Olaparib (Monograph)

Brand name: Lynparza
Drug class: Antineoplastic Agents
- PARP Inhibitors
- Poly(ADP-ribose) Polymerase Inhibitors
VA class: AN900
Chemical name: 4-[[3-[[4-(Cyclopropylcarbonyl)-1- piperazinyl]carbonyl]-4- fluorophenyl]methyl]-1(2H)-phthalazinone
Molecular formula: C₂₄H₂₃FN₄O₃
CAS number: 763113-22-0

Medically reviewed by Drugs.com on Nov 20, 2023. Written by ASHP.

Introduction

Antineoplastic agent; an inhibitor of poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP).¹

Uses for Olaparib

Ovarian Cancer

Used as a single agent for the maintenance treatment of adults with confirmed or suspected deleterious germline or somatic BRCA-mutated advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy¹ (designated an orphan drug by FDA for this use).³ FDA-approved companion diagnostic test required to confirm presence of specific biomarkers prior to initiation of therapy.¹

Used in combination with bevacizumab for the maintenance treatment of adults with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy and whose cancer is associated with homologous recombination deficiency (HRD)-positive status (defined by a confirmed or suspected deleterious BRCA mutation and/or genomic instability)¹ (designated an orphan drug by FDA for this use).³ FDA-approved companion diagnostic test required to confirm presence of specific biomarkers prior to initiation of therapy.¹

Used as a single agent for the maintenance treatment of adults with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy¹ (designated an orphan drug by FDA for this use).³ Biomarker testing not required.¹

Used as a single agent for the treatment of confirmed or suspected deleterious germline BRCA-mutated advanced ovarian cancer previously treated with ≥3 chemotherapy regimens^{1 2} (designated an orphan drug by FDA for this use).³ FDA-approved companion diagnostic test required to confirm presence of specific biomarkers prior to initiation of therapy.¹

Breast Cancer

Used as a single agent for the treatment of adults with confirmed or suspected deleterious germline BRCA-mutated, human epidermal growth factor receptor type 2 (HER2)-negative metastatic breast cancer previously treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic setting.¹ Patients with hormone receptor-positive breast cancer should have received prior endocrine therapy, unless clinically inappropriate.¹ FDA-approved companion diagnostic test required to confirm presence of specific biomarkers prior to initiation of therapy.¹

Pancreatic Adenocarcinoma

Used as a single agent for the first-line maintenance treatment of adults with confirmed or suspected deleterious germline BRCA-mutated metastatic pancreatic adenocarcinoma whose disease has not progressed on at least 16 weeks of a first-line platinum-based chemotherapy regimen¹ (designated an orphan drug by FDA for this use).³ FDA-approved companion diagnostic test required to confirm presence of specific biomarkers prior to initiation of therapy.¹

Prostate Cancer

Used as a single agent for the treatment of adults with confirmed or suspected deleterious germline or somatic homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer who have progressed following prior treatment with enzalutamide or abiraterone.¹ FDA-approved companion diagnostic test required to confirm presence of specific biomarkers prior to initiation of therapy.¹

Related/similar drugs

Kisqali, Ibrance, Piqray, estradiol, Premarin, cyclophosphamide, capecitabine

Olaparib Dosage and Administration

General

Pretreatment Screening

• Complete blood cell count (CBC).^{1 5}

• Do not initiate in patients with grade 2 or greater hematologic toxicity caused by previous chemotherapy.¹

• Pregnancy testing for females of reproductive potential.¹

• Confirm presence of specific biomarkers prior to initiation of olaparib therapy for most indications (see Table 1).¹ Consult FDA website for list of FDA-approved companion diagnostic tests ([Web]).¹

If testing fails or tissue sample is unavailable/insufficient, or when germline testing is negative, consider using an alternative test, if available

Patient Monitoring

• CBC monthly during therapy.^{1 5}

• Signs or symptoms of venous thrombosis and pulmonary embolism.¹

Dispensing and Administration Precautions

• Olaparib capsules (no longer commercially available in the US) not interchangeable on a milligram-to-milligram basis with olaparib tablets.^{29 30} Tablets and capsules use different dosing and have different bioavailability.^{29 30}

Other General Considerations

• Tachyphylaxis of nausea symptoms usually occurs during the first cycle of PARP inhibitor therapy, often without institution of antiemetic therapy or dose reduction.³¹

• A light meal or snack prior to each dose of a PARP inhibitor may mitigate nausea.³¹

• If persistent nausea/vomiting, weight loss >5%, and/or reduction in performance status occurs in the absence of other etiology (e.g., bowel obstruction), ASCO recommends temporarily withholding therapy followed by dosage reduction.³¹

Administration

Oral Administration

Administer orally twice daily with or without food.¹

Swallow tablets whole; do not chew, dissolve, crush, or divide.¹

Store tablets in the original container to protect from moisture.¹

Dosage

Adults

Ovarian Cancer

First-line Maintenance Treatment of BRCA-mutated Advanced Ovarian Cancer

Oral

300 mg twice daily.¹

Continue therapy until disease progression or unacceptable toxicity occurs, or until 2 years of therapy are complete.¹ Patients with a complete response at 2 years should discontinue therapy.¹ Patients with evidence of disease at 2 years may continue therapy beyond 2 years if they may derive clinical benefit from an extended duration of therapy.¹

First-line Maintenance Treatment of HRD-positive Advanced Ovarian Cancer

Oral

300 mg twice daily in combination with bevacizumab (15 mg/kg IV every 3 weeks).¹

Continue olaparib until disease progression or unacceptable toxicity occurs, or until 2 years of therapy are complete.¹ Patients with a complete response at 2 years should discontinue therapy.¹ Patients with evidence of disease at 2 years may continue olaparib beyond 2 years if they may derive clinical benefit from an extended duration of therapy.¹

Continue bevacizumab for a total of 15 months (including use during primary chemotherapy and maintenance treatment).¹

Maintenance Treatment of Recurrent Ovarian Cancer

Oral

300 mg twice daily.¹ Continue therapy until disease progression or unacceptable toxicity occurs.¹

Previously Treated Advanced Germline BRCA-mutated Ovarian Cancer

Oral

300 mg twice daily.¹ Continue therapy until disease progression or unacceptable toxicity occurs.¹

Breast Cancer

Oral

300 mg twice daily.¹ Continue therapy until disease progression or unacceptable toxicity occurs.¹

Pancreatic Adenocarcinoma

Oral

300 mg twice daily.¹ Continue therapy until disease progression or unacceptable toxicity occurs.¹

Prostate Cancer

Oral

300 mg twice daily.¹ Continue therapy until disease progression or unacceptable toxicity occurs.¹

Use with a gonadotropin-releasing hormone (GnRH) analog in patients who have not previously undergone bilateral orchiectomy.¹

Dosage Modification for Toxicity

Oral

If adverse reactions occur, consider interruption of therapy or dosage reduction.¹

If dosage reduction is necessary, reduce dosage to 250 mg twice daily.¹

If further reduction is necessary, reduce dosage to 200 mg twice daily.¹

Concomitant Use with Drugs Affecting Hepatic Microsomal Enzymes

Oral

Avoid concomitant use of moderate or potent inhibitors of CYP3A.¹

If concomitant use of a potent CYP3A inhibitor cannot be avoided, reduce olaparib dosage to 100 mg twice daily.¹

If concomitant use of a moderate CYP3A inhibitor cannot be avoided, reduce olaparib dosage to 150 mg twice daily.¹

If concomitant use of the CYP3A inhibitor is discontinued, return olaparib dosage to the dosage used prior to initiation of the CYP3A inhibitor (after 3–5 terminal half-lives of the CYP3A inhibitor).¹

Special Populations

Dosage in Hepatic Impairment

Mild to moderate hepatic impairment (Child-Pugh class A or B): No initial dosage adjustment necessary.¹

Severe hepatic impairment (Child-Pugh class C): Not studied; no specific dosage recommendation.¹

Dosage in Renal Impairment

Mild renal impairment (Cl_cr 51–80 mL/minute): No initial dosage adjustment necessary.¹

Moderate renal impairment (Cl_cr 31–50 mL/minute): Reduce dosage to 200 mg twice daily.¹

Severe renal impairment or end-stage renal disease (Cl_cr ≤30 mL/minute): Not studied; no specific dosage recommendations.¹

Geriatric Patients

No specific dosage recommendations at this time.¹

Cautions for Olaparib

Contraindications

• Manufacturer states none known.¹

Warnings/Precautions

Myelodysplastic Syndrome (MDS)/Acute Myeloid Leukemia (AML)

MDS and AML reported in approximately 1.5% of olaparib-treated patients; 51% of the cases were fatal.¹ All patients with MDS/AML had received previous chemotherapy with platinum-containing agents and/or other DNA-damaging antineoplastic agents, including radiation therapy.¹ The median duration of olaparib therapy in patients who developed MDS/AML was 2 years, but duration of therapy ranged from <6 months to >10 years.¹

Monitor CBC at baseline and monthly thereafter.¹ Delay initiation of olaparib until patients have recovered to grade 1 or less from hematologic toxicity caused by previous chemotherapy.¹

If prolonged hematologic toxicity occurs during therapy, interrupt therapy and monitor CBC weekly until recovery to grade 1 or less.¹

If myelosuppression persists for >4 weeks following interruption of therapy, refer patient to a hematologist for further evaluation, including bone marrow analysis and cytogenetic testing of a blood sample.¹ If MDS/AML is confirmed, discontinue olaparib.¹

Pneumonitis

Pneumonitis, sometimes fatal, reported in 0.8% of patients.¹

If patient develops new or worsening pulmonary symptoms or a radiologic abnormality occurs, interrupt therapy and initiate prompt diagnostic evaluation.¹ If pneumonitis is confirmed, discontinue olaparib and treat appropriately.¹

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm based on mechanism of action and animal findings; teratogenicity, embryotoxicity, and fetotoxicity demonstrated in animals.¹

Avoid pregnancy during therapy.¹ Verify pregnancy status prior to initiating olaparib.¹ Females of reproductive potential should use effective contraceptive methods while receiving olaparib and for ≥6 months after the drug is discontinued.¹ Males with such female partners or partners who are pregnant should use effective contraceptive methods while receiving olaparib and for 3 months after the drug is discontinued.¹ Males should be advised to refrain from donating sperm while receiving olaparib and for 3 months after the drug is discontinued.¹ If used during pregnancy or patient becomes pregnant, apprise of potential fetal hazard and risk for loss of the pregnancy.¹

Venous Thromboembolic Events

Venous thromboembolic events, including pulmonary embolism, reported in 7% of patients with metastatic castration-resistant prostate cancer receiving olaparib plus androgen deprivation therapy.¹ Pulmonary embolism reported in 6% of patients receiving olaparib plus androgen deprivation therapy.¹

Monitor patients for signs and symptoms of venous thrombosis or pulmonary embolism.¹ If venous thrombosis or pulmonary embolism occurs, treat the patient as medically appropriate (e.g., long-term anticoagulation).¹

Specific Populations

Pregnancy

May cause fetal harm.¹

Verify pregnancy status prior to initiating olaparib.¹ Females of reproductive potential should use effective contraceptive methods while receiving olaparib and for ≥6 months after the drug is discontinued.¹ Males with such female partners or partners who are pregnant should use effective contraceptive methods while receiving olaparib and for 3 months after the drug is discontinued.¹ Males should be advised to refrain from donating sperm while receiving olaparib and for 3 months after the drug is discontinued.¹

Lactation

Not known whether olaparib is distributed into milk.¹ Avoid breast-feeding during olaparib therapy and for 1 month after the last dose of olaparib.¹

Pediatric Use

Safety and efficacy not established in pediatric patients.¹

Geriatric Use

In clinical studies in patients with advanced solid tumors receiving olaparib monotherapy, 25% were ≥65 years of age, 6% were ≥75 years of age, and 0.3% were ≥85 years of age.¹

In clinical studies in patients with advanced solid tumors receiving olaparib in combination with bevacizumab, 38% were ≥65 years of age, and 6% were ≥75 years of age.¹

No differences in overall safety or effectiveness were observed in these patients compared to younger patients.¹

Hepatic Impairment

Increased exposure observed in patients with mild or moderate hepatic impairment; no initial dosage adjustment necessary.¹

Not studied in patients with severe hepatic impairment.¹

Renal Impairment

Increased exposure observed in patients with mild or moderate renal impairment; dosage reduction recommended in patients with moderate renal impairment.¹

Not studied in patients with severe renal impairment or end-stage renal disease.¹

Common Adverse Effects

Olaparib monotherapy (≥10%): Nausea, fatigue (including asthenia), anemia, vomiting, diarrhea, decreased appetite, headache, dysgeusia, cough, neutropenia, dyspnea, dizziness, dyspepsia, leukopenia, thrombocytopenia.¹

Combination therapy with bevacizumab (≥10%): Nausea, fatigue (including asthenia), anemia, lymphopenia, vomiting, diarrhea, neutropenia, leukopenia, urinary tract infection, headache.¹

Drug Interactions

Metabolized principally by CYP3A.¹ Substrate and inhibitor of P-glycoprotein (P-gp) in vitro.¹

Induces CYP2B6 and both inhibits and induces CYP3A in vitro; predicted to be a weak CYP3A inhibitor.¹

Inhibitor of UGT1A1 in vitro.¹

Inhibitor of breast cancer resistance protein (BCRP), organic anion transport protein (OATP) 1B1, organic cation transporter (OCT) 1 and OCT2, organic anion transporter (OAT) 3, and multidrug and toxic compound extrusion (MATE) 1 and MATE2K.¹

Drugs Affecting Hepatic Microsomal Enzymes

Moderate and potent CYP3A inhibitors: Potential increased plasma concentrations and AUC of olaparib.¹ Avoid concomitant use; consider choosing an alternative agent with less CYP3A inhibition potential.¹ If concomitant use of a potent CYP3A inhibitor cannot be avoided, reduce olaparib dosage to 100 mg twice daily.¹ If concomitant use of a moderate CYP3A inhibitor cannot be avoided, reduce olaparib dosage to 150 mg twice daily.¹ If concomitant use of the CYP3A inhibitor is discontinued, return olaparib dosage to the dosage used prior to initiation of the CYP3A inhibitor (after 3–5 terminal half-lives of the CYP3A inhibitor).¹

CYP3A inducers: Potential pharmacokinetic interaction (decreased plasma concentrations and AUC of olaparib).¹ Avoid concomitant use of moderate or potent CYP3A inducers.¹

Specific Drugs and Foods

Olaparib Pharmacokinetics

Absorption

Bioavailability

Following oral administration, peak plasma concentrations are attained in a median of 1.5 hours.¹

Systemic exposure of olaparib increases approximately proportionally with dose over the dose range of 25–450 mg, and peak plasma concentrations increase slightly less than proportionally over the same dose range.¹

Following repeated doses of olaparib, AUC mean accumulation ratio is 1.8.¹

Food

Administration with a high-fat, high-calorie meal decreased the rate (time to peak concentration delayed by 2.5 hours) but did not substantially affect extent of absorption (mean AUC increased by approximately 8%).¹

Special Populations

Mild (Child-Pugh class A) hepatic impairment: Mean peak plasma concentrations and AUC increased by 13 and 15%, respectively, relative to individuals with normal hepatic function.¹

Moderate (Child-Pugh class B) hepatic impairment: Mean peak plasma concentrations decreased by 13% and AUC increased by 8%, relative to individuals with normal hepatic function.¹

Severe (Child-Pugh class C) hepatic impairment: Pharmacokinetics not studied.¹

Mild (Cl_cr 51–80 mL/minute) renal impairment: Mean peak plasma concentrations and AUC increased by 15 and 24%, respectively, relative to individuals with normal renal function.¹

Moderate (Cl_cr 31–50 mL/minute) renal impairment: Mean peak plasma concentrations and AUC increased by 26 and 44%, respectively, relative to individuals with normal renal function.¹

Severe (Cl_cr ≤30 mL/minute) renal impairment or end-stage renal disease: Pharmacokinetics not studied.¹

Distribution

Extent

Not known whether olaparib is distributed into milk.¹

Plasma Protein Binding

Approximately 82% (at recommended dosage).¹

Special Populations

Protein binding not affected by mild to moderate hepatic impairment.¹

Elimination

Metabolism

Primarily metabolized by CYP3A4.¹

Elimination Route

Eliminated in urine (44%) and feces (42%).¹

Half-life

Mean terminal plasma half-life: 14.9 hours.¹

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C).¹ Store in original container to protect from moisture.¹

Actions

• Inhibits mammalian poly(ADP-ribose) polymerase (PARP) enzymes, including PARP-1, PARP-2, and PARP-3.¹ PARP enzymes are involved in normal cellular homeostasis, including DNA transcription and DNA repair.¹

• Olaparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complex, which result in DNA damage and cancer cell death.¹

• PARP inhibitors, including olaparib, appear to be selective for tumor cells harboring certain homologous recombination deficiencies (e.g., BRCA1 and BRCA2 mutations).^{2 10} In vitro, olaparib inhibited growth of such select tumor cell lines.¹

• Reduces tumor growth of xenograft models of human cancer in mice as a single agent or following platinum-based chemotherapy.¹

• Increases cytotoxicity and anti-tumor activity in BRCA-deficient cell lines and mouse tumor models deficient in BRCA1/2, ATM, and other genes involved in homologous recombination repair, and correlates with platinum response.¹

Advice to Patients

• Importance of providing a copy of written patient information (medication guide) each time olaparib is dispensed.¹ Importance of advising patients to read the patient information before taking olaparib and each time the prescription is refilled.¹

• Importance of advising patients to swallow olaparib tablets whole and not to chew, crush, dissolve, or divide tablets.¹ Importance of also advising patients to avoid grapefruit, grapefruit juice, Seville oranges, and Seville orange juice while taking the drug.¹

• If a dose is missed, importance of advising patients not to take an extra dose and to take the next normal dose at the regularly scheduled time.¹

• Importance of informing patients that olaparib tablets should be stored at room temperature (20–25°C) and that exposure to temperatures greater than 30°C should be avoided.¹ Importance of advising patients that olaparib tablets should be stored in the original container to protect from moisture.¹

• Risk of MDS/AML.¹ Importance of informing clinician if fatigue/asthenia, fever, weight loss, frequent infections, bruising, unusual bleeding (including hematuria or bloody stool), or shortness of breath occurs.¹

• Importance of hematologic monitoring during olaparib therapy.¹

• Risk of pneumonitis.¹ Importance of informing clinician if new or worsening respiratory symptoms, including shortness of breath, fever, cough, or wheezing, occur.¹

• Risk of venous thromboembolic events in patients with metastatic castration-resistant prostate cancer.¹ Importance of informing clinician immediately if any signs or symptoms of thromboembolism, including pain or swelling in an extremity, shortness of breath, chest pain, tachypnea, or tachycardia, occur.¹

• Importance of advising patients that mild or moderate nausea and/or vomiting commonly occurs with olaparib therapy; patients experiencing these symptoms should contact their clinician for advice on available antiemetic treatment options.¹

• Risk of fetal harm and pregnancy loss.¹ Necessity of advising females of reproductive potential to avoid pregnancy and to use an effective method of contraception while receiving olaparib and for at least 6 months following discontinuance of therapy.¹ Importance of advising males with female partners of reproductive potential or partners who are pregnant to use an effective method of contraception while receiving olaparib and for 3 months following discontinuance of therapy. ¹ Importance of advising males not to donate sperm while receiving olaparib and for 3 months following discontinuance of therapy.¹ Importance of women informing clinicians immediately if they become pregnant during therapy or think they may be pregnant.¹ If pregnancy occurs, advise pregnant women of potential risk to the fetus.¹

• Importance of advising women to avoid breast-feeding while receiving olaparib therapy and for at least 1 month following discontinuance of therapy.¹

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements (e.g., St. John's wort), as well as any concomitant illnesses (e.g., respiratory disorders, liver or kidney damage).¹

• Importance of informing patients of other important precautionary information.¹

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Distribution of olaparib is restricted. ¹³

Frequently asked questions

• How long does it take Lynparza (olaparib) to work?
• How effective is Lynparza (olaparib)?
• Does Lynparza (olaparib) cause hair loss?

Medical Disclaimer