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Ovarian recurrent olaparib (capsule) SUPERSEDED

This protocol has been superseded due to the availability of superior evidence with the tablet formulation. The preferred protocol is ID 3737 Advanced, metastatic or recurrent olaparib.

Check for clinical trials in this patient group. Link to Australian Clinical Trials website

Multiple formulations: There are two formulations of olaparib available - tablets and capsules - which are not interchangeable and are different strengths and doses. This protocol is for treatment with olaparib capsules only. Read more about transitioning from olaparib capsules to tablets.
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The supportive therapies (e.g. antiemetics, premedications, etc.), infusion times, diluents, volumes and routes of administration, if included, are listed as defaults. They may vary between institutions and can be substituted to reflect individual institutional policy.

Antiemetics if included in the treatment schedule are based upon recommendations from national and international guidelines. These are defaults only and may be substituted to reflect individual institutional policy. Select here for recommended doses of alternative antiemetics.

Continuous treatment
Olaparib (capsule) 400 mg (PO) TWICE a day on an empty stomach, at least two hours before food or one hour after food. If unable to tolerate on an empty stomach can be taken with food.

Continuous until disease progression or unacceptable toxicity

The supportive therapies (e.g. antiemetics, premedications, etc.), infusion times, diluents, volumes and routes of administration, if included, are listed as defaults. They may vary between institutions and can be substituted to reflect individual institutional policy.

Antiemetics if included in the treatment schedule are based upon recommendations from national and international guidelines. These are defaults only and may be substituted to reflect individual institutional policy. Select here for recommended doses of alternative antiemetics.

Continuous treatment
Olaparib (capsule) 400 mg (PO) TWICE a day on an empty stomach, at least two hours before food or one hour after food. If unable to tolerate on an empty stomach can be taken with food.

Continuous until disease progression or unacceptable toxicity

Indications:

  • monotherapy for maintenance treatment of patients with platinum-sensitive relapsed BRCA-mutated high grade serous epithelial ovarian, fallopian tube or primary peritoneal cancer who are in response after at least two courses of platinum-containing regimens.
  • patient must have evidence of a germline class 4 or 5 BRCA1 or BRCA2 mutation.

Cautions:

  • do not initiate olaparib until any haematologic toxicity caused by previous chemotherapy has been resolved.
Caution with oral antineoplastic agents

Select links for information on the safe prescribing, dispensing and administration of orally administered antineoplastic agents. 

Read more about the COSA guidelines and oral anticancer therapy
Emetogenicity LOW

Antiemetics are not routinely required on an ongoing basis; however it is common for patients to experience nausea particularly during the first month of treatment. This is usually self-limiting and resolves within 4 to 6 weeks. Patients should be counselled about this possibility and receive a script for oral antiemetics. Should a patient experience emesis:

Metoclopramide 10 mg three times a day when necessary (maximum of 30 mg/24 hours, up to 5 days) OR

Prochlorperazine 10 mg PO every 6 hours when necessary may be administered.

Read more about preventing antineoplastic induced nausea and vomiting
Pneumonitis

Pneumonitis, including some fatal cases, has been reported in a small number of patients receiving this treatment. Monitor patient for new or worsening respiratory symptoms such as dyspnoea, cough and fever, or a radiological abnormality. If pneumonitis is suspected, this treatment should be withheld and prompt investigation initiated. If pneumonitis is confirmed, this treatment should be discontinued.
Myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML)

Patients may be at an increased risk of myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML). Reported cases in the trials had potential contributing factors, including treatment with other DNA damaging agents, or a history of previous cancer or of bone marrow dysplasia. Hence patients should have regular full blood examination including a blood film while on treatment. Patients with a history of bone marrow dysplasia should not be treated with olaparib.
Blood tests

FBC, EUC and LFTs at baseline and repeat monthly during first year of treatment then as clinically indicated.
Hepatitis B screening and prophylaxis

Routine screening for HBsAg and anti-HBc is NOT usually recommended for patients receiving this treatment.

Read more about hepatitis B screening and prophylaxis in cancer patients requiring cytotoxic and/or immunosuppressive therapy
Vaccinations

Live vaccines, including BCG, MMR, zoster and varicella vaccines, are contraindicated in cancer patients receiving immunosuppressive therapy and/or who have poorly controlled malignant disease.

Refer to the recommended schedule of vaccination for immunocompromised patients, as outlined in the Australian Immunisation Handbook.
Contraception and pregnancy

Pregnancy must be avoided whilst receiving treatment with olaparib. 

Women of child bearing potential must use effective contraception during therapy and continue for one month after receiving the last dose of olaparib. 

Note: olaparib may reduce exposure to CYP3A substrates through enzyme induction, and therefore the efficacy of hormonal contraceptives may be reduced if coadministered with olaparib. 
Evidence for dose modifications is limited, and the recommendations made on eviQ are intended as a guide only. They are generally conservative with an emphasis on safety. Any dose modification should be based on clinical judgement, and the individual patient’s situation including but not limited to treatment intent (curative vs palliative), the antineoplastic regimen (single versus combination therapy versus chemotherapy versus immunotherapy), biology of the cancer (site, size, mutations, metastases), other treatment related side effects, additional co-morbidities, performance status and patient preferences. Suggested dose modifications are based on clinical trial findings, product information and reference committee consensus. Non-haematological gradings are based on Common Terminology Criteria for Adverse Events (CTCAE) unless otherwise specified. Renal and hepatic dose modifications have been standardised where possible. For more information see dosing considerations & disclaimer.
Note:
  • The following dose modification recommendations have been adapted from the study by Ledermannr and by consensus of the reference committee.

Haematological toxicity
ANC x 109/L (at any stage of the cycle) 
less than 1.0

Delay treatment until recovery and consider restarting olaparib as follows:
1stoccurrence: Restart olaparib at 300 mg TWICE a day
2nd occurrence: Restart olaparib at 200 mg TWICE a day
3rd occurrence: Restart olaparib at 100 mg TWICE a day
4thoccurrence: Cease olaparib
Febrile neutropenia Delay treatment until recovery and consider restarting olaparib as follows:
1stoccurrence: Restart olaparib at 300 mg TWICE a day
2ndoccurrence: Restart olaparib at 200 mg TWICE a day
3rd occurrence: Restart olaparib at 100 mg TWICE a day
4thoccurrence: Cease olaparib
Platelets x 109/L (at any stage of the cycle)
less than 75

Delay treatment until recovery and consider restarting olaparib as follows:
1st occurrence: Restart olaparib at 300 mg TWICE a day
2ndoccurrence: Restart olaparib at 200 mg TWICE a day
3rd occurrence: Restart olaparib at 100 mg TWICE a day
4thoccurrence: Cease olaparib
Renal impairment
Creatinine clearance (mL/min)
Mild (CrCl > 50 mL/min) No dose modifications required
Moderate or severe (CrCl <50 mL/min) Not recommended due to limited clinical data. Safety and efficacy have not been established
Hepatic impairment
Hepatic dysfunction
Mild No dose modifications required
Moderate or severe Not recommended due to limited clinical data. Safety and efficacy have not been established
Fatigue

Fatigue is common, especially in the first month(s) of treatment and generally improves with ongoing therapy. Alternative explanations of fatigue should be excluded or managed appropriately. Graded exercise is recommended as a management strategy.

For severe, persistent fatigue, consider a short treatment interruption and/or a reduction in dose if persistent despite treatment breaks
Grade 1 or 2 Continue with treatment
Grade 3 Delay treatment until recovery and consider restarting olaparib as follows:
1stoccurrence: Restart olaparib at 300 mg TWICE a day
2ndoccurrence: Restart olaparib at 200 mg TWICE a day
3rd occurrence: Restart olaparib at 100 mg TWICE a day
4thoccurrence: Cease olaparib
Diarrhoea
Grade 1 or 2 Continue with treatment
Grade 3 or 4 Delay treatment until recovery and consider restarting olaparib as follows:
1stoccurrence: Restart olaparib at 300 mg TWICE a day
2ndoccurrence: Restart olaparib at 200 mg TWICE a day
3rd occurrence: Restart olaparib at 100 mg TWICE a day
4thoccurrence: Cease olaparib
Nausea and vomiting
Nausea and vomiting May be moderate to severe in the first month after initiation of treatment however dose modifications are not normally required. Antiemetics eg. metoclopramide pre-dosing and reassurance that side effects will subside over time are normally sufficient. If not settling with appropriate supportive care then should consider dose reductions as for other toxicities.

References & Disclaimer

Olaparib
  Interaction Clinical management
CYP3A4 and P-gp inhibitors (e.g. amiodarone, aprepitant, azole-antifungals, ritonavir, lapatinib, nilotinib, sorafenib, macrolides, ciclosporin, grapefruit juice, Seville oranges etc.) Increased toxicity of olaparib possible due to reduced clearance Avoid combination or monitor for olaparib toxicity. Dose reduction of olaparib may be required
CYP3A4 inducers (e.g. carbamazepine, phenytoin, phenobarbitone, rifampicin, St John’s wort etc.) Reduced efficacy of olaparib due to increased clearance Avoid combination or monitor for decreased effect of olaparib
Drugs metabolised by CYP3A (e.g. hormonal contraceptives) Reduced efficacy of CYP3A substrates possible due to increased clearance Avoid combination. Consider alternative contraception to hormonal contraceptives
MDR1 substrates (e.g. statins, digoxin, dabigatran, colchicine) Increased effects/toxicity of MDR1 substrates possible due to reduced clearance Avoid combination or monitor closely for toxicity
Myelosuppressive agents(e.g. other anticancer agents, clozapine etc.) Additive myelosuppression Avoid combination with other myelosuppressive agents
General
  Interaction Clinical management
Warfarin Antineoplastic agents may alter the anticoagulant effect of warfarin. Monitor INR regularly and adjust warfarin dosage as appropriate; consider alternative anticoagulant.
Direct oral anticoagulants (DOACs) e.g. apixaban, rivaroxaban, dabigatran

Interaction with both CYP3A4 and P-gp inhibitors /inducers.

DOAC and antineoplastic levels may both be altered, possibly leading to loss of efficacy or toxicity (i.e. increased bleeding).

Apixaban: avoid concurrent use with strong CYP3A4 and P‑gp inhibitors. If treating VTE, avoid use with strong CYP3A4 and P‑gp inducers. 

Rivaroxaban: avoid concurrent use with strong CYP3A4 and P‑gp  inhibitors.

Dabigatran: avoid combination with strong P‑gp inducers and inhibitors.

If concurrent use is unavoidable, monitor closely for efficacy/toxicity of both drugs.
Digoxin Antineoplastic agents can damage the lining of the intestine; affecting the absorption of digoxin. Monitor digoxin serum levels; adjust digoxin dosage as appropriate.
Antiepileptics Both altered antiepileptic and antineoplastic levels may occur, possibly leading to loss of efficacy or toxicity. Where concurrent use of an enzyme-inducing antiepileptic cannot be avoided, monitor antiepileptic serum levels for toxicity, as well as seizure frequency for efficacy; adjust dosage as appropriate.
Also monitor closely for efficacy of the antineoplastic therapy.
Antiplatelet agents and NSAIDs Increased risk of bleeding due to treatment related thrombocytopenia. Avoid or minimise combination.
If combination deemed essential, (e.g. low dose aspirin for ischaemic heart disease) monitor for signs of bleeding.
Serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs e.g. paroxetine) and serotonin noradrenaline reuptake inhibitors (SNRIs e.g. venlafaxine) Increased risk of serotonin syndrome with concurrent use of 5-HT3 receptor antagonists (e.g. palonosetron, ondansetron, granisetron, tropisetron, dolasetron, etc.) Avoid combination.
If combination is clinically warranted, monitor for signs and symptoms of serotonin syndrome (e.g. confusion, agitation, tachycardia, hyperreflexia).
For more information link to TGA Medicines Safety Update
Vaccines Diminished response to vaccines and increased risk of infection with live vaccines. Live vaccines (e.g. BCG, MMR, zoster and varicella) are contraindicated in patients on immunosuppressive therapy. Use with caution in patients on non-immunosuppressive therapy.
For more information; refer to the recommended schedule of vaccination for cancer patients, as outlined in the Australian Immunisation Handbook

Administration

This is a continuous oral treatment

General patient assessment prior to each treatment.

Any toxicity grade 2 or greater may require dose reduction, delay or omission of treatment and review by medical officer before recommencing treatment.

Pre treatment medication

Administer antiemetics if required

Olaparib

  • administer orally TWICE a day
  • to be swallowed whole with a glass of water; do not break, crush or chew
  • to be taken on an empty stomach, at least two hours before food or one hour after food
  • if cannot be tolerated on an empty stomach, may be taken with food.

Note: missed doses should not be replaced; if a dose is forgotten or vomited, normal dosing should be resumed at the next scheduled dose.

Continue safe handling precautions (reproductive risk only) for 7 days after completion of drug(s).

Discharge information

Olaparib capsules
  • Olaparib capsules with written instructions on how to take them.
Antiemetics
  • Antiemetics as prescribed.
Patient information
  • Ensure patient receives patient information sheet.

The side effects listed below are not a complete list of all possible side effects for this treatment. Side effects are categorised into the approximate onset of presentation and should only be used as a guide.

Immediate (onset hours to days)
Nausea and vomiting

Read more about prevention of treatment induced nausea and vomiting
Taste and smell alteration

Read more about taste and smell changes

Early (onset days to weeks)
Neutropenia

Abnormally low levels of neutrophils in the blood. This increases the risk of infection. Any fever or suspicion of infection should be investigated immediately and managed aggressively. 

Read more about neutropenia
Thrombocytopenia

A reduction in the normal levels of functional platelets, increasing the risk of abnormal bleeding.  

Read more about thrombocytopenia
Diarrhoea

Read more about treatment induced diarrhoea
Fatigue

Read more about fatigue

Late (onset weeks to months)
Anaemia

Abnormally low levels of red blood cells (RBCs) or haemoglobin in the blood. 

Read more about anaemia
Pulmonary toxicity

Pulmonary toxicity may include damage to the lungs, airways, pleura and pulmonary circulation. 

Read more about pulmonary toxicity associated with antineoplastic drugs

This protocol has been superseded due to the availability of superior evidence with the tablet formulation. The preferred protocol is ID 3552 Ovarian recurrent olaparib (tablet).

A search of the literature did not find strong evidence to support the use of olaparib in the treatment of platinum-sensitive relapsed BRCA-mutated high grade serous epithelial ovarian, fallopian tube or primary peritoneal cancer. The expert reference panel supported publication of the protocol on the basis of the information summarised below. The committee was most strongly influenced by the study by Ledermann et al 2016.r

Source Study & year published Supports use Is the dose and regimen consistent with the protocol? Comments
Phase II trials Ledermann et al 2016r Yes Yes  -  
Adaptive Study Mateo et alr Yes No Study comparing 400 mg BD vs 300 mg BD with different formulations
Guidelines Date published/revised Supports use Is the dose and regimen consistent with the protocol Comments
NCCN  2016 Yes No doses stated  -  
BCCA  2017 Yes Yes Health Canada approved indication 
CCO  2017 Yes Yes Health Canada approved indication. 

Efficacy

Between August 2008 and Feb 2010, 136 patients were randomised to receive olaparib 400 mg orally twice daily, for 28 day cycles, and 129 patients were randomised to receive placebo.r

The primary end point was progression-free survival (PFS) and secondary end points were time-to-progression (TTP), overall survival (OS), objective response rate, disease-control rate, health-related quality of life and safety and tolerability.  

Olaparib leads to a clinically significant increase in PFS in patients with platinum-sensitive recurrent serous ovarian cancer. The benefit is greatest in those with a BRCA 1 or 2 (gBRCA) mutation. There was no significant benefit in overall survival. 

51% of the overall study population had a germline BRCA (gBRCA) mutation.  After a median follow up of 37 months, the median PFS was 11.2 months in the olaparib group with a gBRCA mutation vs 4.3 months in the placebo group with a gBRCA mutation (HR=0.18; 95% CI 0.10 to 0.31; p<0.0001). In patients with wild-type BRCA, the PFS was 7.4 months in the olaparib group vs 5.5 months in the placebo group (HR=0.54; 95% CI 0.34 to 0.85; p=0.0075).r 

After median follow-up for overall survival of 71 months, there was no significant benefit in overall survival between groups, even in the subset of patients with BRCA mutations (HR 0.62 [95% CI 0.41 to 0.94]; nominal p=0.025; which did not meet required threshold of p<0.0095 for statistical significance).r

Progression-free survival in all patients and according to BRCA mutation statusr

Legend: NC=not calculable. PFS=progression-free survival. *Wild-type BRCA includes patients with no known BRCA mutation and those with a BRCA mutation of unknown significance

The Lancet Oncology © 2014. 

Overall survival in all patients and according to BRCA mutation statusr

(A) All patients (n=265). (B) Patients with BRCAm (n=136). (C) Patients with BRCAwt (n=118). OS=overall survival. 

The Lancet Oncology © 2016

There was no statistically significant difference between treatment arms in regards to health-related quality of life (HR-QOL).r There was no data available on the compliance rate for completion of QOL data.

Toxicity

Olaparib is generally well tolerated. Adverse reactions associated with olaparib monotherapy are generally mild or moderate in severity and in most cases are short term in nature and self limiting. Treatment discontinuation is generally not required.r

In the phase 2 trial, 9 patients (0.05%) in the olaparib group and 2 patients (0.02%) in the placebo group discontinued study treatment due to adverse events.r Dose interruptions and dose reductions occurred in 49 (36%) and 57 (42%) of patients respectively in the olaparib group versus only 21 (16%) and 28 (22%) of patients respectively in the placebo group. This was most commonly due to vomiting, nausea and fatigue.r 

The Lancet Oncology © 2014

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Version 2

Date Summary of changes
03/11/2017 New protocol taken to Medical Oncology Reference Committee meeting
23/04/2018 Protocol approved and published on eviQ
04/12/2018 Title, warning note, treatment schedule and patient information updated to indicate protocol only for use with olaparib capsules 
09/10/2019 Protocol reviewed at Medical Oncology Reference Committee meeting on 30/08/2019. Protocol superseded due to the availability of superior evidence with the tablet formulation. ID 3552 Ovarian recurrent olaparib (tablet) added as a related page. Second cancer risk added to patient information general advice section. Version number changed to V.2. Next review in 2 years.
18/12/2020 Related pages and superseded flag updated- ID 3552 replaced by ID 3737 Advanced, metastatic or recurrent olaparib.

The information contained in this protocol is based on the highest level of available evidence and consensus of the eviQ reference committee regarding their views of currently accepted approaches to treatment. Any clinician (medical oncologist, haematologist, radiation oncologist, medical physicist, radiation therapist, pharmacist or nurse) seeking to apply or consult this protocol is expected to use independent clinical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au

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27 Feb 2021