On August 17, 2017, olaparib -(Lynparza) in tablet form was granted regular approval for maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy.1,2 Olaparib tablets were also approved for treatment of adult patients with deleterious or suspected deleterious germ-line BRCA-mutated advanced ovarian cancer who have received three or more prior lines of chemotherapy; olaparib had previously been approved in this latter indication in capsule form. Olaparib capsules are being phased out of the U.S. market. The tablet formulation substantially reduces the daily pill burden. Capsules must not be substituted for tablets on a mg-to-mg basis.
Supporting Efficacy Data
The approval in maintenance therapy is based on improved progression-free survival vs placebo in two phase III double-blind trials in patients with recurrent ovarian cancers who were in response to platinum-based therapy.2,3 In the SOLO-2 trial,3 295 patients with recurrent germline BRCA-mutated ovarian, fallopian tube, or primary peritoneal cancer were randomized (2:1) to receive olaparib tablets at 300 mg orally twice daily (n = 196) or placebo (n = 99). Median progression-free survival was 19.1 months in the olaparib group vs 5.5 months in the placebo group (hazard ratio [HR] = 0.30, P < .0001). In the second study (Study 19), 265 patients with any BRCA status were randomized to receive olaparib capsules at 400 mg orally twice daily or placebo. Median progression-free survival was 8.4 months vs 4.8 months (HR = 0.35, P < .0001).
How It Works
Olaparib is an inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes, including PARP1, PARP2, and PARP3. The roles of PARP enzymes in normal cellular functions include DNA transcription and DNA repair. Olaparib inhibits the growth of select tumor cell lines in vitro and decreases tumor growth in mouse xenograft models as monotherapy or following platinum-based chemotherapy. Increased cytotoxicity and antitumor activity of olaparib were noted in cell lines and mouse tumor models with deficiencies in BRCA and non-BRCA proteins involved in the homologous recombination repair of DNA damage and were correlated with platinum response. In vitro studies showed that olaparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complex, resulting in DNA damage and cancer cell death.
How It Is Used
The recommended dose of olaparib tablets for both maintenance and later-line treatment is 300 mg (two 150-mg tablets) twice daily, with treatment continued until disease progression or unacceptable toxicity. A 100-mg tablet is available for use in dose reduction. For management of adverse events, dose interruption or dose reduction should be considered. The first dose reduction should be to 250 mg twice daily and the second, to 200 mg twice daily.
Olaparib carries warnings/precautions for myelodysplastic syndrome/acute myeloid leukemia, pneumonitis, and embryofetal toxicity.
Patients with mild renal impairment require no dose reduction. In patients with moderate renal impairment, the dose should be 200 mg twice daily. The pharmacokinetics of olaparib has not been studied in patients with severe renal impairment or end-stage renal disease.
Concomitant use of strong (eg, itraconazole, telithromycin [Ketek], clarithromycin, ketoconazole) or moderate (eg, amprenavir, aprepitant, atazanavir, ciprofloxacin) CYP3A inhibitors should be avoided. If a strong CYP3A inhibitor must be used, the olaparib dose should be reduced to 100 mg twice daily; if a moderate CYP3A inhibitor must be used, the olaparib dose should be reduced to 150 mg twice daily. Concomitant use of strong (phenytoin, rifampicin, carbamazepine, St. John’s wort) or moderate (eg, bosentan, efavirenz, etravirine, modafinil) CYP3A inducers should be avoided, since they may decrease exposure to and efficacy of olaparib.
In the SOLO-2 trial of the tablet formulation, the most common adverse events of any grade in the olaparib group were nausea (76% vs 33% in placebo group), fatigue/asthenia (66% vs 39%), anemia (44% vs 9%), vomiting (37% vs 19%), and respiratory tract infections (36% vs 29%). The most common grade 3 or 4 adverse events were anemia (20% vs 2%) and fatigue/asthenia (4% vs 2%). The most common grade 3 or 4 lab abnormalities were anemia (17% vs 0%) and lymphopenia (11% vs 1%). Adverse events led to dose interruptions in 45% vs 18% of patients and to dose reductions in 27% vs 3%, with the most common causes of dose modification in the olaparib group being anemia (22%), neutropenia (9%), and fatigue/asthenia (8%). Adverse events led to discontinuation of treatment in 11% vs 2% of patients.
Olaparib carries warnings/precautions for myelodysplastic syndrome/acute myeloid leukemia (MDS/AML), pneumonitis, and embryofetal toxicity. MDS/AML occurred in < 1.5% of patients receiving olaparib monotherapy, with the majority of events having a fatal outcome. Patients should be monitored for hematologic toxicity at baseline and monthly thereafter, and treatment should be discontinued if MDS/AML is confirmed. Pneumonitis occurred in < 1% of patients receiving olaparib and was fatal in some cases. Treatment should be interrupted if pneumonitis is suspected and discontinued if pneumonitis is confirmed. ■
1. U.S. Food and Drug Administration: FDA approves olaparib tablets for maintenance treatment in ovarian cancer. Available at https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm572143.htm. Accessed November 2, 2017.
2. Lynparza (olaparib) tablets prescribing information, AstraZeneca, August 2017. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208558s000lbl.pdf. Accessed November 2, 2017.
3. Pujade-Lauraine E, Ledermann JA, Selle F, et al: Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): A double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol 18:1274-1284, 2017.
Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).