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Olaparib (Lynparza) for Metastatic Breast Cancer with Germline BRCA Mutation – Second Line

Olaparib (Lynparza) for Metastatic Breast Cancer with Germline BRCA Mutation – Second Line

Horizon Scanning Research January 2016 & Intelligence Centre

Olaparib (Lynparza) for metastatic breast cancer with germline BRCA mutation – second line

LAY SUMMARY

This briefing is Breast cancer is the most common cancer in the UK. BRCA genes based on make proteins that help repair damaged DNA. Women with a BRCA information available at the time gene mutation have a much higher risk of breast and other cancers. of research and a Most women who get breast cancer are over 50 years of age. limited literature However, people that have a breast cancer with BRCA gene mutation search. It is not often get it at a younger age. intended to be a definitive statement Olaparib is a new treatment for breast cancer with germline BRCA on the safety, mutation that can be taken by mouth as a capsule. Some studies have efficacy or suggested olaparib may be helpful for people whose first effectiveness of the treatment has failed and more studies are now aiming health technology to show how well it works and that it is safe to use. covered and should not be used for NIHR HSRIC ID: 4012 commercial purposes or commissioning without additional information.

This briefing presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health.

NIHR Horizon Scanning Research & Intelligence Centre, University of Birmingham. Email: [email protected] Web: www.hsric.nihr.ac.uk Horizon Scanning Research & Intelligence Centre

TARGET GROUP

• Breast cancer: metastatic; germline BRCA mutation; previous treatment with and , and suitable for single agent chemotherapy – second line.

TECHNOLOGY

DESCRIPTION

Olaparib (Lynparza; AZD2281; KU 0059436) is a potent inhibitor of human poly (ADP ribose) polymerase (PARP 1, PARP2, and PARP3), and has been shown to inhibit the growth of selected tumour cell lines in vitro and tumour growth in vivo, either as a standalone treatment or in combination with established . Olaparib is administered orally twice daily at 300mg.

Olaparib is licensed in the EU for the maintenance treatment of adult patients with platinum- sensitive relapsed BRCA-mutated (germline and/or somatic) ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete response or partial response) to platinum-based chemotherapy. Olaparib monotherapy has been associated with adverse reactions generally of mild or moderate severity and generally not requiring treatment discontinuationa. When olaparib is used for its current licensed indication, very common (>10%) adverse events reported include decreased appetite, headache, dizziness, dysgeusia, nausea, vomiting, diarrhoea, dyspepsia, (including asthenia), anaemia, neutropenia, lymphopaenia, increase in blood creatinine and elevation in mean corpuscular volume1.

Olaparib is also in phase III studies for pancreatic, gastric and prostate cancers as well as being investigated for a range of other tumours in early phase trials.

INNOVATION and/or ADVANTAGES

If licensed, olaparib will offer an additional oral treatment option for this patient group with potentially greater efficacy and lower toxicity when compared to standard alternative chemotherapy treatmentsa.

DEVELOPER

AstraZeneca UK Ltd.

AVAILABILITY, LAUNCH OR MARKETING

Olaparib is a designated orphan drug in the EU and USA. It is currently in phase III clinical trials.

a Company comment.

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PATIENT GROUP

BACKGROUND

Breast cancer arises from the tissues of the breast and most commonly originates in the cells that line the ducts. There are several types of breast cancer described according to the receptors expressed on the surface of tumour cells, stage of diagnosis, and rate of growth2. Hormone-receptor positive (HR-positive) breast cancer includes disease in which tumour cells express either oestrogen receptors (ER-positive) or progesterone receptors (PR- positive)3. Approximately 80% of breast cancers in postmenopausal women are HR-positive3 and around two-thirds of breast cancers are ER-positive. Human epidermal growth factor receptors (HER2) are overexpressed in around 15-25% of women with breast cancer and promote tumour growth4. HER2-negative breast cancer refers to disease that does not overexpress HER24. Both HR-positive and HER2-negative breast cancers are associated with a better prognosis than HR-negative and HER2-positive disease3,4. Advanced or metastatic (stage IV) breast cancer refers to disease that has spread to other parts of the body. Common sites for metastases include the bones, liver, lung and brain3.

The causes of breast cancer are not completely understood. However a number of factors are known to increase its likelihood, such as exposure to radiation, increased alcohol consumption, being taller, being overweight or obese, exposure to oestrogen and hormone replacement therapy, greater breast tissue density, and genetic factors5. The risk of developing breast cancer is also known to increase markedly with inheritance of certain genes (e.g. BRCA1, BRCA2 and TP53). Breast cancer in adults can occur at any age, though there is an increased risk in postmenopausal women, and a previous benign breast lump or diagnosis of early breast cancer further increases the risk5.

Breast cancer is normally characterised by a lump or thickened tissue in the breast area, however not all lumps will be cancerous. Other features include a change in breast size or shape, discharge from the nipple (which may include blood), lumps/swelling in armpits, dimples on the skin of the breast and a rash around the nipple area. Symptoms include pain in the breast or axilla and signs and symptoms can occur in one or both breasts5.

NHS or GOVERNMENT PRIORITY AREA

This topic is relevant to: • Improving Outcomes: A Strategy for Cancer (2011). • NHS England. 2013/14 NHS Standard Contract for Cancer: Chemotherapy (Adult). B15/S/a. • NHS England. 2013/14 NHS Standard Contract for Cancer: Radiotherapy (All Ages). B01/S/a.

CLINICAL NEED and BURDEN OF DISEASE

Breast cancer is the most common cancer in the UK, accounting for 15% of all new cases6. In 2013, there were 44,831 new cases of breast cancer in England7. Breast cancer risk is strongly related to age, with 81% of cases occurring in women aged 50 years and over, and while the incidence of breast cancer is highest in those from higher socioeconomic groups, survival is lowest in those from lower socioeconomic groups8,9. This pattern persists even after allowing for the higher overall premature all-cause mortality observed in lower socioeconomic groups compared to higher socioeconomic groups10. Approximately 5% of

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patients present with metastatic breast cancer, and around 30% of people who present with localised disease will later develop metastases3.

Breast cancer that is ER-negative, PR-negative and HER2-negative are referred to as triple negative and account for about 12-15% of all breast cancers11. BRCA1 and BRCA2 are human genes that produce tumour suppressor proteins that help to repair damaged DNA and therefore play a role in ensuring the stability of the cell’s genetic material. Most breast cancers caused by BRCA1 are triple negative12 whereas those with germline BRCA2 mutations develop breast cancers more in line with the proportions seen in sporadic cases13. Patients with triple negative breast cancer are frequently young or premenopausal women and often have worse outcome than other breast cancer subtypes11. There are also currently more limited treatment options for patients with triple negative breast cancer due to the lack of efficacy of hormone and HER2 targeted therapies in these patientsb.

A woman’s lifetime risk of developing breast and/or is greatly increased if the BRCA1 or BRCA2 mutation is inherited14. About 12% of women in the general population will develop breast cancer at some point during their lives. In contrast, 55% to 65% of women who inherit the BRCA1 mutation and around 45% of women who inherit the BRCA2 mutation will develop cancer by the age of 70 years15,16. Around 1 in 20 (5%) people diagnosed with breast cancer may have inherited a BRCA mutation, accounting for about 2,500 of the cases diagnosed each year in the UK17. However, expert opinion notes that breast screening is currently limited in the NHS to people with a 10% or greater probability of carrying a mutation. Therefore, the estimate of 5% of people diagnosed with breast cancer having a BRCA1 or 2 mutation may be an overestimate13.

In 2014-15, there were 194,585 hospital admissions for breast cancer (ICD-10:C50) in England, resulting in 100,956 bed days and 197,877 finished consultant episodes18. In 2014, 10,158 deaths from breast cancer were registered in England and Wales19.

PATIENT PATHWAY

RELEVANT GUIDANCE

NICE Guidance

• NICE technology appraisal in development. Breast cancer (HER2 positive, metastatic) - pertuzumab (with trastuzumab and ) [ID523]. Expected date of issue to be confirmed. • NICE technology appraisal in development. Breast cancer (HER2 positive, unresectable) - trastuzumab emtansine (after trastuzumab & taxane) [ID603]. Expected date of issue to be confirmed. • NICE technology appraisal. Everolimus in combination with exemestane for treating advanced HER2-negative hormone-receptor-positive breast cancer after endocrine therapy (TA295). August 2013. • NICE technology appraisal. in combination with for the first- line treatment of metastatic breast cancer (TA263). August 2012. • NICE technology appraisal. Lapatinib and trastuzumab in combination with an aromatase inhibitor for the first line treatment of metastatic hormone receptor positive breast cancer which over-expresses HER2 (TA257). June 2012. • NICE technology appraisal. for the treatment of locally advanced or metastatic breast cancer (TA250). April 2012.

b Company comment.

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• NICE technology appraisal. Fulvestrant for the treatment of locally advanced or metastatic breast cancer (TA239). December 2011. • NICE technology appraisal. Bevacizumab in combination with a taxane for the first-line treatment of metastatic breast cancer (TA214). February 2011. • NICE technology appraisal. for the treatment of metastatic breast cancer (TA116). January 2007. • NICE technology appraisal. Guidance on the use of trastuzumab for the treatment of advanced breast cancer (TA34). March 2002.

• NICE clinical guideline. Familial breast cancer: the classification and care of women at risk of familial breast cancer in primary, secondary and tertiary care (CG164). June 2013. • NICE clinical guideline. Advanced breast cancer – diagnosis and treatment (CG81). February 2009. • NICE clinical guideline. Breast cancer (early & locally advanced): diagnosis and treatment (CG80). February 2009. • NICE quality standards. Breast cancer quality standard (QS12). September 2011. • Cancer Service guideline CSGBC. Improving outcomes in breast cancer. August 2002.

Other Guidance

• European Society for Medical Oncology. ESO-ESMO 2nd international consensus guidelines for advanced breast cancer (ABC2). 201420. • American Society of Clinical Oncology. Use of biomarkers to guide decisions on systemic therapy for women with metastatic breast cancer: American Society of Clinical Oncology Clinical Practice Guideline. 201521. • European Society for Medical Oncology. Primary breast cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. 201322. • Scottish Intercollegiate Guidelines Network. Treatment of primary breast cancer (134). 201323. • European Society for Medical Oncology. BRCA in Breast Cancer: ESMO Clinical Practice Guidelines. 201124.

CURRENT TREATMENT OPTIONS

Treatment for patients with advanced breast cancer aims to slow disease progression, manage symptoms and improve quality of life. Most cases of breast cancer with the BRCA1 mutation are triple negative. These are treated by a combination of surgery, chemotherapy and radiotherapy. There is no definitive recommended for germline mutation associated BRCA breast cancer nor any approved treatments specifically for patients with breast cancer harbouring a deleterious BRCA mutation.

Treatment for triple negative advanced breast cancer may include12, 24: • Chemotherapy – anthracycline (such as or ) or taxane-based regimens (such as docetaxel or ). A retrospective study found that treatment in the neoadjuvant setting demonstrated a higher pathological complete response in BRCA1 breast cancer patients compared with other chemotherapies (, and , and taxane based therapies). Another study demonstrated that patients with BRCA1 and 2 had a higher response to than the standard chemotherapy with docetaxel25. • : Poly (ADP-ribose) polymerase (PARP) inhibitors are being developed as single therapeutic agents against BRCA breast and ovarian cancers.

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• Surgery – evidence suggests that those with BRCA breast cancer are more likely to develop a second cancer either in the same breast or the opposite one compared to women without the mutated genes. Therefore, risk reducing mastectomy or oophorectomy may be recommended.

EFFICACY and SAFETY

Trial OlympiAD, NCT02000622, D0819C00003, 2013-005137-20; olaparib vs physicians’ chemotherapy choice; phase III. Sponsor AstraZeneca. Status Ongoing. Source of Trial registry26 and manufacturer. information Location EU (incl UK), USA and other countries. Design Randomised, active-controlled.

Participants n=310 (planned); aged ≥18 years; metastatic breast cancer; germline BRCA 1 or 2 mutation; prior therapy with an anthracycline and a taxane in either an adjuvant or metastatic setting; prior platinum agent only if no breast cancer progression occurring on treatment or if given in adjuvant/neoadjuvant setting ≥12 months before study entry; ER/PR breast cancer positive patients must have received and progressed on at least one endocrine therapy (adjuvant or metastatic), or have disease that the treating physician believes to be inappropriate for endocrine therapy; Eastern Cooperative Oncology Group performance status 0-1. No prior treatment with PARP inhibitor; no HER2 positive disease; ≤2 prior lines of chemotherapy for metastatic breast cancer. Schedule Randomised to olaparib 300mg twice daily (2 x 150mg tablets taken at the same time in the morning and evening, approximately 12 hours apart), or physician’s choice of chemotherapy: capecitabine 2,500mg/m2 oral daily (divided in 2 doses) for 14 days, and repeated every 21 days; or 30mg/m2 intravenously (IV) on days 1 and 8, of a 21 day cycle; or eribulin 1.4mg/m2 IV on days 1 and 8, of a 21 day cycle. Follow-up Data collection up to 7 years. Primary Progression free survival. outcome/s Secondary Overall survival; time from randomisation to second progression or death; objective outcome/s response rate; adjusted mean change from baseline in global quality of life score from the EORTC-QLQ-C30 questionnairec; safety and tolerability by assessment of adverse events, physical examination, vital signs and laboratory parameters. Expected Study completion date reported as Dec 2018. reporting date

ESTIMATED COST and IMPACT

COST

The cost of olaparib is not yet known.

c The European Organization for Research and QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology.

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IMPACT - SPECULATIVE

Impact on Patients and Carers

 Reduced mortality/increased length of survival  Reduced symptoms or disability

 Other:  No impact identified

Impact on Health and Social Care Services

 Increased use of existing services  Decreased use of existing services

 Re-organisation of existing services  Need for new services

 Other:  None identified

Impact on Costs and Other Resource Use

 Increased drug treatment costs  Reduced drug treatment costs

 Other increase in costs:  Other reduction in costs:

 Other: uncertain unit costs compared to  None identified existing therapeutic options.

Other Issues

 Clinical uncertainty or other research question  None identified identified:

REFERENCES

1 electronic Medicines Compendium. Lynparza 50mg hard capsules. http://www.medicines.org.uk/emc/medicine/30359 Accessed 23 November 2015. 2 Breast Cancer Care. Breast cancer facts. http://www.breastcancercare.org.uk/breast-cancer- information/about-breast-cancer/breast-cancer-facts Accessed 23 November 2015. 3 National Institute for Health and Clinical Excellence. Lapatinib or trastuzumab in combination with an aromatase inhibitor for the first-line treatment of metastatic hormone-receptor-positive breast cancer that overexpresses HER2. Technology appraisal TA257. London: NICE; June 2012. 4 Macmillan Cancer Support. HER2 positive breast cancer. http://www.macmillan.org.uk/Cancerinformation/Cancertypes/Breast/Aboutbreastcancer/Typesan drelatedconditions/HER2%20positive.aspx Accessed 29 November 2015. 5 NHS choices. Breast Cancer (female) – Causes. August 2014. http://www.nhs.uk/Conditions/Cancer-of-the-breast-female/Pages/Causes.aspx Accessed 29 November 2015. 6 Cancer Research UK. Cancer incidence statistics in the UK in 2012. http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer- type/breast-cancer#heading-Zero Accessed 21 January 2016. 7 Office for National Statistics. Cancer registration statistics, England, 2013. www.ons.gov.uk 8 Cancer Research UK. Cancer stats – Breast cancer UK May 2009. http://publications.cancerresearchuk.org/downloads/product/CSBREA09breast.pdf Accessed 30 November 2015. 9 Shack L, Jordan C, Thomson C et al. Variation in incidence of breast, lung and cervical cancer and malignant melanoma of skin by socioeconomic group in England. BMC Cancer 2008;8(1):271. 10 National Institute for Health and Clinical Excellence. Breast cancer: diagnosis and treatment: an assessment of need. A report to the National Collaborating Centre for Cancer. Clinical Guidelines, No. 80-81S. Cardiff. February 2009. 11 Couch FJ, Hart SN, Sharma P et al. Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. Journal of Clinical Oncology 2015;33(4):304-311.

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12 Macmillan. Triple negative breast cancer. http://www.macmillan.org.uk/Cancerinformation/Cancertypes/Breast/Aboutbreastcancer/Typesan drelatedconditions/Triplenegativebreastcancer.aspx Accessed 24 November 2015. 13 Horizon Scanning Research & Intelligence Centre. for locally advanced and/or metastatic breast cancer with germline BRCA 1/2 positive mutation. University of Birmingham, September. www.hsric.nihr.ac.uk 14 National Cancer Institute. BRCA1 and BRCA2: Cancer risk and genetic testing. http://www.cancer.gov/about-cancer/causes-prevention/genetics/brca-fact-sheet#r5 Accessed 30 November 2015. 15 Antoniou A, Pharoah PD, Narod S et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: A combined analysis of 22 studies. American Journal of Human Genetics 2003; 72(5):1117–1130. 16 Chen S and Parmigiani G. Meta-analysis of BRCA1 and BRCA2 penetrance. Journal of Clinical Oncology 2007; 25(11):1329–1333. 17 Breast Cancer Campaign. BRCA gene mutations and familial breast cancer. http://www.breastcancercampaign.org/about-breast-cancer/breast-cancer-risk-factors/family- history-and-genetics/brca-gene-mutations-and-breast-cancer Accessed 30 November 2015. 18 Health & Social Care Information Centre. Hospital Episode Statistics for England. Admitted Patient Care, 2014-15. www.hscic.gov.uk 19 Office for National Statistics. Deaths registered in England and Wales (series DR), 2014. www.ons.gov.uk 20 Cardoso F, Costa A, Norton L et al. ESO-ESMO 2nd international consensus guidelines for advanced breast cancer (ABC2). Annals of Oncology 2014;00:1-18. 21 Poznak CV, Somerfield MR, Bast RC et al. Use of biomarkers to guide decisions on systemic therapy for women wth metastatic breast cancer. American Society of Clinical Oncology Clinical Practice Guideline. Journal of Clinical Oncology 2015;33(24):2695-2704. 22 Senkus E, Kyriakides S, Penault-Llorca F et al. Primary breast cancer: ESMO clinical practice guidelins for diagnosis, treatment and follow-up. Annals of Oncology 2013;24(suppl 6):vi7-vi23. 23 Scottish Intercollegiate Guidelines Network. Treatment of primary breast cancer. National Clinical Guideline 134. Edinburgh: SIGN; September 2013. 24 Balmana J, Diez O, Rubio IT et al. BRCA in breast cancer: ESMO Clinical Practice Guidelines. Annals Oncology 2011;22(Suppl 6):vi31-vi34. 25 Tutt A, Ellis P, Kilburn L et al. The TNT trial: A randomised phase III trial of carboplatin (C) compared with docetaxel (D) for patients with metastatic or recurrent locally advanced triple negative or BRCA1/2 breast cancer. San Antonio Breast Cancer Symposium. December 2014. Abstract S3-01. Oral presentation. 26 ClinicalTrials.gov. Assessment of the efficacy and safety of olaparib monotherapy versus physicians choice chemotherapy in the treatment of metastatic breast cancer patients with germline BRCA1/2 mutations (OlympiAD). https://clinicaltrials.gov/ct2/show/NCT02000622 Accessed 24 November 2015.

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