapy were randomized 2:1 to receive oral rucaparib at 600 mg twice daily (n = 372) or placebo (n = 189). Treatment continued until disease progression or unacceptable toxicity.
Tumor samples were examined with a next-generation sequencing assay (FoundationFocus CDx BRCA LOH) to determine whether DNA contained a deleterious somatic or germline BRCA mutation (tBRCA) and to establish the percentage of genomic loss of heterozygosity. Positive HRD status was defined as tBRCA-positive and/or loss of heterozygosity–high. Analysis of patient outcomes was performed among all patients, the HRD subgroup, and the tBRCA subgroup.
The median age of patients was 61 to 62 years (range = 36–85 years); 80% were white; all had an Eastern Cooperative Oncology Group performance status of 0 or 1; the number of prior platinum-based chemotherapies ranged from 2 to 7; 34% were in complete response to their most recent therapy; 22% to 23% had received bevacizumab (Avastin); and 37% had measurable disease. The progression-free interval to the penultimate platinum therapy was 6 to 12 months in 40% of patients and more than 12 months in 60%.
The median investigator-assessed progression-free survival was 10.8 months with rucaparib vs 5.4 months with placebo among all patients (hazard ratio [HR] = 0.36, P < .0001), 13.6 vs 5.4 months in the HRD subgroup of 236 rucaparib patients and 118 placebo patients (HR = 0.32, P < .0001), and 16.6 vs 5.4 months in the tBRCA subgroup of 130 rucaparib patients and 66 placebo patients (HR = 0.23, P < .0001). Overall survival data were not mature at the time of progression-free survival analysis.
How It Works
RUCAPARIB IS AN inhibitor of PARP enzymes, including PARP-1, PARP-2, and PARP-3, which play a role in DNA repair. Studies in vitro have shown that rucaparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes, resulting in DNA damage, apoptosis, and cancer cell death. Increased rucaparib-induced cytotoxicity and antitumor activity were observed in tumor cell lines with deficiencies in BRCA1/2 and other DNA-repair genes. Rucaparib has been shown to decrease tumor growth in mouse xenograft models with or without BRCA deficiencies.
How It Is Used
THE RECOMMENDED DOSE of rucaparib is 600 mg twice daily with or without food, with treatment continued until disease progression or unacceptable toxicity.
For management of adverse reactions, interruption of treatment or dose reduction should be considered. Recommended dose reductions are to 500 mg twice daily, 400 mg twice daily, and 300 mg twice daily for first, second, and third reductions, respectively.
Coadministration of rucaparib can increase the systemic exposure of CYP1A2, CYP3A, CYP2C9, or CYP2C19 substrates, which may increase the risk of toxicities associated with these drugs. The dosage of CYP1A2, CYP3A, CYP2C9, or CYP2C19 substrates should be adjusted if clinically indicated. If coadministration with warfarin (a CYP2C9 substrate) cannot be avoided, an increased frequency of monitoring of the international normalized ratio should be considered.
IN CLINICAL TRIALS of rucaparib, the most common adverse events of any grade (≥ 20% of patients) were nausea, fatigue/asthenia, vomiting, anemia, dysgeusia, aspartate transaminase/alanine transaminase (AST/ALT) elevation, constipation, decreased appetite, diarrhea, thrombocytopenia, neutropenia, stomatitis, nasopharyngitis/upper respiratory infection, rash, abdominal pain/ distention, and dyspnea. The most common laboratory abnormalities of any grade (≥ 25%) have been increased creatinine, increased ALT and AST, increased alkaline phosphatase levels, decreased hemoglobin, increased cholesterol, decreased platelets, decreased leukocytes, decreased lymphocytes, and decreased neutrophils.
In ARIEL3, the median duration of study treatment was 8.3 months (range = < 1 month to 35 months) in the rucaparib group vs 5.5 months in the placebo group. The most common adverse events of any grade in the rucaparib group were nausea (76% vs 36% in the placebo group), fatigue/asthenia (73% vs 46%), abdominal pain/distension (46% vs 39%), rash (43% vs 23%), dysgeusia (40% vs 7%), anemia (39% vs 5%), ALT/AST elevation (38% vs 4%), constipation (37% vs 24%), vomiting (37% vs 15%), and diarrhea (32% vs 22%). The most common grade 3 or 4 adverse events included anemia (21% vs 0.5%), AST/ALT elevation (11% vs 0%), neutropenia (8% vs 1%), fatigue/asthenia (7% vs 3%), and thrombocytopenia (5% vs 0%). Myelodysplastic syndrome or acute myeloid leukemia occurred in seven rucaparib patients and one placebo patient.
Adverse events led to dose interruptions in 65% vs 10% of patients and dose reductions in 55% vs 4%, with the most common causes of such modifications in the rucaparib group being thrombocytopenia, anemia, nausea, and fatigue/asthenia. Adverse events led to discontinuation of treatment in 15% vs 2% of patients, with the most common causes being anemia, thrombocytopenia, and nausea.
Rucaparib carries warnings/precautions for myelodysplastic syndrome or acute myeloid leukemia (including fatal cases) and embryofetal toxicity. Patients should be monitored for hematologic toxicity at baseline and monthly thereafter; and use of rucaparib should be discontinued if myelodysplastic syndrome or acute myeloid leukemia is confirmed. Women should be advised not to breastfeed during rucaparib treatment. ■
1. U.S. Food and Drug Administration: FDA approves rucaparib for maintenance treatment of recurrent ovarian, fallopian tube, or primary peritoneal cancer. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ ucm603997.htm. Accessed September 20, 2018.
2. Rubraca (rucaparib) tablets prescribing information, Clovis Oncology Inc, April 2018. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2018/209115s003lbl.pdf. Accessed September 20, 2018.
3. Coleman RL, Oza AM, Lorusso D, et al: Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 390:1949-1961, 2017.