Horizon Scanning Research February 2016 & Intelligence Centre

Veliparib with and for early-stage triple negative breast cancer ─ neoadjuvant therapy

LAY SUMMARY

Breast cancer is the most common cancer in the UK. Most women This briefing is who get breast cancer are over 50 years of age and have already based on gone through the menopause. information available at the time of research and a There are many types of breast cancer. Triple negative is a form of limited literature breast cancer that does not respond to hormone treatments or other search. It is not newer targeted treatments. Veliparib is a new treatment for women intended to be a with early-stage triple negative breast cancer. Veliparib is given as a definitive statement tablet taken twice daily. It is given in combination with the on the safety, chemotherapy drugs carboplatin every 3 weeks and paclitaxel weekly, efficacy or which are both given directly into the blood. Studies at the moment are effectiveness of the aiming to show how well these treatments work together and that health technology veliparib is safe to use. covered and should not be used for If veliparib is licensed for use in the UK, it will provide a new treatment commercial option for patients with early-stage breast cancer. purposes or commissioning without additional NIHR HSRIC ID: 9522 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: early-stage; oestrogen receptor (ER)-negative, progesterone receptor (PR)-negative, human epidermal growth factor 2 (HER2)–negative ─ neoadjuvant therapy; in combination with carboplatin and paclitaxel.

TECHNOLOGY

DESCRIPTION

Veliparib (ABT 888, NSC-737664) is a poly(ADP-ribose) polymerase (PARP) inhibitor, which acts by inhibiting both PARP-1 and PARP-2 enzymes. It was optimised from a prior lead compound (A 620223) and has an improved pharmacokinetic profile compared with its predecessor. PARP enzymes recognise DNA damage and facilitate DNA repair. Research has shown inhibition of PARP enzymes can potentiate the cytotoxicity of common DNA- damaging cancer therapies such as radiation therapy and alkylating chemotherapeutics. The dosing regimen in the pivotal study was veliparib administered orally at 50mg twice daily for 12 weekly cycles (up to a maximum of 16 weeks if there are dose interruptions or modifications), in combination with IV carboplatin AUCa 6, every 3 weeks and paclitaxel 80mg/m2 weekly on day 1 of each cycle.

Veliparib does not currently have Marketing Authorisation in the EU for any indication.

Veliparib is in phase III clinical trials for non-small cell lung cancer and ovarian cancer, fallopian tube cancer and peritoneal cancer. Veliparib is also in phase II clinical trials for melanoma and colorectal cancer.

INNOVATION and/or ADVANTAGES

If licensed, veliparib will offer an additional treatment option for patients with early-stage triple negative breast cancer.

DEVELOPER

AbbVie Ltd.

AVAILABILITY, LAUNCH OR MARKETING

In phase III clinical trials.

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 growth1. Hormone-receptor (HR) positive breast cancer includes disease in which tumour cells

a Area under curve.

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express either oestrogen receptors (ER) or progesterone receptors (PR)2. Approximately 80% of breast cancers in postmenopausal women are HR-positive 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 growth3. HER2-negative breast cancer refers to disease that does not overexpress HER24. Breast cancer cells that have tested negative for HER2, ER, and PR are termed triple negative breast cancers (TNBC)5.

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 factors4. The risk of developing breast cancer is also known to increase markedly with inheritance of certain genetic mutations (e.g. BRCA2, BRCA1 and TP53). Breast cancer in adults can occur at any age, though there is an increased risk in postmenopausal women6.

TNBC is more common in women from Black ethnic groups, and has been associated with deprivation status, younger age at diagnosis, more advanced disease stage, higher grade, high mitotic indices, a family history of breast cancer, and BRCA1 mutations7. Among breast cancers in patients with a hereditary BRCA1 mutation, over 80% are triple negative8.

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 30% of all cancers in women6. In 2013, there were 44,831 new cases of breast cancer in England9. 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 groups10,11. This pattern persists even after allowing for the higher overall premature all-cause mortality observed in lower socioeconomic groups compared to higher socioeconomic groups12. Approximately 5% of patients present with metastatic breast cancer, and around 30% of people who present with localised disease will later develop metastases3. Approximately 95% of breast cancers are early or locally advanced at presentation13. TNBC accounts for 15-20% of breast cancers5.

In 2014-15, there were 194,585 hospital admissions for breast cancer (ICD-10 C50) in England, resulting in 194,585 finished consultant episodes and 100,956 bed days14. In 2014, 10,158 deaths from breast cancer were registered in England and Wales15.

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PATIENT PATHWAY

RELEVANT GUIDANCE

NICE Guidance

• NICE technology appraisal. Breast cancer (early) – intrabeam radiotherapy system (ID618). Anticipated publication date TBC. • NICE technology appraisal. Paclitaxel for the adjuvant treatment of early node-positive breast cancer (TA108). September 2006. • NICE technology appraisal. for the adjuvant treatment of early node-positive breast cancer (TA109). September 2006. • 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. Breast cancer (early & locally advanced): diagnosis and treatment (CG80). February 2009. • NICE quality standards. Breast cancer quality standard (QS12). September 2011. • NICE interventional procedure guidance. Endoscopic mastectomy and endoscopic wide local excision for breast cancer (IPG296). April 2009. • NICE diagnostic guidelines. Intraoperative tests (RD-100i OSNA system and Metasin test) for detecting sentinel lymph node metastases in breast cancer (DG8). August 2013. • NICE diagnostic guidelines. Gene expression profiling and expanded immunohistochemistry tests for guiding adjuvant chemotherapy decisions in early breast cancer management: MammaPrint, Oncotype DX, IHC4, and MammoStrat (DG10). September 2013.

Other Guidance

• European Society for Medical Oncology. Primary Breast Cancer: ESMO Clinical Practice Guidelines for Diagnosis, Treatment and Follow-up. 201516. • Scottish Intercollegiate Guidelines Network. Treatment of Primary Breast Cancer (134). 201317. • European Society for Medical Oncology. BRCA in Breast Cancer: ESMO Clinical Practice Guidelines. 201118.

CURRENT TREATMENT OPTIONS

Early TNBC is currently treated with a combination of surgery, chemotherapy and radiotherapy. Those with TNBC do not benefit from treatment with hormonal therapy or HER2 targeted agents5. Treatment may include 5, 21, 22: • 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 lumpectomy may be recommended. • Chemotherapy – as adjuvant or neoadjuvant therapy; (such as or ) and/or -based regimens (such as docetaxel or paclitaxel). 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 carboplatin than the standard chemotherapy with docetaxel19. • Radiotherapy – often in combination with chemotherapy in the adjuvant setting.

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• Bisphosphonates

Patients are increasingly being treated with neoadjuvant chemotherapy prior to surgery with a view to downsizing the tumour and improving surgical outcomes. Patients who achieve a complete pathological response to the primary chemotherapy have better long term prognosis. However, for triple negative patients who fail to respond well to neoadjuvant chemotherapy, there are no other systemic treatment options available (unlike ER positive or HER2 positive patients who have the advantage of additional endocrine or anti-HER2 based therapies)b.

EFFICACY and SAFETY

Trial NCT02032277, M14-011, EudraCT 2013-002377-21; ABT888 with carboplatin and paclitaxel vs placebo with paclitaxel and carboplatin vs placebo and paclitaxel, all followed by doxorubicin/cyclophosphamide; phase III. Sponsor AbbVie. Status Ongoing. Source of Trial Registry20. information Location EU (incl. UK), USA, Canada and other countries. Design Randomised, placebo-controlled.

Participants n=624 (planned); 18 years and older; histologically confirmed invasive breast cancer by core needle or incisional biopsy (excisional biopsy is not allowed); Clinical stage T2-3 N0-2 or T1 N1-2 by physical exam or radiologic studies; ER-negative, PR- negative and HER2-negative; Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1; exclusion if previous treatment with carboplatin, paclitaxel, doxorubicin, cyclophosphamide or a PARP inhibitor, or concurrent treatment with an ovarian hormonal replacement therapy or with hormonal agents such as raloxifene, tamoxifen or other selective oestrogen receptor modulator. Schedule Subjects randomised to veliparib, carboplatin and paclitaxel followed by doxorubicin/cyclophosphamide (AC) (arm A); or placebo and carboplatin followed by AC (Arm B); or placebo and paclitaxel followed by AC (Arm C). Veliparib was administered at 50mg taken orally twice daily for 12 weekly cycles (up to a maximum of 16 weeks if there are dose interruptions or modifications), in combination with IV carboplatin AUC 6 IV every 3 weeks and paclitaxel 80mg/m2 IV weekly on day 1 of the cycle, followed by 60 mg/m2 doxorubicin IV and 600mg/m2 cyclophosphamide IV on day 1 of four 14-day cycles or four 21-day cycles. Follow-up Not reported. Primary Pathological complete response (pCR). outcome/s Secondary Eligibility for breast conservation after therapy (BCR) will be determined by the outcome/s subject's surgeon prior to chemotherapy and after completion of chemotherapy. Other outcome measures include: event free survival; overall survival; clinical response rate; pCR plus minimal residual disease; ECOG performance status; breast cancer related quality of life assessed via European Organisation for Research and Treatment of Cancer quality of life questionnaire (QLQ) QLQ-C30, QLQ-BR23 and European Quality of Life Dimensions 5 Level questionnaires (EQ-5D-5L). Expected Study completion date reported as April 2016. reporting date

b Expert Personal Communication.

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ESTIMATED COST and IMPACT

COST

The cost of veliparib is not yet known.

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: increased  Decreased use of existing services use of existing resources due to longer administration time in the chemotherapy unit compared with standard treatmentc

 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  None identified

Other Issues

 Clinical uncertainty or other research question  None identified identified

REFERENCES

1 Breast Cancer Care. Breast cancer facts. www.breastcancercare.org.uk/breast-cancer- information/about-breast-cancer/breast-cancer-facts Accessed 27 January 2016. 2 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 257. London: NICE; June 2012. 3 Macmillan Cancer Support. HER2 positive breast cancer. www.macmillan.org.uk/Cancerinformation/Cancertypes/Breast/Aboutbreastcancer/Typesandrelat edconditions/HER2%20positive.aspx Accessed 27 January 2016. 4 NHS choices. Breast Cancer (female) – Causes. August 2014. www.nhs.uk/Conditions/Cancer-of- the-breast-female/Pages/Causes.aspx Accessed 27 January 2016. 5 Macmillan Cancer Support. Triple negative breast cancer. www.macmillan.org.uk/Cancerinformation/Cancertypes/Breast/Aboutbreastcancer/Typesandrelat edconditions/Triplenegativebreastcancer.aspx Accessed 27 January 2016. 6 Cancer Research UK. Cancer incidence statistics in the UK in 2011. January 2014. www.cancerresearchuk.org Accessed 27 January 2016. 7 Boyle P. Triple negative breast cancer: epidemiological considerations and recommendations. Oxford Journals: Annals of oncology 2012; 23(6):7-12.

c Expert Personal Communication.

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8 Lips EH, Mulder L, Oonk A et al. Triple negative breast cancer: BRCAness and concordance of clinical features with BRCA1-mutation carriers. British Journal of Cancer 2013;108:2172–2177. 9 Office for National Statistics. Cancer registration statistics, England, 2013. www.ons.gov.uk 10 Cancer Research UK. Cancer stats – Breast cancer UK May 2009. http://publications.cancerresearchuk.org/downloads/product/CSBREA09breast.pdf Accessed 27 January 2016. 11 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. 12 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. 13 National Institute for Health and Clinical Excellence. Early and locally advanced breast cancer: costing template. June 2009. http://guidance.nice.org.uk/CG80/CostingTemplate/xls/English 14 Health and Social Care Information Centre. Hospital episode statistics for England. Inpatient statistics, 2014-15. www.hscic.gov.uk 15 Office for National Statistics. Deaths registered in England and Wales (series DR) - 2014. www.ons.gov.uk 16 Senkus E, Kyriakides S, Penault-Llorca F et al. Primary breast cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Annals of Oncology 2015;26(suppl 5):v8-v30. 17 Scottish Intercollegiate Guidelines Network. Treatment of primary breast cancer. National Clinical Guideline 134. Edinburgh:SIGN; September 2013. 18 Balmana J, Diez O, Rubio IT et al. BRCA in breast cancer: ESMO Clinical Practice Guidelines. Annals Oncology 2011;22(Suppl 6):vi31-vi34. 19 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. 20 ClinicalTrials.gov. A study evaluating safety and efficacy of the addition of ABT-888 plus carboplatin versus the addition of carboplatin to standard chemotherapy versus standard chemotherapy in subjects with early stage triple negative breast cancer. clinicaltrials.gov/ct2/show/record/NCT02032277 Accessed 27 January 2016.

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