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Advanced, metastatic or recurrent olaparib

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Drug Dose Route
Olaparib (tablets) 300 mg TWICE a day PO

* 2 x 150 mg tablets

Continuous until disease progression or unacceptable toxicity (refer to Indications and patient population sections for more treatment duration information)

Drug status:

Olaparib is TGA registered but not PBS listed for metastatic breast cancer

Olaparib is PBS authority for advanced or recurrent ovarian cancer and metastatic prostate cancer

Olaparib is available as 100 mg and 150 mg tablets

Cost:
~ $6,550 per month "How this cost is calculated"

The cost displayed on the protocol is intended as rudimentary guide only for the Australian context.

The cost includes anti-cancer drugs only (not antiemetics, supportive medications or consumables), unless otherwise indicated.

Drug unit costs are taken directly from the Pharmaceutical Benefits Scheme (PBS) website (www.pbs.gov.au). These costs are reviewed and updated on eviQ at 6 monthly intervals. Anti-cancer drugs that are not included on the PBS do not have a cost included in eviQ protocols.

Where there are differing unit costs based on vial sizes and tablet strengths, the mean unit cost is used. The cost of oral continuous therapy is based on a 28 day month.

Where oral drugs are available on the PBS for both 30- and 60-day prescriptions, the unit cost for the 30-day supply is used.

The protocol cost is derived from drug dose calculations based upon a default body surface area (BSA) of 1.8 m2; weight of 75 kg; and creatinine clearance of 75 mL/min.

One off loading doses and ongoing maintenance doses are not included in protocol cost calculations.

The cost displayed is the actual drug cost and does not necessarily reflect the cost incurred by the patient as many anti-cancer drugs are reimbursed on the PBS.

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
Metoclopramide 10 mg (PO) one tablet when necessary (maximum of 30 mg/24 hours, up to 5 days). Should be given initially and may be required for the first few weeks, then at clinician discretion thereafter.
Olaparib (tablets) 300 mg (PO) TWICE a day (2 x 150 mg tablets), may be taken with food if required to reduce nausea and vomiting.

Continuous until disease progression or unacceptable toxicity (refer to Indications and patient population sections for more treatment duration information)

Drug Dose Route
Olaparib (tablets) 300 mg TWICE a day PO

* 2 x 150 mg tablets

Continuous until disease progression or unacceptable toxicity (refer to Indications and patient population sections for more treatment duration information)

Drug status:

Olaparib is TGA registered but not PBS listed for metastatic breast cancer

Olaparib is PBS authority for advanced or recurrent ovarian cancer and metastatic prostate cancer

Olaparib is available as 100 mg and 150 mg tablets

Cost:
~ $6,550 per month "How this cost is calculated"

The cost displayed on the protocol is intended as rudimentary guide only for the Australian context.

The cost includes anti-cancer drugs only (not antiemetics, supportive medications or consumables), unless otherwise indicated.

Drug unit costs are taken directly from the Pharmaceutical Benefits Scheme (PBS) website (www.pbs.gov.au). These costs are reviewed and updated on eviQ at 6 monthly intervals. Anti-cancer drugs that are not included on the PBS do not have a cost included in eviQ protocols.

Where there are differing unit costs based on vial sizes and tablet strengths, the mean unit cost is used. The cost of oral continuous therapy is based on a 28 day month.

Where oral drugs are available on the PBS for both 30- and 60-day prescriptions, the unit cost for the 30-day supply is used.

The protocol cost is derived from drug dose calculations based upon a default body surface area (BSA) of 1.8 m2; weight of 75 kg; and creatinine clearance of 75 mL/min.

One off loading doses and ongoing maintenance doses are not included in protocol cost calculations.

The cost displayed is the actual drug cost and does not necessarily reflect the cost incurred by the patient as many anti-cancer drugs are reimbursed on the PBS.

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
Metoclopramide 10 mg (PO) one tablet when necessary (maximum of 30 mg/24 hours, up to 5 days). Should be given initially and may be required for the first few weeks, then at clinician discretion thereafter.
Olaparib (tablets) 300 mg (PO) TWICE a day (2 x 150 mg tablets), may be taken with food if required to reduce nausea and vomiting.

Continuous until disease progression or unacceptable toxicity (refer to Indications and patient population sections for more treatment duration information)

Indications:

  • monotherapy for the treatment of patients with germline BRCA-mutated HER2-negative metastatic breast cancer who have previously been treated with chemotherapy in the neoadjuvant, adjuvant or metastatic setting
    • germline BRCA mutation status should be determined by an experienced laboratory using a validated test method.

Read more about breast cancer - panel testing

Cautions:

  • do not initiate olaparib until haematological toxicity caused by previous chemotherapy has resolved.

Indications:

  • monotherapy for maintenance treatment of patients with advanced (FIGO stage III or IV) BRCA-mutated high grade serous epithelial ovarian, fallopian tube or primary peritoneal cancer who are in partial or complete response to first line platinum-based chemotherapy.
    • patient must have evidence of a pathogenic variant germline or somatic BRCA mutation.

Read more about ovarian cancer - panel testing

Cautions:

  • do not initiate olaparib until haematological toxicity caused by previous chemotherapy has resolved.

Note:

Patients with a complete response (no radiological evidence of disease) at 2 years should stop treatment. Patients with evidence of disease that remains stable at 2 years can continue treatment at clinician discretion if further benefit is expected.

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 partial or complete response following at least two courses of platinum-containing regimens.
    • patient must have evidence of a pathogenic variant germline or somatic BRCA mutation.

Read more about ovarian cancer - panel testing

Cautions:

  • do not initiate olaparib until haematological toxicity caused by previous chemotherapy has resolved.

Note:

There is no data to support retreatment with olaparib as maintenance following subsequent relapse.

Indications:

  • monotherapy for the treatment of patients with BRCA-mutated (germline and/or somatic) metastatic castration-resistant prostate cancer who have progressed following prior therapy that included a new hormonal agent.
    • Tumour BRCA mutation status should be determined by an experienced laboratory using a validated test method.

Read more about prostate cancer - panel testing

Cautions:

  • do not initiate olaparib until haematological toxicity caused by previous chemotherapy has resolved.

Note:

There is no data to support retreatment with olaparib as maintenance following subsequent relapse.

Caution with oral anti-cancer drugs

Select links for information on the safe prescribing, dispensing and administration of orally administered anti-cancer drugs. 

Read more about the Cancer Council Australia guidelines and oral anti-cancer therapy
Emetogenicity minimal or low

Although this treatment is classified as having minimal to low emetogenicity, routine antiemetic premedication may be required. 

Read more about preventing anti-cancer therapy induced nausea and vomiting
Wound healing

This treatment may impair wound healing and temporary interruption of treatment is recommended in patients undergoing major surgical procedures. Resume treatment based on clinical judgement of adequate wound healing.
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 receive this treatment.
Blood tests

FBC, EUC, eGFR 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 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.

Read more about COVID-19 vaccines and cancer.
Fertility, pregnancy and lactation

Cancer treatment can have harmful effects on fertility and this should be discussed with all patients of reproductive potential prior to commencing treatment. There is a risk of foetal harm in pregnant women. A pregnancy test should be considered prior to initiating treatment in females of reproductive potential if sexually active. It is important that all patients of reproductive potential use effective contraception whilst on therapy and after treatment finishes. Effective contraception methods and adequate contraception timeframe should be discussed with all patients of reproductive potential. Possibility of infant risk should be discussed with breastfeeding patients.

Read more about the impact of cancer treatment on fertility
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 anti-cancer 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, published guidelines and reference committee consensus . The dose reduction applies to each individual dose and not to the total number of days or duration of treatment cycle unless stated otherwise. 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 product information, the study by Pujade-Lauraine et alr and by consensus of the reference committee.

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

Delay olaparib treatment until recovery and consider restarting olaparib as follows:

1st occurrence: Restart olaparib at 300 mg TWICE a day
2ndoccurrence: Restart olaparib at 250 mg TWICE a day
3rd occurrence: Restart olaparib at 200 mg TWICE a day
4thoccurrence: Cease olaparib
Febrile neutropenia

Delay olaparib treatment until recovery and consider restarting olaparib as follows:

1st occurrence: Restart olaparib at 300 mg TWICE a day
2ndoccurrence: Restart olaparib at 250 mg TWICE a day
3rd occurrence: Restart olaparib at 200 mg TWICE a day
4thoccurrence: Cease olaparib

For grade 4 febrile neutropenia consider restarting olaparib at a dose reduced by two dose levels
Platelets x 109/L (at any stage of the cycle)
less than 75

Delay olaparib treatment until recovery and consider restarting olaparib as follows:

1st occurrence: Restart olaparib at 300 mg TWICE a day
2ndoccurrence: Restart olaparib at 250 mg TWICE a day
3rd occurrence: Restart olaparib at 200 mg TWICE a day
4thoccurrence: Cease olaparib
Anaemia
Grade 1 or 2 Continue treatment. Investigate and manage any treatable causes of anaemia e.g. iron, vitamin B12 or folate deficiencies
Grade 3 or 4 Delay olaparib treatment until haemoglobin recovery to > 9 g/dL and consider restarting olaparib as follows:
1st occurrence: Restart olaparib at 300 mg TWICE a day
2ndoccurrence: Restart olaparib at 250 mg TWICE a day
3rd occurrence: Restart olaparib at 200 mg TWICE a day
4thoccurrence: Cease olaparib
Kidney dosing recommendations 
eGFR (mL/min/1.73m2) Recommended dose
> 50 No dose modification necessary
31 to 50 Reduce olaparib to 200 mg TWICE a day and monitor for toxicity
< 30 This drug has not been studied in patients with severe kidney dysfunction or end stage kidney disease.
Hepatic impairment
Hepatic dysfunction
Mild or moderate No dose modifications required. Monitor hepatic function and for adverse events.
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:
1st occurrence: Restart olaparib at 250 mg TWICE a day
2nd occurrence: Restart olaparib at 200 mg TWICE a day
3rd occurrence: Cease olaparib
Diarrhoea
Grade 1 or 2 Continue with treatment
Grade 3 or 4 Delay treatment until recovery and consider restarting olaparib as follows:
1st occurrence: Restart olaparib at 250 mg TWICE a day
2nd occurrence: Restart olaparib at 200 mg TWICE a day
3rd occurrence: Cease olaparib
Infection
Grade 3 Delay treatment until recovery and consider restarting olaparib as follows:
1st occurrence: Restart olaparib at same dose or 250mg TWICE a day
2nd occurrence: Restart olaparib at 200 mg TWICE a day
Grade 4 Delay treatment until recovery and restart olaparib at 200 mg TWICE a day or cease olaparib
Dyspnoea / Pneumonitis
Grade 1 to 3

Delay treatment and investigate for common and rare but serious causes of dyspnoea (e.g. anaemia, pneumonitis and opportunistic infections). Restart olaparib upon recovery to Grade 0-1 if deemed not due to pneumonitis. If pneumonitis confirmed, cease olaparib and commence corticosteroids
Grade 4 Cease olaparib
Nausea and vomiting
Nausea and vomiting May be moderate in the first month(s) 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 consider dose reductions as for other toxicities.

The drug interactions shown below are not an exhaustive list. For a more comprehensive list and for detailed information on specific drug interactions and clinical management, please refer to the specific drug product information and the following key resources: 

For more information see 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. If combination with a strong CYP3A4 inhibitor cannot be avoided, reduce olaparib dose to 100 mg twice daily. If combination with a moderate CYP3A4 inhibitor cannot be avoided, reduce olaparib dose to 150 mg twice daily.
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 Anti-cancer drugs 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 anti-cancer drug 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 Anti-cancer drugs 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 anti-cancer drug 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 anti-cancer 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

eviQ provides safe and effective instructions on how to administer cancer treatments. However, eviQ does not provide every treatment delivery option, and is unable to provide a comprehensive list of cancer treatment agents and their required IV line giving set/filter. There may be alternative methods of treatment administration, and alternative supportive treatments that are also appropriate. Please refer to the individual product information monographs via the TGA and Australian Injectable Drugs Handbook websites for further information.

Administration

This is a continuous oral treatment

Pre treatment assessment

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

Anti-cancer drug patient assessment tool prior to each day of treatment.

Pre treatment medication

Administer antiemetics if required.

Olaparib

Administer olaparib:
  • orally TWICE a day (approximately 12 hours apart)
  • 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 to reduce nausea and vomiting

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

Post administration

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

Discharge information

Olaparib tablets - with written instructions on how to take them.

Antiemetics - as/if prescribed.

Patient information

Ensure patient receives protocol 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 immediate management of neutropenic fever
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 anti-cancer drugs
Myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML)

Bone marrow failure and secondary malignancy as a result of treatment.

The evidence supporting this protocol is provided by the phase 3 open-label multicentre international randomised OlympiAD trial.r Olaparib monotherapy was compared with standard chemotherapy in patients with a confirmed germline BRCA mutation and human epidermal growth factor receptor type 2 (HER2)–negative metastatic breast cancer.

Between April 2014 and November 2015, 205 patients were randomly assigned to receive olaparib PO tablets (300 mg twice daily continuously) and 97 patients were assigned to receive physicians’ choice of standard of care single-agent chemotherapy in 21 day cycles (either capecitabine PO 2500 mg/m2 in two divided doses on day 1 to 14, or eribulin IV 1.4 mg/m2 on day 1 and 8, or vinorelbine IV 30 mg/m2 on day 1 and 8). Treatment was continued until disease progression or unacceptable toxicity occurred. Of note, use of platinum based chemotherapy was not allowed. Eligible patients had received no more than two previous chemotherapy regimens for metastatic disease.

The primary end point was progression-free survival (PFS). Secondary endpoints included overall survival (OS), time from randomisation to a second progression event or death after a first progression event, objective response rate, safety outcomes, and scores for health-related quality of life (QOL).

Efficacy

After a median duration of follow-up of 14.5 months in the olaparib group and 14.1 months in the standard-therapy group, median PFS was significantly longer in the olaparib group than in the standard-therapy group (7.0 months vs 4.2 months; HR for disease progression or death=0.58; 95% CI, 0.43 to 0.80; p<0.001).r

Kaplan-Meier curve of progression-free survivalr

©N Engl J Med 2018

The study stratified patients for hormone receptor status, prior platinum chemotherapy, and any prior chemotherapy in the metastatic setting. Subgroup analysis showed statistically significant improvement in PFS in those with triple negative breast cancer (HR=0.43; 95% CI, 0.29 to 0.63), patients who had not received prior platinum containing chemotherapy (HR=0.60; 95% CI, 0.43 to 0.84) and those with a BRCA1 mutation (HR=0.54; 95% CI, 0.37 to 0.79).

The response rate was 59.9% in the olaparib group and 28.8% in the standard-therapy group.

An updated analysis conducted after a median follow-up of 25.3 months in the olaparib group and 26.3 months in the standard-therapy group, showed a median OS of 19.3 months vs 17.1 months respectively (HR=0.90, 95% CI, 0.66 to 1.23, p=0.513).r

Kaplan-Meier curve of overall survivalr​

TPC = standard-therapy group

©Ann Oncol 2019

Health-related QOL was assessed with the use of the 30-item European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30). The median time to a clinically meaningful decrease in QLQ-C30 score, defined as ≥ 10 points, was not reached in the olaparib group and was 15.3 months in the standard-therapy group (HR=0.44; 95% CI, 0.25 to 0.77, p=0.004).

Toxicity

The median total treatment duration was 8.2 months (0.5 to 28.7) in the olaparib group and 3.4 months (0.7 to 23.0) in the standard-therapy group. The rate of grade 3 or higher adverse events was 38.0% in the olaparib group and 49.5% in the standard-therapy group, and the rate of treatment discontinuation due to toxic effects was 4.9% and 7.7%, respectively. Anaemia, nausea, vomiting, fatigue, headache, and cough occurred more frequently in the olaparib group than in the standard-therapy group; neutropenia, palmar–plantar erythrodysaesthesia, and an increase in liver function enzymes were more common in those receiving standard-therapy. There were no treatment related deaths in either group.r

Treatment related adverse eventsr

©Ann Oncol 2019

The evidence supporting this protocol is provided by the SOLO1 trial, a phase III multicentre international double-blind, randomised trial which evaluated the efficacy of olaparib as maintenance therapy in 391 patients with newly diagnosed advanced high grade serous or endometrioid ovarian cancer, primary peritoneal cancer or fallopian tube cancer with a BRCA1 and/or BRCA2 mutation who had complete or partial clinical response after platinum-based chemotherapy. 388 patients had a germline BRCA1/2 mutation and 2 had a centrally confirmed somatic BRCA1/2 mutation.r

Between September 2013 and March 2015, 260 patients were assigned to receive oral olaparib at a dose of 300 mg twice daily while 131 patients received placebo. Treatment continued until investigator-assessed objective disease progression on imaging. Patients who had no evidence of disease at 2 years stopped the intervention, but those who had partial response were permitted to continue.

The primary end point was investigator-assessed progression-free survival (PFS). Secondary end points were second progression-free survival, overall survival (OS), time from randomisation to the first subsequent therapy or death, and health related quality of life.

Efficacy

The SOLO1/GOG 2004 trial supports the use of maintenance olaparib to achieve long-term remission in BRCA-mutated patients with newly diagnosed advanced ovarian cancer. The median duration of treatment was 24.6 months with olaparib and 13.9 months with placebo after a median follow up of approximately 88 months.r

In an updated PFS analysis conducted after a 5-year follow-up, the median PFS was 56.0 months (95% CI, 41.9 to not reached) in the olaparib group compared with 13.8 months (95% CI, 11.1 to 18.2) in the placebo group (Hazard ratio [HR], 0.33; 95% CI, 0.25 to 0.43). On the basis of Kaplan-Meier estimates, 48.3% versus 20.5% of patients, respectively, were progression-free at 5 years.r

After a 7-year follow-up, there was a clinically meaningful, albeit not statistically significant according to pre-specified data, improvement in overall survival (OS) with maintenance olaparib versus placebo. The HR for OS was 0.55 (95% CI, 0.40 to 0.76; P=0.0004) however P< 0.0001 was required to declare statistical significance. At 7 years, 67.0% of olaparib patients versus 46.5% of placebo patients were alive, and 45.3% versus 20.6%, respectively, were alive and had not received a first subsequent treatment (Kaplan-Meier estimates). Additionally, 56.9% of olaparib patients versus 32.5% of placebo patients were alive and had not received a second subsequent treatment after a 7-year follow-up (Kaplan-Meier estimates).r

There were no significant differences in health related quality of life; Functional Assessment of Cancer Therapy–Ovarian Cancer Trial Outcome Index (TOI) score change at 24 months: 0.30 points (95% CI, 0.72 to 1.2) versus 3.30 points (1.84 to 4.7) in the olaparib and placebo arms, respectively (p=0.001). However, mean quality-adjusted PFS was 29.75 months (95% CI, 28.20 to 31.63) in the olaparib group versus 17.58 (15.05 to 20.18) in placebo group (p<0·0001). Mean duration of time without significant symptoms of toxicity was 33.15 months (95% CI, 30.82 to 35.49) versus 20.24 months (17.36 to 23.11) in the olaparib and placebo groups respectively (p<0·0001).r

Kaplan-Meier estimate of PFS at 5 year follow upr

© Lancet Oncol 2021

Kaplan-Meier estimate of OS at 7 year follow upr

© J Clin Oncol 2023 

Kaplan-Meier estimates of (A) Time to first subsequent therapy or death (TFST) and (B) Time to second subsequent therapy or death (TSST)r

© J Clin Oncol 2023 

Toxicity

The most common adverse events (AEs) of any grade reported in olaparib patients were nausea, fatigue/asthenia, vomiting, and anaemia, and the most common grade ≥ 3 AE was anaemia. No new safety signals were detected at the 7-year follow up and the incidence of myelodysplastic syndrome and acute myeloid leukemia remained low, and new primary malignancies remained balanced between treatment groups.r

Summary of adverse eventsr

© J Clin Oncol 2023

The evidence supporting this protocol comes from the SOLO2 trial, a phase III, multicentre international randomised trial involving 295 patients comparing olaparib maintenance therapy against placebo in patients with platinum-sensitive, relapsed high-grade ovarian or endometrial cancer with a BRCA1 or BRCA 2 mutation.r

Between September 2013 and November 2014, 196 patients were randomised to receive oral olaparib tablets at a dose of 300 mg twice daily and 99 patients were randomised to receive matching placebo. Treatment continued until disease progression or lack of clinical benefit.

The primary end point was investigator-assessed progression-free survival (PFS). Secondary end points were time to subsequent therapies, overall survival (OS), toxicity and quality of life.

Efficacy

After a median follow up of 22 months, the median PFS was 19.1 months (95% CI, 16.3 to 25.7) in the olaparib group compared to 5.5 months (95% CI, 5.2 to 5.8) with placebo (HR 0.30; 95% CI, 0.22 to 0.41; p<0.0001).r

Median time to first subsequent therapy was prolonged in the olaparib group at 27.9 months (95% CI, 22.6 to not calculable) vs 7.1 months for placebo (95% CI, 6.3 to 8.3). Olaparib also significantly improved time to second progression (not reached vs 18.4 months) and second subsequent therapy (not reached vs 18.2 months). Immature OS data (45 vs 27 events; 24% maturity) showed no difference between the groups (HR 0.80; 95% CI 0.50 to 1.31; p=0.43; medians not reached in either group). There was no difference in patient-reported quality of life between the two groups.r

After a median follow up of 65.7 months (IQR 63.6 to 69.3) with olaparib and 64.5 months (63.4 to 68.7) with placebo, median OS was 51.7 months (95% CI, 41.5 to 59.1) versus 38.8 months (31.4 to 48. 6) respectively (HR 0.74; 95% CI, 0.54 to 1.00; p=0.054). After adjustment for subsequent PARP inhibitor therapy in the placebo group (38% of patients), median OS was 51.7 months (95% CI, 41.5 to 59.1) with olaparib and 35.4 months (24.2 to 43.5) with placebo (HR 0.56; 95% CI, 0.35 to 0.97).r

Kaplan-Meier curves of progression-free survivalr

©Lancet Oncol 2017 

Kaplan-Meier curve of overall survivalr

©Lancet Oncol 2021

Toxicity

With the exception of haematological side effects, adverse events were generally mild to moderate in severity and did not result in dose modification or treatment discontinuation. The most common grade 3 to 4 adverse events in the olaparib group were anaemia (21%), neutropenia (7%), fatigue and asthenia (6%), nausea (3%) and vomiting (3%). Abdominal pain was similar in both arms (3%).r

At the final analysis, dose interruptions, reductions and discontinuation due to treatment-emergent adverse events occurred in 50%, 28% and 17% of the patients in the olaparib group compared to 19%, 3% and 3% respectively in the placebo group. The most common adverse events leading to discontinuation in the olaparib group were anaemia (4%), AML (2%), myelodysplastic syndrome (1%), neutropenia (1%), and thrombocytopenia (1%). 5 (3%) patients receiving olaparib died from treatment-related adverse events (due to myelodysplastic syndrome and AML).r

Adverse eventsr

©Lancet Oncol 2021

The evidence supporting this protocol comes from the phase 3 multicentre international randomised PROfound trial.r Olaparib was compared with physician’s choice of a second novel hormonal agent (enzalutamide or abiraterone plus prednisone), whichever had not been taken before in 387 patients with stage IV castration-resistant prostate cancer with homologous recombination repair gene alteration, who had progressive disease during treatment with enzalutamide or abiraterone plus prednisone. Of these, 245 patients with one or more of BRCA1 (15), BRCA2 (143), or ATM (90) gene alterations were enrolled in Cohort A; 142 with any alteration in 12 other genes were enrolled in Cohort B. 45% of all participants received prior docetaxel, and another 20% received prior cabazitaxel as well. Treatment continued until disease progression or unacceptable toxicity.r

Between April 2017 and November 2018, 162 of Cohort A patients were randomised to receive olaparib 300 mg twice daily and 83 patients were randomised to receive enzalutamide 160 mg once daily or abiraterone 1000 mg once daily. Of Cohort B patients, 94 received olaparib and 48 received enzalutamide or abiraterone.

The primary end point was radiographic progression-free survival (rPFS) in Cohort A. Key secondary endpoints included rPFS as assessed by independent review in the overall population, objective response rate (ORR), time to pain progression, ≥ 50% reduction in baseline PSA level (PSA50 response) and overall survival (OS). Exploratory end points included rPFS and OS in Cohort B. Crossover was permitted from the control arm to olaparib.

Efficacy

After a median follow up of 12 months, the median rPFS in Cohort A was 7.4 months in the olaparib group compared with 3.6 months in the control group (HR 0.34; 95% CI 0.25 to 0.47; p<0.001).r

Of the 127 patients with evaluable disease, objective response rate in Cohort A was 33% in the olaparib group compared with 2% in the control group (OR 20.86; 95% CI 4.18 to 379.18; p<0.001). Olaparib also significantly delayed time to pain progression (HR 0.44; 95% CI 0.22 to 0.91; p=0.02) and offered higher PSA50 response (43% vs. 8%).

Median OS at final prespecified analyses was also longer in the olaparib group at 19.1 months (95% CI 17.4 to 3.4) vs. 14.7 months (95% CI 11.9 to 18.8) in the control group (HR 0.69; 95% CI 0.50 to 0.97; p=0.02). After adjustment for subsequent crossover from control to olaparib (67% of patients), hazard ratio for death was reduced (HR 0.42; 95% CI 0.19 to 0.91).r

Prespecified subgroup analyses show the majority of benefit in Cohort A was driven by those with BRCA1 and/or BRCA2 gene alteration and not ATM alteration.r Exploratory analyses of Cohort B found no difference in rPFS and OS between olaparib and control group. The trial did not report patient-reported quality of life data.

Kaplan-Meier curve of rPFS in Cohort Ar

© N Engl J Med 2020

Kaplan-Meier curve of OS, including adjustment for crossover in Cohort Ar

© N Engl J Med 2020

rPFS and OS for those with BRCA1 and/or BRCA2 gene alterationr 

© N Engl J Med 2020

rPFS and OS for those with ATM gene alterationr

© N Engl J Med 2020

Toxicity

Olaparib was associated with higher rates of > Grade 3 adverse events, 51% compared with 38% in the control group. The most common event was anaemia which occurred in 21% of those receiving olaparib compared with 5% in the control group. Olaparib was also associated with a higher rate of dose interruption (45%), dose reduction (22%), and treatment discontinuation (18%) due to adverse events.r

No myelodysplastic syndrome or acute myeloid leukaemia were noted. Three patients reported a new primary cancer; one in the olaparib group (glioma) and two in the control group (gastric and urothelial cancer). One death each in the olaparib (lung infection) and control (respiratory failure) group were attributed to treatment.

Adverse events in the overall populationr

© N Engl J Med 2020

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Version 5

Date Summary of changes
02/09/2024

Protocol reviewed at gynaecological reference committee meeting on 26/07/2024. Updated evidence for ovarian advanced presented and approved for publication.

Protocol reviewed at breast reference committee meeting on 09/08/2024. Metoclopramide added to treatment schedule, wound healing added to clinical information, pneumonitis and infection added to dose modifications. 

Version increased to V.5. Next review by breast and gynaecological reference committees in 2 years.

Version 4

Date Summary of changes
01/05/2024

Protocol updated with ADDIKD guideline recommendations.

PDF of previous protocol.

Version number changed to V.4.

Version 3

Date Summary of changes
10/12/2021 New prostate indication approved by Medical Oncology Reference Committee and published on eviQ. Prostate sections added to indications, evidence and patient information. Contraception and pregnancy clinical information updated- contraception timeframe, sperm donation and interaction information removed. Version increased to V.3. Review 1 year by Urogenital Reference Committee.
21/12/2021 Changed antiemetic clinical information block to minimal or low, to align with new categories. See ID 7 Prevention of anti-cancer therapy induced nausea and vomiting (AINV) v5.
01/04/2022 Drug status updated to PBS authority for metastatic prostate cancer.
02/09/2022 Multiple formulations warning regarding olaparib tablets and capsules removed as capsules no longer available.
04/09/2023 Prostate indication reviewed by Medical Oncology Reference Committee. No changes. Review urogenital indication in 2 years.
05/12/2023 Breast indication reviewed by Medical Oncology Reference Committee. No changes. Review breast indication in 2 years.

Version 2

Date Summary of changes
20/08/2021 Protocol reviewed at gynaecological reference committee meeting. Related pages updated to include ID 3662. Ovarian advanced evidence section updated to include SOLO1 new published data. Ovarian recurrent updated section updated with SOLO2 final analysis data. Version increased to V.2. Next review in 2 years.
13/08/2021 Protocol reviewed electronically by breast reference committee. Nil changes.

Version 1

ID 3737 Advanced, metastatic or recurrent olaparib
Date Summary of changes
15/12/2020 New multi-indication protocol approved electronically by Medical Oncology reference committee. Note that this protocol replaces two existing approved protocols ID 3552 and ID 3627.
18/12/2020 Protocol published on eviQ. Next review in 1 year by breast and gynaecology reference committees.

As ID 3737 Advanced, metastatic or recurrent olaparib replaces two existing approved protocols, their individual History sections are included below for consistency in documentation. 

ID 3552 Ovarian recurrent olaparib (tablet) version 1
Date Summary of changes
30/08/2019 Protocol discussed at Medical Oncology Reference Committee meeting.
09/10/2019 Protocol approved and published. Review in 1 year.
ID 3627 Breast metastatic olaparib version 2
Date Summary of changes
30/08/2019 Protocol discussed at Medical Oncology Reference Committee meeting.
08/10/2019 Protocol approved and published. Review in 1 year.
23/11/2020 Protocol reviewed electronically by Medical Oncology Reference Committee. Overall survival and toxicity results updated in evidence section. Version number changed to V.2. Next review in 2 years.

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06 Oct 2024