LYNPARZA 50mg capsules medication leaflet

Lynparza 100 mg film-coated tablets

Lynparza 150 mg film-coated tablets

Lynparza 100 mg film-coated tablets

Each film-coated tablet contains 100 mg olaparib.

Lynparza 150 mg film-coated tablets

Each film-coated tablet contains 150 mg olaparib.

This medicinal product contains 0.24 mg sodium per 100 mg tablet and 0.35 mg sodium per 150 mgtablet.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Lynparza 100 mg film-coated tablets

Yellow to dark yellow, oval, bi-convex tablet, debossed with ‘OP100’ on one side and plain on theother side.

Lynparza 150 mg film-coated tablets

Green to green/grey, oval, bi-convex tablet, debossed with ‘OP150’ on one side and plain on the otherside.

Ovarian cancer

Lynparza is indicated as monotherapy for the:

* maintenance treatment of adult patients with advanced (FIGO stages III and IV) BRCA1/2-mutated (germline and/or somatic) high-grade epithelial ovarian, fallopian tube or primaryperitoneal cancer who are in response (complete or partial) following completion of first-lineplatinum-based chemotherapy.

* maintenance treatment of adult patients with platinum-sensitive relapsed high-grade epithelialovarian, fallopian tube, or primary peritoneal cancer who are in response (complete or partial)to platinum-based chemotherapy.

Lynparza in combination with bevacizumab is indicated for the:

* maintenance treatment of adult patients with advanced (FIGO stages III and IV) high-gradeepithelial ovarian, fallopian tube or primary peritoneal cancer who are in response (completeor partial) following completion of first-line platinum-based chemotherapy in combinationwith bevacizumab and whose cancer is associated with homologous recombination deficiency(HRD) positive status defined by either a BRCA1/2 mutation and/or genomic instability (seesection 5.1).

Breast cancer

Lynparza is indicated as:

* monotherapy or in combination with endocrine therapy for the adjuvant treatment of adultpatients with germline BRCA1/2-mutations who have HER2-negative, high risk early breastcancer previously treated with neoadjuvant or adjuvant chemotherapy (see sections 4.2 and5.1).

* monotherapy for the treatment of adult patients with germline BRCA1/2-mutations, who have

HER2 negative locally advanced or metastatic breast cancer. Patients should have previouslybeen treated with an anthracycline and a taxane in the (neo)adjuvant or metastatic settingunless patients were not suitable for these treatments (see section 5.1). Patients with hormonereceptor (HR)-positive breast cancer should also have progressed on or after prior endocrinetherapy, or be considered unsuitable for endocrine therapy.

Adenocarcinoma of the pancreas

Lynparza is indicated as monotherapy for the maintenance treatment of adult patients with germline

BRCA1/2-mutations who have metastatic adenocarcinoma of the pancreas and have not progressedafter a minimum of 16 weeks of platinum treatment within a first-line chemotherapy regimen.

Prostate cancer

Lynparza is indicated:

* as monotherapy for the treatment of adult patients with metastatic castration-resistant prostatecancer (mCRPC) and BRCA1/2-mutations (germline and/or somatic) who have progressedfollowing prior therapy that included a new hormonal agent.

* in combination with abiraterone and prednisone or prednisolone for the treatment of adultpatients with mCRPC in whom chemotherapy is not clinically indicated (see section 5.1).

Endometrial cancer

Lynparza in combination with durvalumab is indicated for the maintenance treatment of adult patientswith primary advanced or recurrent endometrial cancer that is mismatch repair proficient (pMMR)whose disease has not progressed on first-line treatment with durvalumab in combination withcarboplatin and paclitaxel.

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

Patient selection

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

Before Lynparza treatment is initiated for first-line maintenance treatment of high-grade epithelialovarian cancer (EOC), fallopian tube cancer (FTC) or primary peritoneal cancer (PPC), patients musthave confirmation of deleterious or suspected deleterious germline and/or somatic mutations in thebreast cancer susceptibility genes (BRCA) 1 or 2 using a validated test.

Maintenance treatment of platinum-sensitive relapsed ovarian cancer:

There is no requirement for BRCA1/2 testing prior to using Lynparza for the monotherapymaintenance treatment of relapsed EOC, FTC or PPC who are in a complete or partial response toplatinum-based therapy.

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

Before Lynparza with bevacizumab treatment is initiated for the first-line maintenance treatment of

EOC, FTC or PPC, patients must have confirmation of either deleterious or suspected deleterious

BRCA1/2 mutation and/or genomic instability determined using a validated test (see section 5.1).

Adjuvant treatment of germline BRCA-mutated high risk early breast cancer

Before Lynparza treatment is initiated for adjuvant treatment of HER2 negative high risk early breastcancer, patients must have confirmation of deleterious or suspected deleterious gBRCA1/2 mutationusing a validated test (see section 5.1).

Monotherapy treatment of gBRCA1/2-mutated HER2-negative metastatic breast cancer:

For germline breast cancer susceptibility genes (gBRCA1/2) mutated human epidermal growth factorreceptor 2 (HER2)-negative locally advanced or metastatic breast cancer, patients must haveconfirmation of a deleterious or suspected deleterious gBRCA1/2 mutation before Lynparza treatmentis initiated. gBRCA1/2 mutation status should be determined by an experienced laboratory using avalidated test method. Data demonstrating clinical validation of tumour BRCA1/2 tests in breast cancerare not currently available.

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

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

Monotherapy treatment of BRCA1/2-mutated metastatic castration-resistant prostate cancer:

For BRCA1/2-mutated metastatic castration-resistant prostate cancer (mCRPC), patients must haveconfirmation of a deleterious or suspected deleterious BRCA1/2 mutation (using either tumour orblood sample) before Lynparza treatment is initiated (see section 5.1). BRCA1/2 mutation statusshould be determined by an experienced laboratory using a validated test method.

Treatment of mCRPC in combination with abiraterone and prednisone or prednisolone:

No genomic testing is required prior to using Lynparza in combination with abiraterone andprednisone or prednisolone for the treatment of patients with mCRPC.

First-line maintenance treatment of MMR-Proficient (pMMR) advanced or recurrent endometrialcancer in combination with durvalumab:

Before treatment is initiated, patients must have confirmation of proficient mismatch repair (pMMR)tumour status using a validated test (see section 5.1).

Genetic counselling for patients tested for mutations in BRCA1/2 genes should be performedaccording to local regulations.

Lynparza is available as 100 mg and 150 mg tablets.

The recommended dose of Lynparza in monotherapy or in combination with other agents is 300 mg(two 150 mg tablets) taken twice daily, equivalent to a total daily dose of 600 mg. The 100 mg tablet isavailable for dose reduction.

Lynparza monotherapy

Patients with platinum-sensitive relapsed (PSR) high-grade epithelial ovarian, fallopian tube, orprimary peritoneal cancer who are in response (complete or partial) to platinum-based chemotherapyshould start treatment with Lynparza no later than 8 weeks after completion of their final dose of theplatinum-containing regimen.

Lynparza in combination with bevacizumab

When Lynparza is used in combination with bevacizumab for the first-line maintenance treatment ofhigh-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer following completion offirst-line platinum-based therapy with bevacizumab, the dose of bevacizumab is 15 mg/kg once every3 weeks. Please refer to the full product information for bevacizumab (see section 5.1).

Lynparza in combination with endocrine therapy

Please refer to the full product information of the endocrine therapy combination partner(s) (aromataseinhibitor/anti-oestrogen agent and/or LHRH) for the recommended posology.

Lynparza in combination with abiraterone and prednisone or prednisolone

When Lynparza is used in combination with abiraterone for the treatment of patients with mCRPC, thedose of abiraterone is 1000 mg orally once daily (see section 5.1). Abiraterone should be given withprednisone or prednisolone 5 mg orally twice daily. Please refer to the full product information forabiraterone.

Lynparza in combination with durvalumab

When Lynparza is used in combination with durvalumab for the maintenance treatment of patientswith MMR-Proficient (pMMR) primary advanced or recurrent endometrial cancer whose disease hasnot progressed on first-line treatment with durvalumab in combination with carboplatin and paclitaxel,the dose of durvalumab is 1500 mg every 4 weeks (see section 5.1). Please refer to the full productinformation for durvalumab.

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

Patients can continue treatment until radiological disease progression, unacceptable toxicity or for upto 2 years if there is no radiological evidence of disease after 2 years of treatment. Patients withevidence of disease at 2 years, who in the opinion of the treating physician can derive further benefitfrom continuous treatment, can be treated beyond 2 years.

Maintenance treatment of platinum-sensitive relapsed ovarian cancer:

For patients with platinum-sensitive relapsed high-grade epithelial ovarian, fallopian tube or primaryperitoneal cancer, it is recommended that treatment be continued until progression of the underlyingdisease or unacceptable toxicity.

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

Patients can continue treatment with Lynparza until radiological disease progression, unacceptabletoxicity or for up to 2 years if there is no radiological evidence of disease after 2 years of treatment.

Patients with evidence of disease at 2 years, who in the opinion of the treating physician can derivefurther benefit from continuous Lynparza treatment, can be treated beyond 2 years. Please refer to theproduct information for bevacizumab for the recommended overall duration of treatment of amaximum of 15 months including the periods in combination with chemotherapy and as maintenance(see section 5.1).

Adjuvant treatment of germline BRCA-mutated high risk early breast cancer

It is recommended that patients are treated for up to 1 year, or until disease recurrence, or unacceptabletoxicity, whichever occurs first.

Monotherapy treatment of gBRCA1/2-mutated HER2-negative metastatic breast cancer:

It is recommended that treatment be continued until progression of the underlying disease orunacceptable toxicity.

The efficacy and safety of maintenance retreatment with Lynparza following first or subsequentrelapse in ovarian cancer patients has not been established. There are no efficacy or safety data onretreatment of breast cancer patients (see section 5.1).

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

It is recommended that treatment be continued until progression of the underlying disease orunacceptable toxicity.

Monotherapy treatment of BRCA1/2-mutated metastatic castration-resistant prostate cancer:

It is recommended that treatment be continued until progression of the underlying disease orunacceptable toxicity. Medical castration with luteinising hormone releasing hormone (LHRH)analogue should be continued during treatment in patients not surgically castrated.

Treatment of mCRPC in combination with abiraterone and prednisone or prednisolone:

It is recommended that treatment be continued until progression of the underlying disease orunacceptable toxicity when Lynparza is used in combination with abiraterone and prednisone orprednisolone. Treatment with a gonadotropin-releasing hormone (GnRH) analogue should becontinued during treatment in all patients, or patients should have had prior bilateral orchiectomy.

Please refer to the product information for abiraterone.

There are no efficacy or safety data on retreatment with Lynparza in prostate cancer patients (seesection 5.1).

First-line maintenance treatment of MMR-Proficient (pMMR) advanced or recurrent endometrialcancer in combination with durvalumab:

It is recommended that treatment be continued until progression of the underlying disease orunacceptable toxicity. Please refer to the product information for durvalumab.

Missing dose

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

Dose adjustments for adverse reactions

Treatment may be interrupted to manage adverse reactions such as nausea, vomiting, diarrhoea, andanaemia and dose reduction can be considered (see section 4.8).

The recommended dose reduction is to 250 mg (one 150 mg tablet and one 100 mg tablet) twice daily(equivalent to a total daily dose of 500 mg).

If a further dose reduction is required, then reduction to 200 mg (two 100 mg tablets) twice daily(equivalent to a total daily dose of 400 mg) is recommended.

Dose adjustments for co-administration with CYP3A inhibitors

Concomitant use of strong or moderate CYP3A inhibitors is not recommended and alternative agentsshould be considered. If a strong CYP3A inhibitor must be co-administered, the recommended

Lynparza dose reduction is to 100 mg (one 100 mg tablet) taken twice daily (equivalent to a total dailydose of 200 mg). If a moderate CYP3A inhibitor must be co-administered, the recommended Lynparzadose reduction is to 150 mg (one 150 mg tablet) taken twice daily (equivalent to a total daily dose of300 mg) (see sections 4.4 and 4.5).

No adjustment in starting dose is required for elderly patients.

For patients with moderate renal impairment (creatinine clearance 31 to 50 ml/min) the recommendeddose of Lynparza is 200 mg (two 100 mg tablets) twice daily (equivalent to a total daily dose of400 mg) (see section 5.2).

Lynparza can be administered in patients with mild renal impairment (creatinine clearance 51 to80 ml/min) with no dose adjustment.

Lynparza is not recommended for use in patients with severe renal impairment or end-stage renaldisease (creatinine clearance ≤30 ml/min), as safety and pharmacokinetics have not been studied inthese patients. Lynparza may only be used in patients with severe renal impairment if the benefitoutweighs the potential risk, and the patient should be carefully monitored for renal function andadverse events.

Lynparza can be administered to patients with mild or moderate hepatic impairment (Child-Pughclassification A or B) with no dose adjustment (see section 5.2). Lynparza is not recommended for usein patients with severe hepatic impairment (Child-Pugh classification C), as safety andpharmacokinetics have not been studied in these patients.

There are limited clinical data available in non-Caucasian patients. However, no dose adjustment isrequired on the basis of ethnicity (see section 5.2).

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

No data are available.

Lynparza is for oral use.

Lynparza tablets should be swallowed whole and not chewed, crushed, dissolved or divided. Lynparzatablets may be taken without regard to meals.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Breast-feeding during treatment and for 1 month after the last dose (see section 4.6).

Haematological toxicity has been reported in patients treated with Lynparza, including clinicaldiagnoses and/or laboratory findings of generally mild or moderate (CTCAE grade 1 or 2) anaemia,neutropenia, thrombocytopenia and lymphopenia. Pure red cell aplasia (PRCA) (see Section 4.8)and/or autoimmune haemolytic anaemia (AIHA) have been reported when Lynparza has been used incombination with durvalumab.

Patients should not start treatment with Lynparza until they have recovered from haematologicaltoxicity caused by previous anticancer therapy (haemoglobin, platelet and neutrophil levels should be≤CTCAE grade 1). Baseline testing, followed by monthly monitoring, of complete blood counts isrecommended for the first 12 months of treatment and periodically after this time to monitor forclinically significant changes in any parameter during treatment (see section 4.8).

If a patient develops severe haematological toxicity or blood transfusion dependence, treatment with

Lynparza should be interrupted and appropriate haematological testing should be initiated. If the bloodparameters remain clinically abnormal after 4 weeks of Lynparza dose interruption, bone marrowanalysis and/or blood cytogenetic analysis are recommended. If PRCA or AIHA are confirmed,treatment with Lynparza and durvalumab should be discontinued.

Myelodysplastic syndrome/Acute myeloid leukaemia

The overall incidence of myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML) in patientstreated in clinical trials with Lynparza monotherapy, including long-term survival follow-up, was<1.5%, with higher incidence in patients with BRCAm platinum-sensitive relapsed ovarian cancer whohad received at least two prior lines of platinum chemotherapy and were followed up for 5 years (seesection 4.8). The majority of events had a fatal outcome. The duration of therapy with olaparib inpatients who developed MDS/AML varied from <6 months to >4 years.

If MDS/AML is suspected, the patient should be referred to a haematologist for further investigations,including bone marrow analysis and blood sampling for cytogenetics. If, following investigation forprolonged haematological toxicity, MDS/AML is confirmed, Lynparza should be discontinued and thepatient treated appropriately.

Venous Thromboembolic Events

Venous thromboembolic events, predominantly events of pulmonary embolism, have occurred inpatients treated with Lynparza and had no consistent clinical pattern. A higher incidence was observedin patients with metastatic castration-resistant prostate cancer, who also received androgen deprivationtherapy, compared with other approved indications (see section 4.8). Monitor patients for clinical signsand symptoms of venous thrombosis and pulmonary embolism and treat as medically appropriate.

Patients with a prior history of VTE may be more at risk of a further occurrence and should bemonitored appropriately.

Pneumonitis

Pneumonitis, including events with a fatal outcome, has been reported in <1.0% of patients treatedwith Lynparza in clinical studies. Reports of pneumonitis had no consistent clinical pattern and wereconfounded by a number of pre-disposing factors (cancer and/or metastases in lungs, underlyingpulmonary disease, smoking history, and/or previous chemotherapy and radiotherapy). If patientspresent with new or worsening respiratory symptoms such as dyspnoea, cough and fever, or anabnormal chest radiologic finding is observed, Lynparza treatment should be interrupted and promptinvestigation initiated. If pneumonitis is confirmed, Lynparza treatment should be discontinued andthe patient treated appropriately.

Cases of hepatotoxicity have been reported in patients treated with olaparib (see section 4.8). Ifclinical symptoms or signs suggestive of hepatotoxicity develop, prompt clinical evaluation of thepatient and measurement of liver function tests should be performed. In case of suspected drug-induced liver injury (DILI), treatment should be interrupted. In case of severe DILI treatmentdiscontinuation should be considered as clinically appropriate.

Embryofoetal toxicity

Based on its mechanism of action (PARP inhibition), Lynparza could cause foetal harm whenadministered to a pregnant woman. Nonclinical studies in rats have shown that olaparib causes adverseeffects on embryofoetal survival and induces major foetal malformations at exposures below thoseexpected at the recommended human dose of 300 mg twice daily.

Pregnancy/contraception

Lynparza should not be used during pregnancy. Women of childbearing potential must use two formsof reliable contraception before starting Lynparza treatment, during therapy and for 6 months afterreceiving the last dose of Lynparza. Two highly effective and complementary forms of contraceptionare recommended. Male patients and their female partners of childbearing potential should use reliablecontraception during therapy and for 3 months after receiving the last dose of Lynparza (seesection 4.6).

Lynparza co-administration with strong or moderate CYP3A inhibitors is not recommended (seesection 4.5). If a strong or moderate CYP3A inhibitor must be co-administered, the dose of Lynparzashould be reduced (see sections 4.2 and 4.5).

Lynparza co-administration with strong or moderate CYP3A inducers is not recommended. In theevent that a patient already receiving Lynparza requires treatment with a strong or moderate CYP3Ainducer, the prescriber should be aware that the efficacy of Lynparza may be substantially reduced(see section 4.5).

This medicinal product contains less than 1 mmol sodium (23 mg) per 100 mg or 150 mg tablet, that isto say essentially “sodium-free”.

Clinical studies of olaparib in combination with other anticancer medicinal products, including DNAdamaging agents, indicate a potentiation and prolongation of myelosuppressive toxicity. Therecommended Lynparza monotherapy dose is not suitable for combination with myelosuppressiveanticancer medicinal products.

Combination of olaparib with vaccines or immunosuppressant agents has not been studied. Therefore,caution should be taken if these medicinal products are co-administered with Lynparza and patientsshould be closely monitored.

Effect of other medicinal products on olaparib

CYP3A4/5 are the isozymes predominantly responsible for the metabolic clearance of olaparib.

A clinical study to evaluate the impact of itraconazole, a known CYP3A inhibitor, has shown thatco-administration with olaparib increased mean olaparib Cmax by 42% (90% CI: 33-52%) and mean

AUC by 170% (90% CI: 144-197%). Therefore, known strong (e.g. itraconazole, telithromycin,clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, boceprevir, telaprevir) ormoderate (e.g. erythromycin, diltiazem, fluconazole, verapamil) inhibitors of this isozyme are notrecommended with Lynparza (see section 4.4). If strong or moderate CYP3A inhibitors must beco-administered, the dose of Lynparza should be reduced. The recommended Lynparza dose reductionis to 100 mg taken twice daily (equivalent to a total daily dose of 200 mg) with a strong CYP3Ainhibitor or 150 mg taken twice daily (equivalent to a total daily dose of 300 mg) with a moderate

CYP3A inhibitor (see sections 4.2 and 4.4). It is also not recommended to consume grapefruit juicewhile on Lynparza therapy as it is a CYP3A inhibitor.

A clinical study to evaluate the impact of rifampicin, a known CYP3A inducer, has shown thatco-administration with olaparib decreased olaparib mean Cmax by 71% (90% CI: 76-67%) and mean

AUC by 87% (90% CI: 89-84%). Therefore, known strong inducers of this isozyme (e.g. phenytoin,rifampicin, rifapentine, carbamazepine, nevirapine, phenobarbital and St John’s Wort) are notrecommended with Lynparza, as it is possible that the efficacy of Lynparza could be substantiallyreduced. The magnitude of the effect of moderate to strong inducers (e.g. efavirenz, rifabutin) onolaparib exposure is not established, therefore the co-administration of Lynparza with these medicinalproducts is also not recommended (see section 4.4).

Effect of olaparib on other medicinal products

Olaparib inhibits CYP3A4 in vitro and is predicted to be a mild CYP3A inhibitor in vivo. Therefore,caution should be exercised when sensitive CYP3A substrates or substrates with a narrow therapeuticmargin (e.g. simvastatin, cisapride, cyclosporine, ergot alkaloids, fentanyl, pimozide, sirolimus,tacrolimus and quetiapine) are combined with olaparib. Appropriate clinical monitoring isrecommended for patients receiving CYP3A substrates with a narrow therapeutic marginconcomitantly with olaparib.

Induction of CYP1A2, 2B6 and 3A4 has been shown in vitro with CYP2B6 being most likely to beinduced to a clinically relevant extent. The potential for olaparib to induce CYP2C9, CYP2C19 and

P-gp can also not be excluded. Therefore, olaparib upon co-administration may reduce the exposure tosubstrates of these metabolic enzymes and transport protein. The efficacy of some hormonalcontraceptives may be reduced if co-administered with olaparib (see sections 4.4 and 4.6).

In vitro, olaparib inhibits the efflux transporter P-gp (IC50=76 µM), therefore it cannot be excludedthat olaparib may cause clinically relevant drug interactions with substrates of P-gp (e.g. simvastatin,pravastatin, dabigatran, digoxin and colchicine). Appropriate clinical monitoring is recommended forpatients receiving this type of medicinal product concomitantly.

In vitro, olaparib has been shown to be an inhibitor of BCRP, OATP1B1, OCT1, OCT2, OAT3,

MATE1 and MATE2K. It cannot be excluded that olaparib may increase the exposure to substrates of

BCRP (e.g. methotrexate, rosuvastatin), OATP1B1 (e.g. bosentan, glibenclamide, repaglinide, statinsand valsartan), OCT1 (e.g. metformin), OCT2 (e.g. serum creatinine), OAT3 (e.g. furosemide andmethotrexate), MATE1 (e.g. metformin) and MATE2K (e.g. metformin). In particular, caution shouldbe exercised if olaparib is administered in combination with any statin.

Combination with anastrozole, letrozole and tamoxifen

A clinical study has been performed to assess the combination of olaparib with anastrozole, letrozoleor tamoxifen. No clinically relevant interactions were observed.

Women of childbearing potential should not become pregnant while on Lynparza and not be pregnantat the beginning of treatment. A pregnancy test should be performed on all women of childbearingpotential prior to treatment and considered regularly throughout treatment.

Women of childbearing potential must use two forms of reliable contraception before starting

Lynparza therapy, during therapy and for 6 months after receiving the last dose of Lynparza, unlessabstinence is the chosen method of contraception (see section 4.4). Two highly effective andcomplementary forms of contraception are recommended.

Since it cannot be excluded that olaparib may reduce exposure to substrates of CYP2C9 throughenzyme induction, the efficacy of some hormonal contraceptives may be reduced if co-administeredwith olaparib. Therefore, an additional non-hormonal contraceptive method should be consideredduring treatment (see section 4.5). For women with hormone dependent cancer, two non-hormonalcontraceptive methods should be considered.

Contraception in males

It is not known whether olaparib or its metabolites are found in seminal fluid. Male patients must use acondom during therapy and for 3 months after receiving the last dose of Lynparza when having sexualintercourse with a pregnant woman or with a woman of childbearing potential. Female partners ofmale patients must also use highly effective contraception if they are of childbearing potential (seesection 4.4). Male patients should not donate sperm during therapy and for 3 months after receivingthe last dose of Lynparza.

Studies in animals have shown reproductive toxicity including serious teratogenic effects and effectson embryofoetal survival in the rat at maternal systemic exposures lower than those in humans attherapeutic doses (see section 5.3). There are no data from the use of olaparib in pregnant women,however, based on the mode of action of olaparib, Lynparza should not be used during pregnancy andin women of childbearing potential not using reliable contraception during therapy and for 6 monthsafter receiving the last dose of Lynparza. (See previous paragraph: “Women of childbearingpotential/contraception in females” for further information about birth control and pregnancy testing.)

There are no animal studies on the excretion of olaparib in breast milk. It is unknown whether olaparibor its metabolites are excreted in human milk. Lynparza is contraindicated during breast-feeding andfor 1 month after receiving the last dose, given the pharmacologic property of the product (seesection 4.3).

There are no clinical data on fertility. In animal studies, no effect on conception was observed butthere are adverse effects on embryofoetal survival (see section 5.3).

Lynparza has moderate influence on the ability to drive and use machines. Patients who take Lynparzamay experience fatigue, asthenia or dizziness. Patients who experience these symptoms shouldobserve caution when driving or using machines.

Lynparza has been associated with adverse reactions generally of mild or moderate severity (CTCAEgrade 1 or 2) and generally not requiring treatment discontinuation. The most frequently observedadverse reactions across clinical trials in patients receiving Lynparza monotherapy (≥10%) werenausea, fatigue/asthenia, anaemia, vomiting, diarrhoea, decreased appetite, headache, neutropenia,dysgeusia, cough, leukopenia, dizziness, dyspnoea and dyspepsia.

The Grade ≥3 adverse reactions occurring in > 2% of patients were anaemia (14%), neutropenia (5%),fatigue/asthenia (4%), leukopenia (2%) and thrombocytopenia (2%).

Adverse reactions that most commonly led to dose interruptions and/ or reductions in monotherapywere anaemia (16%), nausea (7%), fatigue/asthenia (6%), neutropenia (6%) and vomiting (6%).

Adverse reactions that most commonly led to permanent discontinuation were anaemia (1.7%), nausea(0.9%), fatigue/asthenia (0.8%), thrombocytopenia (0.7%), neutropenia (0.6%) and vomiting (0.5%).

When Lynparza is used in combination with bevacizumab for ovarian cancer, in combination withabiraterone and prednisone or prednisolone for prostate cancer, or in combination with durvalumabfollowing treatment with durvalumab in combination with platinum-based chemotherapy forendometrial cancer, the safety profile is generally consistent with that of the individual therapies.

When used in combination with bevacizumab, adverse events led to dose interruption and/ orreduction of olaparib in 57% of patients and led to permanent discontinuation of treatment witholaparib and placebo in 21% and 6% of patients, respectively. The adverse reactions that mostcommonly led to dose interruption and/or reduction of olaparib were anaemia (21.7%), nausea (9.5%),fatigue/asthenia (5.4%), vomiting (3.7%), neutropenia (3.6%), thrombocytopenia (3.0%) and diarrhoea(2.6%). The adverse reactions that most commonly led to permanent discontinuation were anaemia(3.7%), nausea (3.6%) and fatigue/asthenia (1.5%).

When used in combination with abiraterone, adverse events led to dose interruption and/or reductionof olaparib in 50.7% of patients and led to permanent discontinuation of treatment with olaparib andplacebo in 19.0% and 8.8% of patients, respectively. The adverse reactions that most commonly led todose interruption and/or reduction of olaparib were anaemia (17.1%), fatigue/asthenia (5.5%), nausea(4.1%), neutropenia (3.4%), vomiting (2.3%), diarrhoea (2.1%) and venous thrombotic events (2.1%).

The adverse reactions that most commonly led to permanent discontinuation were anaemia (4.5%) andfatigue/asthenia (1.3%).

When used in combination with durvalumab following treatment with durvalumab in combinationwith platinum-based chemotherapy, adverse events led to dose interruption and/or reduction ofolaparib in 59.9% of patients and led to permanent discontinuation of treatment with olaparib in 10.9%of patients. The adverse reactions that most commonly led to dose interruption and/or reduction ofolaparib were anaemia (20.8%), nausea (8.3%), neutropenia (7.3%), fatigue/asthenia (5.7%),thrombocytopenia (4.2%), vomiting (4.2%), blood creatinine increased (3.1%), leukopenia (3.1%), anddecreased appetitive (2.6%), diarrhoea (2.1%). The adverse reactions that most commonly led topermanent discontinuation of olaparib were anaemia (3.6%) and neutropenia (1%).

The safety profile is based on pooled data from 4499 patients with solid tumours treated with

Lynparza monotherapy in clinical trials at the recommended dose.

The following adverse reactions have been identified in clinical trials with patients receiving Lynparzamonotherapy where patient exposure is known. Adverse drug reactions are listed by MedDRA System

Organ Class (SOC) and then by MedDRA preferred term in Table 1. Within each SOC, preferredterms are arranged by decreasing frequency and then by decreasing seriousness. Frequencies ofoccurrence of adverse reactions are defined as: very common (≥1/10); common (1/100 to <1/10);uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000); not known(cannot be estimated from available data).

Table 1 Tabulated list of adverse reactions

Adverse reactions

MedDRA Frequency of All CTCAE grades Frequency of CTCAE grade 3

System Organ and above

Class

Neoplasms Uncommon Uncommonbenign, Myelodysplastic syndrome/ Acute myeloid Myelodysplastic syndrome/malignant and leukaemiaa Acute myeloid leukaemiaunspecified(including cystsand polyps)

Blood and Very common Very commonlymphatic Anaemiaa, Neutropeniaa, Leukopeniaa Anaemiaasystem Common Commondisordersb Lymphopeniaa, Thrombocytopeniaa Neutropeniaa,

Thrombocytopeniaa,

Leukopeniaa, Lymphopeniaa

Immune system Uncommon Raredisorders Hypersensitivitya Hypersensitivitya

Rare

Angioedema*

Hepatobiliary Commondisorders Transaminases increaseda

Not known

Drug-induced liver injury*

Metabolism and Very common Uncommonnutrition Decreased appetite Decreased appetitedisorders

Nervous system Very common Uncommondisorders Dizziness, Headache, Dysgeusiaa Dizziness, Headache

Respiratory, Very common Commonthoracic and Cougha, Dyspnoeaa Dyspnoeaamediastinal

Uncommondisorders

Cougha

Gastrointestinal Very common Commondisorders Vomiting, Diarrhoea, Nausea, Dyspepsia Vomiting, Nausea

Common Uncommon

Stomatitisa, Upper abdominal pain Stomatitisa, Diarrhoea

Rare

Dyspepsia, Upper abdominalpain

Adverse reactions

MedDRA Frequency of All CTCAE grades Frequency of CTCAE grade 3

System Organ and above

Class

Skin and Common Uncommonsubcutaneous Rasha

Rashatissue disorders Uncommon Rare

Dermatitisa Dermatitisa

Rare

Erythema nodosum

General Very common Commondisorders and Fatigue (including asthenia) Fatigue (including asthenia)administrationsite conditions

Investigationsb Common Rare

Blood creatinine increased Blood creatinine increased

Uncommon

Mean cell volume increased

Vascular Common Commondisorders Venous thromboembolisma Venous thromboembolismaa MDS/AML includes preferred terms (PTs) of acute myeloid leukaemia, myelodysplastic syndrome andmyeloid leukaemia.

Anaemia includes PTs of anaemia, anaemia macrocytic, erythropenia, haematocrit decreased,haemoglobin decreased, normocytic anaemia and red blood cell count decreased.

Neutropenia includes PTs of febrile neutropenia, neutropenia, neutropenic infection, neutropenic sepsisand neutrophil count decreased.

Thrombocytopenia includes PTs of platelet count decreased and thrombocytopenia.

Leukopenia includes PTs of leukopenia and white blood cell count decreased.

Lymphopenia includes PTs of lymphocyte count decreased and lymphopenia.

Hypersensitivity includes PTs of drug hypersensitivity and hypersensitivity.

Transaminases increased includes PTs of alanine aminotransferase increased, aspartate aminotransferaseincreased, hepatic enzyme increased, and hypertransaminasaemia

Dysgeusia includes PTs of dysgeusia and taste disorder.

Cough includes PTs of cough and productive cough.

Dyspnoea includes PTs of dyspnoea and dyspnoea exertional.

Stomatitis includes PTs of aphthous ulcer, mouth ulceration and stomatitis.

Rash includes PTs of erythema, exfoliative rash, rash, rash erythematous, rash macular, rashmaculo-papular, rash papular and rash pruritic.

Dermatitis includes PTs of dermatitis and dermatitis allergic.

Venous thromboembolism includes PTs of embolism, pulmonary embolism, thrombosis, deep veinthrombosis, vena cava thrombosis and venous thrombosis.

b Registered laboratory data are presented below under Haematological toxicity and Other laboratoryfindings.

* As observed in the post-marketing setting.

For patients receiving Lynparza in combination with durvalumab following treatment withdurvalumab in combination with platinum-based chemotherapy, most adverse reactions occurred at thesame or lower frequency (all grades and CTCAE Grade ≥ 3 AEs) as those shown in the tabulated listof adverse reactions for Lynparza monotherapy above. Adverse reactions reported at a higherfrequency in patients receiving Lynparza in combination with durvalumab were thrombocytopenia andrash (Very Common) and hypersensitivity (Common). The following additional adverse reaction wasalso identified:

Table 2 Additional adverse drug reaction reported in a clinical trial with Lynparza incombination with durvalumab

MedDRA SOC MedDRA Term CIOMS descriptor/ Frequency of CTCAE

Overall Frequency grade 3 and above(All CTCAE grades)

Blood and Pure red cell aplasia Common Commonlymphatic systemdisorders

Anaemia and other haematological toxicities were generally low grade (CTCAE grade 1 or 2),however, there were reports of CTCAE grade 3 and higher events. Anaemia was the most common

CTCAE grade ≥3 adverse reaction reported in clinical studies. Median time to first onset of anaemiawas approximately 4 weeks (approximately 7 weeks for CTCAE grade ≥3 events). Anaemia wasmanaged with dose interruptions and dose reductions (see section 4.2), and where appropriate withblood transfusions. In clinical studies with the tablet formulation, the incidence of anaemia adversereactions was 35.2% (CTCAE grade ≥3 14.8%) and the incidences of dose interruptions, reductionsand discontinuations for anaemia were 16.4%, 11.1% and 2.1%, respectively; 15.6% of patientstreated with olaparib needed one or more blood transfusions. An exposure-response relationshipbetween olaparib and decreases in haemoglobin has been demonstrated. In clinical studies with

Lynparza the incidence of CTCAE grade ≥ 2 shifts (decreases) from baseline in haemoglobin was21%, 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

ULN was approximately 51%. Levels appeared to return to normal after treatment discontinuation anddid not appear to have any clinical consequences.

Baseline testing, followed by monthly monitoring of complete blood counts is recommended for thefirst 12 months of treatment and periodically after this time to monitor for clinically significantchanges in any parameter during treatment which may require dose interruption or reduction and/orfurther treatment (see sections 4.2 and 4.4)..

Myelodysplastic syndrome/Acute myeloid leukaemia

MDS/AML are serious adverse reactions that occurred uncommonly in monotherapy clinical studies atthe therapeutic dose, across all indications (0.9%). The incidence was 0.5% including events reportedduring the long term safety follow up (rate calculated based on overall safety population of 18576patients exposed to at least one dose of oral olaparib in clinical studies). All patients had potentialcontributing factors for the development of MDS/AML, having received previous chemotherapy withplatinum agents. Many had also received other DNA damaging agents and radiotherapy. The majorityof reports were in germline breast cancer susceptibility gene 1 or 2 (gBRCA1/2) mutation carriers. Theincidence of MDS/AML cases was similar among gBRCA1m and gBRCA2m patients (1.6% and 1.2%,respectively). Some of the patients had a history of previous cancer or of bone marrow dysplasia.

In patients with BRCAm platinum-sensitive relapsed ovarian cancer who had received at least twoprior lines of platinum chemotherapy and received study treatment until disease progression (SOLO2study, with olaparib treatment ≥2 years in 45% of patients), the incidence of MDS/AML was 8% inpatients receiving olaparib and 4% in patients receiving placebo at a follow-up of 5 years. In theolaparib arm, 9 out of 16 MDS/AML cases occurred after discontinuation of olaparib during thesurvival follow-up. The incidence of MDS/AML was observed in the context of extended overallsurvival in the olaparib arm and late onset of MDS/AML. The risk of MDS/AML remains low in thefirst-line setting when olaparib maintenance treatment is given after one line of platinumchemotherapy for a duration of 2 years (1.5%) in SOLO1 study at 7 year follow up and 1.1% in

PAOLA-1 study at 5 year follow up. For risk mitigation and management (see section 4.4).

Pure Red Cell Aplasia

Pure Red Cell Aplasia (PRCA) has been reported when Lynparza has been used in combination withdurvalumab. In a clinical study of patients with endometrial cancer treated with Lynparza incombination with durvalumab, the incidence of PRCA was 1.6%. All events were CTCAE Grade 3 or4. Events were manageable following discontinuation of both Lynparza and durvalumab. The majorityof events were managed with blood transfusion and immunosuppression and recovered; there were nofatal events. For risk mitigation and management see section 4.4.

Venous Thromboembolic Events

In men who received olaparib plus abiraterone as first line therapy for mCRPC (PROpel study), theincidence of venous thromboembolic events was 8% in the olaparib plus abiraterone arm, and 3.3% inthe placebo plus abiraterone arm. The median time to onset in this study was 170 days (range: 12 to906 days). The majority of patients recovered from the event and were able to continue olaparib withstandard medical treatment.

Patients with significant cardiovascular disease were excluded. Please refer to the product informationfor abiraterone for cardiovascular exclusion criteria (section 4.4).

Other laboratory findings

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

Gastrointestinal toxicities

Nausea was generally reported very early, with first onset within the first month of Lynparza treatmentin 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 beintermittent for the majority of patients and can be managed by dose interruption, dose reductionand/or antiemetic therapy. Antiemetic prophylaxis is not required.

In first-line ovarian cancer maintenance treatment, patients experienced nausea events (77% onolaparib, 38% on placebo), vomiting (40% on olaparib, 15% on placebo), diarrhoea (34% on olaparib,25% on placebo) and dyspepsia (17% on olaparib, 12% on placebo). Nausea events led todiscontinuation in 2.3% of olaparib-treated patients (CTCAE Grade 2) and 0.8% of placebo-treatedpatients (CTCAE Grade 1); 0.8% and 0.4% of olaparib-treated patients discontinued treatment due tolow grade (CTCAE Grade 2) vomiting and dyspepsia, respectively. No olaparib or placebo-treatedpatients discontinued due to diarrhoea. No placebo-treated patients discontinued due to vomiting ordyspepsia. Nausea events led to dose interruption and dose reductions in 14% and 4%, respectively, ofolaparib-treated patients. Vomiting events led to interruption in 10% of olaparib-treated patients; noolaparib-treated patients experienced a vomiting event leading to dose reduction.

No studies have been conducted in paediatric patients.

Limited safety data are available in non-Caucasian patients.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There is limited experience of overdose with olaparib. No unexpected adverse reactions were reportedin a small number of patients who took a daily dose of up to 900 mg of olaparib tablets over two days.

Symptoms of overdose are not established and there is no specific treatment in the event of Lynparzaoverdose. In the event of an overdose, physicians should follow general supportive measures andshould treat the patient symptomatically.

Pharmacotherapeutic group: Other antineoplastic agents, ATC code: L01XK01

Mechanism of action and pharmacodynamic effects

Olaparib is a potent inhibitor of human poly (ADP-ribose) polymerase enzymes (PARP-1, PARP-2,and PARP-3), and has been shown to inhibit the growth of selected tumour cell lines in vitro andtumour growth in vivo either as a standalone treatment or in combination with establishedchemotherapies or new hormonal agents (NHA).

PARPs are required for the efficient repair of DNA single strand breaks and an important aspect of

PARP-induced repair requires that after chromatin modification, PARP auto-modifies itself anddissociates from the DNA to facilitate access for base excision repair (BER) enzymes. When olaparibis bound to the active site of DNA-associated PARP it prevents the dissociation of PARP and traps iton the DNA, thus blocking repair. In replicating cells this also leads to the formation of DNAdouble-strand breaks (DSBs) when replication forks meet the PARP-DNA adducts. In normal cells,homologous recombination repair (HRR) pathway is effective at repairing these DNA DSBs. In cancercells lacking critical functional components for efficient HRR such as BRCA1 or 2, DNA DSBscannot be repaired accurately or effectively, leading to substantial homologous recombinationdeficiency (HRD). Instead, alternative and error-prone pathways are activated, such as the classicalnon-homologous end joining (NHEJ) pathway, leading to a high degree of genomic instability. After anumber of rounds of replication, genomic instability can reach insupportable levels and result incancer cell death, as cancer cells already have a high DNA damage load relative to normal cells. HRRpathway may be compromised by other mechanisms, although the causative aberrancy and penetranceare not fully elucidated. Absence of fully functional HRR pathway is one of the key determinants ofplatinum sensitivity in ovarian and possibly other cancers.

In BRCA1/2-deficient in vivo models, olaparib given after platinum treatment resulted in a delay intumour progression and an increase in overall survival compared to platinum treatment alone thatcorrelated with the period of olaparib maintenance treatment.

Combined anti-tumour effect with NHAs

Pre-clinical studies in prostate cancer models reported a combined anti-tumour effect when PARPinhibitors and next-generation hormonal agents are administered together. PARP is involved inpositive co-regulation of androgen receptor (AR) signalling, which leads to enhanced AR target genesuppression when PARP/AR signalling is co-inhibited. Other pre-clinical studies reported thattreatment with NHAs inhibit the transcription of some HRR genes, therefore, inducing HRRdeficiency and increased sensitivity to PARP inhibitors via non-genetic mechanisms.

Detection of BRCA1/2 mutations

Genetic testing should be conducted by an experienced laboratory using a validated test. Local orcentral testing of blood and/or tumour samples for germline and/or somatic BRCA1/2 mutations havebeen used in different studies. DNA obtained from a tissue or blood sample has been tested in most ofthe studies, with testing of ctDNA being used for exploratory purposes. Depending on the test usedand the international classification consensus, the BRCA1/2 mutations have been classified asdeleterious/suspected deleterious or pathogenic/likely pathogenic. Homologous recombinationdeficiency (HRD) positive status can be defined by detection of a BRCA1/2 mutation classified asdeleterious/suspected deleterious or pathogenic/likely pathogenic. Detection of these mutations couldbe combined with positive HRD score (below) to determine HRD positive status.

Detection of genomic instability

HR deficiency-associated genomic alterations that have been investigated in Paola-1 include genome-wide loss of heterozygosity, telomeric allelic imbalance and large-scale transition, which arecontinuous measures with pre-defined criteria and score. Composite genomic instability score (GIS,also called HRD score) is determined when the combined measures and respective scores are used toassess the extent of specific genomic aberrations accumulated in tumour cells. Lower score defineslower likelihood of HR deficiency of tumour cells and higher score determines higher likelihood of

HR deficiency of tumour cells at the time of the sample collection relative to exposure to DNAdamaging agents. Validated cut-offs should be used to determine GIS positive status.

HRD positive status can be defined by a composite GIS score for HR deficiency-associated genomicalterations tested by an experienced laboratory using a validated test.

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

SOLO1 Study

The safety and efficacy of olaparib as maintenance therapy were studied in patients with newlydiagnosed advanced (FIGO Stage III-IV) high-grade serous or endometrioid BRCA1/2 mutated(BRCA1/2m) ovarian cancer following completion of first-line platinum-based chemotherapy in a

Phase III randomised, double-blind, placebo-controlled, multicentre trial. In this study 391 patientswere randomised 2:1 to receive either Lynparza (300 mg [2 x 150 mg tablets] twice daily) or placebo.

Patients were stratified by response to first-line platinum chemotherapy; complete response (CR) orpartial response (PR). Treatment was continued until radiological progression of the underlyingdisease, unacceptable toxicity or for up to 2 years. For patients who remained in complete clinicalresponse (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 diseaseprogression) could continue to receive Lynparza beyond 2 years.

Patients with germline or somatic BRCA1/2 mutations were identified prospectively either fromgermline testing in blood via a local test (n=208) or central test (n=181) or from testing a tumoursample using a local test (n=2). By central germline testing, deleterious or suspected deleteriousmutations were identified in 95.3% (365/383) and 4.7% (18/383) of patients, respectively. Largerearrangements in the BRCA1/2 genes were detected in 5.5% (21/383) of the randomised patients. ThegBRCAm status of patients enrolled via local testing was confirmed retrospectively by central testing.

Retrospective testing of patients with available tumour samples was performed using central testingand generated successful results in 341 patients, of which 95% had an eligible mutation (known[n=47] or likely pathogenic [n=277]) and 2 gBRCAwt patients were confirmed to have sBRCAm only.

There were 389 patients who were germline BRCA1/2m and 2 who were somatic BRCA1/2m in

SOLO1.

Demographic and baseline characteristics were generally well balanced between the olaparib andplacebo treatment arms. Median age was 53 years in both arms. Ovarian cancer was the primarytumour in 85% of the patients. The most common histological type was serous (96%), endometrioidhistology was reported in 2% of the patients. Most patients were ECOG performance status 0 (78%),there are no data in patients with performance status 2 to 4. Sixty-three percent (63%) of the patientshad upfront debulking surgery and of these the majority (75%) had no macroscopic residual disease.

Interval debulking surgery was performed in 35% of the patients and of these 82% had nomacroscopic residual disease reported. Seven patients, all stage IV, had no cytoreductive surgery. Allpatients had received first-line platinum-based therapy. There was no evidence of disease at studyentry (CR), defined by the investigator as no radiological evidence of disease and cancer antigen 125(CA-125) within normal range, in 73% and 77% of patients in the olaparib and placebo arms,respectively. PR, defined as the presence of any measurable or non-measurable lesions at baseline orelevated CA-125, was reported in 27% and 23% of patients in the olaparib and placebo arms,respectively. Ninety three percent (93%) of patients were randomised within 8 weeks of their last doseof platinum-based chemotherapy. Patients who had been treated with bevacizumab were excludedfrom the study, therefore there are no safety and efficacy data on olaparib patients who had previouslyreceived bevacizumab. There are very limited data in patients with a somatic BRCA mutation.

The primary endpoint was progression-free survival (PFS) defined as time from randomisation toprogression determined by investigator assessment using modified Response Evaluation Criteria in

Solid Tumors (RECIST) 1.1, or death. Secondary efficacy endpoints included time fromrandomisation to second progression or death (PFS2), overall survival (OS), time from randomisationto discontinuation of treatment or death (TDT), time from randomisation to first subsequent anti-cancer therapy or death (TFST) and health related quality of life (HRQoL). Patients had tumourassessments at baseline and every 12 weeks for 3 years, and then every 24 weeks relative to date ofrandomisation, until objective radiological disease progression.

The study demonstrated a clinically relevant and statistically significant improvement in investigatorassessed PFS for olaparib compared to placebo. The investigator assessment of PFS was supportedwith a blinded independent central radiological (BICR) review of PFS. A descriptive analysisperformed at seven years after the last patient was randomized demonstrated a clinically meaningfulbenefit in OS that numerically favoured the olaparib arm. Efficacy results are presented in Table 3 and

Figures 1 and 2.

Table 3 Efficacy results for newly diagnosed patients with BRCA1/2m advanced ovariancancer in SOLO1

Olaparib 300 mg bd Placeboc

PFS (51% maturity)a

Number of events: Total number of patients (%) 102:260 (39) 96:131 (73)

Median time (months) NR 13.8

HR (95% CI)b 0.30 (0.23-0.41)

P value (2-sided) p<0.0001

PFS2 (31% maturity)

Number of events: Total number of patients (%) 69:260 (27) 52:131 (40)

Median time (months) NR 41.9

HR (95% CI) c 0.50 (0.35-0.72)

P value (2-sided) p=0.0002

OS (38% maturity)d

Number of events: Total number of patients (%) 84:260 (32) 65:131 (50)

Median time (months) NR 75.2

HR (95% CI)b 0.55 (0.40-0.76)

TFST (60% maturity)

Number of events: Total number of patients (%) 135:260 (52) 98:131 (75)

Median time (months) 64.0 15.1

HR (95% CI) c 0.37 (0.28-0.48)a Based on Kaplan-Meier estimates, the proportion of patients that were progression free at 24 and 36 months were 74%and 60% for olaparib versus 35% and 27% for placebo; the median follow-up time was 41 months for both the olapariband placebo arms.b A value <1 favours olaparib. The analysis was performed using a Cox proportional hazards modelincluding response to previous platinum chemotherapy (CR or PR) as a covariate.c Of the 97 patients on the placebo arm who received subsequent therapy, 58 (60%) received a PARP inhibitor.d Based on Kaplan-Meier estimates, the proportion of patients that were alive 84 months was 67% for olaparib versus47% for placebo.

bd Twice daily; NR Not reached; CI Confidence interval; PFS Progression-free survival; PFS2 Time to secondprogression or death; OS Overall survival; TFST Time from randomisation to first subsequent anti-cancer therapy or death.

Figure 1 SOLO1: Kaplan-Meier plot of PFS in newly diagnosed patients with BRCA1/2madvanced ovarian cancer (51% maturity - investigator assessment)

Figure 2 SOLO1: Kaplan-Meier plot of OS in newly diagnosed patients with BRCA1/2madvanced ovarian cancer (38% maturity)

Olaparib 300mg twice daily tablet

Placebo twice daily tablet

Time from randomisation (months)

Number of patients at risk:

Olaparib 300mg twice daily tablet

Placebo twice daily tablet

Consistent results were observed in the subgroups of patients by evidence of the disease at study entry.

Patients with CR defined by the investigator had HR 0.34 (95% CI 0.24-0.47); median PFS notreached on olaparib vs 15.3 months on placebo. At 24 and 36 months, respectively, 68% and 45%patients remained in CR in the olaparib arm, and 34% and 22% of patients in the placebo arm. Patientswith PR at study entry had PFS HR 0.31 (95% CI 0.18, 0.52; median PFS 30.9 months on olaparib vs8.4 months on placebo). Patients with PR at study entry either achieved CR (15% in olaparib arm and4% in the placebo arm at 24 months, remained in CR at 36 months) or had further PR/stable disease(43% in olaparib arm and 15% in the placebo arm at 24 months; 17% in olaparib arm and 15% inplacebo arm at 36 months). The proportion of patients who progressed within 6 months of the last doseof platinum-based chemotherapy was 3.5% for olaparib and 8.4% for placebo.

Maintenance treatment of platinum-sensitive relapsed (PSR) ovarian cancer

SOLO2 Study

The safety and efficacy of olaparib as maintenance therapy were studied in a Phase III randomised,double-blind, placebo-controlled trial in patients with germline BRCA1/2-mutated PSR ovarian,fallopian tube or primary peritoneal cancer. The study compared the efficacy of Lynparza maintenancetreatment (300 mg [2 x 150 mg tablets] twice daily) taken until progression with placebo treatment in295 patients with high-grade serous or endometrioid PSR ovarian cancer (2:1 randomisation: 196olaparib and 99 placebo) who were in response (CR or PR) following completion ofplatinum-containing chemotherapy.

Patients who have received two or more platinum-containing regimens and whose disease hadrecurred >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 havereceived prior bevacizumab, except in the regimen immediately prior to randomisation.

All patients had evidence of gBRCA1/2m at baseline. Patients with BRCA1/2 mutations were identifiedeither from germline testing in blood via a local test or by central testing at Myriad or from testing a

Proportion of patients event freetumour sample using a local test. Large rearrangements in the BRCA1/2 genes were detected in 4.7%(14/295) of the randomised patients.

Demographic and baseline characteristics were generally well balanced between the olaparib andplacebo arms. Median age was 56 years in both arms. Ovarian cancer was the primary tumour in>80% of the patients. The most common histological type was serous (>90%), endometrioid histologywas reported in 6% of the patients. In the olaparib arm 55% of the patients had only 2 prior lines oftreatment with 45% receiving 3 or more prior lines of treatment. In the placebo arm 61% of patientshad received only 2 prior lines with 39% receiving 3 or more prior lines of treatment. Most patientswere ECOG performance status 0 (81%), there are no data in patients with performance status 2 to 4.

Platinum-free interval was >12 months in 60% and >6-12 months in 40% of the patients. Response toprior platinum chemotherapy was complete in 47% and partial in 53% of the patients. In the olapariband placebo arms, 17% and 20% of patients had prior bevacizumab, respectively.

The primary endpoint was PFS determined by investigator assessment using RECIST 1.1. Secondaryefficacy endpoints included PFS2; OS, TDT, TFST, TSST; and HRQoL.

The study met its primary objective demonstrating a statistically significant improvement ininvestigator assessed PFS for olaparib compared with placebo with a HR of 0.30 (95% CI 0.22-0.41;p<0.0001; median 19.1 months olaparib vs 5.5 months placebo). The investigator assessment of PFSwas supported with a blinded independent central radiological review of PFS (HR 0.25; 95% CI0.18-0.35; p<0.0001; median 30.2 months for olaparib and 5.5 months placebo). At 2 years, 43%olaparib-treated patients remained progression free compared with only 15% placebo-treated patients.

A summary of the primary objective outcome for patients with gBRCA1/2m PSR ovarian cancer in

SOLO2 is presented in Table 4 and Figure 3.

Table 4 Summary of primary objective outcome for patients with gBRCA1/2m PSR ovariancancer in SOLO2

Olaparib 300 mg tablet bd Placebo

PFS (63% maturity)

Number of events: Total number of107:196 (55) 80:99 (81)patients (%)

Median time (months) (95% CI) 19.1 (16.3-25.7) 5.5 (5.2-5.8)

HR (95% CI) a 0.30 (0.22-0.41)

P value (2-sided) p<0.0001a HR= Hazard Ratio. A value <1 favours olaparib. The analysis was performed using a Cox proportional hazard modelincluding response to previous platinum chemotherapy (CR or PR), and time to disease progression (>6-12 monthsand >12 months) in the penultimate platinum-based chemotherapy as covariates.

bd Twice daily; PFS progression-free survival; CI confidence interval

Figure 3 SOLO2: Kaplan-Meier plot of PFS in patients with gBRCA1/2m PSR ovariancancer (63% maturity - investigator assessment)

Time from randomisation (months)

- - - - - - - - - Placebo bd --------------Olaparib 300 mg bd

Number of patients at risk:

196 182 156 134 118 104 89 82 32 29 3 2 0 Olaparib 300 mg bd99 70 37 22 18 17 14 12 7 6 0 0 0 Placebo bdbd Twice daily; PFS Progression free survival

At the final analysis of OS (61% maturity) the HR was 0.74 (95% CI 0.54-1.00; p=0.0537; median51.7 months for olaparib vs 38.8 months for placebo) which did not reach statistical significance. Thesecondary endpoints TFST and PFS2 demonstrated a persistent and statistically significantimprovement for olaparib compared with placebo. Results for OS, TFST and PFS2 are presented in

Table 5 and Figure 4.

Proportion of patients event free

Table 5 Summary of key secondary objective outcomes for patients with gBRCA1/2m PSRovarian cancer in SOLO2

Olaparib 300 mg tablet bd Placebo

OS (61% maturity)

Number of events: Total number of 116:196 (59) 65:99 (66)patients (%)

Median time (95% CI), months 51.7 (41.5, 59.1) 38.8 (31.4, 48.6)

HR (95% CI) a 0.74 (0.54-1.00)

P value (2-sided) p=0.0537

TFST (71% maturity)

Number of events: Total number of 139:196 (71) 86:99 (87)patients (%)

Median time (months) (95% CI) 27.4 (22.6-31.1) 7.2 (6.3-8.5)

HR (95% CI) a 0.37 (0.28-0.48)

P value* (2-sided) p<0.0001

PFS2 (40% maturity)

Number of events: Total number of 70:196 (36) 49:99 (50)patients (%)

Median time (months) (95% CI) NR (24.1-NR) 18.4 (15.4-22.8)

HR (95% CI) a 0.50 (0.34-0.72)

P value (2-sided) p=0.0002

* Not controlled for multiplicity.a HR= Hazard Ratio. A value <1 favours olaparib. The analysis was performed using a Cox proportional hazard modelincluding response to previous platinum chemotherapy (CR or PR), and time to disease progression (>6-12 monthsand >12 months) in the penultimate platinum-based chemotherapy as covariates.

bd Twice daily; NR not reached; CI confidence interval; PFS2 time from randomisation to second progression or death;

TFST Time from randomisation to start of first subsequent therapy or death.

Figure 4 SOLO2: Kaplan-Meier plot of OS in patients with gBRCA1/2m PSR ovariancancer (61% maturity)

Olaparib 300mg twice daily tablet

Placebo twice daily tablet

Time from randomisation (months)

Number of patients at risk:

Olaparib 300mg twice daily tablet

Placebo twice daily tablet

Among the patients entering the trial with measurable disease (target lesions at baseline), an objectiveresponse rate of 41% was achieved in the Lynparza arm versus 17% on placebo. Of patients treatedwith Lynparza, who entered the study with evidence of disease (target or non-target lesions atbaseline), 15.0% experienced complete response compared with 9.1% of patients on placebo.

At the time of the analysis of PFS the median duration of treatment was 19.4 months for olaparib and5.6 months for placebo. The majority of patients remained on the 300 mg bd starting dose of olaparib.

The incidence of dose interruptions, reductions, discontinuations due to an adverse event was 45.1%,25.1% and 10.8%, respectively. Dose interruptions occurred most frequently in the first 3 months anddose reductions in the first 3-6 months of treatment. The most frequent adverse reactions leading todose interruption or dose reduction were anaemia, nausea and vomiting.

Patient-reported outcome (PRO) data indicate no difference for the olaparib-treated patients ascompared to placebo as assessed by the change from baseline in the TOI of the FACT-O.

Study 19 (D0810C00019)

The safety and efficacy of olaparib as a maintenance therapy in the treatment of PSR ovarian,including fallopian tube or primary peritoneal cancer patients, following treatment with two or moreplatinum-containing regimens, were studied in a large Phase II randomised, double-blind,placebo-controlled trial (Study 19). The study compared the efficacy of Lynparza maintenancetreatment taken until progression with placebo treatment in 265 (136 olaparib and 129 placebo) PSRhigh grade serous ovarian cancer patients who were in response (CR or PR) following completion ofplatinum-containing chemotherapy. The primary endpoint was PFS based on investigator assessment

Proportion of patients event freeusing RECIST 1.0. Secondary efficacy endpoints included OS, disease control rate (DCR) defined asconfirmed CR/PR + SD (stable disease), HRQoL and disease related symptoms. Exploratory analysesof TFST and TSST were also performed.

Patients whose disease had recurred >6 months after completion of penultimate platinum-basedchemotherapy were enrolled. Enrolment did not require evidence of BRCA1/2 mutation (BRCAmutation status for some patients was determined retrospectively). Patients could not have receivedprior olaparib or other PARP inhibitor treatment. Patients could have received prior bevacizumab,except in the regimen immediately prior to randomisation. Retreatment with olaparib was notpermitted following progression on olaparib.

Patients with BRCA1/2 mutations were identified either from germline testing in blood via a local testor by central testing at Myriad or from testing a tumour sample using a test performed by Foundation

Medicine. Large rearrangements in the BRCA1/2 genes were detected in 7.4% (10/136) of therandomised patients.

Demographic and baseline characteristics were generally well balanced between the olaparib andplacebo arms. Median age was 59 years in both arms. Ovarian cancer was the primary tumour in 86%of the patients. In the olaparib arm 44% of the patients had only 2 prior lines of treatment with 56%receiving 3 or more prior lines of treatment. In the placebo arm 49% of patients had received only 2prior lines with 51% receiving 3 or more prior lines of treatment. Most patients were ECOGperformance status 0 (77%), there are no data in patients with performance status 2 to 4. Platinum-freeinterval was > 12 months in 60% and 6-12 months in 40% of the patients. Response to prior platinumchemotherapy was complete in 45% and partial in 55% of the patients. In the olaparib and placeboarms, 6% and 5% of patients had prior bevacizumab, respectively.

The study met its primary objective demonstrating a statistically significant improvement in PFS forolaparib compared with placebo in the overall population with a HR of 0.35 (95% CI 0.25-0.49;p<0.00001; median 8.4 months olaparib vs 4.8 months placebo). At the final OS analysis (data cut off[DCO] 9 May 2016) at 79% maturity, the hazard ratio comparing olaparib with placebo was 0.73(95% CI 0.55-0.95; p=0.02138 [did not meet pre-specified significance level of <0.0095]; median29.8 months olaparib versus 27.8 months placebo). In the olaparib-treated group, 23.5% (n=32/136) ofpatients remained on treatment for ≥2 years as compared with 3.9% (n=5/128) of the patients onplacebo. Although patient numbers were limited, 13.2% (n=18/136) of the patients in theolaparib-treated group remained on treatment for ≥5 years as compared with 0.8% (n=1/128) in theplacebo group.

Preplanned subgroup analysis identified patients with BRCA1/2-mutated ovarian cancer (n=136,51.3%; including 20 patients identified with a somatic tumour BRCA1/2 mutation) as the subgroupthat derived the greatest clinical benefit from olaparib maintenance monotherapy. A benefit was alsoobserved in patients with BRCA1/2 wild-type/variants of uncertain significance (BRCA1/2 wt/VUS),although of a lesser magnitude. There was no strategy for multiple testing in place for the sub-groupanalyses.

A summary of the primary objective outcome for patients with BRCA1/2-mutated and BRCA1/2wt/VUS PSR ovarian cancer in Study 19 is presented in Table 6 and for all patients in Study 19 in

Table 6 and Figure 5.

Table 6 Summary of primary objective outcome for all patients and patients with BRCA1/2-mutated and BRCA1/2 wt/VUS PSR ovarian cancer in Study 19

All patientsa BRCA1/2-mutated BRCA1/2 wt/VUS

Olaparib Placebo Olaparib Placebo Olaparib Placebo

PFS - DCO 30 June 2010

Number of 60:136 (44) 94:129 (73) 26:74 (35) 46:62 (74) 32:57 (56) 44:61 (72)events: Totalnumber ofpatients (%)

Median time 8.4 4.8 11.2 4.3 7.4 5.5(months) (95% (7.4-11.5) (4.0-5.5) (8.3-NR) (3.0-5.4) (5.5-10.3) (3.7-5.6)

CI)

HR (95% CI) b 0.35 (0.25-0.49) 0.18 (0.10-0.31) 0.54 (0.34-0.85)

P value p<0.00001 p<0.00001 p=0.00745(2-sided)a All patients comprises of the following subgroups: BRCA1/2-mutated, BRCA1/2 wt/VUS and BRCA1/2 statusunknown (11 patients with status unknown, not shown as a separate subgroup in table).b HR= Hazard Ratio. A value <1 favours olaparib. The analysis was performed using a Cox proportional hazardsmodel with factors for treatment, ethnic descent, platinum sensitivity and response to final platinum therapy.

PFS progression-free survival; DCO data cut off; CI confidence interval; NR not reached.

Figure 5 Study 19: Kaplan-Meier plot of PFS in the FAS (58% maturity - investigatorassessment) DCO 30 June 2010

Time from randomisation (months)

- -------------Placebo - - - - - - - - - Olaparib

Number of patients at risk:

136 106 53 24 7 0 Olaparib129 72 24 7 1 0 Placebo

DCO Data cut-off; FAS Full analysis set; PFS progression-free survival

A summary of key secondary objective outcomes for patients with BRCA1/2-mutated and BRCA1/2wt/VUS PSR ovarian cancer in Study 19 is presented in Table 7 and for all patients in Study 19 in

Table 7 and Figure 6.

Proportion of patients event free

Table 7 Summary of key secondary objective outcomes for all patients and patients with

BRCA1/2-mutated and BRCA1/2 wt/VUS PSR ovarian cancer in Study 19

All patientsa BRCA1/2-mutated BRCA1/2 wt/VUS

Olaparib Placebo Olaparib Placebo Olaparib Placebo

OS - DCO 09 May 2016

Number of 98:136 (72) 112:129 49:74 (66) 50:62 (81) c 45:57 (79) 57:61 (93)events: Total (87)number ofpatients (%)

Median time 29.8 27.8 34.9 30.2 24.5 26.6(months) (26.9-35.7) (24.9-33.7) (29.2-54.6) (23.1-40.7) (19.8-35.0) (23.1-32.5)(95% CI)

HR (95% CI)b 0.73 (0.55-0.95) 0.62 (0.42-0.93) 0.84 (0.57-1.25)

P value* p=0.02138 p=0.02140 p=0.39749(2-sided)

TFST - DCO 09 May 2016

Number of 106:136 124:128 55:74 (74) 59:62 (95) 47:57 (83) 60:61 (98)events: Total (78) (97)number ofpatients (%)

Median time 13.3 6.7 15.6 6.2 12.9 6.9(months) (11.3-15.7) (5.7-8.2) (11.9-28.2) (5.3-9.2) (7.8-15.3) (5.7-9.3)(95% CI)

HR (95% CI)b 0.39 (0.30-0.52) 0.33 (0.22-0.49) 0.45 (0.30-0.66)

P value* p<0.00001 p<0.00001 p=0.00006(2-sided)

* There was no strategy for multiple testing in place for the sub-group analyses or for the all patients TFST.a All patients comprises of the following subgroups: BRCA1/2-mutated, BRCA1/2 wt/VUS and BRCA1/2 status unknown(11 patients with status unknown, not shown as a separate subgroup in table).b HR= Hazard Ratio. A value <1 favours olaparib. The analysis was performed using a Cox proportional hazards modelwith factors for treatment, ethnic descent, platinum sensitivity and response to final platinum therapy.c Approximately a quarter of placebo-treated patients in the BRCA-mutated subgroup (14/62; 22.6%) received asubsequent PARP inhibitor.

OS Overall survival; DCO data cut off; CI confidence interval; TFST time from randomisation to start of first subsequenttherapy or death.

Figure 6 Study 19: Kaplan Meier plot of OS in the FAS (79% maturity) DCO 09 May

Time from randomisation (months)

- -------------Placebo - - - - - - - - - Olaparib

Number of patients at risk:

Olaparib

Placebo

DCO Data cut off; FAS Full analysis set; OS Overall survival

At the time of the analysis of PFS the median duration of treatment was 8 months for olaparib and 4months for placebo. The majority of patients remained on the starting dose of olaparib. The incidenceof dose interruptions, reductions and discontinuations due to an adverse event was 34.6%, 25.7% and5.9%, respectively. Dose interruptions and reductions occurred most frequently in the first 3 months oftreatment. The most frequent adverse reactions leading to dose interruption or dose reduction werenausea, anaemia, vomiting, neutropenia and fatigue. The incidence of anaemia adverse reactions was22.8% (CTCAE grade ≥3 7.4%).

Patient-reported outcome (PRO) data indicate no difference for the olaparib-treated patients ascompared to placebo as measured by improvement and worsening rates in the TOI and FACT-O total.

OPINION Study

OPINION, a Phase IIIb single arm, multicentre study, investigated olaparib as a maintenancetreatment in patients with PSR ovarian, fallopian tube or primary peritoneal cancer following 2 ormore lines of platinum based chemotherapy and who did not have a known deleterious or suspecteddeleterious gBRCA mutation. Patients whose disease was in response (CR or PR) followingcompletion of platinum-based chemotherapy were enrolled. A total of 279 patients were enrolled andreceived olaparib treatment in this study until disease progression or unacceptable toxicity. Based oncentral testing 90.7% were confirmed with a non gBRCAm status, in addition 9.7% were identified assBRCAm.

The primary endpoint was investigator-assessed PFS according to modified RECIST v1.1. Secondaryendpoints included OS.

Olaparib, when used as maintenance therapy, demonstrated clinical activity in patients with non-

Proportion of patients alivegBRCAm PSR ovarian cancer. At the final overall survival analysis (DCO 17 September 2021), the

OS data were 52.3% mature.

A summary of the primary PFS and OS secondary objective outcome for patients with non-gBRCAm

PSR ovarian cancer in OPINION is presented in Table 8.

Table 8 Summary of key objective outcome for non-gBRCAm patients with PSR ovarian cancerin OPINION

Olaparib tablets 300 mg bd

PFS (75% maturity) (DCO 2 October 2020)

Number of events: total number of patients (%) 210: 279 (75.3)

Median PFS (95% CI), monthsa 9.2 (7.6, 10.9)

OS (52.3% maturity) (DCO 17 September 2021)

Number of events: total number of patients (%) 146: 279 (52.3)

Median OS (95% CI), monthsa 32.7 (29.5, 35.3)a Calculated using the Kaplan-Meier technique.

Confidence intervals for median PFS and OS were derived based on Brookmeyer Crowley method.

bd Twice daily; PFS Progression-free survival; OS Overall survival; DCO Data cut off; CI Confidence interval.

First-line maintenance treatment of HRD positive advanced ovarian cancer

PAOLA-1 Study

PAOLA-1 was a Phase III randomised, double-blind, placebo-controlled, multicentre trial thatcompared the efficacy and safety of Lynparza (300 mg [2 x 150 mg tablets] twice daily) incombination with bevacizumab (15 mg/kg of body weight given once every 3 weeks as an intravenousinfusion) versus placebo plus bevacizumab for the maintenance treatment of advanced (FIGO Stage

III-IV) high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer following first-lineplatinum-based chemotherapy and bevacizumab. Treatment with bevacizumab was for a total of up to15 months/22 cycles, including the period given with chemotherapy and given as maintenance.

The study randomised 806 patients (2:1 randomisation: 537 olaparib/bevacizumab: 269placebo/bevacizumab) who had no evidence of disease (NED) due to complete surgical resection, orwho were in complete response (CR), or partial response (PR) following completion of first-lineplatinum-containing chemotherapy and bevacizumab. Patients had completed a minimum of 4 and amaximum of 9 cycles, with the majority (63%) having received 6 cycles of first line platinum-taxanebased chemotherapy, including a minimum of 2 cycles of bevacizumab in combination with the 3 lastcycles of chemotherapy. The median number of bevacizumab cycles prior to randomisation was 5.

Patients were stratified by first-line treatment outcome (timing and outcome of cytoreductive surgeryand response to platinum-based chemotherapy) and tBRCAm status, determined by prospective localtesting. 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 theirlast dose of chemotherapy. Treatment with Lynparza was continued until progression of theunderlying disease, unacceptable toxicity or for up to 2 years. Patients who in the opinion of thetreating physician could derive further benefit from continuous treatment could be treated beyond 2years.

Demographic and baseline characteristics were balanced between both arms in the intent to treat (ITT)population and in the biomarker-defined sub-groups by tBRCAm (prospectively and retrospectivelydefined), GIS and HRD status (defined in this study by a combination of both biomarkers). Themedian age of patients was 61 years overall. Most patients in both arms were ECOG performancestatus 0 (70%). Ovarian cancer was the primary tumour in 86% of the patients. The most commonhistological type was serous (96%) and endometrioid histology was reported in 2% of the patients.

Most patients were diagnosed in FIGO stage IIIC (63%). All patients had received first-line platinum-based therapy and bevacizumab. Patients were not restricted by the surgical outcome with 63% havingcomplete cytoreduction at initial or interval debulking surgery and 37% having residual macroscopicdisease. Thirty percent (30%) of patients in both arms were tBRCAm at screening. Demographic andbaseline characteristics in the biomarker sub-groups were consistent with those in the ITT population.

In the HRD-positive subgroup, 65% of patients had complete cytoreduction and 35% of patients hadresidual macroscopic disease. In the overall patient population enrolled, 30% of patients in both armswere tBRCAm (deleterious/pathogenic mutation) at screening by local testing and for 4% of patientsthe BRCAm status was unknown. Retrospective analysis of available clinical samples was conductedin 97% of patients to confirm tBRCAm status and investigate genomic instability score as describedabove. Among non-tBRCAm patients, 29% (19% of the overall population) had positive GIS pre-defined in this study as composite score ≥42. When tBRCAm status and positive GIS were combined,patients with HRD-positive, HRD-negative and HRD unknown status in their tumours represented48%, 34% and 18% of the overall patient population.

The primary endpoint was progression-free survival (PFS), defined as time from randomisation toprogression determined by investigator assessment using modified Response Evaluation Criteria in

Solid Tumors (RECIST) 1.1, or death. Secondary efficacy endpoints included time from randomisationto second progression or death (PFS2), overall survival (OS), time from randomisation to firstsubsequent anti-cancer therapy or death (TFST) and health related quality of life (HRQoL). Patientshad RECIST 1.1 tumour assessments at baseline and every 24 weeks (CT/MRI at 12 weeks if clinicalor CA 125 progression) for up to 42 months or until objective radiological disease progression.

The study met its primary endpoint in the ITT population demonstrating a statistically significantimprovement in investigator assessed PFS for olaparib/bevacizumab compared toplacebo/bevacizumab (HR 0.59, 95% CI 0.49-0.72, p<0.0001 with a median of 22.1 months forolaparib/bevacizumab vs 16.6 months for placebo/bevacizumab). This was consistent with a BICRanalysis of PFS. However, patients defined as biomarker-positive (tBRCAm, GIS, HRD status positivedefined as tBRCAm and/or GIS positive) derived most of the benefit.

Final analysis of PFS2 (DCO 22 March 2020, 53% maturity) in the overall population was statisticallysignificant (HR 0.78, 95% CI 0.64-0.95, p=0.0125 with a median of 36.5 months for olaparib/bevacizumab vs 32.6 months for placebo/bevacizumab).

At the final analysis of OS (DCO 22 March 2022) in the HRD status positive patients (tBRCAm and/or

GIS), there was a numerical improvement in OS with olaparib/bevacizumab arm vsplacebo/bevacizumab arm (see Table 9).

In the tBRCAm as randomised subgroup (241/806 patients) median PFS for the olaparib/bevacizumabarm was 37.2 months vs 22.0 months for the placebo/bevacizumab arm (HR=0.34, 95% CI 0.23, 0.51).

At the final overall survival analysis (DCO 22 March 2022), the tBRCAm as randomised subgroupdemonstrates a numerical reduction in the risk of death for olaparib/bevacizumab compared toplacebo/bevacizumab (HR 0.63; 95% CI 0.41, 0.97).

Efficacy results in other biomarkers subgroup analyses based on retrospectively analysed tumoursamples are presented in Table 9.

Table 9 Summary of key efficacy findings for patients with homologous recombinationdeficiency (HRD) positive status defined by either tBRCAm and/or GIS inadvanced ovarian cancer patients in PAOLA-1tBRCAm*, c GIS positive (HRD HRD positive*positive excluding(n=235)tBRCAm)*, d (n=387)(n=152)

Olaparib/ Placebo/ Olaparib/ Placebo/ Olaparib/ Placebo/bevacizumab bevacizumab bevacizumabbevacizumab bevacizumab bevacizumab

PFS, investigator assessment (46% maturity) DCO 22 March 2019a

Number ofevents: Total44:158 (28) 52:77 (68) 43:97 (44) 40:55 (73) 87:255 (34) 92:132 (70)number ofpatients (%)

Median time37.2 18.8 28.1 16.6 37.2 17.7(months)

HR (95%) CIb 0.28 (0.19, 0.42) 0.43 (0.28, 0.66) 0.33 (0.25, 0.45)

PFS2, investigator assessment (40% maturity) DCO 22 March 2020

Number ofevents: Totalnumber of 44:158 (28) 37:77 (48) 41:97 (42) 33:55 (60) 85:255 (33) 70:132 (53)patients (%)

Median time NR 42.2 50.3 30.1 50.3 35.4(months)

HR (95%) CIb 0.53 (0.34, 0.82) 0.60 (0.38, 0.96) 0.56 (0.41, 0.77)

Final OS (42% maturity) DCO 22 March 2022

Number ofevents: Total 49:158 44:97 93:25537:77 (48.1) 32:55 (58.2) 69:132 (52.3)number of (31.0) (45.4) (36.5)patients (%)

Median time75.2 66.9 NR 52.0 75.2 57.3(months)

HR (95%) CIb 0.57 (0.37, 0.88) 0.71 (0.45, 1.13) 0.62 (0.45, 0.85)

* Pre-planned subgroupa Based on Kaplan-Meier estimates, the proportion of patients that were progression free at 12 and 24 months were 89% and66% for olaparib/bevacizumab versus 71% and 29% for placebo/bevacizumab.

b A value <1 favours olaparib. The analysis was performed using a Cox proportional hazards model stratified by first linetreatment outcome at screening and screening laboratory tBRCA status.c tBRCAm status by Myriadd HRD positive excluding tBRCAm was defined as Genomic instability score (GIS) by Myriad ≥42 (pre-specified cut-off)

CI Confidence interval; HR Hazard ratio; NR not reached

Figure 7 PAOLA-1: Kaplan-Meier plot of PFS for patients with advanced ovarian cancerdefined as HRD positive in PAOLA-1 (46% maturity - investigator assessment)

Olaparib + bevacizumab

Placebo + bevacizumab

Time from randomisation (months)

Number of patients at risk:

Olaparib + bevacizumab

Placebo + bevacizumab

Proportion of patients event free

Figure 8 PAOLA-1: Kaplan-Meier Plot, Final Overall Survival by HRD Status Positive(including tBRCAm) (DCO 22 March 2022)

Time from randomisation (months)

Olaparib + bevacizumab Placebo + bevacizumab

Number of patients at risk:

Olaparib + bevacizumab

Placebo + bevacizumab

Adjuvant treatment of germline BRCA-mutated high risk early breast cancer

OlympiA

The safety and efficacy of olaparib as adjuvant treatment in patients with germline BRCA1/2 mutationsand HER2-negative high risk early breast cancer who had completed definitive local treatment andneoadjuvant or adjuvant chemotherapy was studied in a Phase III randomised, double-blind, parallelgroup, placebo-controlled, multicentre study (OlympiA). Patients were required to have completed atleast 6 cycles of neoadjuvant or adjuvant chemotherapy containing anthracyclines, taxanes or both.

Prior platinum for previous cancer (e.g. ovarian) or as adjuvant or neoadjuvant treatment for breastcancer was allowed. High risk early breast cancer patients were defined as follows:

* patients who received prior neoadjuvant chemotherapy: patients with either triple negativebreast cancer (TNBC) or hormone receptor positive breast cancer must have had residualinvasive cancer in the breast and/or the resected lymph nodes (non-pathologic completeresponse) at the time of surgery. Additionally, patients with hormone receptor positive breastcancer must have had a CPS&EG score of ≥3 based on pre-treatment clinical andpost-treatment pathologic stage (CPS), estrogen receptor (ER) status and histologic grade asshown in Table 10.

Table 10 Early Breast Cancer Stage, Receptor Status and Grade Scoring Requirementsfor Study Enrolment*

Stage/feature Points

Clinical Stage I/IIA 0(pre-treatment) IIB/IIIA 1

IIIB/IIIC 2

Pathologic Stage 0/I 0(post-treatment) IIA/IIB/IIIA/IIIB 1

IIIC 2

Proportion of patients event free

Stage/feature Points

Receptor status ER positive 0

ER negative 1

Nuclear grade Nuclear grade 1-2 0

Nuclear grade 3 1

* Total score of ≥3 required for patients with hormone receptor positive breast cancer.

* patients who have received prior adjuvant chemotherapy: triple negative breast cancer(TNBC) patients must have had node positive disease or node negative disease with a ≥2 cmprimary tumour; HR positive, HER2-negative patients must have had ≥4 pathologicallyconfirmed positive lymph nodes.

Patients were randomised (1:1) to either olaparib 300 mg (2 x 150 mg tablets) twice daily (n=921) orplacebo (n=915). Randomisation was stratified by hormone receptor status (HR positive/ HER2negative versus TNBC), by prior neoadjuvant versus adjuvant chemotherapy, and by prior platinumuse for current breast cancer (yes versus no). Treatment was continued for up to 1 year, or until diseaserecurrence, or unacceptable toxicity. Patients with HR positive tumours also received endocrinetherapy.

The primary endpoint was invasive disease free survival (IDFS), defined as the time fromrandomisation to date of first recurrence, where recurrence is defined as invasive loco-regional, distantrecurrence, contralateral invasive breast cancer, new cancer or death from any cause. Secondaryobjectives included OS, distant disease free survival (DDFS, defined as the time from randomisationuntil evidence of first distant recurrence of breast cancer), the incidence of new primary contralateralbreast cancers (invasive and non-invasive), new primary ovarian cancer, new primary fallopian tubecancer and new primary peritoneal cancer, and patient reported outcomes (PRO) using the FACIT-

Fatigue and EORTC QLQ-C30 questionnaires.

Central testing at Myriad or local gBRCA testing, if available, was used to establish study eligibility.

Patients enrolled based on local gBRCA test results provided a sample for retrospective confirmatorytesting. Out of 1836 patients enrolled into OlympiA, 1623 were confirmed as gBRCAm by centraltesting, either prospectively or retrospectively.

Demographic and baseline characteristics were well balanced between the two treatment arms. Themedian age was 42 years. Sixty-seven percent (67%) of patients were White, 29% Asian and 2.6%

Black. 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 TNBCand 18% had HR positive disease. Fifty percent (50%) of patients had received prior neoadjuvant and50% received prior adjuvant chemotherapy. Ninety-four percent (94%) of patients receivedanthracycline and taxane. Twenty-six percent (26%) of patients overall had received prior platinum forbreast cancer. In the olaparib and placebo arms, 87% and 92% of patients with HR positive diseasewere receiving concomitant endocrine therapy, respectively. Overall, 89.5% of patients with HRpositive disease received an endocrine therapy, which included letrozole (23.7%), tamoxifen (40.9%),anastrozole (17.2%), or exemestane (14.8%).

The study met its primary endpoint demonstrating a statistically significant improvement in IDFS inthe olaparib arm compared with the placebo arm. Two hundred and eighty-four (284) patients had

IDFS events, this represented 12% of patients in the olaparib arm (distant 8%, local/regional 1.4%,contralateral invasive breast cancer 0.9%, non-breast second primary malignancies 1.2%, death 0.2%)and 20% of patients in the placebo arm (distant 13%, local/regional 2.7%, contralateral invasive breastcancer 1.3%, non-breast second primary malignancies 2.3%, death 0%). A statistically significantimprovement in DDFS in the olaparib arm compared with the placebo arm was also observed. At thenext planned OS analysis, a statistically significant improvement in OS was observed in the olaparibarm compared with the placebo arm. Efficacy results in the FAS are presented in Table 11 and

Figures 9 and 10.

Table 11 Efficacy results for adjuvant treatment of patients with germline BRCA-mutatedearly breast cancer in OlympiA

Olaparib 300 mg bd Placebo(N=921) (N=915)

IDFS (15% maturity) - DCO 27 March 2020

Number of events: Total number of patients (%) 106:921 (12) 178:915 (20)

HR (99.5% CI)a 0.58 (0.41, 0.82)

P value (2-sided)b 0.0000073

Percentage (95% CI) of patients invasive diseasec 86 (83, 88) 77 (74, 80)free at 3 years

DDFS (13% maturity) - DCO 27 March 2020

Number of events: Total number of patients (%) 89:921 (10) 152:915 (17)

HR (99.5% CI)a 0.57 (0.39, 0.83)

P value (2-sided)b 0.0000257

Percentage (95% CI) of patients distant diseasec 88 (85, 90) 80 (77, 83)free at 3 years

OS (10% maturity) - DCO 12 July 2021

Number of events: Total number of patients (%) 75:921 (8) 109:915 (12)

HR (98.5% CI)a 0.68 (0.47, 0.97)

P value (2-sided)b 0.0091

Percentage (95% CI) of patients alive at 3 yearsc 93 (91, 94) 89 (87, 91)

Percentage (95% CI) of patients alive at 4 yearsc 90 (87, 92) 86 (84, 89)a Based on the stratified Cox's proportional hazards model, <1 indicates a lower risk with olaparib compared with placeboarm.b P-value from a stratified log-rank test.c Percentages are calculated using KM estimates.

bd = twice daily; CI = confidence interval; DDFS = distant disease free survival; IDFS = invasive disease free survival; KM= Kaplan-Meier; OS = overall survival.

Figure 9 Kaplan-Meier plot of IDFS for adjuvant treatment of patients with germline

BRCA-mutated high risk early breast cancer in OlympiA

Olaparib

Placebo

Months since randomisation

Number of patients at risk:randomisation (months)

Olaparib 300 mg bd

Placebo

Figure 10 Kaplan-Meier plot of OS for adjuvant treatment of patients with germline

BRCA-mutated high risk early breast cancer in OlympiA

Olaparib

Placebo

Months since randomisation

Number of patients at risk:

randomisation (months)

Olaparib 300 mg bd

Placebo

Percentage of patients alive Percentage of patients alive and invasive disease freegBRCA1/2-mutated HER2-negative metastatic breast cancer

OlympiAD (Study D0819C00003)

The safety and efficacy of olaparib in patients with gBRCA1/2-mutations who had HER2-negativemetastatic breast cancer were studied in a Phase III randomised, open-label, controlled trial(OlympiAD). In this study 302 patients with a documented deleterious or suspected deleteriousgBRCA mutation were randomised 2:1 to receive either Lynparza (300 mg [2 x 150 mg tablets] twicedaily) or physician’s choice of chemotherapy (capecitabine 42%, eribulin 35%, or vinorelbine 17%)until progression or unacceptable toxicity. Patients with BRCA1/2 mutations were identified fromgermline testing in blood via a local test or by central testing at Myriad. Patients were stratified basedon: receipt of prior chemotherapy regimens for metastatic breast cancer (yes/no), hormone receptor(HR) positive vs triple negative (TNBC), prior platinum treatment for breast cancer (yes/no). Theprimary 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.

Patients must have received treatment with an anthracycline unless contraindicated and a taxane ineither a (neo)adjuvant or metastatic setting. Patients with HR+ (ER and/or PgR positive) tumours musthave received and progressed on at least one endocrine therapy (adjuvant or metastatic) or had diseasethat the treating physician believed to be inappropriate for endocrine therapy. Prior therapy withplatinum was allowed in the metastatic setting provided there had been no evidence of diseaseprogression during platinum treatment and in the (neo)adjuvant setting provided the last dose wasreceived at least 12 months prior to randomisation. No previous treatment with a PARP inhibitor,including olaparib, was permitted.

Demographic and baseline characteristics were generally well balanced between the olaparib andcomparator arms (see Table 12).

Table 12 Patient demographic and baseline characteristics in OlympiAD

Olaparib 300 mg bd Chemotherapyn=205 n=97

Age - year (median) 44 45

Gender (%)

Female 200 (98) 95 (98)

Male 5 (2) 2 (2)

Race (%)

White 134 (65) 63 (65)

Asian 66 (32) 28 (29)

Other 5 (2) 6 (6)

ECOG performance status (%)0 148 (72) 62 (64)1 57 (28) 35 (36)

Overall disease classification

Metastatic 205 (100) 97 (100)

Locally advanced 0 0

New metastatic breast cancer (%) 26 (13) 12 (12)

Hormone receptor status (%)

HR+ 103 (50) 49 (51)

TNBC 102 (50) 48 (49)gBRCA mutation type (%)gBRCA1 117 (57) 51 (53)gBRCA2 84 (41) 46 (47)gBRCA1 and gBRCA2 4 (2) 0≥2 Metastatic sites (%) 159 (78) 72 (74)

Location of the metastasis (%)

Bone only 16 (8) 6 (6)

Other 189 (92) 91 (94)

Measurable disease by BICR (%) 167 (81) 66 (68)

Progressive disease at time of 159 (78) 73 (75)randomization (%)

Tumour grade at diagnosis

Well differentiated (G1) 5 (2) 2 (2)

Moderately differentiated (G2) 52 (25) 23 (24)

Poorly differentiated (G3) 108 (53) 55 (57)

Undifferentiated (G4) 4 (2) 0

Unassessable (GX) 27 (13) 15 (16)

Missing 9 (4) 2 (2)

Number of prior lines of chemotherapy for metastatic breast cancer (%)0 68 (33) 31 (32)1 80 (39) 42 (43)2 57 (28) 24 (25)

Previous platinum-based therapy 55 (27) 21 (22)(%)in (neo)adjuvant setting only 12 (6) 6 (6)metastatic setting only 40 (20) 14 (14)in (neo)adjuvant and metastatic setting 3 (1) 1 (1)

Previous anthracycline treatmentin (neo) adjuvant setting 169 (82) 76 (78)metastatic setting 41 (20) 16 (17)

Previous taxane treatmentin (neo)adjuvant setting 146 (71) 66 (68)metastatic setting 107 (52) 41 (42)

Previous anthracycline and taxane 204 (99.5) 96 (99)treatment

As subsequent therapy, 0.5% and 8% of patients received a PARP inhibitor in the treatment andcomparator arms, respectively; 29% and 42% of patients, respectively, received subsequent platinumtherapy.

A statistically significant improvement in PFS, the primary efficacy outcome, was demonstrated forolaparib-treated patients compared with those in the comparator arm (see Table 13 and Figure 11).

Table 13 Summary of key efficacy findings for patients with gBRCA1/2-mutated HER2-negative metastatic breast cancer in OlympiAD

Olaparib 300 mg bd Chemotherapy

PFS (77% maturity) - DCO 09 December 2016

Number of events: Total number of163:205 (80) 71:97 (73)patients (%)

Median time (months) (95% CI) 7.0 (5.7-8.3) 4.2 (2.8-4.3)

HR (95% CI) 0.58 (0.43-0.80)

P value (2-sided)a p=0.0009

PFS2 (65% maturity) - DCO 25 September 2017b

Number of events: Total number of 130:205 (63) 65:97 (67)patients (%)

Median time (months) (95% CI) 12.8 (10.9-14.3) 9.4 (7.4-10.3)

HR (95% CI) 0.55 (0.39-0.77)

P value (2-sided)a p=0.0005

OS (64% maturity) - DCO 25 September 2017

Number of events: Total number of 130:205 (63) 62:97 (64)patients (%)

Median time (months) (95% CI) 19.3 (17.2-21.6)c 17.1 (13.9-21.9)

HR (95% CI) 0.90 (0.66-1.23)

P value (2-sided)a p=0.5131

Confirmed ORR - DCO 09 December 2016

Number of objective responders: Total 87: 167 (52)d 15:66 (23)number of patients with measurabledisease (%)95% CI 44.2-59.9 13.3-35.7

DOR - DCO 09 December 2016

Median, months (95% CI) 6.9 (4.2, 10.2) 7.9 (4.5, 12.2)a Based on stratified log-rank test.b Post-hoc analysis.c The median follow-up time in censored patients was 25.3 months for olaparib versus 26.3 months for comparator.d Confirmed responses (by BICR) were defined as a recorded response of either CR/PR, confirmed by repeat imaging notless than 4 weeks after the visit when the response was first observed. In the olaparib arm 8% with measurable diseasehad a complete response versus 1.5% of patients in the comparator arm; 74/167 (44%) of patients in the olaparib armhad a partial response versus 14/66 (21%) of patients in the chemotherapy arm. In the TNBC patient subgroup theconfirmed ORR was 48% (41/86) in the olaparib arm and 12% (4/33) in the comparator arm. In the HR+ patientsubgroup the confirmed ORR was 57% (46/81) in the olaparib arm and 33% (11/33) in the comparator arm.

bd Twice daily; CI Confidence interval; DOR Duration of response; DCO Data cut off; HR Hazard ratio; HR+ Hormonereceptor positive, ORR Objective response rate; OS overall survival; PFS progression-free survival; PFS2 Time tosecond progression or death, TNBC triple negative breast cancer.

Figure 11 OlympiAD: Kaplan-Meier plot of BICR PFS in patients with gBRCA1/2-mutated

HER2-negative metastatic breast cancer (77% maturity) DCO 09 December 2016

Chemotherapy (N = 97)

Olaparib 300 mg twice daily (N = 205)

Time from randomisation (months)

Number of patients at risk

Olaparib 300 mg twice daily tablet

Chemotherapy

Consistent results were observed in all predefined patient subgroups (see Figure 12). Subgroupanalysis indicated PFS benefit of olaparib versus comparator in TNBC (HR 0.43; 95% CI: 0.29-0.63,n=152) and HR+ (HR 0.82; 95% CI: 0.55-1.26, n=150) patient subgroups.

Probability of progression free survival

Figure 12 PFS (BICR), Forest plot, by prespecified subgroup

In a post-hoc analysis of the subgroup of patients that had not progressed on chemotherapy other thanplatinum, the median PFS in the olaparib arm (n=22) was 8.3 months (95% CI 3.1-16.7) and 2.8months (95% CI 1.4-4.2) in the chemotherapy arm (n=16) with a HR of 0.54 (95% CI 0.24-1.23).

However, the number of patients is too limited to make meaningful conclusions on the efficacy in thissubgroup.

Seven male patients were randomised (5 olaparib and 2 comparator). At the time of the PFS analysis,1 patient had a confirmed partial response with a duration of response of 9.7 months in the olaparibarm. There were no confirmed responses in the comparator arm.

Figure 13 OlympiAD: Kaplan-Meier plot of OS in patients with gBRCA1/2-mutated HER2-negative metastatic breast cancer (64% maturity) DCO 25 September 2017

OS analysis in patients with no prior chemotherapy for metastatic breast cancer indicated benefit inthese patients with a HR of 0.45 (95% CI 0.27-0.77), while for further lines of therapy HR exceeded 1.

Maintenance following first-line treatment of germline BRCA-mutated metastatic adenocarcinoma ofthe pancreas:

POLO Study

The safety and efficacy of olaparib as maintenance therapy were studied in a randomised (3:2),double-blind, placebo-controlled, multicentre trial in 154 patients with germline BRCA1/2 mutationswho had metastatic adenocarcinoma of the pancreas. Patients received either Lynparza 300 mg (2 x150 mg tablets) twice daily (n=92) or placebo (n=62) until radiological disease progression orunacceptable toxicity. Patients should have not progressed during first-line platinum-basedchemotherapy and should have received a minimum of 16 weeks of continuous platinum treatment,which could be discontinued at any time thereafter for unacceptable toxicity while the remainingagents continued according to the planned regimen or unacceptable toxicity for other component(s).

Patients who could tolerate complete platinum-containing chemotherapy regimen until progressionhave not been considered for this study. The maintenance therapy was started 4 to 8 weeks after thelast dose of first-line chemotherapy component(s) in the absence of progression and if all toxicitiesfrom previous anti-cancer therapy had been resolved to CTCAE grade 1, except for alopecia, grade 3peripheral neuropathy and Hgb ≥9 g/dL.

Thirty-one percent (31%) of patients with germline BRCA1/2 mutations were identified from priorlocal testing results and 69% of patients by central testing. In the olaparib arm, 32% of patients carrieda germline BRCA1 mutation, 64% a germline BRCA2 mutation and 1% carried both germline BRCA1and germline BRCA2 mutations. In the placebo arm, 26% of patients carried a germline BRCA1mutation, 73% a germline BRCA2 mutation and no patients carried both germline BRCA1 andgermline BRCA2 mutations. The BRCAm status of all patients identified using prior local testingresults was confirmed, where sent, by central testing. Ninety-eight percent (98%) of patients carried adeleterious mutation and 2% carried a suspected deleterious mutation. Large rearrangements in the

BRCA1/2 genes were detected in 5.2 % (8/154) of the randomised patients.

Demographic and baseline characteristics were generally well balanced between the olaparib andplacebo arms. Median age was 57 years in both arms; 30% of patients in the olaparib arm were ≥65years compared to 20% in the placebo arm. Fifty-eight per-cent (58%) of patients in the olaparib armand 50% of patients in the placebo arm were male. In the olaparib arm 89% of patients were Whiteand 11% were non-White; in the placebo arm 95% of patients were White and 5% were non-White.

Most patients were ECOG performance status 0 (71% in the olaparib arm and 61% in the placeboarm). Overall, the sites of metastasis prior to chemotherapy were liver 72%, lung 10% and other sites50%. The median time from original diagnosis to randomisation across both arms was 6.9 months(range 3.6 to 38.4 months).

Overall, 75% of patients received FOLFIRINOX with a median of 9 cycles (range 4-61), 8% received

FOLFOX or XELOX, 4% received GEMOX, and 3% received gemcitabine plus cisplatin; theremaining 10% of patients received other chemotherapy regimens. Duration of the first-linechemotherapy for metastatic disease was 4 to 6 months, >6 to <12 months and ≥12 months,respectively, in 77%, 19% and 4% of patients in the olaparib arm and in 80%, 17% and 3% in theplacebo arm, with around 1 month from the last dose of the first-line chemotherapy component(s) tothe start of study treatment in both arms. As best response on first-line chemotherapy, 7% of olaparibpatients and 5% of placebo patients had a complete response, 44% of olaparib patients and 44% ofplacebo patients had a partial response and 49% of olaparib and 50% of placebo patients had stabledisease. At randomisation, measurable disease was reported in 85% and 84% of patients in theolaparib or placebo arms, respectively. The median time from initiation of the first-line platinum-based chemotherapy to randomisation was 5.7 months (range 3.4 to 33.4 months).

At the time of PFS analysis, 33% of patients in the olaparib arm and 13% on the placebo arm remainedon study treatment. Forty-nine percent of patients (49%) in the olaparib arm and 74% in the placeboarm received subsequent therapy. Forty-two percent (42%) of patients in the olaparib arm and 55% inthe placebo arm received platinum as subsequent therapy. One percent (1%) of patients in the olaparibarm and 15% in the placebo arm received PARP inhibitor as subsequent therapy. Of the 33 (36%) and28 (45%) of patients who received a first subsequent platinum-containing therapy, in the olaparib andplacebo arms, stable disease was reported in 8 vs 6 patients, whereas 1 vs 2 patients had responses,respectively.

The primary endpoint was progression-free survival (PFS), defined as time from randomisation toprogression determined by BICR using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1modified to assess patients with no evidence of disease, or death. Secondary efficacy endpointsincluded overall survival (OS), time from randomisation to second progression or death (PFS2), timefrom randomisation to first subsequent anti-cancer therapy or death (TFST), objective response rate(ORR), duration of response (DoR), response rate, time to response and health related quality of life(HRQoL).

The study demonstrated a statistically significant improvement in PFS for olaparib compared toplacebo (Table 14). The BICR assessment of PFS was consistent with an investigator assessment.

At final analysis of OS, the percentage of patients that were alive and in follow-up was 28% in theolaparib arm and 18% in the placebo arm.

Table 14 Efficacy results for patients with gBRCAm metastatic adenocarcinoma of thepancreas in POLO

Olaparib 300 mg bd Placebo

PFS (68% maturity)a,b (BICR, DCO 15 January 2019)

Number of events: Total number of patients (%) 60:92 (65) 44:62 (71)

Median time, months (95% CI) 7.4 (4.14-11.01) 3.8 (3.52-4.86)

HR (95% CI)c,d 0.53 (0.35-0.82)

P value (2-sided) p=0.0038

OS (70% maturity)e (DCO 21 July 2020)

Number of events: Total number of patients (%) 61:92 (66) 47:62 (76)

Median time (months) (95% CI) 19.0 (15.28-26.32) 19.2 (14.32-26.12)

HR (95% CI)d 0.83 (0.56-1.22)

P value (2-sided) p=0.3487a Based on Kaplan-Meier estimates, the proportion of patients that were alive and progression-free at 12 and 24 monthswere 34% and 22% for olaparib vs 15% and 10% for placebo.b For PFS, the median follow-up time for censored patients was 9.1 months in the olaparib arm and 3.8 months in theplacebo arm.c A value <1 favours olaparib.d The analysis was performed using a log-rank test.e For OS, the median follow-up time for censored patients was 31.3 months in the olaparib arm and 23.9 months in theplacebo arm.

bd Twice daily; CI Confidence interval; HR Hazard Ratio; OS Overall Survival; PFS Progression-free survival.

Figure 14 POLO: Kaplan-Meier plot of PFS for patients with gBRCAm metastaticadenocarcinoma of the pancreas (68% maturity - BICR, DCO 15 January 2019)___ Olaparib 300 mg twice daily tablet_ _ _ Placebo twice daily tablet

Number of patients at risk:

Time from randomisation (months)

Olaparib 300 mg twice daily tablet

Placebo twice daily tablet

Probability of progression-free survival

Figure 15 POLO: Kaplan-Meier plot of OS for patients with gBRCAm metastaticadenocarcinoma of the pancreas (70% maturity, DCO 21 July 2020)

Olaparib 300 mg bid (N=92)

Placebo bid (N=62)

Time from randomisation (months)

Number of patients at risk

Olaparib 300 mg bid

Placebo bid

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

PROfound Study

The safety and efficacy of olaparib were studied in men with metastatic castration-resistant prostatecancer (mCRPC) in a Phase III randomised, open-label, multicentre trial that evaluated the efficacy of

Lynparza versus a comparator arm of investigator’s choice of NHA ([new hormonal agent]enzalutamide or abiraterone acetate).

Patients needed to have progressed on prior NHA for the treatment of metastatic prostate cancerand/or CRPC. For inclusion in Cohort A, patients needed to have deleterious or suspected deleteriousmutations in either BRCA1 or BRCA2 genes. Patients with ATM mutations were also randomised in

Cohort A, but positive benefit-risk could not be demonstrated in this subpopulation of patients.

Patients with mutations in other genes were randomised in Cohort B.

In this study 387 patients were randomised 2:1 to receive either olaparib (300 mg [2 x 150 mg tablets]twice daily) or comparator. In Cohort A there were 245 patients (162 olaparib and 83 comparator) andin Cohort B there were 142 patients (94 olaparib and 48 comparator). Patients were stratified by priortaxane use and evidence of measurable disease. Treatment was continued until disease progression.

Patients randomised to comparator were given the option to switch to olaparib upon confirmedradiological BICR progression. Patients with BRCA1m, BRCA2m detected in their tumours wereenrolled on the basis of prospective central testing, with the exception of 3 patients enrolled using alocal test result. Of the 160 patients with a BRCA1 or BRCA2 mutation in PROfound, 114 patientswere retrospectively tested to determine if the identified BRCA1/2 mutation was germline or somaticin origin. Within these patients, 63 BRCA1/2 mutations were identified in the germline blood sample

Probability of overall survivaland hence were determined to be germline in origin. The remaining 51 patients did not have a tumourdetected BRCA1/2 mutation identified in the germline blood sample and hence the BRCA1/2 mutationsare determined to be somatic in origin. For the remaining 46 patients, somatic or germline origin isunknown.

Demographics and baseline characteristics were generally well balanced between the olaparib andcomparator arms in patients with BRCA1/2 mutations. Median age was 68 years and 67 years in theolaparib 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. Priortherapy 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 armand 55% in the comparator arm had measurable disease at study entry. The proportion of patients withbone, lymph node, respiratory and liver metastases was 89%, 62%, 23% and 12%, respectively in theolaparib arm and 86%, 71%, 16% and 17%, respectively in the comparator arm. Most patients in bothtreatment 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 thecomparator arm. Median baseline PSA was 57.48 µg/L in the olaparib arm and 103.95 µg/L in thecomparator.

The primary endpoint of the study was radiological progression free survival (rPFS) in Cohort Adetermined 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, rPFSby BICR, time to pain progression (TTPP) and overall survival (OS).

The study demonstrated a statistically significant improvement in BICR assessed rPFS and final OSfor olaparib vs comparator in Cohort A.

Results for patients with BRCA1/2 mutations are presented in Table 15. There was a statisticallysignificant improvement in BICR assessed rPFS for olaparib vs the investigators choice of NHA armin BRCA1/2m patients. The final analysis of OS showed a nominally statistically significantimprovement in OS in BRCA1/2m patients randomised to Lynparza vs comparator.

Table 15 Summary of key efficacy findings in patients with BRCA1/2-mutated mCRPC in

PROfound

Olaparib 300 mg bd Investigators choice of(N=102) NHA(N=58)rPFS by BICRa,b,c DCO 4 June 2019

Number of events: Total number of patients (%) 62:102 (61)c 51:58 (88) c

Median rPFS (95% CI) [months] 9.8 (7.6, 11.3) 3.0 (1.8, 3.6)

HR (95% CI)c 0.22 (0.15, 0.32)

Confirmed ORR by BICRa

Number of objective responders: Total number of25:57 (44) 0:33 (0)patients with measurable disease at baseline (%)

Odds ratio (95% CI) NC (NC, NC)

OSa DCO 20 March 2020 c

Number of events: Total number of patients (%) 53:102 (52) 41:58 (71)

Median OS (95% CI) [months] 20.1 (17.4, 26.8) 14.4 (10.7, 18.9)

HR (95% CI) 0.63 (0.42, 0.95)a Not controlled for multiplicityb rPFS 71% maturityc The HR and CI were calculated using a Cox proportional hazards model that contains terms for treatment, factor andtreatment by factor interaction.

bd Twice daily; BICR Blinded independent central review; CI Confidence interval; HR Hazard ratio; NC Not calculable;

NHA New hormonal agent; ORR Objective response rate; OS Overall survival; rPFS Radiological progression-free survival

Figure 16 BRCA1/2m patients: Kaplan-Meier plot of rPFS (by BICR)

Olaparib 300 mg bd

Investigators choice of NHA

Time from randomisation (months)

Number of patients at risk:

Olaparib 300 mg bd

Investigators choice of NHA

Probability of radiological progression free survival

Figure 17 BRCA1/2m patients: Kaplan-Meier plot of OS

Olaparib 300 mg bd

Investigators choice of NHA

Time from randomisation (months)

Number of patients at risk:

Olaparib 300 mg bd

Investigators choice of NHA

Treatment of patients in the first-line mCRPC setting

PROpel

The safety and efficacy of olaparib were studied in men with metastatic castration-resistant prostatecancer (mCRPC) in a Phase III randomised, double-blind, placebo-controlled, multicentre study thatevaluated the efficacy of Lynparza (300 mg [2 x 150 mg tablets] twice daily) in combination withabiraterone (1000 mg [2 x 500 mg tablets] once daily) versus a comparator arm of placebo plusabiraterone. Patients in both arms also received either prednisone or prednisolone 5 mg twice daily.

The study randomised 796 patients (1:1 randomisation; 399 olaparib/abiraterone:397 placebo/abiraterone) who had evidence of histologically confirmed prostate adenocarcinoma and metastaticstatus defined as at least one documented metastatic lesion on either a bone or CT/MRI scan and whowere treatment naïve with no prior chemotherapy or NHA in the mCRPC setting. Prior to the mCRPCstage, treatment with NHAs (except abiraterone) without PSA progression (clinical or radiological)during treatment was allowed, provided the treatment was stopped at least 12 months beforerandomisation. Treatment with first-generation antiandrogen agents (e.g., bicalutamide, nilutamide,flutamide) was also allowed, provided there was a washout period of 4 weeks. Docetaxel treatmentwas allowed during neoadjuvant/adjuvant treatment for localised prostate cancer and at metastatichormone-sensitive prostate cancer (mHSPC) stage, as long as no signs of disease progression occurredduring or immediately after such treatment. All patients received a GnRH analogue or had priorbilateral orchiectomy. Patients were stratified by metastases (bone only, visceral or other) anddocetaxel treatment at mHSPC stage (yes or no). Treatment was continued until radiologicalprogression of the underlying disease or unacceptable toxicity.

Probability of overall survival

Demographic and baseline characteristics were balanced between the two treatment arms. The medianage of patients was 69 years overall, and the majority (71%) of patients were in the ≥65 years agegroup. One hundred and eighty-nine patients (24%) had prior docetaxel treatment at mHSPC stage. Intotal, 434 (55%) patients had bone metastases (metastases in the bone and no other distant site), 105(13%) patients had visceral metastases (distant soft tissue metastases in an organ e.g., liver, lung) and257 (32%) patients had other metastases (this could include, for example, patients with bonemetastases and distant lymph nodes or patients with disease present only in distant lymph nodes).

Most patients in both arms (70%) had an ECOG performance status of 0. There were 103 (25.8%)symptomatic patients in the olaparib group and 80 (20.2%) patients in the placebo group. Symptomaticpatients were characterized by Brief Pain Inventory-Short Form (BPI-SF) item #3 score ≥ 4 and/oropiate use at baseline.

Patient enrolment was not based on biomarker status. HRR gene mutation status was assessedretrospectively by ctDNA and tumour tissue tests to assess the consistency of treatment effect from the

FAS population. Of the patients tested, 198 and 118 were HRRm as determined by ctDNA and tumourtissue, respectively. The distribution of HRRm patients was well balanced between the two arms.

The primary endpoint was rPFS, defined as time from randomisation to radiological progressiondetermined by investigator assessment based on RECIST 1.1 and PCWG-3 criteria (bone). The keysecondary efficacy endpoint was overall survival (OS). Additional secondary endpoints included

PFS2, TFST and HRQoL.

The study met its primary endpoint demonstrating a statistically significant improvement in the risk ofradiological disease progression or death for olaparib/abiraterone compared to placebo/abiraterone asassessed by the investigator, with HR 0.66; 95% CI 0.54, 0.81; p<0.0001; median rPFS 24.8 months inthe olaparib/abiraterone arm vs 16.6 months in the placebo/abiraterone arm. The investigatorassessment of rPFS was supported with a blinded independent central radiological (BICR) review. Thesensitivity analysis of rPFS by BICR was consistent with the investigator-based analysis with HR0.61; 95% CI 0.49, 0.74; p<0.0001; median rPFS 27.6 months in the olaparib/abiraterone arm vs 16.4months in the placebo/abiraterone arm, respectively.

Subgroup results were consistent with the overall results for olaparib/abiraterone compared toplacebo/abiraterone in all pre-defined sub-groups, including patients with or without prior taxane atmHSPC stage, patients with different metastatic disease at baseline (bone only vs visceral vs other)and patients with or without HRRm (Figure 20).

Efficacy results are presented in Table 16, Table 17, Figure 18 and Figure 19.

Table 16 Summary of key efficacy findings for treatment of patients with mCRPC in

PROpel

Olaparib/abiraterone Placebo/abiraterone

N = 399 N = 397rPFS (by investigator assessment) (50% maturity) (DCO 30 July 2021)

Number of events: Total number of patients (%) 168:399 (42.1) 226:397 (56.9)

Median time (95% CI) (months) 24.8 (20.5, 27.6) 16.6 (13.9, 19.2)

HR (95% CI)a 0.66 (0.54, 0.81)p-valueb <0.0001

Final OS (48% maturity) (DCO 12 October 2022)

Number of events: Total number of patients (%) 176:399 (44.1) 205:397 (51.6)

Median time (95% CI) (months) 42.1 (38.4, NC) 34.7 (31.0, 39.3)

Olaparib/abiraterone Placebo/abiraterone

N = 399 N = 397

HR (95% CI)a 0.81 (0.67, 1.00)p-valueb p=0.0544% Alive at 36 months (95% CI) c 56.9 (51.7, 61.7) 49.5 (44.3, 54.5)a The HR and CI were calculated using a Cox proportional hazards model adjusted for the variables selected in the primarypooling strategy: metastases, docetaxel treatment at mHSPC stage. The Efron approach was used for handling ties. A HR <1favours olaparib 300 mg bd + abiraterone 1000 mg qd.b The 2-sided p-value was calculated using the log-rank test stratified by the same variables selected in the primary poolingstrategy.c Calculated using the Kaplan-Meier technique.

Table 17 rPFS subgroup analyses by investigator assessment in PROpel (DCO 30 July 2021)

Olaparib/abiraterone Placebo/abiraterone

Radiological Progression-Free Survival (rPFS) by investigator assessment

Aggregate HRRm Subgroup Analyses a

HRRm N=111 N=115

Number of events: Total number of patients (%) 43:111 (38.7) 73:115 (63.5)

Median (months) NC 13.86

Hazard ratio (95% CI) b 0.50 (0.34, 0.73)

Non-HRRm N=279 N=273

Number of events: Total number of patients (%) 119:279 (42.7) 149:273 (54.6)

Median (months) 24.11 18.96

Hazard ratio (95% CI) b 0.76 (0.60, 0.97)

Aggregate BRCAm Subgroup Analyses a

BRCAm N=47 N=38

Number of events: Total number of patients (%) 14:47 (29.8) 28:38 (73.7)

Median (months) NC 8.38

Hazard ratio (95% CI) b 0.23 (0.12, 0.43)

Non-BRCAm N=343 N=350

Number of events: Total number of patients (%) 148:343 (43.1) 194:350 (55.4)

Median (months) 24.11 18.96

Hazard ratio (95% CI) b 0.76 (0.61, 0.94)a Aggregate subgroups were derived from ctDNA and tissue-based groupings.b The analysis was performed using a Cox proportional hazards model including terms for treatment group, the subgroupfactor, and a treatment by subgroup interaction. Confidence interval calculated using the profile likelihood method. An HR< 1 favors olaparib 300 mg bd.

Figure 18 PROpel: Kaplan-Meier plot of rPFS (investigator assessed) (50% maturity)

DCO 30 July 2021

Olaparib 300 mg bd + Abiraterone 1000 mg qd (N=399)

Placebo bd + Abiraterone 1000 mg qd (N=397)

Time from randomisation (Months)

Number of patients at risk:

Olaparib 300 mg bd + Abiraterone 1000 mg qd

Placebo bd + Abiraterone 1000 mg qd

Figure 19 PROpel: Kaplan-Meier plot of OS (48% maturity) DCO 12 October 2022

Olaparib 300 mg bd + Abiraterone 1000 mg qd (N=399)

Placebo bd + Abiraterone 1000 mg qd (N=397)

Time from randomisation (Months)

Number of patients at risk:

Olaparib 300 mg bd + Abiraterone 1000 mg qd

Placebo bd + Abiraterone 1000 mg qd

Probability of Radiographic Progression-free Survival

Probability of Overall Survival

Figure 20 PROpel: Forest plot of subgroup analysis of rPFS (investigator assessed) (50%maturity) DCO 30 July 2021

Hazard R atio for Abirat erone Abi raterone

Progression or Death + Olaparib + Placebo(95% CI) Number of events/Number of patients(%)

All patients

Age at random assignment: <65yr

Age at random assignment: ≥65yr

ECOG performance status at baseline = 0*

ECOG performance status at baseline = 1*

Metastasis: Bone only

Metastasis: Visceral

Metastasis: Other

Docetaxel treatment at mHSPC stage

No docetaxel treatment at mHSPCstage

Baseline PSA: Below medianbaseline PSA*

Baseline PSA: Above or equal to medianbaseline PSA*

HRRm status (aggregate): HRRm

HRRm status (aggregate): non-HRRm

Asia region

Europe region

North and South America region

White race

Black/African American race

NC

Asian race0.1 1 10

Other race

Abiraterone + Olaparib Better Abiraterone + Placebo Better

Abiraterone + Olaparib Better Abiraterone + Placebo Better

Each subgroup analysis was performed using a Cox proportional hazards model that contained a term for treatment, factor,and treatment by factor interaction. A hazard ratio < 1 implies a lower risk of progression on olaparib. The size of a circle isproportional to the number of events. All subgroups in this figure are based upon data from the eCRF.

*Excludes patients with no baseline assessment. CI: confidence interval, ECOG: Eastern Cooperative Oncology Group;

HRRm: homologous recombination repair gene mutation; mHSPC: metastatic hormone-sensitive prostate cancer; NC:

noncalculable; PSA: prostate-specific antigen.

First-line maintenance treatment of mismatch repair proficient (pMMR) advanced or recurrentendometrial cancer

DUO-E Study

DUO-E was a randomised, multicentre, double-blind, placebo-controlled, Phase III study of first-lineplatinum-based chemotherapy in combination with durvalumab, followed by durvalumab with orwithout olaparib in patients with advanced or recurrent endometrial cancer. Patients had to haveendometrial cancer in one of the following categories: newly diagnosed Stage III disease (measurabledisease per RECIST 1.1 following surgery or diagnostic biopsy), newly diagnosed Stage IV disease(with or without disease following surgery or diagnostic biopsy), or recurrence of disease (measurableor non-measurable disease per RECIST 1.1) where the potential for cure by surgery alone or incombination is poor. For patients with recurrent disease, prior chemotherapy was allowed only if itwas administered in the adjuvant setting and there was at least 12 months from the date of last dose ofchemotherapy administered to the date of subsequent relapse. The study included patients withepithelial endometrial carcinomas of all histologies, including carcinosarcomas. Patients withendometrial sarcoma were excluded.

Randomisation was stratified by tumour tissue’s mismatch repair (MMR) status (proficient versusdeficient), disease status (recurrent versus newly diagnosed), and geographic region (Asia versus restof the world). Patients were randomised 1:1:1 to one of the following arms:

* Platinum-based chemotherapy: Platinum-based chemotherapy (paclitaxel and carboplatin)every 3 weeks for a maximum of 6 cycles with durvalumab placebo every 3 weeks. Followingcompletion of chemotherapy treatment, patients without objective disease progressionreceived durvalumab placebo every 4 weeks and olaparib placebo tablets twice daily asmaintenance treatment until disease progression.

* Platinum-based chemotherapy + durvalumab: Platinum-based chemotherapy (paclitaxel andcarboplatin) every 3 weeks for a maximum of 6 cycles with 1120 mg durvalumab every 3weeks. Following completion of chemotherapy treatment, patients without objective diseaseprogression received 1500 mg durvalumab every 4 weeks with olaparib placebo tablets twicedaily as maintenance treatment until disease progression.

* Platinum-based chemotherapy + durvalumab + olaparib: Platinum-based chemotherapy(paclitaxel and carboplatin) every 3 weeks for a maximum of 6 cycles with 1120 mgdurvalumab every 3 weeks. Following completion of chemotherapy treatment, patientswithout objective disease progression received 1500 mg durvalumab every 4 weeks with 300mg olaparib tablets twice daily as maintenance treatment until disease progression.

Patients who discontinued either product (olaparib/placebo or durvalumab/placebo) for reasons otherthan disease progression could continue treatment with the other product if appropriate based ontoxicity considerations and investigator discretion.

Treatment was continued until RECIST v1.1-defined progression of disease or unacceptable toxicity.

Assessment of tumour status was performed every 9 weeks for the first 18 weeks relative torandomisation and every 12 weeks thereafter.

The primary endpoint was PFS, defined as time from randomisation to progression determined byinvestigator assessment using RECIST 1.1, or death. Secondary efficacy endpoints included OS, ORRand DoR.

The study demonstrated a statistically significant improvement in PFS in the ITT population forpatients treated with platinum-based chemotherapy + durvalumab + olaparib compared to platinum-based chemotherapy alone (HR 0.55; 95% CI: 0.43, 0.69). At the time of PFS analysis, interim OSdata were 28% mature with events in 199 of 718 patients.

Mismatch repair (MMR) status was determined centrally using an MMR immunohistochemistry panelassay. Of a total of 718 patients randomized in the study, 575 (80%) patients had MMR-proficient(pMMR) tumour status and 143 (20%) patients had MMR-deficient (dMMR) tumour status.

Among patients with pMMR tumour status, demographic and baseline characteristics were generallywell balanced between the treatment arms. Baseline demographics across all three arms were asfollows: median age of 64 years (range: 22 to 86); 48% age 65 or older; 8% age 75 or older; 56%

White, 30% Asian, and 6% Black or African American. Disease characteristics were as follows:

ECOG PS of 0 (69%) or 1 (31%); 47% newly diagnosed and 53% recurrent disease. The histologicsubtypes were endometrioid (54%), serous (26%), carcinosarcoma (8%), mixed epithelial (4%), clearcell (3%), undifferentiated (2%), mucinous (<1%), and other (3%).

Results in patients with pMMR tumour status are summarised in Table 18 and Figure 21. The medianfollow-up time in censored patients with pMMR tumour status was 15.2 months in the platinum-basedchemotherapy + durvalumab + olaparib arm and 12.8 months in the platinum-based chemotherapyarm. At the time of PFS analysis, interim OS data were 29% mature with events in 110 of 383 patients.

Table 18 Summary of efficacy results in patients with advanced or recurrent endometrialcancer in DUO-E (Patients with pMMR tumour status)

Platinum-based Platinum-basedchemotherapy + chemotherapydurvalumab +olaparib

N=191 N=192

PFS (by investigator assessment) (DCO 12 April 2023)

Number of events: Total number of patients (%) 108:191 (56.5) 148:192 (77.1)

Mediana (95% CI), months 15.0 (12.4, 18.0) 9.7 (9.2, 10.1)

HR (95% CI) 0.57 (0.44, 0.73)

OSb (DCO 12 April 2023)

Number of events: Total number of patients (%) 46:191 (24.1) 64:192 (33.3)

Mediana (95% CI), months NR (NR, NR) 25.9 (25.1, NR)

HR (95% CI) 0.69 (0.47, 1.00)

Objective response ratec (DCO 12 April 2023)

Number of objective responders: Total number of90:147 (61.2) 92:156 (59.0)patients with measurable disease at baseline (%)

Duration of Response (DCO 12 April 2023)

Mediana (95% CI), months 18.7 (10.5, NR) 7.6 (7.1, 10.2)a Calculated using the Kaplan-Meier techniquebBased on first interim analysiscResponse: Best objective response as confirmed complete response or partial response.

CI Confidence interval; DCO Data cutoff; HR Hazard ratio; NR Not reached; OS Overall survival; PFS

Progression-free survival

Figure 21 DUO-E: Kaplan-Meier plot of PFS (Patients with pMMR tumour status)

Platinum-based chemotherapy + durvalumab + olaparib

Platinum-based chemotherapy

Time from randomisation (months)

Number of patients at risk:

Platinum-based chemotherapy + durvalumab + olaparib

Platinum-based chemotherapy

* Platinum-based chemotherapy

Among patients with pMMR tumour status, the PFS HRs were 0.44 (95% CI: 0.31, 0.61) in patientswith PD-L1 expression positive status (236/383; 62%) and 0.87 (95% CI: 0.59, 1.28) in patients with

PD-L1 expression negative status (140/383; 37%), for the platinum-based chemotherapy +durvalumab + olaparib arm vs the platinum-based chemotherapy arm. PD-L1 expression positive wasdefined as tumour area positive (TAP) ≥ 1%.

The European Medicines Agency has waived the obligation to submit the results of studies with

Lynparza in all subsets of the paediatric population, in ovarian carcinoma (excludingrhabdomyosarcoma and germ cell tumours) (see section 4.2 for information on paediatric use).

The pharmacokinetics of olaparib at the 300 mg tablet dose are characterised by an apparent plasmaclearance of ~7 L/h, an apparent volume of distribution of ~158 L and a terminal half-life of 15 hours.

On multiple dosing, an AUC accumulation ratio of 1.8 was observed and PK appeared to betime-dependent to a small extent.

Following oral administration of olaparib via the tablet formulation (2 x 150 mg), absorption is rapidwith median peak plasma concentrations typically achieved 1.5 hours after dosing.

Co-administration with food slowed the rate (tmax delayed by 2.5 hours and Cmax reduced byapproximately 21%) but did not significantly affect the extent of absorption of olaparib (AUCincreased 8%). Consequently, Lynparza may be taken without regard to food (see section 4.2).

The in vitro plasma protein binding is approximately 82% at 10 µg/mL which is approximately Cmax.

Proportion of patients event free

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

In vitro, CYP3A4/5 were shown to be the enzymes primarily responsible for the metabolism ofolaparib (see section 4.5).

Following oral dosing of 14C-olaparib to female patients, unchanged olaparib accounted for themajority of the circulating radioactivity in plasma (70%) and was the major component found in bothurine and faeces (15% and 6% of the dose, respectively). The metabolism of olaparib is extensive. Themajority of the metabolism was attributable to oxidation reactions with a number of the componentsproduced undergoing subsequent glucuronide or sulfate conjugation. Up to 20, 37 and 20 metaboliteswere detected in plasma, urine and faeces, respectively, the majority of them representing <1% of thedosed material. A ring-opened piperazin-3-ol moiety, and two mono-oxygenated metabolites (each~10%) were the major circulating components, with one of the mono-oxygenated metabolites alsobeing the major metabolite in the excreta (6% and 5% of the urinary and faecal radioactivity,respectively).

In vitro, olaparib produced little/no inhibition of UGT1A4, UGT1A9, UGT2B7, or CYPs 1A2, 2A6,2B6, 2C8, 2C9, 2C19, 2D6 or 2E1 and is not expected to be a clinically significant time dependentinhibitor of any of these CYP enzymes. Olaparib inhibited UGT1A1 in vitro, however, PBPKsimulations suggest this is not of clinical importance. In vitro, olaparib is a substrate of the effluxtransporter P-gp, however, this is unlikely to be of clinical significance (see section 4.5).

In vitro, data also show that olaparib is not a substrate for OATP1B1, OATP1B3, OCT1, BCRP or

MRP2 and is not an inhibitor of OATP1B3, OAT1 or MRP2.

Following a single dose of 14C-olaparib, ~86% of the dosed radioactivity was recovered within a 7-daycollection period, ~44% via the urine and ~42% via the faeces. Majority of the material was excretedas metabolites.

In population based PK analyses, patient age, gender, bodyweight, tumour location or race (including

White and Japanese patients) were not significant covariates.

In patients with mild renal impairment (creatinine clearance 51 to 80 ml/min), AUC increased by 24%and Cmax by 15% compared with patients with normal renal function. No Lynparza dose adjustment isrequired for patients with mild renal impairment.

In patients with moderate renal impairment (creatinine clearance 31 to 50 ml/min), AUC increased by44% and Cmax by 26% compared with patients with normal renal function. Lynparza dose adjustmentis recommended for patients with moderate renal impairment (see section 4.2).

There are no data in patients with severe renal impairment or end-stage renal disease (creatinineclearance <30 ml/min).

In patients with mild hepatic impairment (Child-Pugh classification A), AUC increased by 15% and

Cmax by 13% and in patients with moderate hepatic impairment (Child-Pugh classification B), AUCincreased by 8% and Cmax decreased by 13% compared with patients with normal hepatic function. No

Lynparza dose adjustment is required for patients with mild or moderate hepatic impairment (seesection 4.2). There are no data in patients with severe hepatic impairment (Child-Pugh classification

C).

No studies have been conducted to investigate the pharmacokinetics of olaparib in paediatric patients.

In repeat-dose toxicity studies of up to 6 months duration in rats and dogs, daily oral doses of olaparibwere well-tolerated. The major primary target organ for toxicity in both species was the bone marrow,with associated changes in peripheral haematology parameters. These changes were reversible within4 weeks of cessation of dosing. In rats, minimal degenerative effects on gastrointestinal tract were alsonoted. These findings occurred at exposures below those seen clinically. Studies using human bonemarrow cells also showed that direct exposure to olaparib can result in toxicity to bone marrow cells inex vivo assays.

Olaparib showed no mutagenic potential, but was clastogenic in mammalian cells in vitro. Whendosed orally to rats, olaparib induced micronuclei in bone marrow. This clastogenicity is consistentwith the known pharmacology of olaparib and indicates potential for genotoxicity in man.

Carcinogenicity studies have not been conducted with olaparib.

In a female fertility study where rats were dosed until implantation, although extended oestrus wasobserved in some animals, mating performance and pregnancy rate was not affected. However, therewas a slight reduction in embryofoetal survival.

In rat embryofoetal development studies, and at dose levels that did not induce significant maternaltoxicity, olaparib caused reduced embryofoetal survival, reduced foetal weight and foetaldevelopmental abnormalities, including major eye malformations (e.g. anophthalmia,microphthalmia), vertebral/rib malformation and visceral and skeletal abnormalities.

Copovidone

Silica, colloidal anhydrous

Mannitol

Sodium stearyl fumarate

Hypromellose

Macrogol 400

Titanium dioxide (E171)

Iron oxide yellow (E172)

Iron oxide black (E172) (150 mg tablets only)

Not applicable.

4 years.

Store in the original package in order to protect from moisture.

This medicinal product does not require any special temperature storage conditions.

Alu/Alu non-perforated blister containing 8 film-coated tablets.

56 film-coated tablets (7 blisters).

Multipack containing 112 (2 packs of 56) film-coated tablets.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

AstraZeneca AB

SE-151 85 Södertälje

Sweden

EU/1/14/959/002 56 film-coated tablets (100 mg)

EU/1/14/959/003 112 film-coated tablets (2 packs of 56) (100 mg)

EU/1/14/959/004 56 film-coated tablets (150 mg)

EU/1/14/959/005 112 film-coated tablets (2 packs of 56) (150 mg)

Date of first authorisation: 16 December 2014

Date of latest renewal: 1 October 2019

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.