On May 8, 2020, olaparib was granted an expanded indication to include use in combination with bevacizumab for first-line maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy. The treatment is intended for those whose disease is associated with homologous recombination deficiency (HRD)-positive status defined by either a deleterious or suspected deleterious BRCA mutation and/or genomic instability.1,2 The U.S. Food and Drug Administration (FDA) simultaneously approved myChoice CDx as a companion diagnostic for olaparib.
Supporting Efficacy Data
The approval was based on findings in the double-blind, multicenter, phase III PAOLA-1 trial.2,3 In the trial, 806 patients with advanced, high-grade epithelial ovarian cancer (86% of patients in each group), fallopian tube, or primary peritoneal cancer in response to first-line platinum-based chemotherapy and bevacizumab were randomly assigned 2:1 to receive oral olaparib at 300 mg twice daily plus bevacizumab at 15 mg/kg every 3 weeks (n = 537) or placebo plus bevacizumab (n = 269). Patients continued bevacizumab as maintenance and began olaparib at 3 to 9 weeks following their last chemotherapy dose. Olaparib was continued for up to 2 years or until disease progression or unacceptable toxicity. Tumor BRCA mutation status was determined by prospective local testing, with all available clinical samples being retrospectively tested with myChoice CDx.
Olaparib has warnings/precautions for myelodysplastic syndrome/acute myeloid leukemia (MDS/AML), pneumonitis, and embryofetal toxicity. MDS/AML has occurred in less than 1.5% of patients receiving olaparib monotherapy, with the majority of events having a fatal outcome.
Among the 806 patients, 387 had HRD-positive tumors identified postrandomization using the myChoice HRD Plus tumor test, including 255 in the olaparib/bevacizumab group and 132 in the placebo/bevacizumab group. The current approval is based on investigator-assessed progression-free survival using Response Evaluation Criteria in Solid Tumors, version 1.1, in the HRD-positive population.
Median progression-free survival was 37.2 months in the olaparib/bevacizumab group vs 17.7 months in the placebo/bevacizu-mab group (hazard ratio = 0.33, 95% confidence interval = 0.25–0.45). Results of a blinded independent review showed progression-free survival results consistent with investigator assessment. Overall survival data were not mature at the time of analysis, with a 16% mortality rate among patients.
How It Works
Olaparibis an inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes, including PARP1, PARP2, and PARP3. PARP enzymes are involved in normal cellular functions, including DNA transcription and DNA repair. Olaparib inhibits the growth of select tumor cell lines in vitro and decreases tumor growth in mouse xenograft models of human cancers, both as monotherapy and after platinum-based chemotherapy. Increased cytotoxicity and antitumor activity following treatment with olaparib were observed in cell lines and mouse models with deficiencies in BRCA and non-BRCA proteins involved in homologous recombination repair of DNA damage and were correlated with platinum response. Studies in vitro have shown that olaparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes, resulting in DNA damage and cancer cell death.
How It Is Used
For the current expanded indication, patients must be selected for treatment on the basis of HRD-positive status based on the presence of either deleterious or suspected deleterious BRCA mutations and/or genomic instability as detected by an FDA-approved companion diagnostic for olaparib. In the current setting, the recommended dosage of olaparib is 300 mg twice daily, continuing until disease progression, unacceptable toxicity, or completion of 2 years of treatment. Patients with a complete response at 2 years should stop treatment. Patients with evidence of disease at 2 years can continue if their health-care provider believes they can derive further benefit from continuous treatment. When used with olaparib in this setting, the recommended dose of bevacizumab is 15 mg/kg every 3 weeks, administered for a total of 15 months, including the periods given with chemotherapy and as maintenance.
For management of adverse reactions, interruption of treatment or dose reduction should be considered. The recommended dose reductions are first to 250 mg twice daily and then to 200 mg twice daily if required. The recommended starting dose is 200 mg twice daily in patients with moderate renal impairment. Concomitant use of olaparib with strong or moderate CYP3A inhibitors should be avoided.
Safety data are from the total safety population of 535 patients receiving olaparib/bevacizumab and 267 receiving placebo/bevacizumab in PAOLA-1. The most common adverse events of any grade, which occurred in ≥ 10% of the olaparib/bevacizumab group and at an incidence ≥ 5% higher vs the placebo/bevacizumab group, were nausea, fatigue/asthenia, anemia, lymphopenia, vomiting, and leukopenia. Other any-grade adverse events occurring in ≥ 10% of the olaparib/bevacizumab group included hypertension, diarrhea, neutropenia, urinary tract infection, and headache. Venous thromboembolic events occurred in 5% vs 1.9% of patients. The most common grade 3 or 4 adverse events in the olaparib/bevacizumab group included anemia, lymphopenia, and fatigue/asthenia.
Serious adverse events occurred in 31% of patients in the olaparib/bevacizumab group; those adverse events occurring in more than 5% included hypertension and anemia. Adverse events led to dose interruption in 54% of patients and to dose reduction in 41%. Discontinuation of treatment due to adverse events occurred in 20% of patients, most commonly due to anemia and nausea.
Olaparib has warnings/precautions for myelodysplastic syndrome/acute myeloid leukemia (MDS/AML), pneumonitis, and embryofetal toxicity. MDS/AML has occurred in less than 1.5% of patients receiving olaparib monotherapy, with the majority of events resulting in fatal outcomes. Patients should be monitored for hematologic toxicity at baseline and monthly thereafter, and treatment should be discontinued if MDS/AML is confirmed. Treatment should be interrupted if pneumonitis is suspected and discontinued if confirmed. Patients should be advised not to breastfeed while receiving olaparib.
1. U.S. Food and Drug Administration: FDA approves olaparib plus bevacizumab as maintenance treatment for ovarian, fallopian tube, or primary peritoneal cancers. Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-olaparib-plus-bevacizumab-maintenance-treatment-ovarian-fallopian-tube-or-primary. Accessed May 19, 2020.
2. U.S. Food and Drug Administration: Highlights of prescribing information for Lynparza (olaparib) tablets. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/208558s013lbl.pdf. Accessed May 19, 2020.
3. Ray‑Coquard I, Pautier P, Pignata S, et al: Olaparib plus bevacizumab as first-line maintenance in ovarian cancer. N Engl J Med 381:2416-2428, 2019.