Olaparib

Olaparib is a potent inhibitor of the human poly(ADP-ribose) polymerase enzymes PARP-1, PARP-2 and PARP-3. It inhibits the growth of selected tumour cell lines in vitro and tumour growth in vivo, as a stand-alone treatment or together with established chemotherapies or new hormonal agents.

Mechanism of Action

• Role of PARP: PARP enzymes are needed for efficient repair of DNA single-strand breaks by base excision repair. After chromatin modification, PARP modifies itself and then leaves the DNA, which gives repair enzymes access to the damage.
• PARP trapping: when olaparib is bound to the active site of DNA-associated PARP, it prevents PARP from leaving the DNA and so blocks repair. In replicating cells this leads to double-strand breaks when replication forks meet the PARP–DNA complexes.
• Synthetic lethality: normal cells repair double-strand breaks by homologous recombination repair (HRR). Cancer cells that lack key HRR components such as BRCA1 or BRCA2 cannot repair them accurately, which produces homologous recombination deficiency (HRD). Error-prone pathways, such as non-homologous end joining, take over, genomic instability builds up over several rounds of replication, and the cells die.
• Platinum sensitivity: the absence of a fully functional HRR pathway is one of the key determinants of platinum sensitivity in ovarian and possibly other cancers.
• Preclinical activity: olaparib was active in cell lines and mouse models with deficiencies in BRCA1/2, ATM or other genes involved in HRR.

Pharmacokinetics

• Absorption: rapid; median peak plasma concentrations are reached about 1.5 hours after a tablet dose. Food slows the rate (time to peak delayed by 2.5 hours, Cmax down by about 21%) but not the extent of absorption (AUC up 8%), so tablets can be taken without regard to meals. On repeated dosing the AUC accumulation ratio is 1.8.
• Distribution: apparent volume of distribution about 158 L. Plasma protein binding is about 82% in vitro at 10 µg/mL and depends on concentration (about 91% at 1 µg/mL and 70% at 40 µg/mL); about 56% is bound to albumin and 29% to α1-acid glycoprotein.
• Metabolism: extensive, mainly by CYP3A4/5, through oxidation followed by glucuronide or sulfate conjugation. Unchanged olaparib makes up 70% of circulating radioactivity. The main circulating metabolites are a ring-opened piperazin-3-ol and two mono-oxygenated metabolites (about 10% each).
• Elimination: at the 300 mg tablet dose the apparent clearance is about 7 L/h and the terminal half-life 15 hours. After a radiolabelled dose, about 86% was recovered within 7 days, about 44% in urine and about 42% in faeces, mostly as metabolites.
• Special populations: age, sex, body weight, tumour location and race were not significant covariates. In mild renal impairment (creatinine clearance 51–80 mL/min) AUC rose by 24% and Cmax by 15%; in moderate impairment (31–50 mL/min) AUC rose by 44% and Cmax by 26%. In mild hepatic impairment (Child-Pugh A) AUC rose by 15% and in moderate (Child-Pugh B) by 8%. There are no data in severe renal impairment, end-stage renal disease or severe hepatic impairment.

Olaparib is indicated in adults as follows.

Ovarian, fallopian tube or primary peritoneal cancer

• Monotherapy, first-line maintenance: advanced (FIGO stages III and IV) BRCA1/2-mutated (germline and/or somatic) high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer in response (complete or partial) after first-line platinum-based chemotherapy.
• Monotherapy, relapsed disease: maintenance treatment of platinum-sensitive relapsed high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer in response (complete or partial) to platinum-based chemotherapy.
• With bevacizumab: maintenance treatment of advanced (FIGO stages III and IV) high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer in response after first-line platinum-based chemotherapy with bevacizumab, where the cancer is associated with homologous recombination deficiency (HRD) positive status, defined by a BRCA1/2 mutation and/or genomic instability.

Breast cancer

• Adjuvant treatment: as monotherapy or with endocrine therapy, in patients with germline BRCA1/2 mutations who have HER2-negative, high-risk early breast cancer previously treated with neoadjuvant or adjuvant chemotherapy.
• Locally advanced or metastatic disease: as monotherapy in patients with germline BRCA1/2 mutations and HER2-negative disease. Patients should have been treated before with an anthracycline and a taxane in the (neo)adjuvant or metastatic setting, unless they were unsuitable for these treatments. Patients with hormone receptor (HR)-positive disease should also have progressed on or after prior endocrine therapy, or be considered unsuitable for it.

Adenocarcinoma of the pancreas

• Maintenance monotherapy: patients with germline BRCA1/2 mutations and metastatic disease who have not progressed after at least 16 weeks of platinum treatment within a first-line chemotherapy regimen.

Prostate cancer

• Monotherapy: metastatic castration-resistant prostate cancer (mCRPC) with BRCA1/2 mutations (germline and/or somatic) that has progressed after prior therapy that included a new hormonal agent.
• With abiraterone and prednisone or prednisolone: mCRPC in patients in whom chemotherapy is not clinically indicated.

Endometrial cancer

• With durvalumab: maintenance treatment of primary advanced or recurrent endometrial cancer that is mismatch repair proficient (pMMR), whose disease has not progressed on first-line treatment with durvalumab in combination with carboplatin and paclitaxel.

• Hypersensitivity to olaparib or to any of the excipients.
• Breastfeeding during treatment and for 1 month after the last dose.

Olaparib has been associated with adverse reactions that are generally mild or moderate (CTCAE grade 1 or 2) and usually do not require stopping treatment. The profile is based on pooled data from 4,499 patients with solid tumours treated with monotherapy. The most frequently observed reactions (10% or more) were nausea, fatigue or asthenia, anaemia, vomiting, diarrhoea, decreased appetite, headache, neutropenia, dysgeusia, cough, leukopenia, dizziness, dyspnoea and dyspepsia. Grade 3 or higher reactions in more than 2% of patients were anaemia (14%), neutropenia (5%), fatigue or asthenia (4%), leukopenia (2%) and thrombocytopenia (2%). The reactions that most often led to dose interruption or reduction were anaemia (16%), nausea (7%), fatigue or asthenia (6%), neutropenia (6%) and vomiting (6%); those that most often led to permanent discontinuation were anaemia (1.7%), nausea (0.9%), fatigue or asthenia (0.8%), thrombocytopenia (0.7%), neutropenia (0.6%) and vomiting (0.5%).

Very common (≥1/10): anaemia, neutropenia, leukopenia, decreased appetite, dizziness, headache, dysgeusia, cough, dyspnoea, vomiting, diarrhoea, nausea, dyspepsia, fatigue (including asthenia).

Common (≥1/100 to <1/10): lymphopenia, thrombocytopenia, raised transaminases, stomatitis, upper abdominal pain, rash, raised blood creatinine, venous thromboembolism.

Uncommon (≥1/1,000 to <1/100): myelodysplastic syndrome or acute myeloid leukaemia, hypersensitivity, pneumonitis, dermatitis, increased mean cell volume.

Rare (≥1/10,000 to <1/1,000): angioedema (reported after marketing), erythema nodosum.

Not known: drug-induced liver injury (reported after marketing).

In combination with bevacizumab, abiraterone or durvalumab the safety profile is generally consistent with that of the individual medicines. After durvalumab with platinum-based chemotherapy, most reactions occurred at the same or a lower frequency than in the monotherapy table; thrombocytopenia and rash were very common, hypersensitivity was common, and pure red cell aplasia (common, all grade 3 or 4) was an additional reaction.

Important serious reactions include myelodysplastic syndrome or acute myeloid leukaemia (most with fatal outcome; in relapsed BRCA-mutated ovarian cancer with at least two prior platinum lines the incidence was 8% on olaparib and 4% on placebo after 5 years, and in first-line maintenance 1.5% and 1.1% in two studies), pneumonitis, venous thromboembolism (8% with olaparib plus abiraterone versus 3.3% with placebo plus abiraterone) and anaemia (15.6% of patients needed one or more blood transfusions). Nausea usually began in the first month and vomiting within two months; both were intermittent and could be managed by dose interruption or reduction or with antiemetic treatment, and antiemetic prophylaxis is not required. Blood creatinine rose by a median of up to 23% from baseline, stayed constant and returned to baseline after stopping, without apparent clinical effects.

Olaparib is cleared mainly by CYP3A4/5. It is a mild CYP3A inhibitor in vivo and, in vitro, an inhibitor of several transporters.

• Anticancer medicines that suppress the bone marrow: combinations with DNA-damaging agents can potentiate and prolong myelosuppression. The recommended monotherapy dose is not suitable for combination with myelosuppressive anticancer medicines.
• Vaccines and immunosuppressants: the combination has not been studied, so caution and close monitoring are advised.
• CYP3A inhibitors: itraconazole raised olaparib Cmax by 42% and AUC by 170%. Strong inhibitors (itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, boceprevir, telaprevir) and moderate inhibitors (erythromycin, diltiazem, fluconazole, verapamil) are not recommended. If one must be used, the olaparib dose is reduced (see Administration and Dosage).
• Grapefruit juice: it is a CYP3A inhibitor and is not recommended during treatment.
• CYP3A inducers: rifampicin lowered olaparib Cmax by 71% and AUC by 87%. Strong inducers (phenytoin, rifampicin, rifapentine, carbamazepine, nevirapine, phenobarbital, St John’s wort) are not recommended because the effect of olaparib could be substantially reduced. The size of the effect of moderate to strong inducers such as efavirenz and rifabutin is not established, so these are not recommended either.
• CYP3A substrates: caution with sensitive substrates or those with a narrow therapeutic margin (simvastatin, cisapride, ciclosporin, ergot alkaloids, fentanyl, pimozide, sirolimus, tacrolimus, quetiapine), with appropriate clinical monitoring.
• Enzyme induction: in vitro, olaparib induced CYP1A2, CYP2B6 and CYP3A4, and induction of CYP2C9, CYP2C19 and P-gp cannot be excluded. It may therefore lower the exposure to their substrates, and the efficacy of some hormonal contraceptives may be reduced.
• Transporters: in vitro olaparib inhibits P-gp, BCRP, OATP1B1, OCT1, OCT2, OAT3, MATE1 and MATE2K, so it cannot be excluded that it raises the exposure to their substrates: P-gp (for example simvastatin, pravastatin, dabigatran, digoxin, colchicine), BCRP (methotrexate, rosuvastatin), OATP1B1 (bosentan, glibenclamide, repaglinide, statins, valsartan), OCT1 and MATE1/MATE2K (metformin), OCT2 (serum creatinine) and OAT3 (furosemide, methotrexate). Appropriate clinical monitoring is recommended, and caution especially with any statin.
• Anastrozole, letrozole and tamoxifen: no clinically relevant interaction was found.
• Food: olaparib can be taken with or without food. Grapefruit juice and St John’s wort should be avoided.

Treatment should be started and supervised by a physician experienced in the use of anticancer medicinal products. The tablets are swallowed whole, with or without food, and must not be chewed, crushed, dissolved or divided.

Patient Selection

• First-line maintenance, advanced ovarian cancer (monotherapy): a deleterious or suspected deleterious germline and/or somatic BRCA1/2 mutation must be confirmed with a validated test.
• First-line maintenance with bevacizumab: BRCA1/2 mutation and/or genomic instability (HRD-positive status) must be confirmed with a validated test.
• Platinum-sensitive relapsed ovarian cancer: BRCA1/2 testing is not required.
• Breast cancer (adjuvant and metastatic): a deleterious or suspected deleterious germline BRCA1/2 mutation must be confirmed with a validated test. Data on the clinical validation of tumour BRCA1/2 tests in breast cancer are not currently available.
• Pancreatic adenocarcinoma: a germline BRCA1/2 mutation must be confirmed with a validated test.
• Prostate cancer: for monotherapy, a BRCA1/2 mutation must be confirmed (tumour or blood sample); no genomic testing is needed with abiraterone.
• Endometrial cancer: proficient mismatch repair (pMMR) tumour status must be confirmed with a validated test.
• Genetic counselling for patients tested for BRCA1/2 mutations should follow local regulations.

Recommended Dose

• 300 mg (two 150 mg tablets) twice daily, a total daily dose of 600 mg, as monotherapy or in combination. The 100 mg tablet is available for dose reduction.
• Platinum-sensitive relapsed ovarian cancer: treatment starts no later than 8 weeks after the last dose of the platinum-containing regimen.
• With bevacizumab: bevacizumab is given at 15 mg/kg once every 3 weeks (see its own SmPC).
• With endocrine therapy (adjuvant breast cancer): the aromatase inhibitor, anti-oestrogen and/or LHRH agonist are dosed according to their own SmPCs.
• With abiraterone: abiraterone 1,000 mg once daily with prednisone or prednisolone 5 mg twice daily. Treatment with a GnRH analogue continues in all patients unless they have had a bilateral orchiectomy.
• With durvalumab: durvalumab 1,500 mg every 4 weeks (see its own SmPC).

Duration of Treatment

• First-line maintenance in BRCA-mutated advanced ovarian cancer, and with bevacizumab: until radiological disease progression or unacceptable toxicity, or for up to 2 years if there is no radiological evidence of disease after 2 years. Patients with evidence of disease at 2 years who, in the physician’s opinion, can benefit from continued treatment can be treated beyond 2 years. The recommended overall duration of bevacizumab is a maximum of 15 months, including the periods with chemotherapy and as maintenance.
• Adjuvant treatment of early breast cancer: up to 1 year, or until recurrence or unacceptable toxicity, whichever comes first.
• All other indications (relapsed ovarian cancer, advanced breast cancer, pancreatic and endometrial cancer, prostate cancer alone or with abiraterone): until progression of the underlying disease or unacceptable toxicity. In prostate cancer monotherapy, medical castration with an LHRH analogue continues in patients who have not had surgical castration.
• The efficacy and safety of maintenance retreatment after relapse in ovarian cancer have not been established, and there are no data on retreatment in breast or prostate cancer.

Dose Adjustments

• Treatment may be interrupted to manage reactions such as nausea, vomiting, diarrhoea and anaemia, and a dose reduction can be considered.
• The recommended first reduction is to 250 mg twice daily (one 150 mg and one 100 mg tablet), a total of 500 mg per day. A further reduction is to 200 mg twice daily (two 100 mg tablets), a total of 400 mg per day.
• Strong or moderate CYP3A inhibitors: avoid and consider alternatives. If a strong inhibitor must be used, reduce to 100 mg twice daily (200 mg per day); with a moderate inhibitor, reduce to 150 mg twice daily (300 mg per day).

Special Populations

• Elderly: no adjustment of the starting dose.
• Renal impairment: no adjustment in mild impairment (creatinine clearance 51–80 mL/min). In moderate impairment (31–50 mL/min) the dose is 200 mg (two 100 mg tablets) twice daily, a total of 400 mg per day. It is not recommended in severe impairment or end-stage renal disease (30 mL/min or less) because safety and pharmacokinetics have not been studied; it may be used only if the benefit outweighs the risk, with careful monitoring of renal function and adverse events.
• Hepatic impairment: no adjustment in mild or moderate impairment (Child-Pugh A or B). Not recommended in severe impairment (Child-Pugh C).
• Non-Caucasian patients: clinical data are limited, but no dose adjustment is needed on the basis of ethnicity.
• Children and adolescents: safety and efficacy below 18 years have not been established.

Missed Dose

If a dose is missed, take the next normal dose at its scheduled time.

Haematological Toxicity

Anaemia, neutropenia, thrombocytopenia and lymphopenia, mostly mild or moderate, have been reported. Patients should not start olaparib until they have recovered from haematological toxicity of earlier anticancer therapy (haemoglobin, platelets and neutrophils at CTCAE grade 1 or better). A complete blood count is taken at baseline and monthly for the first 12 months, then periodically. For severe haematological toxicity or dependence on blood transfusion, treatment is interrupted and haematological testing started; if blood parameters stay abnormal after 4 weeks of interruption, bone marrow and/or blood cytogenetic analysis is recommended. Pure red cell aplasia and autoimmune haemolytic anaemia have been reported with durvalumab; if either is confirmed, olaparib and durvalumab are stopped.

Myelodysplastic Syndrome and Acute Myeloid Leukaemia

These conditions have occurred, and most cases were fatal. Patients with BRCA-mutated platinum-sensitive relapsed ovarian cancer who had received at least two prior lines of platinum chemotherapy were at higher risk. Treatment duration in affected patients ranged from under 6 months to over 4 years. If either condition is suspected, the patient is referred to a haematologist for bone marrow analysis and cytogenetic blood tests; if it is confirmed, olaparib is stopped.

Venous Thromboembolic Events

Venous thromboembolic events, mostly pulmonary embolism, have occurred, with no consistent clinical pattern. The incidence was higher in patients with metastatic castration-resistant prostate cancer who also received androgen deprivation therapy. Patients should be monitored for signs of venous thrombosis and pulmonary embolism; those with a previous venous thromboembolism may be at higher risk of another.

Pneumonitis

Pneumonitis, including fatal cases, has been reported. If new or worsening breathlessness, cough or fever, or an abnormal chest radiograph, appears, olaparib is interrupted and prompt investigation started. If pneumonitis is confirmed, olaparib is stopped.

Hepatotoxicity

Cases of hepatotoxicity have been reported. With suggestive symptoms or signs, prompt clinical evaluation and liver function tests are needed. In suspected drug-induced liver injury treatment is interrupted, and in severe cases discontinuation should be considered.

Pregnancy, Contraception and Embryofoetal Toxicity

• Women of childbearing potential: they must not be pregnant at the start of treatment. A pregnancy test is performed before treatment and considered regularly during treatment. Two forms of reliable contraception (two highly effective and complementary methods) are needed before starting, during treatment and for 6 months after the last dose, unless abstinence is the chosen method.
• Hormonal contraceptives: olaparib may reduce exposure to CYP2C9 substrates, so the efficacy of some hormonal contraceptives may be reduced and an additional non-hormonal method should be considered. For women with hormone-dependent cancer, two non-hormonal methods should be considered.
• Men: those having sexual intercourse with a pregnant woman or a woman of childbearing potential must use a condom during treatment and for 3 months after the last dose, and the female partner must also use highly effective contraception if she can become pregnant. It is not known whether olaparib or its metabolites are present in seminal fluid. Men should not donate sperm during treatment and for 3 months after the last dose.
• Pregnancy: olaparib should not be used in pregnancy. Rat studies showed serious malformations and effects on embryofoetal survival at exposures below those in humans at the therapeutic dose, and there are no data in pregnant women.
• Breastfeeding: olaparib is contraindicated during breastfeeding and for 1 month after the last dose.
• Fertility: there are no clinical data. In animal studies there was no effect on conception, but there were adverse effects on embryofoetal survival.

Sodium

Each tablet contains less than 1 mmol (23 mg) of sodium, that is, it is essentially sodium-free.

Effect on Driving

Olaparib has a moderate influence on the ability to drive and use machines. Patients who feel fatigue, weakness or dizziness should be careful when driving or using machines.

Lynparza tablets need no special temperature conditions, but they must be kept in the original package to protect them from moisture. They are supplied in aluminium/aluminium non-perforated blisters of 8 tablets, in packs of 56 tablets (7 blisters) and a multipack of 112 tablets (2 packs of 56); not all pack sizes may be marketed. Keep out of the sight and reach of children.

4 years. Do not use after the expiry date stated on the pack.

Prescription only (Rx): treatment is started and supervised by a physician experienced in the use of anticancer medicinal products. Olaparib is a tablet taken at home, so it is supplied to the patient or to the treating clinic on prescription.