LYNPARZA

Olaparib is a selective and potent inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes, PARP1 and PARP2. 8, 9, 13 PARP inhibitors represent a novel class of anti-cancer therapy and they work by taking advantage of a defect in DNA repair in cancer cells with BRCA mutations and inducing cell death.

Olaparib is used to treat a number of BRCA-associated tumours, including ovarian cancer, breast cancer, pancreatic cancer, and prostate cancer. 8, 9, 13 It was first approved by the FDA and EU in December and by Health Canada in April 2016.

Ovarian cancer

Olaparib is indicated for the maintenance treatment of adults 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. 8, 11 Olaparib is indicated in combination with bevacizumab for the maintenance treatment of adults 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. 8, 11 Olaparib 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. 8, 11 Breast cancer Olaparib is indicated for the adjuvant treatment of adult patients with deleterious or suspected deleterious g BRCA m human epidermal growth factor receptor 2 (HER2)-negative high risk early breast cancer who have been treated with neoadjuvant or adjuvant chemotherapy. 8, 11, 12 Olaparib is indicated for the treatment of adult patients with deleterious or suspected deleterious g BRCA m, 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. 8, 11 Pancreatic cancer Olaparib 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. 8, 11 Prostate cancer Olaparib is indicated for the treatment of adult patients with deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC) who have progressed following prior treatment with a hormone agent, 11 such as enzalutamide or abiraterone.

It is also indicated in combination with abiraterone and prednisone or prednisolone for the treatment of adult patients with deleterious or suspected deleterious BRCA-mutated (BRCAm) metastatic castration-resistant prostate cancer (mCRPC).

Olaparib is a cytotoxic and anti-tumour agent.

Olaparib inhibits the growth of selective tumour cell lines in vitro and decreases tumour growth in mouse xenograft models of human cancer, both as monotherapy or following platinum-based chemotherapy.

The drug exerts anti-tumour effects in cell lines and mouse tumour models with deficiencies in BRCA1/2, ATM, or other genes involved in the homologous recombination repair (HRR) of DNA damage and correlated with platinum response.

In preclinical models of cancer, olaparib demonstrated anti-tumour activity when used alone, in combination with chemotherapeutic agents, or radiotherapy.

Olaparib can act as a chemosensitizer to potentiate the cytotoxicity of DNA-damaging chemotherapeutic agents such as alkylating agents and platinum-based drugs.

It can also act as a radiosensitizer by preventing PARP-mediated DNA repair. 2, 4.

Poly polymerase 1 Inhibitor Poly polymerase 2 Inhibitor Protein mono-ADP-ribosyltransferase PARP3 Inhibitor.

Following oral administration, olaparib is rapidly absorbed.

After administration of a single 300 mg dose of olaparib, the mean (CV%) C max was 5.4 μg/mL (32%) and AUC was 39.2 μg x h/mL (44%).

The steady state C max and

AUC following a dose of 300 mg twice daily was 7.6 μg/mL (35%) and 49.2 μg x h/mL (44%), respectively.

T max is 1.5 hours.

A high-fat and high-calorie meal may delay T max, but does not significantly alter the extent of olaparib absorption.

The mean (± standard deviation) apparent volume of distribution of olaparib is 158 ± 136 L following a single 300 mg dose.

Olaparib is metabolized by cytochrome

P450 (CYP) 3A4/5 in vitro.

Following an oral dose of radiolabeled olaparib to female patients, unchanged olaparib accounted for 70% of the circulating radioactivity in plasma.

Olaparib undergoes oxidation reactions as well as subsequent glucuronide or sulfate conjugation.

In humans, olaparib can also undergo hydrolysis, hydroxylation, and dehydrogenation.

While up to 37 metabolites of olaparib were detected in plasma, urine, and feces, the majority of metabolites represent less than 1% of the total administered dose and they have not been fully characterized.

The major circulating metabolites are a ring-opened piperazin-3-ol moiety and two mono-oxygenated metabolites.

The pharmacodynamic activity of the metabolites is unknown.

Hover over products below to view reaction partners Olaparib Olaparib M1 metabolite Olaparib M10 metabolite Olaparib M12 metabolite.

Following a single dose of radiolabeled olaparib, 86% of the dosed radioactivity was recovered within a seven-day collection period, mostly in the form of metabolites.

About 44% of the drug was excreted via the urine and 42% of the dose was excreted via the feces.

Following an oral dose of radiolabeled olaparib to female patients, the unchanged drug accounted for 15% and 6% of the radioactivity in urine and feces, respectively.

Following a single oral dose in patients with cancer, the mean terminal half-life was 6.10 hours.

Following a single oral dose in patients with cancer, the mean apparent plasma clearance was 4.55 L/h.

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The oral

LD in rats is approximately 240-300 mg/kg.

There is limited information regarding the overdose of olaparib.

• Recommended dosage is 300 mg taken orally twice daily with or without food.

Information for the recommended duration.

• Patients receiving Lynparza for mCRPC should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy.

• For moderate renal impairment (CLcr 31-50 mL/min), reduce Lynparza dosage to 200 mg orally twice daily. 2.1 Patient Selection Information on FDA-approved tests for the detection of genetic mutations is available at.

Select patients for treatment with

Lynparza based on the presence of deleterious or suspected deleterious HRR gene mutations, including BRCA mutations, or genomic instability based on the indication, biomarker, and sample type (Table 1).

Table 1 Biomarker Testing for Patient Selection Where testing fails or tissue sample is unavailable/insufficient, or when germline testing is negative, consider using an alternative test, if available.

Indication Biomarker Sample type Tumor Blood

Plasma (ctDNA) First-line maintenance treatment of germline or somatic BRCAm advanced ovarian cancer BRCA1 m, BRCA2 m X X First-line maintenance treatment of HRD-positive advanced ovarian cancer in combination with bevacizumab BRCA1 m, BRC A2m and/or genomic instability X Maintenance treatment of germline or somatic BRCA m recurrent ovarian cancer BRCA1 m, BRCA2 m X X Adjuvant treatment of gBRCA m HER2-negative high risk early breast cancer gBRCA1 m, gBRCA2 m X g BRCA m HER2-negative metastatic breast cancer gBRCA1 m, gBRCA2 m X First-line maintenance treatment of germline BRCA -mutated metastatic pancreatic adenocarcinoma gBRCA1 m, gBRCA2 m X Germline or somatic HRR gene-mutated metastatic castration-resistant prostate cancer ATM m, BRCA1 m, BRCA2 m, BARD1 m, BRIP1 m, CDK12 m, CHEK1 m, CHEK2 m, FANCL m, PALB2 m, RAD51B m, RAD51C m, RAD51D m, RAD54L m X g BRCA1 m, g BRCA2 m X ATM m, BRCA1 m, BRCA2 m X BRCA -mutated metastatic castration-resistant prostate cancer in combination with abiraterone and prednisone or prednisolone BRCA1 m, BRCA2 m X X X 2.2 Recommended Dosage The recommended dosage of Lynparza is 300 mg taken orally twice daily, with or without food.

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.

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 HRD-positive Advanced Ovarian Cancer in Combination with Bevacizumab Continue Lynparza treatment until disease progression, unacceptable toxicity, or completion of 2 years of 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.

Information for bevacizumab when used in combination with Lynparza for more information.

Adjuvant Treatment of Germline BRCA -mutated

HER2-negative High Risk Early Breast Cancer Continue treatment for a total of 1 year, or until disease recurrence, or unacceptable toxicity, whichever occurs first.

Patients receiving Lynparza for hormone receptor positive HER2-negative breast cancer should continue concurrent treatment with endocrine therapy as per current clinical practice guidelines.

• Maintenance treatment of germline or somatic BRCA -mutated recurrent ovarian cancer.

• Germline BRCA -mutated HER-2 negative metastatic breast cancer.

• First-line maintenance treatment of germline BRCA -mutated metastatic pancreatic adenocarcinoma.

• HRR gene-mutated metastatic castration-resistant prostate cancer.

BRCA -mutated Metastatic Castration-Resistant Prostate Cancer in Combination with Abiraterone and Prednisone or Prednisolone Continue treatment until disease progression or unacceptable toxicity.

Lynparza, the recommended dose of abiraterone is 1000 mg taken orally once daily.

Abiraterone should be given in combination with prednisone or prednisolone 5 mg orally twice daily.

Information for abiraterone for dosing information.

Patients with mCRPC should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy. 2.3 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. 2.4 Dosage Modifications for Concomitant Use with Strong or Moderate CYP3A Inhibitors Avoid concomitant use of strong or moderate CYP3A inhibitors with Lynparza.

• 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 to 5 elimination half-lives, resume the Lynparza dose taken prior to initiating the CYP3A inhibitor. 2.5 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.

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 20ºC to 25ºC (68ºF to 77ºF), excursions permitted to 15ºC to 30ºC (59ºF to 86ºF) .

Store in original bottle to protect from moisture.

Based on findings in animals and its mechanism of action, 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.

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.

In a fertility and early embryonic development study in female rats, olaparib was administered orally for 14 days before mating through to Day 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 (AUC 0-24h ) 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 (AUC 0-24h ) 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.

Safety and effectiveness of

Lynparza have not been established in pediatric patients.

Of the 2901 patients with advanced solid tumors who received Lynparza as a single agent, 680 (23%) patients were aged ≥65 years, and this included 206 (7%) patients who were aged ≥75 years.

Thirteen (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 (PAOLA-1), 204 (38%) patients were aged ≥65 years, and this included 31 (6%) patients who were aged ≥75 years.

Of the 398 patients with advanced solid tumors who received Lynparza tablets 300 mg orally twice daily in combination with abiraterone and prednisone or prednisolone (PROpel), 268 (67%) patients were aged ≥65 years, and this included 95 (24%) patients who were aged ≥75 years.

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