Olaparib is an orally available medicine available by the brand name of Lynparza. It is a PARP inhibitor that is used in the treatment of breast and ovarian cancers.

Olaparib (Lynparza) Uses:

• Breast cancer, metastatic (BRCA-mutated, HER2-negative):

  • Tablets: Treatment of deleterious or suspected deleterious germline BRCA-mutated (gBRCAm), HER2-negative metastatic breast cancer (select patients for therapy based on an approved olaparib companion diagnostic test) in patients who have been treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic setting;
  • Patients with hormone receptor-positive disease should have been previously treated with endocrine therapy (or be considered inappropriate for endocrine therapy).

• Advanced (BRCA-mutated) ovarian cancer:

  • Tablets, capsules: Treatment of deleterious or suspected deleterious gBRCAm advanced ovarian cancer (select patients for therapy based on an approved olaparib companion diagnostic test) in patients who have been previously treated with 3 or more lines of chemotherapy

• Advanced (BRCA-mutated) ovarian cancer as a first-line maintenance therapy:

  • Tablets: Firstline maintenance treatment of deleterious or suspected deleterious gBRCAm or somatic BRCAmutated (sBRCAm) advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer in adult patients with complete or partial response to first-line platinum-based chemotherapy (select patients for therapy based on an approved olaparib companion diagnostic test).

• Ovarian cancer, recurrent (maintenance therapy):

  • Tablets: Maintenance treatment of recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients with complete or partial response to platinum-based chemotherapy.

• Off Label Use of Olaparib in Adults:

  • Pancreatic cancer
  • metastatic, BRCA-mutated (maintenance therapy)

Olaparib (Lynparza) Dose in Adults

Note:

• Available in 100 mg and 150 mg tablet dosage and as 50 mg capsules.
• Do not substitute the 50 mg capsules for the 100 mg or 150 mg tablets on an mg-per-mg basis due to differences in dosing and bioavailability.

Olaparib (Lynparza) Dose in the treatment of metastatic, HER2-negative, germline BRCA-mutated (gBRCAm) Breast cancer:

• Oral: Tablets: 300 mg twice daily, continued until disease progression or unacceptable toxicity.

Olaparib (Lynparza) Dose in the treatment of Advanced Ovarian cancer, gBRCAm: Oral:

• Tablets: 300 mg twice daily, continued until disease progression or unacceptable toxicity.
• Capsules: 400 mg twice daily, continued until disease progression or unacceptable toxicity.

Olaparib (Lynparza) Dose in the treatment of Advanced Ovarian cancer, g BRCA m or somatic BRCA-mutated (s BRCA m), first-line maintenance therapy:

• Oral: Tablets: 300 mg twice daily, continued until disease progression or unacceptable toxicity or completion of 2 years of therapy.
• Patients with a complete response (no radiologic evidence of disease) at 2 years should discontinue olaparib;
• For patients with evidence of disease at 2 years may continue treatment (beyond 2 years) if further olaparib treatment may provide benefit (Moore 2018).

Olaparib (Lynparza) Dose in the maintenance treatment of recurrent ovarian cancer:

• Oral: Tablets: 300 mg twice daily, continued until disease progression or unacceptable toxicity.

Olaparib (Lynparza) Dose in the maintenance treatment of metastatic, BRCA-mutated Pancreatic cancer  (off-label):

• Oral: Tablets: 300 mg twice daily (start 4 to 8 weeks after the last dose of first-line platinum-based chemotherapy); continue until disease progression or unacceptable toxicity.

• Missed doses:

  • In case of the missed dose, administer the next dose at its scheduled time.

• Dosage adjustment for concomitant therapy:

  • CYP3A inhibitors:

    • Avoid concomitant use with moderate or strong CYP3A inhibitors (consider alternative agents with less CYP3A inhibition).
    • If must be administered with a moderate CYP3A inhibitor, reduce dose to 150 mg twice daily (tablets), or 200 mg twice daily (capsules).
    • If coadministration with a strong CYP3A inhibitor unavoidable, reduce dose to 100 mg twice daily (tablets) or 150 mg twice daily (capsules).

  • CYP3A inducers:

    • Avoid concomitant use with moderate or strong CYP3A4 inducers; a potential for reduced olaparib efficacy exists if moderate CYP3A inducers cannot be avoided.

Olaparib (Lynparza) Pregnancy Risk Category:

• Based on animal reproduction studies and the mechanism of action, it is possible that fetal harm could result from in utero exposure.
• It is a good idea to test for pregnancy before initiating treatment in females with reproductive potential.
• For women with reproductive potential, it is important to use effective contraception throughout therapy and for at most 6 months after the last dose of olaparib.
• Effective contraception should be used by males who have female partners with reproductive potential and those with pregnant female partners for the duration of treatment.
• The last dose of olaparib should also be administered for three months. Male patients shouldn't donate sperm during treatment or for the 3 months thereafter.

Use of Olaparib during lactation:

• It is not known if breast milk contains olaparib.
• The manufacturer suggests that breastfeeding mothers refrain from breastfeeding during treatment or for at least 1 month after receiving the last dose of olaparib.

Olaparib (Lynparza) Dose in Kidney Disease:

• CrCl 51 to 80 mL/minute:

  • No dosage adjustment needed; monitor closely for toxicity, as an increase in mean AUC has been seen in patients with mild impairment.

• CrCl 31 to 50 mL/minute:

  • Tablets: Reduce dose to 200 mg twice daily.
  • Capsules: Reduce dose to 300 mg twice daily.

• CrCl ≤30 mL/minute:

  • No studies conducted in patients with a CrCl of less than 30 ml/minute, there are no dosage adjustments provided in the manufacturer's labeling.

• ESRD:

  • No studies conducted in ESRD, there are no dosage adjustments provided in the manufacturer's labeling.

Olaparib (Lynparza) Dose in Liver Disease:

• Tablets:

  • Mild to moderate impairment (Child-Pugh classes A and B):
    • No dosage adjustment needed.
  • Severe impairment (Child-Pugh class C):
  • No studies conducted in severe liver disease, there are no dosage adjustments provided in the manufacturer's labeling.

• Capsules:

  • Mild impairment (Child-Pugh class A):
    • No dosage adjustment necessary.
  • Moderate to severe impairment (Child-Pugh classes B and C):
    • No studies conducted in severe liver disease, there are no dosage adjustments provided in the manufacturer's labeling.

Common Side Effects of Olaparib (Lynparza):

• Cardiovascular:

  • Peripheral Edema

• Central Nervous System:

  • Fatigue
  • Headache
  • Dizziness

• Endocrine & Metabolic:

  • Hypomagnesemia

• Gastrointestinal:

  • Nausea
  • Abdominal Pain
  • Vomiting
  • Diarrhea
  • Constipation
  • Dysgeusia
  • Dyspepsia
  • Decreased Appetite
  • Stomatitis

• Genitourinary:

  • Urinary Tract Infection

• Hematologic & Oncologic:

  • Increased MCV
  • Decrease In Absolute Neutrophil Count
  • Anemia
  • Neutropenia
  • Leukopenia
  • Thrombocytopenia

• Infection:

  • Influenza

• Neuromuscular & Skeletal:

  • Asthenia
  • Arthralgia
  • Myalgia
  • Musculoskeletal Pain
  • Back Pain

• Renal:

  • Increased Serum Creatinine

• Respiratory:

  • Nasopharyngitis
  • Respiratory Tract Infection
  • Rhinitis
  • Sinusitis
  • Bronchitis
  • Cough
  • Dyspnea

Less Common Side Effects Of Olaparib (Lynparza):

• Cardiovascular:

  • Edema
  • Pulmonary Embolism
  • Venous Thrombosis

• Central Nervous System:

  • Peripheral Neuropathy
  • Depression
  • Insomnia

• Dermatologic:

  • Skin Rash
  • Dermatitis

• Gastrointestinal:

  • Upper Abdominal Pain

• Hematologic & Oncologic:

  • Lymphocytopenia
  • Myelodysplastic Syndrome

• Hypersensitivity:

  • Hypersensitivity Reaction

• Miscellaneous:

  • Fever

Contraindications to Olaparib (Lynparza):

The US labeling of the manufacturer does not list any contraindications.

Canadian labeling

• Hypersensitivity to olaparib and any component of the formulation

Warnings and precautions

• Suppression of bone marrow

  • There have been reports of anemia, neutropenia and thrombocytopenia.
  • Complete blood counts should be monitored at baseline and every month thereafter.
  • You should not start olaparib unless any hematologic toxicities caused by prior chemotherapy have resolved to =grade 1.
  • If hematologic toxicemia persists during treatment, stop the therapy immediately and keep track of blood counts until you are fully recovered.
  • If counts don't recover to grade 1 within 4 weeks, additional evaluation is required (including bone marrow or cytogenetic analysis).

• Toxicity to the GI:

  • Sometimes, nausea and vomiting can occur (usually mild to moderate).

• Hypersensitivity

  • There have been cases of hypersensitivity reactions including rash or dermatitis.

• Toxicity in the lungs:

  • Rarely has pneumonitis occurred (including some fatalities). Interrupt treatment of new or worsening symptoms like cough, dyspnea or fever, wheezing or radiologic abnormalities.
  • If you suspect that you have pneumonitis, get checked immediately and stop taking any medication.

• Secondary malignancy

  • In clinical trials and long-term monitoring, myelodysplastic syndrome/acute leukemia (MDS/AML), have been rarely reported. This is mostly due to patients who have a confirmed BRCA mutation.
  • MDS/AML cases involving most patients were fatal. Patients treated with olaparib as part of combination studies or postmarketing reports have also been affected by MDS/AML.
  • Prior to developing secondary cancers, the duration of olaparib treatment ranged between 6 months and >2 years.
  • All patients had previously received chemotherapy with platinum agents or other DNA-damaging drugs including radiation. Some patients had a history of more than one primary malignancy.
  • If hematologic toxicities persist for more than 4 weeks and blood counts don't recover to =grade 1 within that time, additional evaluation is required. This includes bone marrow analysis and cytogenetic analyses. Stop all therapy if MDS/AML is confirmed.

• Renal impairment

  • Patients with mild or moderate kidney impairment should be closely monitored for toxicities. Moderate impairment may require dosage adjustment.

Olaparib: Drug Interaction

Monitoring Parameters:

BRCA-mutation status: Metastatic breast cancer, advanced-ovarian cancer and first-line maintenance of advanced ovarian carcinoma;

• Complete blood count at baseline, and monthly thereafter or as indicated by the physician (weekly up to recovery for prolonged hematologic toxicities).
• Tests of renal function
• Pregnancy test (before treatment begins in females with reproductive potential)
• Monitor for signs/symptoms such as acute myeloidleukemia/myelodysplastic Syndrome (AML/MDS), and pneumonitis.
• You must ensure that you adhere to the rules.

How to administer Olaparib (Lynparza)?

• Orally administer the medication twice daily, with or without food.
• Take the tablets in your mouth and swallow them.
• Take the capsules in a single swallow. If capsules are deformed or show signs of leakage, do not give them.
• A pharmacokinetic study in tablets showed that the absorption rate and peak exposure were slower when the tablet was taken with high-fat meals.
• However, the degree of absorption was not affected.
• Nausea and vomiting increased when olaparib is administered while fasting.
• Olaparib comes in 100mg and 150mg tablets, as well as 50 mg capsules. 
• Because of differences in bioavailability and dosing, the 50 mg capsules should not be substituted for the 100 mg or150 mg tablets.

Mechanism of action of Olaparib (Lynparza):

• Olaparib is an inhibitor of poly (ADPribose polymerase) enzymes (PARP), including PARP1, PARP2, PARP3, and PARP3. PARP enzymes play a role in DNA transcription, cell cycle regulation and DNA repair.
• Olaparib, an oral PARP inhibitor strong in strength, induces synthetic lethality of BRCA1/2-deficient tumor cells by forming double-stranded DNA breakages that cannot be repaired accurately.
• This causes disruption of cell homeostasis as well as cell death.

Absorption:

• Rapid;
• delayed with a high-fat meal (extent of absorption not significantly altered)

Protein binding:

• ~82%

Metabolism:

• It is metabolized primarily in the liver via CYP3A4/5;
• Most of metabolism is through oxidation with some metabolites undergoing glucuronide or sulfate conjugation later on.

Bioavailability:

• Tablet formulation has a higher bioavailability than the capsule formulation.

Terminal Half-life elimination:

• Tablet: 14.9 ± 8.2 hours;
• Capsule: 11.9 ± 4.8 hours

Time to peak:

• Tablet: 1.5 hours;
• Capsule: 1 to 3 hours

Excretion:

• Urine (44%, mostly metabolites);
• feces (42%, mostly metabolites)

International Brand Names of Olaparib:

• Lynparza
• Lynparza Hard

Olaparib Brand Names in Pakistan:

• No Brands Available in Pakistan.

However, one can acquire it after getting permission from DRAP for individual's use.