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What is Lynparza and how is it used?

Lynparza is a prescription medicine used to treat adults who have:

• advanced ovarian cancer, fallopian tube cancer, or primary peritoneal cancer with a certain type of inherited (germline) or acquired (somatic) abnormal BRCA gene. Lynparza is used alone as maintenance treatment after the cancer has responded to your first treatment with platinum-based chemotherapy. Your healthcare provider will perform a test to make sure that Lynparza is right for you.
• advanced ovarian cancer, fallopian tube cancer or primary peritoneal cancer with a certain type of abnormal BRCA gene or a positive laboratory tumor test for genomic instability called HRD. Lynparza is used in combination with another anti-cancer medicine, bevacizumab, as maintenance treatment after the cancer has responded to your first treatment with platinum-based chemotherapy. Your healthcare provider will perform a test to make sure that Lynparza is right for you.
• ovarian cancer, fallopian tube cancer, or primary peritoneal cancer, as maintenance treatment, when the cancer has come back. Lynparza is used after the cancer has responded to treatment with platinum-based chemotherapy.
• advanced ovarian cancer with a certain type of abnormal inherited BRCA gene, and have received treatment with 3 or more prior types of chemotherapy medicines. Your healthcare provider will perform a test to make sure that Lynparza is right for you.
• a certain type of abnormal inherited BRCA gene, human epidermal growth factor receptor 2 (HER2)-negative breast cancer that has spread to other parts of the body (metastatic). You should have received chemotherapy medicines, either before or after your cancer has spread. If you have hormone receptor (HR)-positive disease, you should have been treated with hormonal therapy. Your healthcare provider will perform a test to make sure that Lynparza is right for you.
• metastatic pancreatic cancer with a certain type of abnormal inherited BRCA gene. Lynparza is used as maintenance treatment after your cancer has not progressed on at least 16 weeks of treatment with platinum-based chemotherapy. Your healthcare provider will perform a test to make sure that Lynparza is right for you.

It is not known if Lynparza is safe and effective in children.

What are the possible side effects of Lynparza?

Lynparza may cause serious side effects.

See “What is the most important information I should know about Lynparza?”

The most common side effects of Lynparza are:

• nausea or vomiting. Tell your healthcare provider if you get nausea or vomiting. Your healthcare provider may prescribe medicines to treat these symptoms.
  • low number of red or white blood cells
  • stomach-area (abdominal) pain
  • dizziness
  • tiredness or weakness
  • sore throat or runny nose
  • diarrhea
  • joint, muscle, and back pain
  • headache
  • constipation
  • mouth sores
  • respiratory tract infections
  • changes in kidney function blood test
  • changes in the way food tastes
  • loss of appetite
  • low number of platelets
  • indigestion or heartburn

These are not all of the possible side effects of Lynparza.

Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

DESCRIPTION

Olaparib is an inhibitor of the mammalian polyadenosine 5’-diphosphoribose polymerase (PARP) enzyme.

The chemical name is 4-[(3-{[4-(cyclopropylcarbonyl)piperazin-1-yl]carbonyl}-4- fluorophenyl)methyl]phthalazin-1(2H)-one and it has the following chemical structure:

The empirical molecular formula for Lynparza is C24H23FN4O3 and the relative molecular mass is 434.46.

Olaparib is a crystalline solid, is non-chiral and shows pH-independent low solubility across the physiological pH range.

Lynparza tablets for oral administration contain 100 mg or 150 mg of olaparib. Inactive ingredients in the tablet core are copovidone, mannitol, colloidal silicon dioxide and sodium stearyl fumarate. The tablet coating consists of hypromellose, polyethylene glycol 400, titanium dioxide, ferric oxide yellow and ferrosoferric oxide (150 mg tablet only).

INDICATIONS

First-Line Maintenance Treatment Of BRCA-Mutated Advanced Ovarian Cancer

Lynparza is indicated for the maintenance treatment of adult patients with deleterious or suspected deleterious germline or somatic BRCA-mutated advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza [see DOSAGE AND ADMINISTRATION].

First-Line Maintenance Treatment Of Advanced Ovarian Cancer In Combination With Bevacizumab

Lynparza is indicated in combination with bevacizumab for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy and whose cancer is associated with homologous recombination deficiency (HRD) positive status defined by either:

• a deleterious or suspected deleterious BRCA mutation, and/or
• genomic instability.

Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza [see DOSAGE AND ADMINISTRATION].

Maintenance Treatment Of Recurrent Ovarian Cancer

Lynparza is indicated for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer, who are in complete or partial response to platinum-based chemotherapy.

Advanced Germline BRCA-Mutated Ovarian Cancer After 3 Or More Lines Of Chemotherapy

Lynparza is indicated for the treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza [see DOSAGE AND ADMINISTRATION].

Germline BRCA-Mutated HER2-Negative Metastatic Breast Cancer

Lynparza is indicated for the treatment of adult patients with deleterious or suspected deleterious gBRCAm, HER2-negative metastatic breast cancer, who have been treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic setting. Patients with hormone receptor (HR)-positive breast cancer should have been treated with a prior endocrine therapy or be considered inappropriate for endocrine therapy. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza [see DOSAGE AND ADMINISTRATION].

First-Line Maintenance Treatment Of Germline BRCA-Mutated Metastatic Pancreatic Adenocarcinoma

Lynparza is indicated for the maintenance treatment of adult patients with deleterious or suspected deleterious gBRCAm metastatic pancreatic adenocarcinoma whose disease has not progressed on at least 16 weeks of a first-line platinum-based chemotherapy regimen. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza [see DOSAGE AND ADMINISTRATION].

DOSAGE AND ADMINISTRATION

Patient Selection

First-Line Maintenance Treatment Of BRCA-Mutated Advanced Ovarian Cancer

Select patients with advanced ovarian cancer who are in complete or partial response to first-line platinum-based chemotherapy for maintenance treatment with Lynparza monotherapy based on the presence of deleterious or suspected deleterious germline or somatic BRCA mutation [see Clinical Studies]. Information on FDA-approved tests for the detection of BRCA mutations is available at http://www.fda.gov/companiondiagnostics.

First-Line Maintenance Treatment Of HRD Positive Advanced Ovarian Cancer In Combination With Bevacizumab

Select patients with advanced ovarian cancer who are in complete or partial response to first-line platinum-based chemotherapy for maintenance treatment with Lynparza in combination with bevacizumab associated with HRD positive status based on either deleterious or suspected deleterious BRCA mutation and/or genomic instability [see Clinical Studies].

Information on FDA-approved tests for the detection of BRCA mutations or genomic instability are available at http://www.fda.gov/companiondiagnostics

Germline BRCAm Advanced Ovarian Cancer, HER2-Negative Metastatic Breast Cancer, And Metastatic Pancreatic Adenocarcinoma

Select patients for treatment with Lynparza based on the presence of deleterious or suspected deleterious germline BRCA mutation [see Clinical Studies]. Information on FDA-approved tests for the detection of BRCA mutations is available at http://www.fda.gov/companiondiagnostics.

Recommended Dosage

The recommended dosage of Lynparza is 300 mg taken orally twice daily, with or without food.

First-Line Maintenance Treatment Of BRCA-Mutated Advanced Ovarian Cancer

Continue treatment until disease progression, unacceptable toxicity, or completion of 2 years of treatment. Patients with a complete response (no radiological evidence of disease) at 2 years should stop treatment. Patients with evidence of disease at 2 years, who in the opinion of the treating healthcare provider can derive further benefit from continuous treatment, can be treated beyond 2 years.

First-Line Maintenance Treatment Of Advanced Ovarian Cancer In Combination With Bevacizumab

Continue Lynparza treatment until disease progression, unacceptable toxicity, or completion of 2 years of treatment. Patients with a complete response (no radiological evidence of disease) at 2 years should stop treatment. Patients with evidence of disease at 2 years, who in the opinion of the treating healthcare provider can derive further benefit from continuous Lynparza treatment, can be treated beyond 2 years.

When used with Lynparza, the recommended dose of bevacizumab is 15 mg/kg every three weeks. Bevacizumab should be given for a total of 15 months including the period given with chemotherapy and given as maintenance. Refer to the Prescribing Information for bevacizumab when used in combination with Lynparza for more information.

Recurrent Ovarian Cancer, Germline BRCAm Advanced Ovarian Cancer, HER2-Negative Metastatic Breast Cancer, And Metastatic Pancreatic Adenocarcinoma

Continue treatment until disease progression or unacceptable toxicity for:

• Maintenance treatment of recurrent ovarian cancer
• Advanced germline BRCA-mutated ovarian cancer
• Germline BRCA-mutated HER-2 negative metastatic breast cancer
• First-line maintenance treatment of germline BRCA-mutated metastatic pancreatic adenocarcinoma.

If a patient misses a dose of Lynparza, instruct patient to take their next dose at its scheduled time. Instruct patients to swallow tablets whole. Do not chew, crush, dissolve, or divide tablet.

Dosage Modifications For Adverse Reactions

To manage adverse reactions, consider interruption of treatment or dose reduction. The recommended dose reduction is 250 mg taken twice daily.

If a further dose reduction is required, then reduce to 200 mg taken twice daily.

DosageModifications For Concomitant Use With Strong Or Moderate CYP3A Inhibitors

Avoid concomitant use of strong or moderate CYP3A inhibitors with Lynparza.

If concomitant use cannot be avoided, reduce Lynparza dosage to:

• 100 mg twice daily when used concomitantly with a strong CYP3A inhibitor.
• 150 mg twice daily when used concomitantly with a moderate CYP3A inhibitor.

After the inhibitor has been discontinued for 3 to 5 elimination half-lives, resume the Lynparza dose taken prior to initiating the CYP3A inhibitor [see DRUG INTERACTIONS and CLINICAL PHARMACOLOGY].

Dosage Modifications For Renal Impairment

Moderate Renal Impairment

In patients with moderate renal impairment (CLcr 31-50 mL/min), reduce the Lynparza dosage to 200 mg orally twice daily [see Use In Specific Populations and CLINICAL PHARMACOLOGY].

HOW SUPPLIED

Dosage Forms And Strengths

Tablets:

• 150 mg: green to green/grey, oval, bi-convex, film-coated, with debossment ‘OP150’ on one side and plain on the reverse side.
• 100 mg: yellow to dark yellow, oval, bi-convex, film-coated, with debossment ‘OP100’ on one side and plain on the reverse side.

Storage And Handling

Lynparza is available as 150 mg and 100 mg tablets.

• 150 mg tablets: green to green/grey, oval, bi-convex, film-coated tablet, with debossment ‘OP150’ on one side and plain on the reverse, are available in:
  • Bottles of 60 tablets (NDC 0310-0679-60) and
  • Bottles of 120 tablets (NDC 0310-0679-12).
• 100 mg tablets: yellow to dark yellow, oval, bi-convex, film-coated tablet, with debossment ‘OP100’ on one side and plain on the reverse, are available in:
  • Bottles of 60 tablets (NDC 0310-0668-60) and
  • Bottles of 120 tablets (NDC 0310-0668-12).

Store at 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Store in original bottle to protect from moisture.

Distributed by: AstraZeneca Pharmaceuticals LP Wilmington, DE 19850. Revised: N/A

SIDE EFFECTS

The following adverse reactions are discussed elsewhere in the labeling:

• Myelodysplastic Syndrome/Acute Myeloid Leukemia [see WARNINGS AND PRECAUTIONS]
• Pneumonitis [see WARNINGS AND PRECAUTIONS]

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

First-Line Maintenance Treatment Of BRCA-Mutated Advanced Ovarian Cancer

SOLO-1

The safety of Lynparza for the maintenance treatment of patients with BRCA-mutated advanced ovarian cancer following first-line treatment with platinum-based chemotherapy was investigated in SOLO-1 [see Clinical Studies]. Patients received Lynparza tablets 300 mg orally twice daily (n=260) or placebo (n=130) until disease progression or unacceptable toxicity. The median duration of study treatment was 25 months for patients who received Lynparza and 14 months for patients who received placebo.

Among patients who received Lynparza, dose interruptions due to an adverse reaction of any grade occurred in 52% and dose reductions due to an adverse reaction occurred in 28%. The most frequent adverse reactions leading to dose interruption or reduction of Lynparza were anemia (23%), nausea (14%), and vomiting (10%). Discontinuation due to adverse reactions occurred in 12% of patients receiving Lynparza. The most frequent adverse reactions that led to discontinuation of Lynparza were fatigue (3.1%), anemia (2.3%), and nausea (2.3%).

Tables 1 and 2 summarize adverse reactions and laboratory abnormalities in SOLO-1.

Table 1: Adverse Reactions* in SOLO-1 (≥10% of Patients Who Received Lynparza)

In addition, the adverse reactions observed in SOLO-1 that occurred in <10% of patients receiving Lynparza were increased blood creatinine (8%), lymphopenia (6%), hypersensitivity (2%), dermatitis (1%), and increased mean cell volume (0.4%).

Table 2: Laboratory Abnormalities Reported in ≥25% of Patients in SOLO-1

First-Line Maintenance Treatment Of Advanced Ovarian Cancer In Combination With Bevacizumab

PAOLA-1

The safety of Lynparza in combination with bevacizumab for the maintenance treatment of patients with advanced ovarian cancer following first-line treatment containing platinum-based chemotherapy and bevacizumab was investigated in PAOLA-1 [see Clinical Studies This study was a placebocontrolled, double-blind study in which 802 patients received either Lynparza 300 mg BID in combination with bevacizumab (n=535) or placebo in combination with bevacizumab (n=267) until disease progression or unacceptable toxicity. The median duration of treatment with Lynparza was 17.3 months and 11 months for bevacizumab post-randomization on the Lynparza/bevacizumab arm.

Fatal adverse reactions occurred in 1 patient due to concurrent pneumonia and aplastic anemia. Serious adverse reactions occurred in 31% of patients who received Lynparza/bevacizumab. Serious adverse reactions in >5% of patients included hypertension (19%) and anemia (17%).

Dose interruptions due to an adverse reaction of any grade occurred in 54% of patients receiving Lynparza/bevacizumab and dose reductions due to an adverse reaction occurred in 41% of patients who received Lynparza/bevacizumab.

The most frequent adverse reactions leading to dose interruption in the Lynparza/bevacizumab arm were anemia (21%), nausea (7%), vomiting (3%), and fatigue (3%), and the most frequent adverse reactions leading to reduction in the Lynparza/bevacizumab arm were anemia (19%), nausea (7%), and fatigue (4%).

Discontinuation due to adverse reactions occurred in 20% of patients receiving Lynparza/bevacizumab. Specific adverse reactions that most frequently led to discontinuation in patients treated with Lynparza/bevacizumab were anemia (4%) and nausea (3%).

Tables 3 and 4 summarize adverse reactions and laboratory abnormalities in PAOLA-1, respectively.

Table 3: Adverse Reactions* Occurring in ≥10% of Patients Treated with Lynparza/bevacizumab in PAOLA-1 and at ≥5% FrequencyCompared to the Placebo/bevacizumab Arm

The most common adverse reactions (≥ 10%) for patients receiving Lynparza/bevacizumab irrespective of the frequency compared with the placebo/bevacizumab arm were nausea (53%), fatigue (including asthenia) (53%), anemia (41%), lymphopenia, vomiting (22%), diarrhea (18%), neutropenia (18%), leukopenia (18%), urinary tract infection (15%), and headache (14%).

The adverse reactions that occurred in <10% of patients receiving Lynparza/bevacizumab were dysgeusia (8%), dyspnea (8%), stomatitis (5%), dyspepsia (4.3%), erythema (3%), dizziness (2.6%), and hypersensitivity (1.7%).

In addition, venous thromboembolic events occurred more commonly in patients receiving Lynparza/bevacizumab (5%) than in those receiving placebo/bevacizumab (1.9%).

Table 4: Laboratory Abnormalities Reported in ≥25% of Patients in PAOLA-1*

Maintenance Treatment Of Recurrent Ovarian Cancer

SOLO-2

The safety of Lynparza for the maintenance treatment of patients with platinum sensitive gBRCAm ovarian cancer was investigated in SOLO-2 [see Clinical Studies]. Patients received Lynparza tablets 300 mg orally twice daily (n=195) or placebo (n=99) until disease progression or unacceptable toxicity. The median duration of study treatment was 19.4 months for patients who received Lynparza and 5.6 months for patients who received placebo.

Among patients who received Lynparza, dose interruptions due to an adverse reaction of any grade occurred in 45% and dose reductions due to an adverse reaction occurred in 27%. The most frequent adverse reactions leading to dose interruption or reduction of Lynparza were anemia (22%), neutropenia (9%), and fatigue/asthenia (8%). Discontinuation due to an adverse reaction occurred in 11% of patients receiving Lynparza.

Tables 5 and 6 summarize adverse reactions and laboratory abnormalities in SOLO-2.

Table 5 Adverse Reactions* in SOLO-2 (≥20% of Patients Who Received Lynparza)

In addition, the adverse reactions observed in SOLO-2 that occurred in <20% of patients receiving Lynparza were neutropenia (19%), cough (18%), leukopenia (16%), hypomagnesemia (14%), thrombocytopenia (14%), dizziness (13%), dyspepsia (11%), increased creatinine (11%), edema (8%), rash (6%), and lymphopenia (1%).

Table 6: Laboratory Abnormalities Reported in ≥25% of Patients in SOLO-2

Study 19

The safety of Lynparza as maintenance monotherapy was evaluated in patients with platinum sensitive ovarian cancer who had received 2 or more previous platinum containing regimens in Study 19 [see Clinical Studies]. Patients received Lynparza capsules 400 mg orally twice daily (n=136) or placebo (n=128). At the time of final analysis, the median duration of exposure was 8.7 months in patients who received Lynparza and 4.6 months in patients who received placebo.

Adverse reactions led to dose interruptions in 35% of patients receiving Lynparza; dose reductions in 26% and discontinuation in 6% of patients receiving Lynparza.

Tables 7 and 8 summarize adverse reactions and laboratory abnormalities in Study 19.

Table 7: Adverse Reactions* in Study 19 (≥20% of Patients Who Received Lynparza)

In addition, the adverse reactions in Study 19 that occurred in <20% of patients receiving Lynparza were dysgeusia (16%), dizziness (15%), dyspnea (13%), pyrexia (10%), stomatitis (9%), edema (9%), increase in creatinine (7%), neutropenia (5%), thrombocytopenia (4%), leukopenia (2%), and lymphopenia (1%).

Table 8: Laboratory Abnormalities Reported in ≥25% of Patients in Study 19

Advanced Germline BRCA-Mutated Ovarian Cancer After 3 Or More Lines Of Chemotherapy

Pooled Data

The safety of Lynparza was investigated in 223 patients (pooled from 6 studies) with gBRCAm advanced ovarian cancer who had received 3 or more prior lines of chemotherapy [see Clinical Studies]. Patients received Lynparza capsules 400 mg orally twice daily until disease progression or unacceptable tolerability. The median exposure to Lynparza in these patients was 5.2 months.

There were 8 (4%) patients with adverse reactions leading to death, two were attributed to acute leukemia, and one each was attributed to COPD, cerebrovascular accident, intestinal perforation, pulmonary embolism, sepsis, and suture rupture. Adverse reactions led to dose interruption in 40% of patients, dose reduction in 4%, and discontinuation in 7%.

Tables 9 and 10 summarize the adverse reactions and laboratory abnormalities from the pooled studies.

Table 9: Adverse Reactions Reported in Pooled Data (≥20% of Patients Who Received Lynparza)

Table 10: Laboratory Abnormalities Reported in ≥25% of Patients in Pooled Data

The following adverse reactions and laboratory abnormalities have been identified in ≥10 to <20% of the 223 patients receiving Lynparza and not included in the table: cough (16%), constipation (16%), dysgeusia (16%), headache (15%), peripheral edema (14%), back pain (14%), urinary tract infection (14%), dyspnea (13%) and dizziness (11%).

The following adverse reactions and laboratory abnormalities have been identified in <10% of the 223 patients receiving Lynparza and not included in the table: leukopenia (9%), pyrexia (8%), peripheral neuropathy (5%), hypomagnesemia (5%), rash (5%), stomatitis (4%) and venous thrombosis (including pulmonary embolism) (1%).

Germline BRCA-Mutated HER2-Negative Metastatic Breast Cancer

OlympiAD

The safety of Lynparza was evaluated in gBRCAm patients with HER2-negative metastatic breast cancer who had previously received up to two lines of chemotherapy for the treatment of metastatic disease in OlympiAD [see Clinical Studies]. Patients received either Lynparza tablets 300 mg orally twice daily (n=205) or a chemotherapy (capecitabine, eribulin, or vinorelbine) of the healthcare provider’s choice (n=91) until disease progression or unacceptable toxicity. The median duration of study treatment was 8.2 months in patients who received Lynparza and 3.4 months in patients who received chemotherapy.

Among patients who received Lynparza, dose interruptions due to an adverse reaction of any grade occurred in 35% and dose reductions due to an adverse reaction occurred in 25%. Discontinuation due to an adverse reaction occurred in 5% of patients receiving Lynparza.

Tables 11 and 12 summarize the adverse reactions and laboratory abnormalities in OlympiAD.

Table 11 Adverse Reactions* in OlympiAD (≥20% of Patients Who Received Lynparza)

In addition, adverse reactions in OlympiAD that occurred in <20% of patients receiving Lynparza were cough (18%), decreased appetite (16%), thrombocytopenia (11%), dysgeusia (9%), lymphopenia (8%), dyspepsia (8%), dizziness (7%), stomatitis (7%), upper abdominal pain (7%), rash (5%), increase in serum creatinine (3%), and dermatitis (1%).

Table 12: Laboratory Abnormalities Reported in ≥25% of Patients in OlympiAD

First-Line Maintenance Treatment Of Germline BRCA-MutatedMetastatic Pancreatic Adenocarcinoma

POLO

The safety of Lynparza as maintenance treatment of germline BRCA-mutated metastatic pancreatic adenocarcinoma following first-line treatment with platinum-based chemotherapy was evaluated in POLO [see Clinical Studies]. Patients received Lynparza tablets 300 mg orally twice daily (n=90) or placebo (n=61) until disease progression or unacceptable toxicity.Among patients receiving Lynparza, 34% were exposed for 6 months or longer and 25% were exposed for greater than one year.

Among patients who received Lynparza, dosage interruptions due to an adverse reaction of any grade occurred in 35% and dosage reductions due to an adverse reaction occurred in 17%. The most frequent adverse reactions leading to dosage interruption or reduction in patients who received Lynparza were anemia (11%), vomiting (5%), abdominal pain (4%), asthenia (3%), and fatigue (2%). Discontinuation due to adverse reactions occurred in 6% of patients receiving Lynparza. The most frequent adverse reaction that led to discontinuation of Lynparza was fatigue (2.2%).

Tables 13 and 14 summarize the adverse reactions and laboratory abnormalities in patients in POLO.

Table 13: Adverse Reactions*in POLO (Occurring in ≥10% of Patients who Received Lynparza)

In addition, the adverse reactions observed in POLO that occurred in <10% of patients receiving Lynparza were cough (9%), abdominal pain upper (7%), blood creatinine increased (7%), dizziness (7%), headache (7%), dyspepsia (5%), leukopenia (5%), hypersensitivity (2%) and lymphopenia (2%).

Table 14: Laboratory AbnormalitiesReported in ≥25% of Patients in POLO

Postmarketing Experience

The following adverse reactions have been identified during post approval use of Lynparza. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune System Disorders: Hypersensitivity (rash/dermatitis).

DRUG INTERACTIONS

Use With Anticancer Agents

Clinical studies of Lynparza with other myelosuppressive anticancer agents, including DNA damaging agents, indicate a potentiation and prolongation of myelosuppressive toxicity.

Effect Of Other Drugs On Lynparza

Strong And Moderate CYP3A Inhibitors

Coadministration of CYP3A inhibitors can increase olaparib concentrations, which may increase the risk for adverse reactions [see CLINICAL PHARMACOLOGY].Avoid coadministration of strong or moderate CYP3A inhibitors. If the strong or moderate inhibitor must be coadministered, reduce the dose of Lynparza [see DOSAGE AND ADMINISTRATION].

Strong And Moderate CYP3A Inducers

Concomitant use with a strong or moderate CYP3A inducer decreased olaparib exposure, which may reduce Lynparza efficacy [see CLINICAL PHARMACOLOGY]. Avoid coadministration of strong or moderate CYP3A inducers.

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONS

Myelodysplastic Syndrome/Acute Myeloid Leukemia

Overall, the incidence of Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML) in patients treated with Lynparza monotherapy in clinical trials, including long-term follow up, was <1.5% (30/2783) and the majority of events had a fatal outcome. Of these, 26/30 patients had a documented BRCA mutation, 2 patients had gBRCA wildtype and in 2 patients the BRCA mutation status was unknown. Additional cases of MDS/AML have been documented in patients treated with Lynparza in combination studies and in postmarketing reports. The duration of therapy with Lynparza in patients who developed secondary MDS/cancer-therapy related AML varied from <6 months to >2 years. All of these patients had received previous chemotherapy with platinum agents and/or other DNA damaging agents including radiotherapy. Some of these patients also had a history of more than one primary malignancy or of bone marrow dysplasia.

Do not start Lynparza until patients have recovered from hematological toxicity caused by previous chemotherapy (≤Grade 1). Monitor complete blood count for cytopenia at baseline and monthly thereafter for clinically significant changes during treatment. For prolonged hematological toxicities, interrupt Lynparza and monitor blood counts weekly until recovery. If the levels have not recovered to Grade 1 or less after 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is confirmed, discontinue Lynparza.

Pneumonitis

Pneumonitis, including fatal cases, occurred in <1% of patients treated with Lynparza. If patients present with new or worsening respiratory symptoms such as dyspnea, cough and fever, or a radiological abnormality occurs, interrupt Lynparza treatment and promptly assess the source of the symptoms. If pneumonitis is confirmed, discontinue Lynparza treatment and treat the patient appropriately.

Embryo-Fetal Toxicity

Lynparza can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. In an animal reproduction study, administration of olaparib to pregnant rats during the period of organogenesis caused teratogenicity and embryo-fetal toxicity at exposures below those in patients receiving the recommended human dose of 300 mg twice daily. Apprise pregnant women of the potential hazard to a fetus and the potential risk for loss of the pregnancy. Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of Lynparza. Based on findings from genetic toxicity and animal reproduction studies, advise male patients with female partners of reproductive potential or who are pregnant to use effective contraception during treatment and for 3 months following the last dose of Lynparza [see Use In Specific Populations].

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

MDS/AML

Advise patients to contact their healthcare provider if they experience weakness, feeling tired, fever, weight loss, frequent infections, bruising, bleeding easily, breathlessness, blood in urine or stool, and/or laboratory findings of low blood cell counts, or a need for blood transfusions. This may be a sign of hematological toxicity or a more serious uncommon bone marrow problem called ‘myelodysplastic syndrome’ (MDS) or ‘acute myeloid leukemia’ (AML) which have been reported in patients treated with Lynparza [see WARNINGS AND PRECAUTIONS].

Pneumonitis

Advise patients to contact their healthcare provider if they experience any new or worsening respiratory symptoms including shortness of breath, fever, cough, or wheezing [see WARNINGS AND PRECAUTIONS].

Embryo-Fetal Toxicity

Inform pregnant women of the risk to a fetus and potential loss of the pregnancy. Advise females to inform their healthcare provider of known or suspected pregnancy [see Use In Specific Populations].

Advise females of reproductive potential to use effective contraception during treatment with Lynparza and for 6 months after the last dose [see Use In Specific Populations].

Advise male patients with female partners of reproductive potential or who are pregnant to use effective contraception during treatment and for 3 months after receiving the last dose of Lynparza. Advise male patients not to donate sperm during therapy and for 3 months following the last dose of Lynparza [see WARNINGS AND PRECAUTIONS and Use In Specific Population].

Lactation

Advise patients not to breastfeed while taking Lynparza and for one month after receiving the last dose [see Use In Specific Populations].

Drug Interactions

Advise patients and caregivers to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products. Inform patients to avoid grapefruit, grapefruit juice, Seville oranges, and Seville orange juice while taking Lynparza [see DRUG INTERACTIONS].

Nausea/Vomiting

Advise patients that mild or moderate nausea and/or vomiting is very common in patients receiving Lynparza and that they should contact their healthcare provider who will advise on available antiemetic treatment options [see ADVERSE REACTIONS].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenicity studies have not been conducted with olaparib.

Olaparib was clastogenic in an in vitro chromosomal aberration assay in mammalian Chinese hamster ovary (CHO) cells and in an in vivo rat bone marrow micronucleus assay. This clastogenicity is consistent with genomic instability resulting from the primary pharmacology of olaparib and indicates potential for genotoxicity in humans. Olaparib was not mutagenic in a bacterial reverse mutation (Ames) test.

In a fertility study, female rats received oral olaparib at doses of 0.05, 0.5, and 15 mg/kg/day for at least 14 days before mating through the first week of pregnancy. There were no adverse effects on mating and fertility rates at doses up to 15 mg/kg/day (maternal systemic exposures approximately 7% of the human exposure (AUC0-24h) at the recommended dose).

In a male fertility study, olaparib had no effect on mating and fertility in rats at oral doses up to 40 mg/kg/day following at least 70 days of olaparib treatment (with systemic exposures of approximately 5% of the human exposure (AUC0-24h) at the recommended dose).

Use In Specific Populations

Pregnancy

Risk Summary

Based on findings in animals and its mechanism of action [see CLINICAL PHARMACOLOGY], Lynparza can cause fetal harm when administered to a pregnant woman. There are no available data on Lynparza use in pregnant women to inform the drug-associated risk. In an animal reproduction study, the administration of olaparib to pregnant rats during the period of organogenesis caused teratogenicity and embryo-fetal toxicity at exposures below those in patients receiving the recommended human dose of 300 mg twice daily (see Data). Apprise pregnant women of the potential hazard to the fetus and the potential risk for loss of the pregnancy.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. The estimated background risk in the U.S. general population of major birth defects is 2-4%; and the risk for spontaneous abortion is approximately 15-20% in clinically recognized pregnancies.

Data

Animal Data

In a fertility and early embryonic development study in female rats, olaparib was administered orally for 14 days before mating through to Day 6 of pregnancy, which resulted in increased post-implantation loss at a dose level of 15 mg/kg/day (with maternal systemic exposures approximately 7% of the human exposure (AUC0-24h) at the recommended dose).

In an embryo-fetal development study, pregnant rats received oral doses of 0.05 and 0.5 mg/kg/day olaparib during the period of organogenesis. A dose of 0.5 mg/kg/day (with maternal systemic exposures approximately 0.18% of human exposure (AUC0-24h) at the recommended dose) caused embryo-fetal toxicities including increased post-implantation loss and major malformations of the eyes (anophthalmia, microphthalmia), vertebrae/ribs (extra rib or ossification center; fused or absent neural arches, ribs, and sternebrae), skull (fused exoccipital) and diaphragm (hernia). Additional abnormalities or variants included incomplete or absent ossification (vertebrae/sternebrae, ribs, limbs) and other findings in the vertebrae/sternebrae, pelvic girdle, lung, thymus, liver, ureter and umbilical artery. Some findings noted above in the eyes, ribs and ureter were observed at a dose of 0.05 mg/kg/day olaparib at lower incidence.

Lactation

Risk Summary

No data are available regarding the presence of olaparib in human milk, or on its effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in the breastfed infants from Lynparza, advise a lactating woman not to breastfeed during treatment with Lynparza and for one month after receiving the last dose.

Females And Males Of Reproductive Potential

Pregnancy Testing

Recommend pregnancy testing for females of reproductive potential prior to initiating treatment with Lynparza.

Contraception

Females

Lynparza can cause fetal harm when administered to a pregnant woman [see Pregnancy]. Advise females of reproductive potential to use effective contraception during treatment with Lynparza and for at least 6 months following the last dose.

Males

Based on findings in genetic toxicity and animal reproduction studies, advise male patients with female partners of reproductive potential or who are pregnant to use effective contraception during treatment and for 3 months following the last dose of Lynparza. Advise male patients not to donate sperm during therapy and for 3 months following the last dose of Lynparza [see Pregnancy and Nonclinical Toxicology].

Pediatric Use

Safety and effectiveness of Lynparza have not been established in pediatric patients.

Geriatric Use

Of the 1585 patients with advanced solid tumors who received Lynparza tablets 300 mg orally twice daily as monotherapy, 443 (28%) patients were aged ≥65 years, and this included 109 (7%) patients who were aged ≥75 years. Six (0.4%) patients were aged ≥85 years.

Of the 535 patients with advanced solid tumors who received Lynparza tablets 300 mg orally twice daily in combination with bevacizumab, 204 (38%) patients were aged ≥65 years, and this included 31 (6%) patients who were aged ≥75 years.

No overall differences in the safety or effectiveness of Lynparza were observed between these patients and younger patients.

Renal Impairment

No dosage modification is recommended in patients with mild renal impairment (CLcr 51 to 80 mL/min estimated by Cockcroft-Gault). Reduce Lynparza dosage to 200 mg twice daily in patients with moderate renal impairment (CLcr 31 to 50 mL/min) [see DOSAGE AND ADMINISTRATION]. There are no data in patients with severe renal impairment or end-stage disease (CLcr ≤30 mL/min) [see CLINICAL PHARMACOLOGY].

Hepatic Impairment

No adjustment to the starting dose is required in patients with mild or moderate hepatic impairment (Child-Pugh classification A and B). There are no data in patients with severe hepatic impairment (Child- Pugh classification C) [see CLINICAL PHARMACOLOGY].

OVERDOSE

No Information provided

CONTRAINDICATIONS

None.

CLINICAL PHARMACOLOGY

Mechanism Of Action

Olaparib is an inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes, including PARP1, PARP2, and PARP3. PARP enzymes are involved in normal cellular functions, such as DNA transcription and DNA repair. Olaparib has been shown to inhibit growth of select tumor cell lines in vitro and decrease tumor growth in mouse xenograft models of human cancer, both as monotherapy or following platinumbased chemotherapy. Increased cytotoxicity and anti-tumor activity following treatment with olaparib were noted in cell lines and mouse tumor models with deficiencies in BRCA and non-BRCA proteins involved in the homologous recombination repair (HRR) of DNA damage and correlated with platinum response. In vitro studies have shown that olaparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes, resulting in DNA damage and cancer cell death.

Pharmacodynamics

Cardiac Electrophysiology

The effect of olaparib on cardiac repolarization was assessed in 119 patients following a single dose of 300 mg and in 109 patients following multiple dosing of 300 mg twice daily. No clinically relevant effect of olaparib on QT interval was observed.

Pharmacokinetics

The area under the curve (AUC) of olaparib increases approximately proportionally following administration of single doses of 25 mg to 450 mg (0.08 to 1.5 times the recommended dose) and maximal concentrations (Cmax) increased slightly less than proportionally for the same dose range.

Olaparib showed time-dependent pharmacokinetics and an AUC mean accumulation ratio of 1.8 is observed at steady state following a dose of 300 mg twice daily.

The mean (CV%) olaparib Cmax is 5.8 μg/mL (36%) and AUC is 42 μg*h/mL(51%) following a single 300 mg dose. The mean steady state olaparib Cmax and AUC is 7.7 μg/mL (40%) and 49 μg*h/mL (52%), following a dose of 300 mg twice daily.

Absorption

Following oral administration of olaparib, the median time to peak plasma concentration is 1.5 hours.

Effect of Food

Co-administration of a high fat and high calorie meal (800-1000 kcal, 50% of the calorie content made up from fat) with olaparib slowed the rate (tmax delayed by 2.5 hours) of absorption, but did not significantly alter the extent of olaparib absorption (mean AUC increased by approximately 8%).

Distribution

The mean (± standard deviation) apparent volume of distribution of olaparib is 158 ± 136 L following a single 300 mg dose of Lynparza. The protein binding of olaparib is approximately 82% in vitro.

Elimination

The mean (± standard deviation) terminal plasma half-life of olaparib is 14.9 ± 8.2 hours and the apparent plasma clearance is 7.4 ± 3.9 L/h following a single 300 mg dose of Lynparza.

Metabolism

Olaparib is metabolized by cytochrome P450 (CYP) 3A in vitro.

Following an oral dose of radiolabeled olaparib to female patients, unchanged olaparib accounted for 70% of the circulating radioactivity in plasma. It was extensively metabolized with unchanged drug accounting for 15% and 6% of radioactivity in urine and feces, respectively. The majority of the metabolism is attributable to oxidation reactions with a number of the components produced undergoing subsequent glucuronide or sulfate conjugation.

Excretion

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

Specific Populations

Patients With Renal Impairment

In a renal impairment trial, the mean AUC increased by 24% and Cmax by 15%, when olaparib was dosed in patients with mild renal impairment (CLcr=51-80 mL/min defined by the Cockcroft-Gault equation; n=13) and by 44% and 26%, respectively, when olaparib was dosed in patients with moderate renal impairment (CLcr=31-50 mL/min; n=13), compared to those with normal renal function (CLcr ≥81 mL/min; n=12). There was no evidence of a relationship between the extent of plasma protein binding of olaparib and creatinine clearance. There are no data in patients with severe renal impairment or end-stage renal disease (CLcr ≤30 mL/min).

Patients With Hepatic Impairment

In a hepatic impairment trial, the mean AUC increased by 15% and the mean Cmax increased by 13% when olaparib was dosed in patients with mild hepatic impairment (Child-Pugh classification A; n=10) and the mean AUC increased by 8% and the mean Cmax decreased by 13% when olaparib was dosed in patients with moderate hepatic impairment (Child-Pugh classification B; n=8), compared to patients with normal hepatic function (n=13). Hepatic impairment had no effect on the protein binding of olaparib and, therefore, total plasma exposure was representative of free drug. There are no data in patients with severe hepatic impairment (Child-Pugh classification C).

Drug Interaction Studies

Clinical Studies

CYP3A Inhibitors

Concomitant use of itraconazole (strong CYP3A inhibitor) increased olaparib Cmax by 42% and AUC by 170%. Concomitant use of fluconazole (moderate CYP3A inhibitor) is predicted to increase olaparib Cmax by 14% and AUC by 121%.

CYP3A Inducers

Concomitant use of rifampicin (strong CYP3A inducer) decreased olaparib Cmax by 71% and AUC by 87%. Concomitant use of efavirenz (moderate CYP3A inducer) is predicted to decrease olaparib Cmax by 31% and AUC by 60%.

In Vitro Studies

CYP Enzymes

Olaparib is both an inhibitor and inducer of CYP3A and an inducer of CYP2B6. Olaparib is predicted to be a weak CYP3A inhibitor in humans.

UGT Enzymes

Olaparib is an inhibitor of UGT1A1.

Transporters

Olaparib is an inhibitor of BCRP, OATP1B1, OCT1, OCT2, OAT3, MATE1, and MATE2K. Olaparib is a substrate and inhibitor of the efflux transporter P-gp. The potential for olaparib to induce P-gp has not been evaluated.

Clinical Studies

First-Line Maintenance Treatment Of BRCA-Mutated Advanced Ovarian Cancer

Solo-1

The efficacy of Lynparza was evaluated in SOLO-1 (NCT01844986), a randomized (2:1), double-blind, placebo-controlled, multi-center trial in patients with BRCA-mutated advanced ovarian, fallopian tube, or primary peritoneal cancer following first-line platinum-based chemotherapy. Patients were randomized to receive Lynparza tablets 300 mg orally twice daily or placebo. Treatment was continued for up to 2 years or until disease progression or unacceptable toxicity; however, patients with evidence of disease at 2 years, who in the opinion of the treating healthcare provider could derive further benefit from continuous treatment, could be treated beyond 2 years. Randomization was stratified by response to first-line platinum-based chemotherapy (complete or partial response). The major efficacy outcome was investigator-assessed progression-free survival (PFS) evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1.

A total of 391 patients were randomized, 260 to Lynparza and 131 to placebo. The median age of patients treated with Lynparza was 53 years (range: 29 to 82) and 53 years (range: 31 to 84) among patients on placebo. The ECOG performance status (PS)was 0 in 77% of patients receiving Lynparza and 80% of patients receiving placebo. Of all patients, 82% were White, 36% were enrolled in the U.S. or Canada, and 82% were in complete response to their most recent platinum-based regimen. The majority of patients (n=389) had germline BRCA mutation (gBRCAm), and 2 patients had somatic BRCAm (sBRCAm).

Of the 391 patients randomized in SOLO-1, 386 were retrospectively or prospectively tested with a Myriad BRACAnalysis test and 383 patients were confirmed to have deleterious or suspected deleterious gBRCAm status; 253 were randomized to the Lynparza arm and 130 to the placebo arm. Two out of 391 patients randomized in SOLO-1 were confirmed to have sBRCAm based on an investigational Foundation Medicine tissue test.

SOLO-1 demonstrated a statistically significant improvement in investigator-assessed PFS for Lynparza compared to placebo. Results from a blinded independent review were consistent. At the time of the analysis of PFS, overall survival (OS) data were not mature (21% of patients had died). Efficacy results are presented in Table 15 and Figure 1.

Table 15: EfficacyResults – SOLO-1 (InvestigatorAssessment)

Figure 1: Kaplan-Meier Curves of Investigator-Assessed Progression-Free Survival - SOLO-1

First-Line Maintenance Treatment Of Advanced Ovarian Cancer In Combination With Bevacizumab

Paola-1

PAOLA-1 (NCT03737643) was a randomized, double-blind, placebo-controlled, multi-center trial that compared the efficacy of Lynparza in combination with bevacizumab versus placebo/bevacizumab for the maintenance treatment of advanced high-grade epithelial ovarian cancer, fallopian tube or primary peritoneal cancer following first-line platinum-based chemotherapy and bevacizumab. Randomization was stratified by first-line treatment outcome (timing and outcome of cytoreductive surgery and response to platinum-based chemotherapy) and tBRCAm status, determined by prospective local testing. All available clinical samples were retrospectively tested with Myriad myChoice® CDx. Patients were required to have no evidence of disease (NED) due to complete surgical resection, or who were in complete response (CR), or partial response (PR) following completion of first-line platinum-containing chemotherapy and bevacizumab. Patients were randomized (2:1) to receive Lynparza tablets 300 mg orally twice daily in combination with bevacizumab (n=537) 15 mg/kg every three weeks or placebo/bevacizumab (n=269) Patients continued bevacizumab in the maintenance setting and started treatment with Lynparza after a minimum of 3 weeks and up to a maximum of 9 weeks following completion of their last dose of chemotherapy. Lynparza treatment was continued for up to 2 years or until progression of the underlying disease or unacceptable toxicity. Patients who in the opinion of the treating physician could derive further benefit from continuous treatment could be treated beyond 2 years. Treatment with bevacizumab was for a total of up to 15 months, including the period given with chemotherapy and given as maintenance.

The major efficacy outcome measure was investigator-assessed PFS evaluated according to RECIST, version 1.1. An additional efficacy endpoint was overall survival (OS).

The median age of patients in both arms was 61 years overall (range 26 to 87). Ovarian cancer was the primary tumor type in 86% of patients in both arms. Ninety six percent (96%) were serous histological type. The ECOG performance score was 0 in 70% of patients and 1 in 28% of patients, overall. All patients had received first-line platinum-based therapy and bevacizumab. First-line treatment outcomes at screening indicated that patients had no evidence of disease with complete macroscopic resection at initial debulking surgery (32%, both arms), no evidence of disease/ CR with complete macroscopic resection at interval debulking surgery (31%, both arms), no evidence of disease/ CR in patients who had either incomplete resection (at initial or interval debulking surgery) or no debulking surgery (15%, both arms) and patients with a partial response (22%, both arms). Thirty percent (30%) of patients in both arms had a deleterious mutation. Patients were not restricted by the surgical outcome with 65% having complete cytoreduction at initial or interval debulking surgery and 35% having residual macroscopic disease. Demographics and baseline disease characteristics were balanced and comparable between the study and placebo arms in the Intention to Treat (ITT) population and also in the HRD positive subgroup.

Efficacy results from a biomarker subgroup analysis of 387 patients with HRD positive tumors, identified post-randomization using the Myriad myChoice® HRD Plus tumor test, who received Lynparza/bevacizumab (n=255) or placebo/bevacizumab (n=132), are summarized in Table 16 and Figure 2. Results from a blinded independent review of PFS were consistent. Overall survival data in this subpopulation were immature with 16% deaths.

Table 16: EfficacyResults – PAOLA-1 (HRD positive status*, InvestigatorAssessment)

Figure 2: Kaplan-Meier Curves of Investigator-Assessed Progression-Free Survival – PAOLA-1 (HRD positive status)

Maintenance Treatment Of Recurrent Ovarian Cancer

The efficacy of Lynparza was investigated in two randomized, placebo-controlled, double-blind, multicenter studies in patients with recurrent ovarian cancers who were in response to platinum-based therapy.

SOLO-2

The efficacy of Lynparza was evaluated in SOLO-2 (NCT01874353), a randomized (2:1) double-blind, placebo-controlled trial in patients with gBRCAm ovarian, fallopian tube, or primary peritoneal cancer. Patients were randomized to Lynparza tablets 300 mg orally twice daily or placebo until unacceptable toxicity or progressive disease. Randomization was stratified by response to last platinum chemotherapy (complete versus partial) and time to disease progression in the penultimate platinum-based chemotherapy prior to enrollment (6-12 months versus >12 months). All patients had received at least two prior platinum-containing regimens and were in response (complete or partial) to their most recent platinum-based regimen. The major efficacy outcome measure was investigator-assessed PFS evaluated according to RECIST, version 1.1. An additional efficacy outcome measure was OS.

A total of 295 patients were randomized, 196 to Lynparza and 99 to placebo. The median age of patients treated with Lynparza was 56 years (range: 28 to 83) and 56 years (range: 39 to 78) among patients treated with placebo. The ECOG PS was 0 in 83% of patients receiving Lynparza and 78% of patients receiving placebo. Of all patients, 89% were White, 17% were enrolled in the U.S. or Canada, 47% were in complete response to their most recent platinum-based regimen, and 40% had a progression-free interval of 6-12 months since their penultimate platinum regimen. Prior bevacizumab therapy was reported for 17% of those treated with Lynparza and 20% of those receiving placebo. Approximately 44% of patients on the Lynparza arm and 37% on placebo had received three or more lines of platinum-based treatment.

All patients had a deleterious or suspected deleterious germline BRCA mutation as detected either by a local test (n=236) or central Myriad CLIA test (n=59), subsequently confirmed by BRACAnalysis CDx® (n=286).

SOLO-2 demonstrated a statistically significant improvement in investigator-assessed PFS in patients randomized to Lynparza as compared with placebo. Results from a blinded independent review were consistent. At the time of the analysis of PFS, OS data were not mature with 24% of events. Efficacy results are presented in Table 17 and Figure 3.

Table 17: EfficacyResults – SOLO-2 (InvestigatorAssessment)

Figure 3: Kaplan-Meier Curves of Investigator-Assessed Progression-Free Survival – SOLO-2

Study 19

The efficacy of Lynparza was evaluated in Study 19 (NCT00753545), a randomized (1:1) double-blind, placebo-controlled trial in patients with platinum-sensitive ovarian cancer who had received 2 or more previous platinum-containing regimens. Patients were randomized to Lynparza capsules 400 mg orally twice daily or placebo until unacceptable toxicity or progressive disease. Randomization was stratified by response to last platinum chemotherapy (complete response versus partial response), time to disease progression in the penultimate platinum-based chemotherapy (6-12 months versus >12 months), and descent (Jewish versus non-Jewish). The major efficacy outcome measure was investigator-assessed PFS according to RECIST, version 1.0.

A total of 265 patients were randomized, 136 to Lynparza and 129 to placebo. The median age of patients treated with Lynparza was 58 years (range: 21 to 89) and 59 years (range 33 to 84) among patients treated with placebo. ECOG PS was 0 in 81% of patients receiving Lynparza and 74% of patients receiving placebo. Of all patients, 97% were White, 19% were enrolled in the US or Canada, 45% were in complete response following their most recent platinum chemotherapy regimen, and 40% had a progression-free interval of 6-12 months since their penultimate platinum. Prior bevacizumab therapy was reported for 13% of patients receiving Lynparza and 16% of patients receiving placebo.

A retrospective analysis for germline BRCA mutation status, some performed using the Myriad test, indicated that 36% (n=96) of patients from the ITT population had deleterious gBRCA mutation, including 39% (n=53) of patients on Lynparza and 33% (n=43) of patients on placebo.

Efficacy results are presented in Table 18 and Figure 4. Study 19 demonstrated a statistically significant improvement in investigator-assessed PFS in patients treated with Lynparza versus placebo.

Table 18: EfficacyResults - Study 19 (InvestigatorAssessment)

Figure 4: Kaplan-Meier Curves of Investigator-Assessed Progression-Free Survival – Study 19

AdvancedGermline BRCA-Mutated Ovarian Cancer Treated With 3 Or More Prior Lines Of Chemotherapy

The efficacy of Lynparza was investigated in a single-arm study of patients with deleterious or suspected deleterious gBRCAm advanced cancers. A total of 137 patients with measurable, advanced gBRCAm ovarian cancer treated with three or more prior lines of chemotherapy were enrolled. All patients received Lynparza capsules 400 mg orally twice daily until disease progression or intolerable toxicity. The efficacy outcome measures were objective response rate (ORR) and duration of response (DOR) as assessed by the investigator according to RECIST, version 1.0.

The median age of the patients was 58 years, the majority were White (94%) and 93% had an ECOG PS of 0 or 1. Deleterious or suspected deleterious gBRCAm status was verified retrospectively in 97% (59/61) of the patients for whom blood samples were available by the BRACAnalysis CDxTM.

Efficacy results are summarized in Table 19.

Table 19: Overall Response and Duration of Response in Patients with gBRCA-Mutated Advanced Ovarian Cancer Who Received 3 or More Lines of Chemotherapy

Treatment Of Germline BRCA-Mutated HER2-Negative Metastatic Breast Cancer

OlympiAD

The efficacy of Lynparza was evaluated in OlympiAD (NCT02000622), an open-label randomized (2:1) study in patients with gBRCAm HER2-negative metastatic breast cancer. Patients were required to have received treatment with an anthracycline (unless contraindicated) and a taxane, in the neoadjuvant, adjuvant or metastatic setting. Patients with hormone receptor-positive disease must have progressed on at least 1 endocrine therapy (adjuvant or metastatic), or have disease that the treating healthcare provider believed to be inappropriate for endocrine therapy. Patients with prior platinum therapy were required to have no evidence of disease progress during platinum treatment. No prior treatment with a PARP inhibitor was permitted. Patients were randomized to Lynparza tablets 300 mg orally twice daily or healthcare provider’s choice of chemotherapy (capecitabine, eribulin, or vinorelbine, at standard doses) until progression or unacceptable toxicity. Randomization was stratified by prior use of chemotherapy for metastatic disease (yes vs no), hormone receptor status (hormone receptor positive vs triple negative), and previous use of platinum-based chemotherapy (yes vs no). The major efficacy outcome measure was PFS assessed by blinded independent central review (BICR) using RECIST version 1.1.

A total of 302 patients were randomized, 205 to Lynparza and 97 to chemotherapy. Among the 205 patients treated with Lynparza, the median age was 44 years (range: 22 to 76), 65% were White, 4% were males and all the patients had an ECOG PS of 0 or 1. Approximately 50% of patients had triple-negative tumors and 50% had estrogen receptor and/or progesterone receptor positive tumors and the proportions were balanced across treatment arms. Patients in each treatment arm had received a median of 1 prior chemotherapy regimen for metastatic disease; approximately 30% had not received a prior chemotherapy regimen for metastatic breast cancer. Twenty-one percent of patients in the Lynparza arm and 14% in the chemotherapy arm had received platinum therapy for metastatic disease. Seven percent of patients in each treatment arm had received platinum therapy for localized disease.

Of the 302 patients randomized onto OlympiAD, 299 were tested with the BRACAnalysis CDx® and 297 were confirmed to have deleterious or suspected deleterious gBRCAm status; 202 were randomized to the Lynparza arm and 95 to the healthcare provider’s choice of chemotherapy arm.

A statistically significant improvement in PFS was demonstrated for the Lynparza arm compared to the chemotherapy arm. Efficacy data for OlympiAD are displayed in Table 20 and Figure 5. Consistent results were observed across patient subgroups defined by study stratification factors. An exploratory analysis of investigator-assessed PFS was consistent with the BICR-assessed PFS results.

Table 20: EfficacyResults - OlympiAD (BICR-assessed)

Figure 5: Kaplan-Meier Curves of Progression-Free Survival – OlympiAD

First-Line Maintenance Treatment Of Germline BRCA-Mutated Metastatic Pancreatic Adenocarcinoma

Polo

The efficacy of Lynparza was evaluated in POLO (NCT02184195), a randomized (3:2), double-blind placebo-controlled, multi-center trial. Patients were required to have metastatic pancreatic adenocarcinoma with a deleterious or suspected deleterious germline BRCA mutation (gBRCAm) and absence of disease progression after receipt of first-line platinum-based chemotherapy for at least 16 weeks. Patients were randomized to receive Lynparza tablets 300 mg orally twice daily or placebo until disease progression or unacceptable toxicity. The major efficacy outcome measure was PFS by BICR using RECIST, version 1.1 modified to assess patients with clinical complete response at entry who were assessed as having no evidence of disease unless they had progressed based on the appearance of new lesions. Additional efficacy outcome measures were OS and ORR.

A total of 154 patients were randomized, 92 to Lynparza and 62 to placebo. The median age was 57 years (range 36 to 84); 54% were male; 92% were White, 4% were Asian and 3% were Black; baseline ECOG PS was 0 (67%) or 1 (31%). The median time from initiation of first-line platinum-based chemotherapy to randomization was 5.8 months (range 3.4 to 33.4 months). Seventy-five percent (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; 49% achieved a complete or partial response to platinum-based chemotherapy.

All patients had a deleterious or suspected deleterious germline BRCA-mutation as detected by the Myriad BRACAnalysis® or BRACAnalysis CDx® at a central laboratory only (n=106), local BRCA test only (n=4), or both local and central testing (n=44). Among the 150 patients with central test results, 30% had a mutation in BRCA1; 69% had a mutation in BRCA2; and 1 patient (1%) had mutations in both BRCA1 and BRCA2.

Efficacy results of POLO are provided in Table 21 and Figure 6.

Table 21: EfficacyResults - POLO (BICR-assessed)

The result of an OS interim analysis conducted based on 67% information fraction did not show a statistically significant improvement in OS for Lynparza compared to placebo.

Figure 6: Kaplan-Meier Curves of BICR-Assessed Progression-Free Survival - POLO

PATIENT INFORMATION

Lynparza®
(Lin-par-zah)
(olaparib) tablets

What is the most important information I should know about Lynparza?

Lynparza may cause serious side effects, including:

Bone marrow problems called Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukemia (AML). Some people who have ovarian cancer or breast cancer and who have received previous treatment with chemotherapy, radiotherapy or certain other medicines for their cancer have developed MDS or AML during treatment with Lynparza.MDS or AML may lead to death. If you develop MDS or AML, your healthcare provider will stop treatment with Lynparza.

Symptoms of low blood cell counts are common during treatment with Lynparza, but can be a sign of serious bone marrow problems, including MDS or AML. Symptoms may include:

• weakness
• weight loss
• fever
• frequent infections
• blood in urine or stool
• shortness of breath
• feeling very tired
• bruising or bleeding more easily

Your healthcare provider will do blood tests to check your blood cell counts:

• before treatment with Lynparza
• every month during treatment with Lynparza
• weekly if you have low blood cell counts that last a long time. Your healthcare provider may stop treatment with Lynparza until your blood cell counts improve.

Lung problems (pneumonitis). Tell your healthcare provider if you have any new or worsening symptoms of lung problems, including shortness of breath, fever, cough, or wheezing. Your healthcare provider may do a chest x-ray if you have any of these symptoms. Your healthcare provider may temporarily or completely stop treatment if you develop pneumonitis. Pneumonitis may lead to death.

What is Lynparza?

Lynparza is a prescription medicine used to treat adults who have:

• advanced ovarian cancer, fallopian tube cancer, or primary peritoneal cancer with a certain type of inherited (germline) or acquired (somatic) abnormal BRCA gene. Lynparza is used alone as maintenance treatment after the cancer has responded to your first treatment with platinum-based chemotherapy. Your healthcare provider will perform a test to make sure that Lynparza is right for you.
• advanced ovarian cancer, fallopian tube cancer or primary peritoneal cancer with a certain type of abnormal BRCA gene or a positive laboratory tumor test for genomic instability called HRD. Lynparza is used in combination with another anti-cancer medicine, bevacizumab, as maintenance treatment after the cancer has responded to your first treatment with platinum-based chemotherapy. Your healthcare provider will perform a test to make sure that Lynparza is right for you.
• ovarian cancer, fallopian tube cancer, or primary peritoneal cancer, as maintenance treatment, when the cancer has come back. Lynparza is used after the cancer has responded to treatment with platinum-based chemotherapy.
• advanced ovarian cancer with a certain type of abnormal inherited BRCA gene, and have received treatment with 3 or more prior types of chemotherapy medicines. Your healthcare provider will perform a test to make sure that Lynparza is right for you.
• a certain type of abnormal inherited BRCA gene, human epidermal growth factor receptor 2 (HER2)-negative breast cancer that has spread to other parts of the body (metastatic). You should have received chemotherapy medicines, either before or after your cancer has spread. If you have hormone receptor (HR)-positive disease, you should have been treated with hormonal therapy. Your healthcare provider will perform a test to make sure that Lynparza is right for you.
• metastatic pancreatic cancer with a certain type of abnormal inherited BRCA gene. Lynparza is used as maintenance treatment after your cancer has not progressed on at least 16 weeks of treatment with platinum-based chemotherapy. Your healthcare provider will perform a test to make sure that Lynparza is right for you.

It is not known if Lynparza is safe and effective in children.

Before taking Lynparza, tell your healthcare provider about all of your medical conditions,including if you:

• have lung or breathing problems
• have kidney problems
• are pregnant, become pregnant, or plan to become pregnant. Lynparza can harm your unborn baby and may cause loss of pregnancy (miscarriage).
  • If you are able to become pregnant, your healthcare provider may do a pregnancy test before you start treatment with Lynparza.
  • Females who are able to become pregnant should use effective birth control (contraception) during treatment with Lynparza and for 6 months after the last dose of Lynparza. Talk to your healthcare provider about birth control methods that may be right for you. Tell your healthcare provider right away if you become pregnant or think you might be pregnant following treatment with Lynparza.
  • Males with female partners who are pregnant or able to become pregnant should use effective birth control (contraception) during treatment with Lynparza and for 3 months after the last dose of Lynparza.
  • Do not donate sperm during treatment with Lynparza and for 3 months after your final dose.
• are breastfeeding or plan to breastfeed. It is not known if Lynparza passes into your breast milk. Do not breastfeed during treatment with Lynparza and for 1 month after receiving the last dose of Lynparza. Talk to your healthcare provider about the best way to feed your baby during this time.

Tell your healthcare provider about all the medicines you take, including prescription and over-thecounter medicines, vitamins, and herbal supplements. Taking Lynparza and certain other medicines may affect how Lynparza works and may cause side effects.

How should I take Lynparza?

Your healthcare provider may temporarily stop treatment with Lynparza or change your dose of Lynparza if you experience side effects.

• Take Lynparza tablets exactly as your healthcare provider tells you.
• Do not change your dose or stop taking Lynparza unless your healthcare provider tells you to.
• Your healthcare provider will decide how long you stay on treatment.
• Do not take more than 4 Lynparza tablets in 1 day. If you have any questions about Lynparza, please talk to your healthcare provider or pharmacist.
• Take Lynparza by mouth 2 times a day.
• Each dose should be taken about 12 hours apart.
• Swallow Lynparza tablets whole. Do not chew, crush, dissolve, or divide the tablets.
• Take Lynparza with or without food.
• If you miss a dose of Lynparza, take your next dose at your usual scheduled time. Do not take an extra dose to make up for a missed dose.
• If you take too much Lynparza, call your healthcare provider or go to the nearest hospital emergency room right away.

What should I avoid while taking Lynparza?

Avoid grapefruit, grapefruit juice, Seville oranges and Seville orange juice during treatment with Lynparza since they may increase the level of Lynparza in your blood.

What are the possible side effects of Lynparza?

Lynparza may cause serious side effects.

See “What is the most important information I should know about Lynparza?”

The most common side effects of Lynparza are:

• nausea or vomiting. Tell your healthcare provider if you get nausea or vomiting. Your healthcare provider may prescribe medicines to treat these symptoms.
  • low number of red or white blood cells
  • stomach-area (abdominal) pain
  • dizziness
  • tiredness or weakness
  • sore throat or runny nose
  • diarrhea
  • joint, muscle, and back pain
  • headache
  • constipation
  • mouth sores
  • respiratory tract infections
  • changes in kidney function blood test
  • changes in the way food tastes
  • loss of appetite
  • low number of platelets
  • indigestion or heartburn

These are not all of the possible side effects of Lynparza.

Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Lynparza?

• Store Lynparza at room temperature, between 68°F to 77°F (20°C to 25°C).
• Store Lynparza in the original bottle to protect it from moisture.

Keep Lynparza and all medicines out of the reach of children.

General information about the safe and effective use of Lynparza.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Lynparza for a condition for which it was not prescribed. Do not give Lynparza to other people, even if they have the same symptoms you have. It may harm them.

You can ask your healthcare provider or pharmacist for information about Lynparza that is written for health professionals.

What are the ingredients in Lynparza?

Active ingredient: olaparib

Inactive ingredients:

Tablet contains: copovidone, mannitol, colloidal silicon dioxide and sodium stearyl fumarate Tablet coating contains: hypromellose, polyethylene glycol 400, titanium dioxide, ferric oxide yellow and ferrosoferric oxide (150 mg tablet only)

This Medication Guide has been approved by the U.S. Food and Drug Administration.