Olaparib

Registered South African indications:

• Ovarian cancer
• Breast cancer
• Adenocarcinoma of the pancreas
• Prostate cancer

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Pregnancy
• Breastfeeding and for one month after receiving the last dose of olaparib
• Severe renal impairment (CrCl<30ml/min)
• Severe hepatic impairment (Child-Pugh class C)

Contraindications registered in other jurisdictions

• Hypersensitivity to the active ingredient or any of its excipients
• Breastfeeding and for one month after receiving the last dose of olaparib

South African recommendations

• Women of childbearing potential and for 1 month after receiving the last dose of olaparib (unless on effective contraception)
• Males of reproductive potential for 3 months after receiving the last dose of olaparib when having sexual intercourse with a pregnant woman or with a woman of childbearing potential
• Moderate renal impairment (31-50ml/min)
• Haematological toxicity caused by previous anti-cancer therapy
• Potential contributing factors for the development of myelodysplastic syndrome/acute myeloid leukaemia
  - Previous chemotherapy with platinum medicines 
  - Previous DNA damaging treatments
  - Germline BRCA mutation (gBRCAm) carriers
  - History of more than one primary malignancy or bone marrow dysplasia 
• Pre-disposing factors for pneumonitis
  - Cancer and/or metastases in lungs
  - Underlying pulmonary disease
  - Smoking history
  - Previous chemotherapy
  - Previous radiotherapy
• Coadministration with strong or moderate CYP3A inhibitors or inducers
• Coadministration with myelosuppressive anticancer medicines (at the recommended olaparib monotherapy dose)
• May impair ability to drive and operate machinery

Recommendations in other jurisdictions

• Pregnancy
  - Women of childbearing potential and for 1 month after receiving the last dose of olaparib (unless on effective contraception)
• Males of reproductive potential for 3 months after receiving the last dose of olaparib when having sexual intercourse with a pregnant woman or with a woman of childbearing potential
• Moderate to severe renal impairment (CrCI≤50ml/min) or end-stage renal disease ​​​​​​
• Severe hepatic impairment (Child-Pugh class C)
• Haematological toxicity caused by previous anti-cancer therapy
• BRCAm platinum-sensitive relapsed ovarian cancer patients who have received at least two prior lines of platinum chemotherapy
• Pre-disposing factors for pneumonitis
  - Cancer and/or metastases in lungs
  - Underlying pulmonary disease
  - Smoking history
  - Previous chemotherapy
  - Previous radiotherapy
• Coadministration with strong or moderate CYP3A inhibitors or inducers
• Coadministration with myelosuppressive anticancer medicines (at the recommended olaparib monotherapy dose)
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: fct

South African registered indications and dosages

Treatment with olaparib should be initiated and supervised by a medical practitioner experienced in the use of anticancer medicines. Detection of BRCA and other HRR gene mutation status should be determined by an experienced laboratory using a validated test method

Used for the treatment of

Ovarian cancer
- As monotherapy for the maintenance treatment of patients with advanced BRCA mutated high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer who are in response (complete response or partial response) to first-line platinum-based chemotherapy

• Oral (fct): 300mg (two 150mg tab), twice daily; Total daily dose: 600mg; Treatment duration: Can continue for 2 years or until radiological disease progression

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Patients must have confirmation of a breast cancer susceptibility gene (BRCA) mutation (identified by either germline or tumour testing) before olaparib treatment is initiated

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Patients with a complete response (no radiological evidence of disease) at 2 years should stop treatment. Patients with evidence of disease at 2 years, who in the opinion of the treating medical practitioner can derive further benefit from continuous treatment, can be treated beyond 2 years

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- As monotherapy for the maintenance treatment of patients with platinum-sensitive relapsed high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer who are in response (complete response or partial response) to platinum-based chemotherapy

• Oral (fct): 300mg (two 150mg tab), twice daily; Total daily dose: 600mg; Treatment duration: Until progression of the underlying disease or unacceptable toxicity

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Patients must have confirmation of a BRCA mutation (identified by germline testing) before olaparib treatment is initiated

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- In combination with bevacizumab for maintenance treatment of patients with advanced high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer who are in response (complete response or partial response) to first-line platinum-based chemotherapy with bevacizumab (Additional agent required)

• Oral (fct): 300mg (two 150mg tab), twice daily; Total daily dose: 600mg; Treatment duration: Can continue for 2 years or until radiological disease progression, unacceptable toxicity

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Patients with a complete response (no radiological evidence of disease) at 2 years should stop treatment. Patients with evidence of disease at 2 years, who in the opinion of the treating medical practitioner can derive further benefit from continuous olaparib  treatment, can be treated beyond 2 years. When olaparib is used in combination with bevacizumab, refer to the Prescribing Information for bevacizumab for recommended dosing information

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Breast cancer
- As monotherapy for the treatment of patients with germline BRCA-mutated HER2-negative metastatic breast cancer who have previously been treated with chemotherapy. These patients could have received chemotherapy in the neoadjuvant, adjuvant or metastatic setting

• Oral (fct): 300mg (two 150mg tab), twice daily; Total daily dose: 600mg; Treatment duration: Until progression of the underlying disease or unacceptable toxicity

Adenocarcinoma of the pancreas
- As monotherapy for the maintenance treatment of patients with germline BRCA-mutated metastatic adenocarcinoma of the pancreas whose disease has not progressed on first-line platinum-based chemotherapy

• Oral (fct): 300mg (two 150mg tab), twice daily; Total daily dose: 600mg; Treatment duration: Until progression of the underlying disease or unacceptable toxicity

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Patients must have confirmation of a BRCA mutation (identified by germline testing) before olaparib treatment is initiated

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Prostate cancer
- As monotherapy for the treatment of patients with metastatic castration-resistant prostate cancer and homologous recombination repair gene mutations (germline and/or somatic) who have progressed following a prior new hormonal agent

• Oral (fct): 300mg (two 150mg tab), twice daily; Total daily dose: 600mg; Treatment duration: Until progression of the underlying disease or unacceptable toxicity

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Patients must have confirmation of a homologous recombination repair (HRR) gene mutation (using either tumour DNA from a tissue sample, ctDNA obtained from a plasma sample or germline DNA obtained from a blood or another non-tumour sample) before olaparib treatment is initiated. HRR genetic status should be determined by an experienced laboratory using a validated test method

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The 100mg tablet is available for dose reduction

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If a patient misses a dose of olaparib, they should take their next normal dose at its scheduled time

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Method of administration
Olaparib is for oral use. Olaparib tablets should be swallowed whole and not chewed, crushed, dissolved or divided. Olaparib tablets may be taken with or without food

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See additional prescribing points for dose adjustments for adverse events

Not established for use in children and adolescents

Pregnancy 

South African recommendations

• Contraindicated
• Olaparib is contraindicated during pregnancy due to the teratogenic and genotoxic potential of olaparib
• Female partners of male patients taking olaparib should also avoid pregnancy
• No studies have been conducted in pregnant women
• If a female patient or a female partner of a male patient receiving olaparib becomes pregnant, she should be apprised of the potential hazard to the foetus or potential risk of loss of the pregnancy
• Based on its mechanism of action (PARP inhibition), olaparib could cause foetal harm when administered to a pregnant woman
• Nonclinical studies in rats have shown that olaparib causes adverse effects on embryofoetal survival and induces major foetal malformations at exposures below those expected at the recommended human dose of 300mg twice daily
• Olaparib should not be taken during pregnancy. If the patient becomes pregnant while taking olaparib, the patient should be apprised of the potential hazard to a foetus
• Women of childbearing potential must use two forms of effective contraception before starting olaparib treatment during therapy and for one month after receiving the last dose of olaparib
• A pregnancy test should be performed on all women of childbearing potential prior to treatment, and pregnancy tests should be performed at regular intervals during treatment and at one month after receiving the last dose
• Two highly effective and complementary forms of contraception are recommended
• Male patients and their female partners of childbearing potential should be advised that they must use effective contraception during olaparib treatment and for 3 months after receiving the last dose of olaparib
• It is not known whether olaparib or its metabolites are found in seminal fluid. Male patients must use a condom during therapy and for 3 months after receiving the last dose of olaparib when having sexual intercourse with a pregnant woman or with a woman of childbearing potential. Female partners of male patients must also use effective contraception if they are of childbearing potential
• Male patients should not donate sperm during therapy and for 3 months after receiving the last dose of olaparib 

Recommendations in other jurisdictions

• Caution; positive evidence of risk in animal studies
• Studies in animals have shown reproductive toxicity including serious teratogenic effects and effects on embryofoetal survival in the rat at maternal systemic exposures lower than those in humans at therapeutic doses
• There are no data from the use of olaparib in pregnant women, however, based on the mode of action of olaparib, olaparib should not be used during pregnancy and in women of childbearing potential not using reliable contraception during therapy and for 1 month after receiving the last dose of olaparib
• Women of childbearing potential should not become pregnant while on olaparib and not be pregnant at the beginning of treatment. A pregnancy test should be performed on all women of childbearing potential prior to treatment and considered regularly throughout treatment
• Women of childbearing potential must use two forms of reliable contraception before starting olaparib therapy, during therapy and for 1 month after receiving the last dose of olaparib, unless abstinence is the chosen method of contraception
• Two highly effective and complementary forms of contraception are recommended
• Since it cannot be excluded that olaparib may reduce exposure to substrates of CYP2C9 through enzyme induction, the efficacy of some hormonal contraceptives may be reduced if co-administered with olaparib
• Therefore, an additional non-hormonal contraceptive method should be considered during treatment
• For women with hormone dependent cancer, two non-hormonal contraceptive methods should be considered
• It is not known whether olaparib or its metabolites are found in seminal fluid. Male patients must use a condom during therapy and for 3 months after receiving the last dose of olaparib when having sexual intercourse with a pregnant woman or with a woman of childbearing potential
• Female partners of male patients must also use highly effective contraception if they are of childbearing potential
• Male patients should not donate sperm during therapy and for 3 months after receiving the last dose of olaparib

Breastfeeding

South African recommendations

• Contraindicated
• Mothers must not breastfeed their infants while taking olaparib, nor for one month after the last dose

Recommendations in other jurisdictions

• Contraindicated 
• There are no animal studies on the excretion of olaparib in breast milk
• It is unknown whether olaparib or its metabolites are excreted in human milk. Olaparib is contraindicated during breastfeeding and for 1 month after receiving the last dose, given the pharmacologic property of the product

Fertility

Recommendations below are applicable to South Africa and other jurisdictions

• There are no clinical data on human fertility. In animal studies, no effect on conception was observed but there are adverse effects on embryofoetal survival

South African recommendations

• Mild (CrCI>51-80ml/min): No dose adjustment recommended 
• Moderate (CrCl 31-50ml/min): Caution; dose adjustment recommended 
  Oral (tab): 200mg (two 100mg tab), 12hrly; Total daily dose: 400mg
• Severe (CrCl≤30ml/min)/ End-stage renal disease: Contraindicated

Recommendations in other jurisdictions

• Mild (CrCI>51-80ml/min): No dose adjustment recommended 
• Moderate (CrCl 31-50ml/min): Caution; dose adjustment recommended 
  Oral (tab): 200mg (two 100mg tab), 12hrly; Total daily dose: 400mg
• Severe (CrCl≤30ml/min)/ End-stage renal disease: Not recommended for use
  Safety and pharmacokinetics have not been studied in these patients
  Olaparib may only be used in patients with severe renal impairment if the benefit outweighs the potential risk, and the patient should be carefully monitored for renal function and adverse events

South African recommendations

• Mild to moderate (Child-Pugh class A and B): No dose adjustment recommended
• Severe (Child-Pugh class C): Contraindicated

Recommendations in other jurisdictions

• Mild to moderate (Child-Pugh class A and B): No dose adjustment recommended
• Severe (Child-Pugh class C): Not recommended for use
  Safety and pharmacokinetics have not been studied in these patients

South African recommendations

• No dose adjustment recommended 
  There are limited clinical data in patients ≥75 years

Recommendations in other jurisdictions

• No dose adjustment recommended 

Central Nervous System Disorders

• Dizziness
• Headache
• Dysgeusia
  - Taste disorder
• Fatigue

Respiratory Disorders

• Cough
  - Productive cough
• Dyspnoea
  - Exertional dyspnoea
• Pneumonitis

Gastrointestinal Disorders

• Decreased appetite
• Diarrhoea
• Nausea and vomiting
• Dyspepsia
• Stomatitis
  - Aphthous ulcer
  - Mouth ulceration
• Upper abdominal pain

Skin and Subcutaneous Tissue Disorders

• Rash 
  - Erythema
  - Exfoliative rash
  - Erythematous rash
  - Macular rash
  - Maculopapular rash
  - Papular rash
  - Pruritic rash
• Dermatitis
  - Allergic dermatitis
• Erythema nodosum

Immune, Blood and Lymphatic System Disorders

• Hypersensitivity
  - Drug hypersensitivity
• Angioedema
• Myelodysplastic syndrome
• Acute myeloid leukaemia
• Anaemia
  - Macrocytic anaemia
  - Erythropenia
  - Decreased haematocrit
  - Decreased haemoglobin
  - Normocytic anaemia
  - Decreased red blood cell count
• Neutropenia
  - Febrile neutropenia
  - Neutropenic infection
  - Neutropenic sepsis
  - Decreased neutrophil count
• Thrombocytopenia
  - Decreased platelet count
• Leukopenia
  - Decreased white blood cell count
• Lymphopenia
• Increased blood creatinine
• Increased mean cell volume
• Fever

• Strong CYP3A inhibitors
• Itraconazole
• Telithromycin
• Clarithromycin
• Protease inhibitors boosted with ritonavir
• Cobicistat
• Boceprevir
• Telaprevir
• Moderate CYP3A inhibitors
• Erythromycin
• Diltiazem
• Fluconazole
• Verapamil
• Strong CYP3A inducers
• Phenytoin
• Rifampicin
• Rifapentine
• Carbamazepine
• Nevirapine
• Phenobarbital
• CYP3A substrates or substrates with a narrow therapeutic margin
• Simvastatin
• Cisapride
• Cyclosporine
• Ergot alkaloids
• Fentanyl
• Pimozide
• Sirolimus
• Tacrolimus
• Quetiapine
• CYP2B6, CYP2C9, CYP2C19 and P-gp substrates
• Pravastatin
• Dabigatran
• Digoxin
• Colchicine
• Hormonal contraceptives
• BCRP substrates
• Methotrexate
• Rosuvastatin
• OATP1B1 substrates
• Bosentan
• Glibenclamide
• Repaglinide
• Statins
• Valsartan
• OCT1  substrates
• Metformin
• OCT2 substrates
• OAT3 substrates
• Furosemide
• MATE1 and MATE2K substrates
• Myelosuppressive anticancer medicinal agents
• Vaccines
• Immunosuppressant agents

Other interactions

• Grapefruit juice
• St John's wort

• BRCA-mutation status
• Homologous recombination deficiency (HRD) positive status
• Homologous recombination repair (HRR) gene mutation
• Full blood count
• Renal function
• Hepatitis B virus (HBV) screening
  - Hepatitis B surface antigen
  - Hepatitis B core antibody
  - Total Ig or IgG
  - Antibody to hepatitis B surface antigen

Specific cases may require

• Pregnancy status

Additional observations

• Sign/symptoms of:
  - Venous thrombosis
  - Pulmonary embolism
  - Acute myeloid leukaemia/myelodysplastic syndrome
  - Pneumonitis
• Monitor adherence

 Dose adjustments

For adverse events

• Treatment may be interrupted to manage adverse events (such as nausea, vomiting, diarrhoea and anaemia) and dose reduction can be considered 
• Recommended dose reduction: Oral (fct): 250mg (one 150mg tablet and one 100mg tablet), twice daily; Total daily dose: 500mg
• If a further dose reduction is required: Oral (fct): 200mg (two 100mg tablets) twice daily; Total daily dose: 400mg

Coadministration with CYP3A inhibitors

• Concomitant use of strong or moderate CYP3A inhibitors is not recommended, and alternative medicines should be considered
• If a strong CYP3A inhibitor must be coadministered, the recommended olaparib dose reduction: Oral (fct): 100mg (one 100mg tablet), twice daily; Total daily dose: 200mg
• If a moderate CYP3A inhibitor must be coadministered, the recommended olaparib dose reduction: Oral (fct): 150mg (one 150mg tablet), twice daily; Total daily dose: 300mg

Olaparib in combination with bevacizumab

• When olaparib is used in combination with bevacizumab for the first-line maintenance treatment of high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer following completion of first-line platinum-based therapy with bevacizumab, the dose of bevacizumab is 15mg/kg once every 3 weeks
• Please refer to the product information for bevacizumab for the recommended overall duration of treatment of a maximum of 15 months including the periods in combination with chemotherapy and as maintenance

Patient selection

First-line maintenance treatment of BRCA-mutated advanced ovarian cancer:

• Before olaparib treatment is initiated for first-line maintenance treatment of high-grade epithelial ovarian cancer (EOC), fallopian tube cancer (FTC) or primary peritoneal cancer (PPC), patients must have confirmation of deleterious or suspected deleterious germline and/or somatic mutations in the breast cancer susceptibility genes (BRCA) 1 or 2 using a validated test

Maintenance treatment of platinum-sensitive relapsed ovarian cancer:

• There is no requirement for BRCA1/2 testing prior to using olaparib for the monotherapy maintenance treatment of relapsed EOC, FTC or PPC who are in complete or partial response to platinum-based therapy

First-line maintenance treatment of HRD positive advanced ovarian cancer in combination with bevacizumab:

• Before olaparib with bevacizumab treatment is initiated for the first-line maintenance treatment of EOC, FTC or PPC, patients must have confirmation of either deleterious or suspected deleterious BRCA1/2 mutation and/or genomic instability determined using a validated test

gBRCA1/2-mutated HER2-negative metastatic breast cancer:

• For germline breast cancer susceptibility genes (gBRCA1/2) mutated human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer, patients must have confirmation of a deleterious or suspected deleterious gBRCA1/2 mutation before olaparib treatment is initiated
• gBRCA1/2 mutation status should be determined by an experienced laboratory using a validated test method. Data demonstrating clinical validation of tumour BRCA1/2 tests in breast cancer are not currently available

First-line maintenance treatment of gBRCA-mutated metastatic adenocarcinoma of the pancreas:

• For first-line maintenance treatment of germline BRCA1/2-mutated metastatic adenocarcinoma of the pancreas, patients must have confirmation of a deleterious or suspected deleterious gBRCA1/2 mutation before olaparib treatment is initiated
• gBRCA1/2 mutation status should be determined by an experienced laboratory using a validated test method
• Data demonstrating clinical validation of tumour BRCA1/2 tests in adenocarcinoma of the pancreas are not currently available

BRCA1/2-mutated metastatic castration-resistant prostate cancer:

• For BRCA1/2-mutated metastatic castration-resistant prostate cancer (mCRPC), patients must have confirmation of a deleterious or suspected deleterious BRCA1/2 mutation (using either tumour or blood sample) before olaparib treatment is initiated
• BRCA1/2 mutation status should be determined by an experienced laboratory using a validated test method

Embryofoetal toxicity

• Based on its mechanism of action (PARP inhibition), olaparib could cause foetal harm when administered to a pregnant woman
• Nonclinical studies in rats have shown that olaparib causes adverse effects on embryofoetal survival and induces major foetal malformations at exposures below those expected at the recommended human dose of 300mg twice daily

Pharmacokinetics

• Elimination half-life (t_1/2) = 15 hours
• Elimination: ~44% via the urine; ~42% via the faeces

Olaparib is a potent inhibitor of human poly (ADP-ribose) polymerase enzymes (PARP-1, PARP-2, and PARP-3), and has been shown to inhibit the growth of selected tumour cell lines in vitro and tumour growth in vivo either as a standalone treatment or in combination with established chemotherapies. PARPs are required for the efficient repair of DNA single strand breaks and an important aspect of PARP-induced repair requires that after chromatin modification, PARP auto-modifies itself and dissociates from the DNA to facilitate access for base excision repair (BER) enzymes. When olaparib is bound to the active site of DNA-associated PARP it prevents the dissociation of PARP and traps it on the DNA, thus blocking repair. In replicating cells this also leads to the formation of DNA double-strand breaks (DSBs) when replication forks meet the PARP-DNA adducts. In normal cells, homologous recombination repair (HRR) pathway is effective at repairing these DNA DSBs. In cancer cells lacking critical functional components for efficient HRR such as BRCA1 or 2, DNA DSBs cannot be repaired accurately or effectively, leading to substantial homologous recombination deficiency (HRD). Instead, alternative and error-prone pathways are activated, such as the classical non-homologous end joining (NHEJ) pathway, leading to a high degree of genomic instability. After a number of rounds of replication, genomic instability can reach insupportable levels and result in cancer cell death, as cancer cells already have a high DNA damage load relative to normal cells. HRR pathway may be compromised by other mechanisms, although the causative aberrancy and penetrance are not fully elucidated. Absence of fully functional HRR pathway is one of the key determinants of platinum sensitivity in ovarian and possibly other cancers.

Film coated tablet 100mg

• Lynparza (AstraZeneca Pharmaceuticals) originator

Film coated tablet 150mg

• Lynparza (AstraZeneca Pharmaceuticals) originator