EARLY IN 2018, olaparib tablets (Lynparza) were granted regular approval for treatment of patients with deleterious or suspected deleterious germline BRCA-mutated, HER2-negative metastatic breast cancer who have been treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic setting.^1,2 Olaparib is the first U.S. Food and Drug Administration (FDA)-approved treatment for germline BRCA-mutated HER2-negative metastatic breast cancer. Patients with hormone receptor–positive disease should have been treated with prior endocrine therapy or considered inappropriate for endocrine treatment. 

Patients must be selected for therapy based on an FDA-approved companion diagnostic for olaparib. The FDA also granted marketing authorization for the BRACAnalysis CDx test for use as an aid in identifying patients with breast cancer with deleterious or suspected deleterious germline BRCA-mutated who may be eligible for olaparib. 

Supporting Efficacy Data 

APPROVAL WAS BASED on the findings of the open-label phase III OlympiAD trial, in which 302 patients with germline BRCA-mutated, HER2-negative metastatic breast cancer were randomized 2:1 to receive oral olaparib at 300 mg twice daily (n = 205) or physician’s choice of chemotherapy with capecitabine, vinorelbine, or eribulin (Halaven; n = 97).^2,3 All patients had to have received chemotherapy in the neoadjuvant, adjuvant, or metastatic setting. Randomization was stratified by the use of chemotherapy for metastatic disease, hormone receptor–positive vs triple-negative status, and previous platinum-based chemotherapy. The primary endpoint was progression-free survival on blinded independent central review. 

Among the 205 patients in the olaparib group, the median age was 44 years (range = 22–76 years), 65% were white, 4% were men, and all had an Eastern Cooperative Oncology Group performance status of 0 or 1. Approximately 50% of patients had triple-negative tumors, and 50% had estrogen receptor– or progesterone receptor–positive tumors in both groups. Patients in both groups had received a median of one prior chemotherapy regimen for metastatic disease, and approximately 30% had not received prior chemotherapy for metastatic disease; 21% of the olaparib group vs 14% of the chemotherapy group had received platinum therapy for metastatic disease, and 7% in each group had received platinum therapy for localized disease. 

The estimated median progression-free survival was 7.0 months in the olaparib group vs 4.2 months in the chemotherapy group (hazard ratio [HR] = 0.58, P = .0009). The results were consistent across stratification subgroups. Among 167 and 66 patients with measurable disease, objective response rates were 52% vs 23%, respectively. 

How It Works 

OLAPARIB IS 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 both as monotherapy and after platinum-based chemotherapy. Increased cytotoxicity and antitumor activity after 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 

OLAPARIB IS ALSO available as a 50-mg capsule. Olaparib tablets (100 and 150 mg) must not be substituted with capsules on a mg-to-mg basis due to differences in dosing and bioavailability of each formulation. Patients should be selected for treatment of HER2-negative metastatic breast cancer based on the presence of deleterious or suspected deleterious germline BRCA-mutation. 

The recommended dose of olaparib in the current indication is 300 mg (two 150-mg tablets) twice daily, for a total daily dose of 600 mg. The 100-mg tablet is available for dose reduction. Treatment should continue until disease progression or unacceptable toxicity. Patients with mild renal impairment require no dose reduction. In patients with moderate renal impairment, the dose should be 200 mg twice daily. 

For management of adverse reactions, interruption of treatment or dose reduction should be considered. The recommended reduced dose is 250 mg (one 150-mg tablet and one 100-mg tablet) twice daily, for a total daily dose of 500 mg. If a further dose reduction is required, the reduced dose is 200 mg (two 100-mg tablets) twice daily, for a total daily dose of 400 mg. 

Concomitant use of olaparib with strong (eg, itraconazole, clarithromycin, ketoconazole) or moderate (eg, amprenavir, aprepitant, 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 olaparib with strong (phenytoin, rifampicin, carbamazepine) or moderate (eg, bosentan, efavirenz, modafinil) CYP3A inducers should be avoided, since they may decrease exposure to and efficacy of olaparib. 

Safety Profile 

THE MOST COMMON adverse events of any grade reported in at least 20% of patients taking olaparib in clinical trials were anemia, nausea, fatigue/asthenia, vomiting, neutropenia, leukopenia, nasopharyngitis/upper respiratory tract infection/influenza, respiratory tract infection, diarrhea, arthralgia/myalgia, dysgeusia, headache, dyspepsia, decreased appetite, constipation, and stomatitis. The most common laboratory abnormalities of any grade (≥ 25%) were decreased hemoglobin, increased mean corpuscular volume, decreased lymphocytes, decreased leukocytes, decreased absolute neutrophil count, increased serum creatinine, and decreased platelets. 

Olaparib carries warnings/precautions for myelodysplastic syndrome/acute myeloid leukemia (MDS/AML), pneumonitis, and embryofetal toxicity. MDS/AML occurred in less than 1.5% of patients receiving olaparib monotherapy, with the majority of events being fatal. 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 less than 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. ■

REFERENCES 

1. U.S. Food and Drug Administration: FDA approves olaparib for germline BRCA-mutated metastatic breast cancer. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm592357.htm. Accessed July 6, 2018. 

2. Lynparza (olaparib) tablets prescribing information, AstraZeneca, January 2018. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2018/208558s001lbl.pdf. Accessed July 6, 2018. 

3. Robson M, Im SA, Senkus E, et al: Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med 377:523-533, 2017.