In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.
On December 19, 2014, olaparib (Lynparza) was granted accelerated approval as monotherapy for treatment of patients with deleterious or suspected deleterious germline BRCA-mutated advanced ovarian cancer who have received at least three prior lines of chemotherapy; mutations must be detected by a U.S. Food and Drug Administration (FDA)-approved test.1,2 The FDA concurrently approved the BRACAnalysis CDx test for the qualitative detection and classification of variants in the BRCA1 and BRCA2 genes.
Supporting Study
Approval is based on objective response rate observed in an international single-arm trial including 137 patients with measureable deleterious or suspected deleterious germline BRCA-mutated advanced ovarian cancer who had received at least three prior lines of chemotherapy. Patients had a median age of 58 years, 94% were white, and 93% had an Eastern Cooperative Oncology Group performance status of 0 or 1.
Deleterious or suspected deleterious germline BRCA mutation status was verified retrospectively in 97% (59/61) of the patients with available blood samples by the companion diagnostic BRACAnalysis CDx. Patients received 400 mg twice daily until disease progression or intolerable toxicity.
The objective response rate was 34% (95% confidence interval [CI] = 26%–42%), with complete response in 2%, and the median response duration was 7.9 months (95% CI = 5.6–9.6 months).
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 homeostasis include DNA transcription, cell-cycle regulation, and DNA repair. The drug inhibits 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. In vitro studies showed that olaparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complex, resulting in disruption of cellular homeostasis and cell death.
How It Is Given
The recommended dosage of olaparib is 400 mg twice daily, with treatment continued until disease progression or unacceptable toxicity. For management of adverse events, recommended dose reductions are to 200 mg twice daily and subsequently to 100 mg twice daily.
Concomitant use of strong (eg, clarithromycin, indinavir, ketoconazole) or moderate (eg, aprepitant, ciprofloxacin, imatinib) CYP3A inhibitors should be avoided; if use of such an agent cannot be avoided, the olaparib dose should be reduced to 150 mg twice daily for concurrent use of a strong CYP3A inhibitor and 200 mg twice daily for use of a moderate CYP3A inhibitor. Concomitant use of strong CYP3A inducers (eg, rifampin, carbamazepine, St. John’s wort), which may reduce olaparib efficacy, should be avoided.
No adjustment to the starting dose is required in patients with mild renal impairment, although patients should be monitored closely for toxicity. Patients with bilirubin greater than 1.5 times upper limit of normal and AST/ALT at least 2.5 times the upper limit of normal (≥ 5 times upper limit of normal in the presence of liver metastases) were excluded from olaparib clinical trials. No data are available on olaparib use in patients with hepatic impairment or moderate or severe renal impairment.
Safety Profile
The most common adverse events of any grade among 223 patients with germline BRCA-mutated ovarian cancer who received at least three prior lines of chemotherapy in olaparib clinical trials (median exposure, 158 days) were fatigue/asthenia (66%), nausea (64%), abdominal pain/discomfort (43%), vomiting (43%), anemia (34%), and diarrhea (31%). The most common grade 3 or 4 adverse events were anemia (18%), abdominal pain/discomfort (8%), and fatigue/asthenia (8%). The most common grade 3 or 4 laboratory abnormalities were lymphopenia (17%), anemia (15%), and neutropenia (7%).
Adverse reactions led to dose interruption in 40% of patients, dose reduction in 4%, and discontinuation in 7%. Adverse events led to death in eight patients (4%), with two deaths attributed to acute leukemia and one each to chronic obstructive pulmonary disease, cerebrovascular accident, intestinal perforation, pulmonary embolism, sepsis, and suture rupture.
Myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) was observed in 2% of patients in a single-arm trial of olaparib monotherapy in patients with deleterious or suspected deleterious germline BRCA-mutated advanced cancers and 2% of patients in a randomized comparison with placebo in advanced ovarian cancer.
Olaparib carries warnings/precautions for MDS/AML, including fatal cases, pneumonitis, including fatal cases, and embryo-fetal toxicity. Patients should be monitored for hematologic toxicity at baseline and monthly thereafter, and olaparib should be interrupted for prolonged hematologic toxicity and discontinued for MDS/AML. Treatment should be interrupted for suspected pneumonitis and discontinued in confirmed cases. ■
References
1. U.S. Food and Drug Administration: Olaparib. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm427598.htm. Accessed January 14, 2015.
2. LynparzaTM (olaparib) capsules prescribing information, AstraZeneca, December 2014. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2014/206162lbl.pdf. Accessed January 14, 2015.
Report Adverse Events
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 http://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).
