On December 27, 2019, the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib was approved for the maintenance treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated metastatic pancreatic adenocarcinoma, as detected by a U.S. Food and Drug Administration (FDA)-approved test, whose disease has not progressed on at least 16 weeks of a first-line platinum-based chemotherapy regimen.1,2 The FDA also approved the BRACAnalysis CDx test as a companion diagnostic for the selection of patients with pancreatic cancer for treatment with olaparib based upon the identification of deleterious or suspected deleterious germline mutations in BRCA1 or BRCA2.
Supporting Efficacy Data
Approval was based on findings from the double-blind phase III POLO trial (ClinicalTrials.gov identifier NCT02184195), in which 154 patients were randomly assigned 3:2 to olaparib at 300 mg orally twice daily (n = 92) or placebo (n = 62) until disease progression or unacceptable toxicity.2,3 The main efficacy outcome measure was progression-free survival on blinded independent central review using Response Evaluation Criteria in Solid Tumors, version 1.1.
The median age of study patients was 57 years (range, 36–84 years); 54% were male; 92% were white; an Eastern Cooperative Oncology Group performance status was 0 in 67% and 1 in 31%. The median time from initiation of first-line platinum-based chemotherapy to randomization was 5.8 months. In total, 49% of patients had a complete or partial response to platinum-based chemotherapy. Among 150 patients with central test results, 30% had a mutation in BRCA1, 69% had a mutation in BRCA2, and 1 patient (1%) had mutations in both BRCA1 and BRCA2.
The median progression-free survival was 7.4 months (95% confidence interval [CI] = 4.1–11.0 months) in the olaparib group vs 3.8 months (95% CI = 3.5–4.9 months) in the placebo group (hazard ratio [HR] = 0.53, 95% CI = 0.35–0.81, P = .0035). At the interim analysis, the median overall survival was 18.9 months vs 18.1 months (HR = 0.91, P = .683). Objective response rates among 78 vs 52 patients with measurable disease at baseline were 23% vs 12%; the median response durations were 25 vs 4 months.
How It Works
Olaparib is an inhibitor of 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 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 indication, patients should be selected for olaparib maintenance treatment on the basis of the presence of deleterious or suspected deleterious germline BRCA mutations. The recommended olaparib dose is 300 mg taken orally twice daily with or without food, with treatment continued until disease progression or unacceptable toxicity.
To manage adverse reactions, interruption of treatment or dose reduction should be considered. The recommended dose reduction is to 250 mg twice daily; if further dose reduction is required, the reduction should be to 200 mg twice daily.
Concomitant use of strong (eg, itraconazole, telithromycin, clarithromycin) or moderate (eg, amprenavir, aprepitant, atazanavir) 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. After the inhibitor has been discontinued for three to five elimination half-lives, the olaparib dose used prior to initiating the CYP3A inhibitor should be resumed.
The olaparib dose should be reduced to 200 mg twice daily in patients with moderate renal impairment. The pharmacokinetics of olaparib have not been studied in patients with severe renal impairment or end-stage renal disease.
The most common adverse events of any grade (≥ 10%) observed in patients receiving olaparib in clinical trials have been nausea, fatigue (including asthenia), vomiting, abdominal pain, anemia, diarrhea, dizziness, neutropenia, leukopenia, nasopharyngitis/upper respiratory tract infection/influenza, respiratory tract infection, arthralgia/myalgia, dysgeusia, headache, dyspepsia, decreased appetite, constipation, stomatitis, dyspnea, and thrombocytopenia.
Among the 91 patients receiving olaparib in the POLO trial, 34% were exposed for at least 6 months and 25% for at least 1 year. The most common adverse events of any grade in the olaparib group were fatigue, nausea, abdominal pain, diarrhea, anemia, decreased appetite, constipation, and vomiting. The most common grade 3 or 4 adverse events were anemia and fatigue. The most common grade 3 or 4 laboratory abnormalities were decreased hemoglobin and decreased lymphocytes.
Adverse events led to dose interruption in 35% of patients and to dose reduction in 1%, with the most common causes being anemia, vomiting, abdominal pain, asthenia, and fatigue. Adverse events led to treatment discontinuation in 6% of patients, with the most common cause being fatigue.
Olaparib has warnings/precautions for myelodysplastic syndrome/acute myeloid leukemia (MDS/AML); pneumonitis; and embryofetal toxicity. MDS/AML has occurred in up to 1.5% of patients receiving olaparib monotherapy, with the majority of events resulting in 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 has occurred in up to 1% of patients receiving olaparib and was fatal in some cases. Treatment should be interrupted if pneumonitis is suspected and discontinued if confirmed. Women should be advised not to breastfeed while receiving olaparib.
1. U.S. Food and Drug Administration: FDA approves olaparib for gBRCAm metastatic pancreatic adenocarcinoma. Available at www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-olaparib-gbrcam-metastatic-pancreatic-adenocarcinoma. Accessed January 13, 2020.
2. Lynparza (olaparib) tablets prescribing information, AstraZeneca, December 2019. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2019/208558s010lbl.pdf. Accessed January 13, 2020.
3. Golan T, Hammel P, Reni M, et al: Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N Engl J Med 381:317-327, 2019.