Consumer medicine information

Lynparza Tablets

Olaparib

BRAND INFORMATION

Brand name

Lynparza Tablets

Active ingredient

Olaparib

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Lynparza Tablets.

What is in this leaflet

This leaflet answers some common questions about LYNPARZA tablets. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking LYNPARZA tablets against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What LYNPARZA tablets are used for

LYNPARZA tablets are used to treat

  • a certain type of ovarian cancer (BRCA-mutated) that is newly diagnosed. It is used once the cancer has responded to treatment with standard platinum-based chemotherapy. A test is used to determine whether you have BRCA-mutated ovarian cancer.
  • ovarian cancer that has recurred and it has responded to previous treatment with platinum-based chemotherapy.
  • ovarian cancer in combination with another anti-cancer medicine called bevacizumab. These medicines are used together once the cancer has responded to the first treatment with standard platinum-based chemotherapy.
  • a certain type of breast cancer (germline BRCA-mutated, human epidermal growth factor receptor 2-negative (HER2-negative)) which has spread beyond the original tumour. You should have received chemotherapy medicines either before or after your cancer has spread. A test is used to determine if you have germline BRCA mutated breast cancer.
  • a certain type of pancreatic cancer (germline BRCA-mutated) which has spread beyond the original tumour. It is used if the cancer has not progressed after treatment with chemotherapy. A test is used to determine whether you have BRCA-mutated pancreatic cancer.
  • a certain type of prostate cancer (BRCA-mutated) which has spread beyond the original tumour and no longer responds to medical or surgical treatment that lowers testosterone. You should have already received certain hormonal treatments such as abiraterone acetate or enzalutamide. A test is used to determine whether you have this type of prostate cancer.

LYNPARZA belongs to a group of medicines called PARP (Poly (ADP-Ribose) Polymerase enzymes) inhibitors. PARP inhibitors can destroy cancer cells that are not good at repairing DNA damage. These specific cancer cells can be identified by response to platinum chemotherapy or by looking for faulty DNA repair genes such as BRCA (BReast CAncer) genes.

When LYNPARZA is given in combination with other anti-cancer medicines it is important that you also read the package leaflets of these other medicines. If you have any questions about these medicines, ask your doctor.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

This medicine is available only with a doctor's prescription.

Before you take LYNPARZA tablets

When you must not take it

Do not take LYNPARZA tablets if you have an allergy to:

  • any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin.

Do not take this medicine if you are pregnant or if you (male or female) are planning to have a baby. It may affect your developing baby if you take it during pregnancy. Your doctor will advise women to ensure they are using effective contraception when using the medicine and for at least 1 month after stopping the medicine. Male patients and their partners must use effective contraception when using the medicine for at least 3 months after stopping the medicine.

Do not breast-feed if you are taking this medicine. It is not known if the active ingredient in LYNPARZA tablets passes into breast milk. Breast-feeding mothers are advised not to breast-feed during treatment with LYNPARZA tablets and for one month after receiving the last dose.

Do not give this medicine to children. Safety and effectiveness in children younger than 18 years have not been established.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

  • problems with your kidneys or liver (renal or hepatic impairment)
  • problems with your blood (e.g. anaemia, low white blood cell counts).

Tell your doctor if you are pregnant or plan to become pregnant or are breast-feeding.

If you are a man, tell your doctor if you are planning to have a baby with your partner. Your doctor can discuss with you the risks and benefits involved. Whether you are male or female, your doctor will advise you to use an effective form of contraception while taking LYNPARZA and for at least 1 month for women and 3 months for men after stopping treatment. Female partners of male patients taking LYNPARZA must also use a suitable method of contraception. Male patients must not donate sperm whilst taking LYNPARZA and for 3 months after stopping treatment.

If you have not told your doctor about any of the above, tell them before you start taking LYNPARZA tablets.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Some medicines or foods and LYNPARZA may interfere with each other and reduce effectiveness. These include:

  • medicines used to treat fungal infections (antifungals) with active ingredients such as fluconazole, ketoconazole, itraconazole
  • medicines used to treat bacterial infections (antibiotics) with active ingredients such as clarithromycin, rifampicin, rifabutin, ciprofloxacin, erythromycin
  • medicines used to treat viral infections (especially HIV) with active ingredients such as ritonavir, indinavir, saquinavir, nevirapine, boceprevir, cobicistat, etravirine and efavirenz
  • medicines used to treat epilepsy with active ingredients such as phenytoin, carbamazepine
  • medicines with active ingredients such as modafinil used to treat a sleep disorder called narcolepsy (where you may experience very sleepy periods at odd times during the day)
  • medicines to treat high blood pressure, angina (chest pain), irregular heartbeat or heart failure such as diltiazem, digoxin, furosemide, valsartan and verapamil
  • medicines called statins used to treat high cholesterol such as rosuvastatin and atorvastatin
  • medicines used to treat diabetes, such as glibenclamide and metformin
  • bosentan, a medicine used to treat high blood pressure in the lungs
  • medicines used to suppress the immune system, such as ciclosporin, tacrolimus and sirolimus
  • fentanyl, a medicine used to treat cancer pain
  • methotrexate, a medicine used to treat cancer, rheumatoid arthritis and psoriasis
  • quetiapine, a medicine used to treat mental disorders
  • colchicine, a medicine used to treat gout
  • dabigatran, a medicine to prevent blood clots
  • grapefruit, Seville oranges and star fruit
  • St John's Wort, used to treat depression.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

If you have not told your doctor about any of these things, tell them before you take any LYNPARZA tablets.

How to take LYNPARZA tablets

Your doctor has prescribed LYNPARZA tablets for you.

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions on the pack, ask your doctor or pharmacist for help.

How much to take

The usual dose is two 150 mg tablets taken twice each day (a total of 4 tablets each day).

Your doctor may prescribe a different dose if you have problems with your kidneys, or are taking certain medicines that may interact with LYNPARZA tablets or if you experience certain side effects while you are taking LYNPARZA tablets.

Your doctor will tell you how many tablets of LYNPARZA to take and it is important that you take the total recommended daily dose.

How to take it

Swallow the tablets whole with a glass of water. Do not chew, crush, dissolve or divide the tablets as this may affect how quickly the drug gets into your body.

When to take it

Take LYNPARZA tablets at about the same time each morning and evening. Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

LYNPARZA tablets can be taken with or without food.

How long to take it

Continue taking your medicine for as long as your doctor tells you.

It is important to keep taking your medicine even if you feel well.

If you forget to take it

If you forget to take LYNPARZA, take your next normal dose at its scheduled time. Do not take a double dose (two doses at the same time) to make up for forgotten tablets.

If you are not sure what to do, ask your doctor.

If you have trouble remembering to take your medicine, ask your doctor or pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much LYNPARZA. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are using LYNPARZA tablets

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking LYNPARZA.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine. It may affect other medicines used during surgery.

If you become pregnant while taking this medicine or within 1 month after receiving the last dose of LYNPARZA, tell your doctor immediately.

If you are a man and your partner becomes pregnant while you are taking this medicine or within 3 months of stopping this medicine, tell your doctor immediately. Ensure you are using effective contraception. Even if you stop treatment, you should continue to use effective contraception for at least a further 1 month for female patients and 3 months for male patients.

Male patients must use a condom whilst taking LYNPARZA and for 3 months after receiving the last dose when having sexual intercourse with a female partner, even if they are pregnant. Your female partner must also use a suitable method of contraception. Male patients must not donate sperm whilst taking LYNPARZA and for 3 months after receiving the last dose.

Keep all of your doctor's appointments so that your progress can be checked. Your doctor may do some tests from time to time to make sure the medicine is working and to prevent unwanted side effects. Your doctor will test your blood every month for the first year of treatment and periodically thereafter.

Things you must not do

Do not take LYNPARZA tablets to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Do not stop taking your medicine or lower the dosage without checking with your doctor. If you stop taking it suddenly, your condition may worsen.

Your doctor may interrupt your treatment or reduce your dose if you are having unwanted side effects.

Things to be careful of

Be careful driving or operating machinery until you know how LYNPARZA affects you. This medicine may cause dizziness and tiredness in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking LYNPARZA tablets.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor straight away if you notice any of the following:

  • feeling or being sick (nausea or vomiting)
  • dizziness, tiredness or weakness
  • indigestion or heartburn
  • loss of appetite
  • headache
  • change in taste of food (if it worries you)
  • diarrhoea
  • sore mouth
  • cough
  • pain in the stomach area under the ribs
  • shortness of breath and/or a dry cough which can be due to inflammation of the lungs (pneumonitis).
  • rash itchy swollen reddened skin
  • facial swelling

The above list includes serious side effects that may require medical attention and can be life-threatening, especially if not treated.

If any of the following happen, tell your doctor immediately, or go to Accident and Emergency at your nearest hospital:

  • tightness of the chest, wheezing, coughing or difficulty breathing.
  • swelling of the face, lips, tongue or other parts of the body.
  • severe skin reaction which may include rash, itching, redness, blistering or peeling of the skin.

These are very serious side effects. If you have them, you may have had a serious allergic reaction to LYNPARZA. You may need urgent medical attention or hospitalisation.

Some other serious side effects may only become known through tests. Your doctor will test your blood every month for the first year of treatment and periodically thereafter. The blood tests may show:

  • a condition where there is damage to the blood-forming cells in your bone marrow (myelodysplastic syndrome/acute myeloid leukaemia)
  • decrease in the number of red blood cells (anaemia) which can be associated with shortness of breath, fatigue, pale skin, or fast heart beat
  • decrease in the number of white blood cells which can be associated with fever or infection
  • increase in blood creatinine which can mean your kidneys are not working as well
  • decrease in the number of platelets, which can result in bruising or bleeding for longer than normal if injured.

These conditions may also be life-threatening, especially if not treated.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Your doctor may prescribe other medicines to control unwanted side effects.

After using LYNPARZA tablets

Storage

Keep your tablets in the blister pack until it is time to take them. If you take the tablets out of the blister they may not keep well.

Keep your tablets in a cool dry place where the temperature stays below 30°C.

Do not store LYNPARZA tablets or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

LYNPARZA 100 mg tablet is a yellow to dark yellow, oval, bi-convex, film-coated tablet, marked with 'OP100' on one side and plain on the other.

LYNPARZA 150 mg tablet is a green to green/grey oval, bi-convex, film-coated tablet, marked with 'OP150' on one side and plain on the other.

LYNPARZA tablets are available in blisters containing 56 film-coated tablets, packed in cartons containing 7 blisters of 8 tablets.

Ingredients

LYNPARZA tablets contain 100 mg or 150 mg of olaparib as the active ingredient and the following inactive ingredients:

  • copovidone
  • colloidal anhydrous silica
  • mannitol
  • sodium stearylfumarate
  • hypromellose
  • macrogol 400
  • titanium dioxide
  • iron oxide yellow
  • iron oxide black (150 mg tablet only)

This medicine does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

Manufacturer/Distributor/ Supplier

LYNPARZA is sponsored and supplied in Australia by:

AstraZeneca Pty Ltd
ABN 54 009 682 311
66 Talavera Road
MACQUARIE PARK NSW 2113
Telephone: 1800 805 342
© Copyright 2021

This leaflet was prepared on 26 July 2023

LYNPARZA 100 mg Tablets - AUST R 288613

LYNPARZA 150 mg Tablets - AUST R 288614

Doc ID-003845279 v11

Published by MIMS September 2023

BRAND INFORMATION

Brand name

Lynparza Tablets

Active ingredient

Olaparib

Schedule

S4

 

1 Name of Medicine

Olaparib.

2 Qualitative and Quantitative Composition

Lynparza tablets consist of either 100 mg or 150 mg olaparib drug substance and the following inactive ingredients: copovidone, colloidal anhydrous silica, mannitol, sodium stearylfumarate, hypromellose, macrogol 400, titanium dioxide and iron oxide yellow. Lynparza 150 mg tablets also contain iron oxide black.

3 Pharmaceutical Form

Lynparza 150 mg tablets are a green to green/grey, oval, bi-convex tablet debossed with 'OP 150' on one side and plain on the reverse.
Lynparza 100 mg tablets are a yellow to dark yellow, oval, bi-convex tablet debossed with 'OP 100' on one side and plain on the reverse.

4 Clinical Particulars

4.1 Therapeutic Indications

Ovarian cancer.

Lynparza is indicated as monotherapy for the:
maintenance treatment of adult patients who have advanced, high-grade, epithelial ovarian, fallopian tube or primary peritoneal cancer with a deleterious or suspected deleterious, breast cancer susceptibility gene (BRCA) mutation (germline or somatic), which is in response (complete or partial) to first-line platinum-based chemotherapy;
maintenance treatment of adult patients who have platinum-sensitive relapsed, high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer which is in response (complete or partial) after platinum-based chemotherapy. Prior treatment must have included at least 2 courses of platinum-based regimens.
Lynparza in combination with bevacizumab is indicated for the:
maintenance treatment of adult patients who have advanced, epithelial ovarian, fallopian tube or primary peritoneal cancer which is in response (complete or partial) to first-line platinum-based chemotherapy and whose cancer is associated with homologous recombination deficiency (HRD)-positive status defined by either: a deleterious or suspected deleterious BRCA mutation (germline or somatic), and/or genomic instability.

Breast cancer.

Lynparza is indicated as monotherapy for the:
adjuvant treatment of adult patients who have HER2-negative, high-risk early breast cancer with a deleterious or suspected deleterious germline BRCA-mutation (gBRCAm), for which they have previously been treated with neoadjuvant or adjuvant chemotherapy.
treatment of adult patients who have HER2-negative metastatic breast cancer with a deleterious or suspected deleterious gBRCAm, for which they have previously been treated with chemotherapy in the neoadjuvant, adjuvant or metastatic setting.

Adenocarcinoma of the pancreas.

Lynparza is indicated as monotherapy for the:
maintenance treatment of adult patients who have metastatic pancreatic adenocarcinoma with a deleterious or suspected deleterious gBRCAm, which has not progressed on at least 16 weeks of a first-line platinum-based chemotherapy regimen.

Prostate cancer.

Lynparza is indicated as monotherapy for the:
treatment of adult patients who have metastatic castration-resistant prostate cancer (mCRPC) with a deleterious or suspected deleterious BRCA mutation (germline or somatic), which has progressed following prior therapy that included a new hormonal agent.
Lynparza in combination with abiraterone and either prednisone or prednisolone is indicated for the:
treatment of adult patients who have mCRPC with a deleterious or suspected deleterious BRCA mutation (germline or somatic).

4.2 Dose and Method of Administration

Treatment with Lynparza should be initiated and supervised by a physician experienced in the use of anticancer medicinal products.

Patient selection.

Companion diagnostic (CDx) testing using an in vitro diagnostic (IVD), including notified assays performed by a NATA accredited laboratory, is essential for the use of olaparib to be safe and effective in indications that are BRCA and/or HRD specific. Where specified in the indication, confirmation of the relevant BRCA mutation (BRCAm) or HRD status must be obtained prior to initiating treatment with Lynparza.
Testing used in clinical practice should be comparable to the testing used in the relevant pivotal studies (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
In these studies, deleterious or suspected deleterious BRCAm were identified in tumour DNA from a tumour tissue sample, or in germline DNA obtained from a non-tumour (usually blood) sample. In the prostate cancer studies deleterious or suspected deleterious BRCAm were also identified in circulating tumour DNA [ctDNA] obtained from a plasma sample. If a ctDNA test is used and the result is negative, this does not rule out the presence of a BRCAm.

Method of administration.

Lynparza tablets should be swallowed whole (not chewed, crushed, dissolved or divided) at approximately the same time each day, and can be taken with or without food.

Dosage in adults.

The recommended dose of Lynparza (whether as monotherapy or in combination) is 300 mg twice a day, taken orally.
When olaparib is used in combination with other medicines, refer to the Product Information for the other medicines for their recommended dosing information. The studied doses are described in Section 5.1 Pharmacodynamic Properties, Clinical trials.

Duration of treatment.

The recommended duration of treatment for each indication is summarised in Table 1.
The efficacy and safety of maintenance retreatment with Lynparza following first or subsequent relapse in ovarian cancer patients has not been established. There are no efficacy or safety data on retreatment with Lynparza of breast cancer, prostate cancer and pancreatic cancer patients.

Missing dose.

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

Dose adjustments.

Treatment interruption can be used to manage adverse reactions such as nausea, vomiting, diarrhoea, and anaemia. Dose reduction can be considered.
Gastrointestinal toxicities are frequently reported with olaparib therapy (see Section 4.8 Adverse Effects (Undesirable Effects)) and are generally low grade (CTCAE grade 1 or 2) and intermittent. In addition to dose interruption or reduction, concomitant medicinal products (e.g. antiemetic therapy) may also be considered. Antiemetic prophylaxis is not required. See Table 2 for recommended dose adjustments to manage adverse reactions.

Co-administration with CYP3A inhibitors.

Concomitant use of strong or moderate CYP3A inhibitors is not recommended: consider alternative agents. If a strong CYP3A inhibitor must be co-administered, reduce the dose of Lynparza tablets to 100 mg twice a day. If a moderate CYP3A inhibitor must be co-administered, reduce the Lynparza dose to 150 mg twice a day. The patient should be carefully monitored for adverse events. See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

Special patient populations.

Children or adolescents.

Lynparza is not indicated for use in paediatric patients, as safety and efficacy of Lynparza in children and adolescents have not been established.

Elderly (> 65 years).

No adjustment in starting dose is required for elderly patients. There are limited clinical data in patients aged 75 years and over.

Renal impairment.

For patients with moderate renal impairment (creatinine clearance 31-50 mL/min) the recommended dose of Lynparza tablets is 200 mg twice a day. Lynparza is not recommended for patients with severe renal impairment or end-stage renal disease (creatinine clearance ≤ 30 mL/min) as safety and pharmacokinetics have not been studied in these patients. Lynparza can be administered to patients with mild renal impairment (creatinine clearance 51-80 mL/min) with no dose adjustment. Patients should be monitored closely for renal function and adverse events.

Hepatic impairment.

Lynparza can be administered to patients with mild or moderate hepatic impairment (Child-Pugh classification A or B) with no dose adjustment, however, patients should be monitored closely for hepatic function and adverse events (see Section 5.2 Pharmacokinetic Properties). Lynparza is not recommended for use in patients with severe hepatic impairment (Child-Pugh classification C), as safety and pharmacokinetics have not been studied in these patients.

4.3 Contraindications

Hypersensitivity to the active substance (olaparib) or to any of the excipients.

4.4 Special Warnings and Precautions for Use

Haematological toxicity.

Olaparib commonly causes haematological toxicity (see Section 4.8 Adverse Effects (Undesirable Effects)). While the majority were generally mild or moderate (CTCAE grade 1 or 2), grade 3 or higher events of anaemia (decrease in haemoglobin) occurred in 7.4% of patients in Study 19, and one patient died from a haemorrhagic stroke associated with thrombocytopenia.
Patients should not start treatment with Lynparza until they have recovered from haematological toxicity caused by previous anti-cancer therapy (haemoglobin, platelet, and neutrophil levels should be ≤ CTCAE grade 1). Check full blood count at baseline, then monthly for the first year of treatment, and periodically after that. If a patient develops severe haematological toxicity or blood transfusion dependence, interrupt treatment with Lynparza and initiate haematological testing. If blood parameters remain clinically abnormal after 4 weeks of Lynparza dose interruption, bone marrow analysis and/or blood cytogenetic analysis are recommended.

Myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML).

Lynparza may cause MDS/AML, and the majority of events reported had a fatal outcome (see Section 4.8 Adverse Effects (Undesirable Effects)). The incidence of MDS/AML in patients treated in clinical trials with Lynparza monotherapy, including during long-term survival follow up, was 1.5%. In a Phase III placebo-controlled clinical trial (SOLO2), a higher incidence was reported in Lynparza treated patients with BRCAm platinum-sensitive relapsed ovarian cancer, who had received at least two prior lines of platinum chemotherapy and were followed up for 5 years, compared to the placebo arm in the SOLO2 study (and to patients receiving Lynparza in clinical trials in other indications). The reports were typical of secondary MDS/cancer therapy-related AML. The duration of therapy with Lynparza in patients who developed secondary MDS/AML varied from < 6 months to > 4 years. The majority of reports were in germline BRCA mutation (gBRCAm) carriers and some of the patients had a history of previous more than one primary malignancy or of bone marrow dysplasia.
If MDS and/or AML are confirmed while on treatment with Lynparza, permanently discontinue Lynparza.

Pneumonitis.

Pneumonitis has been reported in patients treated with Lynparza in clinical studies (see Section 4.8 Adverse Effects (Undesirable Effects), including some fatal cases when used in combination with other therapies.
If patients present with new or worsening respiratory symptoms such as dyspnoea, cough and fever, or an abnormal chest radiological finding is observed, Lynparza treatment should be interrupted and prompt investigation initiated. If pneumonitis is confirmed, Lynparza treatment should be discontinued.

Venous thromboembolism.

Venous thromboembolic events (VTE), including severe or fatal pulmonary embolism (PE), have occurred in patients treated with Lynparza. In the combined data from two randomised, placebo-controlled clinical studies (PROfound and PROpel) in patients with mCRPC who were also receiving androgen deprivation therapy (N = 1180), VTE occurred in 8% of patients who received Lynparza, including PE in 6%. In the control arms, VTE occurred in 2.5% including PE in 1.5%. The incidence of VTE/PE in these patients was higher than seen in other approved indications (see Section 4.8 Adverse Effects (Undesirable Effects)). Monitor patients for clinical signs and symptoms of venous thrombosis and pulmonary embolism and treat as medically appropriate, which may include long-term anticoagulation as clinically indicated.

Drug-induced liver injury.

Cases of drug-induced liver injury (DILI) have been reported in patients treated with Lynparza in the post-marketing setting (see Section 4.8 Adverse Effects (Undesirable Effects)). If DILI is suspected, treatment should be interrupted. If DILI is confirmed, treatment should be discontinued.

Use in hepatic impairment.

Exposure is increased in hepatic impairment (see Section 5.2 Pharmacokinetic Properties; Section 4.2 Dose and Method of Administration).

Use in renal impairment.

Exposure is increased in renal impairment (see Section 5.2 Pharmacokinetic Properties; Section 4.2 Dose and Method of Administration).

Use in the elderly.

There are limited clinical data in patients aged 75 years and over (see Section 4.2 Dose and Method of Administration).

Patients with worsened performance status.

There are very limited clinical data available in patients with Eastern Cooperative Oncology Group performance status 2 to 4.

Paediatric use.

The safety and efficacy of Lynparza in children and adolescents have not been established.

Effects on laboratory tests.

No data available.

Interactions with other medicinal products.

Olaparib co-administration with strong or moderate CYP3A inhibitors is not recommended (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). If a strong or moderate CYP3A inhibitor must be co-administered, the dose of olaparib should be reduced (see Section 4.2 Dose and Method of Administration).
Olaparib co-administration with strong or moderate CYP3A inducers is not recommended (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). In the event that a patient already receiving olaparib requires treatment with a strong or moderate CYP3A inducer, the efficacy of olaparib may be substantially reduced (see Section 4.2 Dose and Method of Administration).

4.5 Interactions with Other Medicines and Other Forms of Interactions

Clinical studies of olaparib in combination with other anticancer agents, including DNA damaging agents, indicate a potentiation and prolongation of myelosuppressive toxicity. The recommended Lynparza monotherapy dose is not suitable for combination with other myelosuppressive anticancer agents.

Effect of other drugs on olaparib.

Strong and moderate CYP3A inhibitors.

CYP3A4/5 are the isozymes predominantly responsible for the metabolic clearance of olaparib. Co-administration of olaparib with a strong CYP3A inhibitor (itraconazole) increased olaparib Cmax by 42% (90% CI: 33% to 52%) and mean AUC by 170% (90% CI: 144% to 197%). It is therefore recommended that known strong inhibitors of these isozymes are not co-administered with Lynparza. These include but are not limited to inhibitors such as itraconazole, clarithromycin, boosted protease inhibitors with ritonavir or cobicistat, indinavir, saquinavir and boceprevir (see Section 4.4 Special Warnings and Precautions for Use).
Physiologically-based pharmacokinetic modelling has suggested that moderate CYP3A inhibitors will alter the clearance of olaparib and therefore concomitant use of moderate CYP3A inhibitors such as, but not limited to ciprofloxacin, erythromycin, diltiazem, fluconazole and verapamil is not recommended with Lynparza (see Section 4.4 Special Warnings and Precautions for Use).
If a strong or moderate CYP3A inhibitor must be co-administered, the dose of Lynparza should be reduced (see Section 4.2 Dose and Method of Administration).
Patients should avoid star fruit, grapefruit and Seville oranges because these foods are known to inhibit CYP3A enzymes.

Strong and moderate CYP3A inducers.

A clinical study to evaluate the impact of rifampicin, a known CYP3A inducer has shown that co-administration with olaparib decreased olaparib Cmax by 71% (90% CI: 76% to 67%) and mean AUC by 87% (90% CI: 89% to 84%). It is therefore possible that CYP3A inducers could substantially diminish the clinical efficacy of Lynparza and as such, concomitant use of strong inducers such as, but not limited to phenytoin, rifabutin, rifampicin, carbamazepine, nevirapine, phenobarbital and St John's wort (Hypericum perforatum) is not recommended with Lynparza.
Physiologically-based pharmacokinetic modelling has suggested that moderate CYP3A inducers will decrease olaparib AUC by approximately 60% and therefore concomitant use of moderate CYP3A inducers such as, but not limited to, bosentan, efavirenz, etravirine and modafinil is not recommended with Lynparza. If a moderate CYP3A inducer must be co-administered, the prescriber should be aware of a potential for decreased efficacy of Lynparza (see Section 4.4 Special Warnings and Precautions for Use).

Effect of olaparib on other drugs.

CYP and UGT interactions.

Both induction and inhibition of CYP3A4 has been shown in vitro, however, physiologically based pharmacokinetic modelling simulations and clinical data suggest that the net effect of olaparib in vivo is weak inhibition of CYP3A. Therefore, caution should be exercised when sensitive CYP3A substrates or substrates with a narrow therapeutic margin (e.g. simvastatin, ciclosporin, midazolam, ergot alkaloids, sirolimus, fentanyl, tacrolimus and quetiapine) are combined with Lynparza. Appropriate clinical monitoring is recommended for patients receiving CYP3A substrates with a narrow therapeutic margin concomitantly with Lynparza.
Induction of CYP1A2 and 2B6 has been shown in vitro. Therefore, Lynparza upon co-administration may reduce the exposure to substrates of these metabolic enzymes.
Olaparib produced little/no direct inhibition in vitro of UGT1A4, UGT1A9, UGT2B7 or CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6 or 2E1. Olaparib was not a time dependent inhibitor of CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2D6 or 2E1. Olaparib inhibited UGT1A1 in vitro. Based on evaluation using enzyme activity, olaparib was not an inducer of CYP2C9 or 2C19.

Drug transporter interactions.

In vitro, olaparib inhibits the efflux transporter P-gp (IC50 = 76 microM). Therefore, it cannot be excluded that Lynparza may cause clinically relevant drug interactions with substrates of P-gp (e.g. simvastatin, pravastatin, dabigatran, digoxin, colchicine). Appropriate clinical monitoring is recommended for patients receiving this type of medication concomitantly. The potential for olaparib to induce P-gp has not been evaluated.
Olaparib has also been shown to be an in vitro inhibitor of OATP1B1, OCT1, OCT2, OAT3, MATE1 and MATE2K. The clinical relevance of these findings is unknown, however, it cannot be excluded that Lynparza may increase the exposure to substrates of OATP1B1 (e.g. bosentan, glibenclamide, repaglinide, statins, and valsartan), OCT1 (e.g. metformin), OCT2 (e.g. serum creatinine), OAT3 (e.g. furosemide and methotrexate), MATE1 (e.g. metformin and cisplatin) and MATE2K (e.g. metformin). In particular, caution should be exercised if Lynparza is administered in combination with any statin.
In vitro data also show that olaparib is not a substrate for OATP1B1, OATP1B3, OCT1, BCRP or MRP2, is a weak inhibitor of BCRP and not an inhibitor of OATP1B3, OAT1 or MRP2.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

The effects of Lynparza on human fertility are not known. Exposures achieved in animal fertility and embryofetal development studies were subclinical.
(Category D)
Based on its mechanism of action and findings in animal studies Lynparza has teratogenic and genotoxic potential and could cause fetal harm if administered to a pregnant person or their sexual partner. Advise patients of the risk of embryofetal harm and potential for embryofetal lethality. Studies in rats have shown that olaparib causes embryofetal lethality and induces major fetal malformations (major eye and vertebral/rib malformations) at exposures below those expected at the recommended human dose.
Lynparza should not be used during pregnancy due to the teratogenic and genotoxic potential of olaparib. Female partners of male patients taking Lynparza should also avoid pregnancy. No studies have been conducted in pregnant women.
If a female patient or female partner of a male patient receiving Lynparza becomes pregnant, she should be informed of the potential hazard to the fetus or potential risk of loss of the pregnancy.
Patients who could become pregnant must use effective contraception during Lynparza treatment and for 6 months after receiving the last dose. Verify pregnancy status prior to treatment, at regular intervals during treatment and at one month after receiving the last dose.
It is not known whether olaparib or its metabolites are found in seminal fluid. Male patients whose sexual partners are pregnant, or who could become pregnant, must use condoms when having intercourse at any time during Lynparza treatment, and during the 3 months after receiving the last dose. Patients must not donate sperm during Lynparza treatment and for 3 months after receiving the last dose.
 There are no data on the use of Lynparza in breast-feeding. The excretion of olaparib in milk has not been studied in animals or humans. A risk to the breast-feeding child cannot be excluded. Patients must not breast-feed during treatment with Lynparza and for one month after receiving the last dose.

4.7 Effects on Ability to Drive and Use Machines

No studies to establish the effects of olaparib on the ability to drive and use machinery have been conducted. However, during treatment with Lynparza, fatigue and dizziness have been reported and those patients who experience these symptoms should observe caution when driving or using machines.

4.8 Adverse Effects (Undesirable Effects)

Summary of adverse drug reactions during clinical trials.

The safety profile summary table is based on pooled data from 4499 patients with solid tumours treated with Lynparza monotherapy, 535 patients treated with Lynparza in combination with bevacizumab and 469 patients treated with Lynparza in combination with abiraterone and prednisone or prednisolone in clinical trials at the recommended dose.
When Lynparza is used in combination with bevacizumab for ovarian cancer or in combination with abiraterone and prednisone or prednisolone for prostate cancer, the safety profile is generally consistent with that of the individual therapies.
Adverse events led to dose interruption and/or reduction of olaparib in 57.4% of patients when used in combination with bevacizumab and led to permanent discontinuation of treatment with olaparib/bevacizumab and placebo/bevacizumab in 20.4% and 5.6% of patients, respectively. The adverse reactions that most commonly led to dose interruption and/or reduction were anaemia (20.6%) and nausea (7.5%). The adverse reactions that most commonly led to permanent discontinuation were anaemia (3.6%), nausea (3.4%) and fatigue/asthenia (1.5%).
The following adverse reactions have been identified in clinical studies with patients receiving Lynparza monotherapy where patient exposure is known. Adverse drug reactions are organised by MedDRA System Organ Class (SOC) and then by MedDRA preferred term in Table 3. Within each SOC, preferred terms are arranged by decreasing frequency and then by decreasing seriousness. Frequencies of occurrence of adverse reactions are defined as: very common (≥ 1/10; ≥ 10%); common (≥ 1/100 to < 1/10; ≥ 1% and < 10%); uncommon (≥ 1/1,000 to < 1/100; ≥ 0.1% and < 1%); rare (≥ 1/10,000 to < 1/1000; 0.01% and < 0.1%); very rare (< 1/10,000; < 0.01%) including isolated reports.

Adverse events in individual clinical trials.

First-line maintenance treatment of BRCA-mutated advanced ovarian cancer. The safety of Lynparza for the maintenance treatment of patients with BRCA-mutated advanced ovarian cancer following first-line treatment with platinum-based chemotherapy was investigated in SOLO-1. Table 4 and Table 5 summarise adverse reactions and laboratory abnormalities in SOLO-1.
Among patients who received Lynparza, dose interruptions or reductions due to an adverse event of any grade occurred in 55.%. Discontinuation due to adverse events occurred in 11.9% of patients receiving Lynparza. The most frequent adverse reactions leading to dose interruption or reduction of Lynparza were anaemia (23.8%), nausea (14.6%), and vomiting (11.9%). The most frequent adverse reactions that led to discontinuation of Lynparza were fatigue/asthenia (2.3%), anaemia (2.3%), and nausea (2.3%).
Clinically relevant adverse reactions that occurred in < 10% of patients receiving Lynparza were increased blood creatinine (9%), lymphopenia (6%), VTE (4%), hypersensitivity (2%), MDS/AML (2%), pneumonitis (2%), dermatitis (1%), and increased mean cell volume (0.4%).
First-line maintenance treatment of HRD-positive advanced ovarian cancer in combination with bevacizumab. The safety of Lynparza in combination with bevacizumab for the maintenance treatment of patients with advanced ovarian cancer following first-line treatment containing platinum-based chemotherapy and bevacizumab was investigated in PAOLA-1. Table 6 and Table 7 summarise adverse reactions and laboratory abnormalities in PAOLA-1, respectively.
Clinically relevant adverse reactions that occurred in < 10% of patients receiving Lynparza/bevacizumab were dysgeusia (8%), dyspnoea (8%), stomatitis (5%), dyspepsia (4.3%), erythema (3%), dizziness (2.6%), hypersensitivity (1.7%), and MDS/AML (0.7%).
Venous thromboembolism occurred more commonly in patients receiving Lynparza/bevacizumab (5%) than in those receiving placebo/bevacizumab (1.9%).
Maintenance treatment of recurrent ovarian cancer.

SOLO-2.

The safety of Lynparza for the maintenance treatment of patients with platinum sensitive gBRCAm ovarian cancer was investigated in SOLO-2. Table 8 and Table 9 summarise adverse reactions and laboratory abnormalities in SOLO-2.
Clinically relevant adverse reactions that occurred in < 20% of patients receiving Lynparza were neutropenia (19%), cough (18%), leukopenia (16%), hypomagnesemia (14%), thrombocytopenia (14%), dizziness (13%), dyspepsia (11%), increased creatinine (11%), MDS/AML (8%), oedema (8%), rash (6%), VTE (5%), and lymphopenia (1%).

Study 19.

The safety of Lynparza as maintenance monotherapy was evaluated in patients with platinum sensitive ovarian cancer who had received 2 or more previous platinum-containing regimens in Study 19. Table 10 and Table 11 summarise adverse reactions and laboratory abnormalities in Study 19.
Clinically relevant adverse reactions that occurred in < 20% of patients receiving Lynparza were dysgeusia (16%), dizziness (15%), dyspnoea (13%), pyrexia (10%), stomatitis (9%), oedema (9%), increase in creatinine (7%), neutropenia (5%), thrombocytopenia (4%), leukopenia (2%), MDS/AML (1%), VTE (1%), and lymphopenia (1%).
Adjuvant treatment of germline BRCA-mutated HER2-negative high risk early breast cancer. The safety of Lynparza as monotherapy for the adjuvant treatment of patients with gBRCA-mutated HER2-negative high risk early breast cancer was investigated in OlympiA. Table 12 and Table 13 summarise the adverse reactions and laboratory abnormalities, respectively, in patients in OlympiA.
Clinically relevant adverse reactions that occurred in < 10% of patients receiving Lynparza were cough (9.2%), lymphopenia (7%), dyspepsia (6%), upper abdominal pain (4.9%), rash (4.9%), dyspnoea (4.2%), thrombocytopenia (4.2%), increase in creatinine (2%), hypersensitivity (0.9%), VTE (0.5%), dermatitis (0.5%), increase in mean corpuscular volume (0.2%), and MDS/AML (0.2%).
Germline BRCA-mutated HER2-negative metastatic breast cancer. The safety of Lynparza was evaluated in gBRCAm patients with HER2-negative metastatic breast cancer who had previously received up to two lines of chemotherapy for the treatment of metastatic disease in OlympiAD. Table 14 and Table 15 summarise the adverse reactions and laboratory abnormalities in OlympiAD.
Clinically relevant adverse reactions that occurred in < 20% of patients receiving Lynparza were cough (18%), decreased appetite (16%), thrombocytopenia (11%), dysgeusia (9%), lymphopenia (8%), dyspepsia (8%), dizziness (7%), stomatitis (7%), upper abdominal pain (7%), rash (5%), increase in serum creatinine (3%), dermatitis (1%), and VTE (1%).
First-line maintenance treatment of germline BRCA-mutated metastatic pancreatic adenocarcinoma. The safety of Lynparza as maintenance treatment of germline BRCA-mutated metastatic pancreatic adenocarcinoma following first-line treatment with platinum-based chemotherapy was evaluated in POLO. Table 16 and Table 17 summarise the adverse reactions and laboratory abnormalities in patients in POLO.
Clinically relevant adverse reactions that occurred in < 10% of patients receiving Lynparza were cough (9%), abdominal pain upper (7%), blood creatinine increased (7%), dizziness (7%), headache (7%), dyspepsia (5%), leukopenia (5%), VTE (3%), hypersensitivity (2%), and lymphopenia (2%).
HRR gene-mutated metastatic castration resistant prostate cancer. The safety of Lynparza as monotherapy was evaluated in patients with mCRPC and HRR gene mutations who have progressed following prior treatment with enzalutamide or abiraterone in PROfound. Table 18 and Table 19 summarise the adverse reactions and laboratory abnormalities, respectively, in patients in PROfound.
Clinically relevant adverse reactions that occurred in < 10% of patients receiving Lynparza were neutropenia (9%), VTE (7%), dizziness (7%), dysgeusia (7%), dyspepsia (7%), headache (6%), pneumonia (5%), stomatitis (5%), rash (4%), blood creatinine increase (4%), pneumonitis (2%), upper abdominal pain (2%), and hypersensitivity (1%).
Treatment of BRCA-mutated metastatic castration resistant prostate cancer in combination with abiraterone and prednisone or prednisolone. The safety of Lynparza in combination with abiraterone and prednisone or prednisolone for the treatment of patients in the first-line mCRPC setting was investigated in PROpel. Table 20 and Table 21 summarise adverse reactions and laboratory abnormalities in PROpel, respectively.
Clinically relevant adverse reactions that occurred in < 10% for patients receiving Lynparza plus abiraterone were headache (9%), VTE (8%), rash (7%), dysgeusia (6%), acute kidney injury (3%), and stomatitis (2.5%).

Description of selected adverse reactions.

Myelodysplastic syndrome/acute myeloid leukaemia.

In clinical studies, across all indications, MDS/AML occurred uncommonly in patients on treatment and during the 30-day safety follow up, and < 1.5% at any time after starting olaparib, including cases actively solicited during the long term follow up for overall survival. All patients had potential contributing factors for the development of MDS/AML, having received previous chemotherapy with platinum agents. Many had also received other DNA damaging treatments.
In patients with BRCAm platinum-sensitive relapsed ovarian cancer who had received at least two prior lines of platinum chemotherapy and received study treatment until disease progression (SOLO2 study, with olaparib treatment ≥ 2 years in 45% of patients), the incidence of MDS/AML was 8.2% in patients receiving olaparib and 4.0% in patients receiving placebo at a follow-up of 5 years. In the olaparib arm, 9 out of 16 MDS/AML cases occurred after discontinuation of olaparib during the survival follow-up. The incidence of MDS/AML was observed in the context of extended overall survival in the olaparib arm and late onset of MDS/AML. The median exposure to olaparib was 2.3 years among those patients who developed MDS/AML, which is slightly longer than the median olaparib exposure overall in the olaparib arm (19.5 months - 1.6 years). The risk of MDS/AML remains < 1.5% at 5 year follow up in the first-line setting when olaparib maintenance treatment is given after one line of platinum chemotherapy for a duration of 2 years.

Haematological toxicity.

Anaemia and other haematological toxicities are generally low grade (CTCAE grade 1 or 2), however, there are reports of CTCAE grade 3 and higher events. Anaemia was the most common CTCAE grade ≥ 3 adverse reaction reported in clinical studies with first onset generally reported in the first 3 months of treatment. An exposure-response relationship between olaparib and decreases in haemoglobin has been demonstrated. In clinical studies with Lynparza monotherapy the incidence of CTCAE grade ≥ 2 shifts (decreases) from baseline in haemoglobin was 21%, absolute neutrophils 17%, platelets 5%, lymphocytes 26% and leucocytes 19% (all % approximate).
The incidence of elevations in mean corpuscular volume from low or normal at baseline to above the upper limit of normal was approximately 51%. Levels appeared to return to normal after treatment discontinuation and did not appear to have any clinical consequences.
Baseline testing, followed by monthly monitoring, of complete blood counts is recommended for the first 12 months of treatment, and periodically after this time, to monitor for clinically significant changes in any parameter during treatment which may require dose interruption or reduction and/or further treatment (see Section 4.4 Special Warnings and Precautions for Use; Section 4.2 Dose and Method of Administration).

Other laboratory findings.

In clinical studies with Lynparza monotherapy the incidence of CTCAE grade ≥ 2 shifts (elevations) from baseline in blood creatinine was approximately 11%. Data from a double-blind placebo-controlled study showed median increase up to 23% from baseline remaining consistent over time and returning to baseline after treatment discontinuation, with no apparent clinical sequelae. 90% of patients had creatinine values of CTCAE grade 0 at baseline and 10% were CTCAE grade 1 at baseline.

Nausea and vomiting.

Nausea was generally reported very early, with first onset within the first month of Lynparza treatment in the majority of patients. Vomiting was reported early, with first onset within the first two months of Lynparza treatment in the majority of patients. Both nausea and vomiting were reported to be intermittent for the majority of patients.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

Symptoms of overdose are not established and there is no specific treatment in the event of Lynparza overdose. In the event of an overdose, physicians should follow general supportive measures and should treat the patient symptomatically.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Olaparib is an orally active inhibitor of human poly (ADP-ribose) polymerase enzymes, including PARP-1, PARP-2, and PARP-3. PARP enzymes are involved in normal cellular functions, such as DNA transcription and repair of DNA single strand breaks. An important aspect of PARP-induced DNA 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. When replication forks meet the PARP-DNA adducts in replicating cells, this leads to DNA double strand breaks (DSBs), which are cytotoxic.
In normal cells, the homologous recombination repair (HRR) pathway is effective at repairing DNA double-strand breaks. Breast cancer susceptibility gene 1 (BRCA1) and BRCA2 encode key components required for HRR, and cells with deleterious BRCA mutations are more susceptible to cytotoxicity caused by the accumulation of DNA damage. Absence of a fully functional HRR pathway is one of the key determinants of platinum sensitivity in ovarian and other cancers. In the absence of BRCA1 or BRCA2 mutations, the HRR pathway may be compromised by other mechanisms, although the causative aberrancy and penetrance are not fully elucidated.
Olaparib has been shown to inhibit the growth of certain tumour cell lines in vitro, and to decrease tumour growth in mouse xenograft models of human cancer, whether given as monotherapy or following platinum-based chemotherapy. Increased cytotoxicity and anti-tumour activity following treatment with olaparib were noted in cell lines and mouse tumour models with deficiencies in BRCA1, BRCA2, ATM, or other genes involved in the homologous recombination repair (HRR) of DNA damage and correlated with platinum response. In prostate cancer models, PARP1 has been shown to contribute to androgen receptor (AR) activity regulation. The combination of olaparib and AR inhibition resulted in cytotoxicity in vitro, and anti-tumour activity in mouse xenograft models.

Clinical trials.

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

SOLO1 study in newly diagnosed advanced ovarian cancer with a BRCA mutation.

SOLO1 was a Phase III randomised, double-blind, placebo-controlled, multicentre trial of maintenance treatment with Lynparza in advanced (FIGO Stage III-IV) high-grade serous or endometrioid BRCA-mutated (BRCAm) ovarian (including primary peritoneal and/or fallopian tube) cancer. Eligible patients were in response (CR [complete response] or PR [partial response]) following completion of first-line platinum-containing chemotherapy, and had a deleterious or suspected deleterious BRCAm based on local or central testing of a blood or tumour sample.
Patients were randomised (2:1) to receive olaparib (300 mg twice a day) or matching placebo. Randomisation was stratified by response to first-line platinum chemotherapy (CR or PR). Treatment was continued for 2 years or until progression of the underlying disease. For patients who remained in complete clinical response (i.e. no radiological evidence of disease), the maximum duration of treatment was 2 years; however, patients who had evidence of disease that remained stable (i.e. no evidence of disease progression) could continue to receive Lynparza beyond 2 years.
The primary endpoint was progression-free survival (PFS), defined as time from randomisation to progression determined by investigator assessment using modified Response Evaluation Criteria in Solid Tumours (RECIST) 1.1, or death. Secondary efficacy endpoints included time from randomisation to second progression or death (PFS2) and overall survival (OS). Patients had tumour assessments at baseline and every 12 weeks for 3 years, and then every 24 weeks relative to the date of randomisation, until objective radiological disease progression.
A total of 391 patients were randomised: 260 to olaparib and 131 to placebo. The median age was 53 years in each arm, and 78% of patients had an ECOG performance status of 0. The primary tumour was ovarian for 85% of patients, and 96% of patients had a cancer showing serous histology, while endometrioid histology was reported in 2%. Of the 391 patients randomised in SOLO-1, 386 were retrospectively or prospectively tested with the Myriad Integrated BRACAnalysis test or the Myriad BRACAnalysis CDx and 383 patients were confirmed to have deleterious or suspected deleterious gBRCAm status; 253 were randomised to the Lynparza arm and 130 to the placebo arm. Two out of 391 patients randomised in SOLO-1 were confirmed to have sBRCAm based on the Foundation Medicine FoundationOne CDxTM Clinical Trial Assay. All patients had received first-line platinum-based therapy; response to prior platinum chemotherapy was complete in 82% and partial in 18% of patients. Ninety three percent of patients were randomised within 8 weeks of their last dose of platinum-based chemotherapy.
A summary of key efficacy findings from SOLO-1 is presented in Table 22. At the time of primary PFS analysis, the median follow-up time was 41 months in both arms. PFS results based on blinded independent central radiological (BICR) review were consistent.
An interim analysis of OS was conducted seven years after the last patient was randomised, with a data cut-off of 7 MAR 2022 (38% maturity). See Figure 2. A statistically significant difference in OS was not demonstrated, based on the pre-specified significance boundary of 0.0001. The OS hazard ratio (95% CI) was 0.55 (0.40, 0.76), p=0.0004. Thirty-eight patients (15%) in the olaparib arm, and 58 patients (44%) in the placebo arm received a PARP inhibitor as a subsequent therapy.
Treatment of platinum-sensitive relapsed (PSR) ovarian cancer. The efficacy of Lynparza in the maintenance treatment setting in platinum-sensitive relapsed (PSR) ovarian, fallopian tube or primary peritoneal cancer is supported by two randomised, double-blind, placebo-controlled trials in patients with PSR and BRCA-mutated disease (SOLO2) and in patients with PSR disease agnostic of BRCA status (Study 19). In both studies, PSR patients who were in response following completion of platinum-based chemotherapy and whose disease had recurred > 6 months after completion of penultimate platinum-based chemotherapy were enrolled. Patients could not have received prior olaparib or other PARP inhibitor treatment. Patients could have received prior bevacizumab, except in the regimen immediately prior to randomisation. Patients with BRCA mutations were identified either from germline testing in blood via a local test or the Myriad CLIA Integrated BRACAnalysis test or from testing a tumour sample using a local test or a test performed by Foundation Medicine.

SOLO2 study in patients with PSR ovarian cancer with a germline BRCA mutation.

SOLO2 compared the efficacy of Lynparza tablets as maintenance treatment (300 mg twice a day, taken until disease progression or unacceptable toxicity) against placebo treatment in patients with high-grade serous or endometrioid PSR ovarian (including primary peritoneal and/or fallopian-tube) cancer who were in response (CR or PR) following completion of platinum-containing chemotherapy. All patients had a deleterious or suspected deleterious germline BRCA mutation as detected either by a local test (n=236) or central Myriad test (n=59), subsequently confirmed by a commercial assay (BRACAnalysis CDx) (n=286).
A total of 295 patients were randomised, 196 to Lynparza and 99 to placebo. The median age was 56 years (range: 28 to 83) among patients treated with Lynparza and 56 years (range: 39 to 78) among patients treated with placebo. The ECOG PS was 0 in 83% of patients receiving Lynparza and 78% of patients receiving placebo. Of all patients, 89% were Caucasian, 47% were in complete response to their most recent platinum-based regimen, and 40% had a progression-free interval of 6-12 months since their penultimate platinum regimen. Prior bevacizumab therapy was reported for 17% of those treated with Lynparza and 20% of those receiving placebo. Approximately 44% of patients on the Lynparza arm and 37% on placebo had received three or more lines of platinum-based treatment.
The primary endpoint was PFS determined by investigator assessment using RECIST 1.1. Secondary efficacy endpoints included time from randomisation to PFS2 and OS.
A summary of key efficacy findings for patients with gBRCAm PSR ovarian cancer in SOLO2 is presented in Table 23. PFS results from a blinded independent review were consistent. At the final analysis (61% maturity) a statistically significant difference in OS was not demonstrated. Also, see Figures 3 and 4.

Study 19 in patients with PSR ovarian cancer agnostic of BRCA status.

Study 19 was a randomised, double-blind, placebo-controlled, phase 2 trial conducted (using the older capsule formulation of olaparib) in patients with PSR ovarian (including primary peritoneal and/or fallopian-tube) cancer who were in response (CR or PR) following completion of platinum-containing chemotherapy. Patients were randomised (1:1) to receive maintenance treatment with either Lynparza capsules 400 mg twice a day, or matching placebo, taken until disease progression or unacceptable toxicity. Randomisation was stratified by response to last platinum chemotherapy (CR versus PR), time to disease progression in the penultimate platinum-based chemotherapy (6-12 months versus longer than 12 months), and descent (Jewish versus non-Jewish). The primary endpoint was PFS based on investigator assessment using RECIST 1.0. Secondary efficacy endpoints included OS.
A total of 265 patients were randomised: 136 to Lynparza and 129 to placebo. The median age was 58 years (range: 21 to 89) among patients treated with Lynparza and 59 years (range: 33 to 84) among patients treated with placebo. ECOG PS was 0 in 81% of patients receiving Lynparza and 74% of patients receiving placebo. Of all patients, 97% were Caucasian, 45% were in complete response following their most recent platinum chemotherapy regimen, and 40% had a progression-free interval of 6-12 months since their penultimate platinum regimen. Prior bevacizumab therapy was reported for 13% of patients receiving Lynparza and 16% of patients receiving placebo.
A summary of efficacy findings for patients with PSR ovarian cancer (including patients with a BRCAm) in Study 19 is presented in Table 24. At the final analysis (data cut off [DCO] 9 May 2016; 79% maturity), the OS comparison did not meet the prespecified significance level (< 0.0095).
BRCA mutation status was confirmed retrospectively. Whilst not controlled for multiplicity, a preplanned subgroup analysis suggested that patients with BRCA-mutated (germline and somatic) ovarian cancer (n = 136, 51.3%) derived the greatest clinical benefit from Lynparza maintenance monotherapy. However, a PFS benefit of olaparib over placebo was also suggested in patients in whom a deleterious germline BRCA mutation was not identified [HR 0.54 (95% CI: 0.34, 0.85); nominal p < 0.0075)].
First-line maintenance treatment of HRD-positive advanced ovarian cancer.

PAOLA-1 study in newly diagnosed advanced ovarian cancer with a BRCA mutation and/or genomic instability.

PAOLA-1 (NCT02477644) was a Phase III randomised, double-blind, placebo-controlled, multi-centre trial that compared the efficacy of Lynparza in combination with bevacizumab versus placebo/ bevacizumab for the maintenance treatment of advanced high-grade epithelial ovarian cancer (including fallopian tube or primary peritoneal) cancer following first-line platinum-based chemotherapy and bevacizumab. Randomisation was stratified by first-line treatment outcome (timing and outcome of cytoreductive surgery and response to platinum-based chemotherapy) and tBRCAm status, determined by prospective local testing. All available clinical samples were retrospectively tested with Myriad myChoice CDx. Patients were required to have no evidence of disease (NED) due to complete surgical resection, or who were in complete response (CR), or partial response (PR) following completion of first-line platinum-containing chemotherapy and bevacizumab. Patients were randomized (2:1) to receive Lynparza tablets 300 mg orally twice a day in combination with bevacizumab (n = 537) 15 mg/kg every three weeks or placebo/bevacizumab (n = 269). Patients continued bevacizumab in the maintenance setting and started treatment with Lynparza after a minimum of 3 weeks and up to a maximum of 9 weeks following completion of their last dose of chemotherapy. Lynparza treatment was continued for up to 2 years or until progression of the underlying disease or unacceptable toxicity. Patients who in the opinion of the treating physician could derive further benefit from continuous treatment could be treated beyond 2 years. Treatment with bevacizumab was for a total of up to 15 months, including the period given with chemotherapy and given as maintenance.
The primary efficacy endpoint was investigator-assessed PFS evaluated according to RECIST, version 1.1. Additional efficacy endpoints included PFS2 and overall survival (OS).
The median age of patients in both arms was 61 years overall (range 26 to 87). Ovarian cancer was the primary tumour type in 86% of patients in both arms. Ninety six percent (96%) were serous histological type. The ECOG performance score was 0 in 70% of patients and 1 in 28% of patients, overall. All patients had received first-line platinum-based therapy and bevacizumab. First-line treatment outcomes at screening indicated that patients had no evidence of disease with complete macroscopic resection at initial debulking surgery (32%, both arms), no evidence of disease/ CR with complete macroscopic resection at interval debulking surgery (31%, both arms), no evidence of disease/ CR in patients who had either incomplete resection (at initial or interval debulking surgery) or no debulking surgery (15%, both arms) and patients with a partial response (22%, both arms). Thirty percent (30%) of patients in both arms had a deleterious BRCA mutation. Patients were not restricted by the surgical outcome with 65% having complete cytoreduction at initial or interval debulking surgery and 35% having residual macroscopic disease. Demographics and baseline disease characteristics were balanced and comparable between the study and placebo arms in the Intention to Treat (ITT) population and also in the HRD-positive subgroup.
The study demonstrated increased PFS and PFS2 in the ITT population with addition of olaparib to bevacizumab. However, efficacy was not demonstrated in patients with HRD-negative status.
A final analysis of OS (DCO 22 March 2022) found no significant difference between arms in the ITT population. Rates of post-study therapy with a PARP inhibitor were 20% in the olaparib/bevacizumab arm and 46% in the placebo/bevacizumab arm. Exploratory analysis of OS in the HRD-positive subgroup showed a median OS of 75 months amongst those in the olaparib/bevacizumab arm and 57 months amongst those in the placebo/bevacizumab arm, with a descriptive HR of 0.62 (95% CI 0.45, 0.85).
Efficacy results from a biomarker subgroup analysis of 387 patients with HRD-positive tumours (including BRCA mutation), identified post-randomisation using the Myriad myChoice HRD Plus tumour test, who received Lynparza/bevacizumab (n=255) or placebo/bevacizumab (n=132), are summarised in Table 25 and Figure 5. Results from a blinded independent review of PFS were consistent.
Adjuvant treatment of BRCA-mutated, HER2-negative, high-risk early breast cancer.

OlympiA study in patients with HER2-negative, high-risk early breast cancer and a germline BRCA mutation.

OlympiA was a Phase III randomised, double-blind, placebo-controlled, international study in patients with a germline BRCA mutation and HER2-negative, high-risk early breast cancer, who had completed definitive local treatment and neoadjuvant or adjuvant chemotherapy (but not both). Patients were randomised to receive either olaparib tablets (300 mg twice a day) or placebo as adjuvant treatment, continued for 1 year unless disease progression or unacceptable toxicity occurred first. Patients were required to have completed at least 6 cycles of neoadjuvant or adjuvant chemotherapy containing anthracyclines and/or taxanes. Prior platinum for previous cancer (e.g. ovarian) or as adjuvant or neoadjuvant treatment for breast cancer was allowed. For the purpose of determining study eligibility, "high-risk" (of recurrence) was defined differently depending on whether the tumour was hormone receptor (oestrogen receptor (ER) and/or progesterone receptor)-positive (HR-positive), and whether the patient had received their chemotherapy in the neoadjuvant or the adjuvant setting, as follows:
For patients who had received prior neoadjuvant chemotherapy: patients must have had residual invasive cancer in the breast and/or the resected lymph nodes (non-pathological complete response) at the time of surgery. Additionally, patients with HR-positive tumours required a risk score of ≥ 3 based on pre-treatment clinical and post-treatment pathological stage (CPS), oestrogen receptor (ER) status and histological grade as shown in Table 26.
Alternatively, for patients who had received prior adjuvant chemotherapy: triple negative breast cancer (TNBC) must have had node-positive disease or node-negative disease with a ≥ 2 cm primary tumour. HR-positive breast cancer must have had ≥ 4 pathologically confirmed positive lymph nodes.
Patients were randomised in a 1:1 ratio to either olaparib (n=921) or placebo (n=915). Randomisation was stratified by hormone receptor status (HR-positive versus TNBC), by whether prior chemotherapy was neoadjuvant versus adjuvant, and by prior platinum use for breast cancer (yes versus no).
The primary endpoint was invasive disease-free survival (IDFS), defined as the time from randomisation to date of first recurrence, where recurrence was defined as loco-regional, distant recurrence, contralateral invasive breast cancer, new cancer or death from any cause. Secondary endpoints included OS and distant disease free survival [(DDFS, defined as the time from randomisation until evidence of first distant recurrence of breast cancer), the incidence of new primary contralateral breast cancers (invasive and non-invasive), new primary ovarian cancer, new primary fallopian tube cancer and new primary peritoneal cancer].
Patients who were enrolled based on local gBRCA test results provided a sample for retrospective confirmatory testing with BRACAnalysis. Out of 1836 patients enrolled into OlympiA, 1623 were confirmed as gBRCAm by Myriad BRACAnalysis, either prospectively or retrospectively.
Demographic and baseline characteristics were well balanced between the arms. The median age was 42 years. Most patients (67%) were Caucasian and 29% were Asian. Two patients (0.2%) in the olaparib arm and four patients (0.4%) in the placebo arm were male. Sixty-one percent (61%) of patients were pre-menopausal. Eighty-nine percent (89%) of patients were ECOG performance status 0 and 11% ECOG PS 1. Eighty-two percent (82%) of patients had TNBC and 18% had hormone receptor-positive disease (defined as ER positive and/or PgR positive). Fifty percent (50%) of patients had received prior neoadjuvant and 50% received prior adjuvant chemotherapy. Ninety-four percent (94%) of patients received anthracycline and taxane. Twenty-six (26%) of patients overall had received prior platinum for breast cancer. In the olaparib and placebo arms, 87% and 92% of patients with HR positive disease were receiving concomitant endocrine therapy, respectively.
The main efficacy results from OlympiA are presented in Table 27, Figure 6, Figure 7 and Figure 8. Findings were consistent across subgroups based on the stratification factors.
Treatment of germline BRCA-mutated HER2-negative metastatic breast cancer.

OlympiAD study in patients with a gBRCA mutation and HER2-negative metastatic breast cancer after prior chemotherapy.

This study was a Phase 3 open-label, randomised trial that compared the efficacy of olaparib tablets (300 mg twice a day) taken to progression with a comparator arm of physician's choice of chemotherapy (capecitabine, eribulin, or vinorelbine). In the study 302 patients with gBRCAm HER2-negative metastatic breast cancer who had previously received up to two lines of chemotherapy for the treatment of metastatic disease were randomised (2:1 randomisation: 205 olaparib and 97 comparator). Patients were stratified based on: receipt of prior chemotherapy regimens for metastatic breast cancer, oestrogen receptor (ER) and/or progesterone receptor (PgR) positive vs ER and PgR negative, prior platinum for breast cancer. The primary endpoint was PFS assessed by blinded independent central review (BICR) using RECIST 1.1. Secondary endpoints included PFS2, OS, objective response rate (ORR) and HRQoL.
All patients had received prior treatment with anthracycline (unless contraindicated) and a taxane in either the neoadjuvant, adjuvant or metastatic setting. Prior therapy with platinum for metastatic breast cancer was allowed provided there had been no evidence of disease progression during platinum treatment. Prior therapy with platinum in the (neo)adjuvant setting was allowed provided the last dose was received at least 12 months prior to randomisation. Patients could not have received prior olaparib or other PARP inhibitor treatment. Patients with ER and/or PgR-positive disease must have received and progressed on at least one endocrine therapy (adjuvant or metastatic) or had disease that the treating physician believed to be inappropriate for endocrine therapy. Patients had tumour assessments at baseline and every 6 weeks for the first 24 weeks, and then every 12 weeks relative to date of randomisation, until objective radiological disease progression.
The results of OlympiAD are presented in Table 28 and Figure 9. A statistically significant difference in OS between arms was not demonstrated, with a median follow-up time for censored patients of 25.3 months in the olaparib arm and 26.3 months in the comparator arm. The median time to onset of response was 47 days for olaparib vs 45 days for comparator. The median duration of response was 6.4 months for olaparib vs 7.1 months for comparator.
Consistent results were observed across patient subgroups.
A significant difference in global health status/QoL (assessed using the EORTC QLQ-C30 questionnaire which uses a 0-100 point scale) in favour of olaparib was observed (adjusted mean difference in change from baseline score was 7.5 points [95% CI: 2.48-12.44; p = 0.0035]). Time to deterioration (≥ 10 points decrease from baseline) in global health status/QoL score was statistically significantly longer on the olaparib arm (HR 0.44; 95% CI: 0.25-0.77; p = 0.0043; median not reached for olaparib vs. 15.3 months for comparator arm).
First-line maintenance treatment of germline BRCA-mutated metastatic adenocarcinoma of the pancreas.

POLO study in gBRCAm pancreatic adenocarcinoma after first-line chemotherapy.

POLO was a Phase III, randomised, double-blind, placebo-controlled, multi-centre trial that compared the efficacy of Lynparza tablets as maintenance treatment (300 mg twice a day) against placebo in gBRCA-mutated metastatic adenocarcinoma of the pancreas. The study randomised 154 patients (3:2 randomisation: 92 olaparib and 62 placebo) whose disease had not progressed following at least 16 weeks of first-line platinum-based chemotherapy. There was no upper limit to the duration of chemotherapy received. After 16 weeks of continuous platinum-based chemotherapy, the platinum could be discontinued at any time for toxicity and the other agents continued; the patients were eligible for randomisation as long as there was no evidence of progression at any time during chemotherapy treatment. All toxicities from previous anti-cancer therapy must have been resolved to CTCAE grade 1, except for alopecia, grade 3 peripheral neuropathy and Hgb ≥ 9 g/dL. Lynparza treatment was continued until disease progression or unacceptable toxicity.
Patients with germline BRCA mutations were identified from prior local testing results or by central testing using the Myriad BRACAnalysis or Myriad BRACAnalysis CDx test. The BRCAm status of all patients identified using prior local testing results was confirmed, where sent, using the Myriad BRACAnalysis or Myriad BRACAnalysis CDx test.
Demographic and baseline characteristics were generally well balanced between the olaparib and placebo arms. Median age was 57 years in both arms; 30% of patients in the olaparib arm were ≥ 65 years compared to 21% in the placebo arm. Most patients had an ECOG performance status of 0 (67%) and 58% of patients were male. The majority of patients (96%) were randomised within 8 weeks of their last dose of platinum-based chemotherapy. The median time from initiation of first-line platinum-based chemotherapy to randomisation was 5.8 months (range 3.4 to 33.4 months) and 49% of patients were in complete or partial response to their most recent platinum-based regimen.
The primary endpoint was progression-free survival (PFS), defined as time from randomisation to progression determined by BICR using modified Response Evaluation Criteria in Solid Tumours (RECIST) 1.1, or death. Secondary efficacy endpoints included overall survival (OS), objective response rate (ORR) and duration of response (DoR). Patients had tumour assessments at baseline and every 8 weeks for 40 weeks, and then every 12 weeks relative to the date of randomisation, until objective radiological disease progression. For the primary analysis (PFS), the median follow-up time for censored patients was 9.1 months in the olaparib arm and 3.8 months in the placebo arm. At the final analysis of OS, the median follow-up time for censored patients was 31.3 months in the olaparib arm and 23.9 months in the placebo arm.
The study results are presented in Table 29, Figure 10 and Figure 11. A sensitivity analysis of PFS by investigator assessment was consistent with that by BICR. Based on descriptive Kaplan-Meier estimates, the proportion of patients that were alive and progression-free at 12, 24 and 36 months were 34%, 28% and 22% for olaparib vs 15%, 10% and 10% for placebo.
At the final analysis (70% maturity), there was no difference in OS demonstrated between arms.
Treatment of BRCA-mutated metastatic castration-resistant prostate cancer (mCRPC).

PROfound study in patients with a homologous recombination repair gene mutation and mCRPC after progression on prior NHA treatment.

PROfound was a Phase III randomised, open-label, multicentre trial that evaluated the efficacy of Lynparza tablets (300 mg twice a day) versus a comparator arm of investigator's choice of NHA (new hormonal agent: enzalutamide or abiraterone acetate) in men with mCRPC.
To be eligible, patients had to have progressed on prior NHA for the treatment of metastatic prostate cancer and/or CRPC, and have a tumour mutation in one of 15 genes involved in the homologous recombination repair (HRR) pathway, as detected by prospective central testing using a clinical trial assay. Cohort A comprised patients with deleterious or suspected deleterious mutations in BRCA1, BRCA2 or ATM. Although patients with gene mutations other than BRCA1/2 were enrolled in the trial, Lynparza is not indicated for the treatment of patients with gene mutations other than BRCA1/2 since favourable benefit-risk is not established beyond BRCA1/2.
All patients continued on a luteinising hormone releasing hormone (LHRH) analogue or had prior bilateral orchiectomy.
A total of 245 patients were randomised in Cohort A (162 olaparib and 83 comparator). Randomisation was stratified by prior taxane use and evidence of measurable disease. Treatment was continued until disease progression. Patients randomised to the NHA comparator were given the option to switch to olaparib upon confirmed radiological BICR progression.
Of the 160 patients with a BRCA1 or BRCA2 mutation enrolled in PROfound, 114 patients underwent retrospective testing to determine if the identified BRCA1/2 mutation was germline or somatic in origin. Germline BRCA1/2 mutations were identified in 63 patients, and for the remaining 51 patients, the BRCA1/2 mutation was determined to be somatic in origin based on the absence of evidence of germline BRCA1/2 mutation.
Demographics and baseline characteristics were generally well balanced between the olaparib and comparator arms in patients with BRCA1/2 mutations. Median age was 68 years and 67 years in the olaparib and comparator arms, respectively. Prior therapy in the olaparib arm was 71% taxane, 41% enzalutamide, 37% abiraterone acetate and 20% both enzalutamide and abiraterone acetate. Prior therapy in the comparator arm was 60% taxane, 50% enzalutamide, 36% abiraterone acetate and 14% both enzalutamide and abiraterone acetate. Fifty-eight percent (58%) of patients in the olaparib arm and 55% in the comparator arm had measurable disease at study entry. The proportion of patients with bone, lymph node, liver and respiratory metastases was 89%, 62%, 12% and 23%, respectively in the olaparib arm and 86%, 71%, 17% and 16%, respectively in the comparator arm. Most patients in both treatment arms had an ECOG of 0 or 1 (93%). Baseline pain scores (BPI-SF worst pain) were 0 - < 2 (52%), 2-3 (10%) or > 3 (34%) in the olaparib arm and 0 - < 2 (45%), 2-3 (7%) or > 3 (45%) in the comparator arm. Median baseline PSA was 57.48 microgram/L in the olaparib arm and 103.95 microgram/L in the comparator arm.
The primary endpoint of the study was radiological progression free survival (rPFS) in Cohort A determined by BICR using RECIST 1.1 (soft tissue) and Prostate Cancer Working Group (PCWG3) (bone). Key secondary endpoints included confirmed objective response rate (ORR) by BICR, time to pain progression (TTPP) and overall survival (OS).
The study demonstrated a clinically meaningful and statistically significant improvement in BICR-assessed rPFS and final OS for olaparib vs comparator in Cohort A, attributable to patients with BRCA1/2 gene mutations. Results for patients with BRCA1/2 mutations are presented in Table 30. Also, see Figures 12 and 13.
Sensitivity analyses showed similar efficacy in patients for whom mutations could be identified using the Foundation Medicine F1CDx assay, the Foundation Medicine F1 Liquid CDx assay, or the Myriad BRACAnalysis CDx assay.
PROpel study in the first-line setting for patients with mCRPC. PROpel was a Phase III randomised, double-blind, placebo-controlled, multicentre study conducted in patients with mCRPC. Patients (n=796) were randomised (1:1) to receive either Lynparza tablets 300 mg twice a day (n=399) or a matching placebo (n=397) as first-line treatment, in combination with abiraterone (1000 mg once daily) and either prednisone or prednisolone 5 mg twice a day, as well as a gonadotropin-releasing hormone (GnRH) analogue unless they had prior bilateral orchiectomy. Patients could not have received any prior abiraterone, other NHA within 12 months or first-generation antiandrogen agents within 4 weeks of randomisation. Docetaxel was allowed for prior hormone-sensitive prostate cancer (mHSPC), as long as no signs of disease progression occurred during or immediately after such treatment. Randomisation was stratified by metastases (bone only, visceral or other) and docetaxel treatment at mHSPC stage (yes or no). Treatment was continued until objective radiological disease progression (determined by investigator) or unacceptable toxicity.
Assessment for somatic or germline deleterious or suspected deleterious BRCA gene mutations (BRCAm) was conducted after randomisation and before primary analysis by both NGS-based tumour tissue (FoundationOne CDx [F1CDx]) and ctDNA (FoundationOne Liquid CDx) tests.
The primary endpoint was rPFS, defined as time from randomisation to progression determined by investigator assessment based on RECIST v1.1 and Prostate Cancer Working Group (PCWG-3) criteria (bone). The key secondary efficacy endpoint was overall survival (OS).
Of the 796 patients, BRCAm status was unknown for a third of patients in each arm according to the tissue test, and for 8% of patients in each arm according to the ctDNA test. There were 85 patients in the total study (11%) who had a BRCAm according to either test.
Among the 85 BRCAm patients, the median age was 68 years (range 43 to 85), and 67% were 65 years or older; 72% were Caucasian and 22% were Asian; 66% had ECOG performance status (PS) 0 and 34% had ECOG PS 1; 25% had prior docetaxel treatment for mHSPC; 53% had bone-only metastases, 15% had visceral metastases, and 32% had other metastases.
A statistically significant improvement in rPFS for Lynparza/abiraterone compared to placebo/abiraterone was observed in the intention to treat (ITT) population. Exploratory analysis based on BRCAm status were conducted among 711 patients with no BRCAm - either according to either both tests, or according to one test where no valid result was obtained for the second test - the exploratory subgroup rPFS hazard ratio was 0.77 (95% CI: 0.63, 0.96) and the OS hazard ratio was 0.92 (95% CI: 0.74, 1.14).
These exploratory analyses indicated that the improvement in the ITT population was primarily attributable to the results seen in the subgroup of patients with BRCAm. Results of an exploratory analysis in the subgroup of 85 patients with BRCAm who participated in PROpel are summarised in Table 31 and Figure 14. Also, see Figure 15.
Effect on the QT interval. There is no clinically relevant effect of olaparib on cardiac repolarisation (as evaluated by an effect on the QT interval) following 300 mg twice a day multiple dosing of olaparib.
Retreatment on relapse. There are no data to support rechallenge with olaparib after relapse or progression on olaparib treatment, in any setting.

5.2 Pharmacokinetic Properties

Olaparib displays high inter-patient variability in PK parameters, including Cmax, AUC, Vd and CL/F.
The pharmacokinetics of olaparib at the 300 mg tablet dose are characterised by an apparent plasma clearance of ~7 L/h, an apparent volume of distribution of ~158 L and a terminal half-life of 15 hours after dosing. On multiple dosing, an AUC accumulation ratio of 1.8 was observed and PK appeared to be time-dependent to a small extent.

Absorption.

Following oral administration of 300 mg olaparib (tablet formulation), absorption is rapid with peak plasma concentrations typically achieved between 1.5 hours after dosing.
Co-administration with food slowed the rate (tmax delayed by 2.5 hours and Cmax reduced by approximately 21%) but did not significantly affect the extent of absorption of olaparib (AUC treatment ratio: 1.08; 90% CI: 1.01, 1.16). Consequently, patients may take Lynparza without regard to food (see Section 4.2 Dose and Method of Administration).

Distribution.

In vitro, human plasma protein binding of olaparib was dose-dependent; the fraction bound was approximately 91% at 1 microgram/mL, reducing to 82% at 10 microgram/mL and to 70% at 40 microgram/mL. In solutions of purified proteins, the olaparib fraction bound to albumin was approximately 56%, which was independent of olaparib concentrations. Using the same assay, the fraction bound to alpha-1 acid glycoprotein was 29% at 10 microgram/mL with a trend of decreased binding at higher concentrations.

Metabolism.

In vitro, CYP3A4/5 were shown to be the enzymes primarily responsible for the metabolism of olaparib.
Following oral dosing of 14C-olaparib to female patients, unchanged olaparib accounted for the majority of the circulating radioactivity in plasma (70%) and was the major component found in both urine and faeces (15% and 6% of the dose respectively). The metabolism of olaparib is extensive with the main site of metabolism being the piperazine and fluorobenzyl ring structures. The majority of the metabolism was attributable to oxidation reactions with a number of the components produced undergoing subsequent glucuronide or sulphate conjugation. Up to 20, 37 and 20 metabolites were detected in plasma, urine and faeces, respectively, the majority of them representing < 1% of the dosed material. A ring-open piperazin-3-ol moiety, and two mono-oxygenated metabolites (each ~10%) were the major circulating components, with one of the mono-oxygenated metabolites also being the major metabolite in the excreta (6% and 5% of the urinary and faecal radioactivity respectively).

Excretion.

Following a single dose of 14C-olaparib, ~86% of the dosed radioactivity was recovered within a 7 day collection period, ~44% via the urine and ~42% via the faeces. The majority of the material was excreted as metabolites.

Special populations.

Renal impairment.

Following a single oral 300 mg dose of olaparib to patients with mild renal impairment (creatinine clearance: 51 to 80 mL/min), AUC increased by 24% (90% CI: 6% to 47%) and Cmax by 15% (90% CI: 4% to 27%) compared with patients with normal renal function. No Lynparza dose adjustment is required for patients with mild renal impairment, however, patients should be monitored closely for renal function and adverse events (see Section 4.2 Dose and Method of Administration).
Following a single oral 300 mg dose of olaparib to patients with moderate renal impairment (creatinine clearance: 31 to 50 mL/min), AUC increased by 44% (90% CI: 10% to 89%) and Cmax by 26% (90% CI: 6% to 48%) compared with patients with normal renal function. Lynparza dose adjustment is recommended for patients with moderate renal impairment and patients should be monitored closely for renal function and adverse events (see Section 4.2 Dose and Method of Administration). Renal clearance of olaparib was lower in patients with mild and moderate renal impairment compared to patients with normal renal function (1.48 L/h). For patients with mild or moderate renal impairment, arithmetic mean CLR was 59% (0.614 L/h) and 80% (0.299 L/h) lower, respectively, than that observed in patients with normal renal function.
Olaparib has not been studied in patients with severe renal impairment or end-stage renal disease (creatinine clearance ≤ 30 mL/min).

Hepatic impairment.

Following a single oral 300 mg dose of olaparib to patients with mild hepatic impairment (Child-Pugh classification A) AUC increased by 15% (90% CI: -23% to 28%) and Cmax by 13% (90% CI: 18% to 55%) and to patients with moderate hepatic impairment (Child-Pugh classification B) AUC increased by 8% (90% CI: 0.66, 1.74) and Cmax decreased by 13% (90% CI: 0.63, 1.22) compared with patients with normal hepatic function. No Lynparza dose adjustment is required in patients with mild or moderate hepatic impairment, however, patients should be monitored closely for hepatic function and adverse events (see Section 4.2 Dose and Method of Administration).
Olaparib has not been studied in patients with severe hepatic impairment (Child-Pugh classification C).

Other.

In population based PK analyses, patient age, gender, bodyweight, tumour location or race (including Caucasian [n = 516] and Asian [n = 126] patients) were not significant covariates.

5.3 Preclinical Safety Data

Genotoxicity.

Olaparib showed no mutagenic potential in bacterial cells, but was clastogenic in mammalian cells in vitro. When dosed orally to rats, olaparib induced micronuclei in bone marrow. This clastogenicity is consistent with the primary pharmacology of olaparib and indicates potential for genotoxicity in man.

Carcinogenicity.

Carcinogenicity studies have not been conducted with olaparib.

6 Pharmaceutical Particulars

6.1 List of Excipients

See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C. Store in original container to protect from moisture.

6.5 Nature and Contents of Container

Lynparza is supplied in cartons containing 56 tablets in aluminium/aluminium blister platforms.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Olaparib is a white to pale yellow crystalline powder, which is very slightly soluble in aqueous solutions (0.10-0.13 mg/mL at 37°C), slightly soluble in ethanol (5.5 mg/mL at 37°C) and has a pKa of 12.07.

Chemical structure.

The chemical name for olaparib is: 4-[[3-[[4-(cyclopropylcarbonyl)-1-piperazinyl]carbonyl]-4-fluorophenyl]methyl]-1(2H)-phthalazinone.
The chemical structure of olaparib is:
Molecular formula: C24H23FN4O3.
Molecular weight: 434.46.

CAS number.

CAS number: 763113-22-0.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes