Talazoparib for Locally Advanced And/Or Metastatic Breast Cancer with Germline BRCA 1/2 Positive Mutation

Horizon Scanning Research September 2015 & Intelligence Centre

Talazoparib for locally advanced and/or metastatic breast cancer with germline BRCA 1/2 positive mutation

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 gene mutation have a much higher risk of breast and other cancers. available at the time 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 Talazoparib is a new treatment for breast cancer with germline BRCA on the safety, mutation and that has spread locally or to other parts of the body. efficacy or Some studies have suggested talazoparib may be helpful for people effectiveness of the whose first chemotherapy treatment has failed and whose disease has health technology spread and more studies are now aiming to show how well it works covered and should and that it is safe to use. not be used for commercial purposes or NIHR HSRIC ID: 9302 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: locally advanced and/or metastatic; germline BRCA1 or 2 mutation positive.

TECHNOLOGY

DESCRIPTION

Talazoparib (BMN 673; LT 006673; LT 673; talazoparib tosylate) is a novel, dual-mechanism poly (ADP-ribose) polymerase (PARP) inhibitor. PARP is involved in the detection and initiation of DNA repair. In cells deficient in other DNA repair pathways, such as those seen with BRCA gene mutations, inhibition of PARP can lead to cancer cell death. In a phase III clinical trial, talazoparib was administered at a dose of 1.0mg orally once daily until disease progression or unacceptable toxicity1.

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

Talazoparib is also in phase II trials for breast cancer (first line, neoadjuvant therapy), ovarian cancer, and other cancers with specific mutations.

INNOVATION and/or ADVANTAGES

If licensed, talazoparib will offer an additional treatment option for patients with advanced or metastatic breast cancer with the BRCA1 or 2 germline mutation.

DEVELOPER

BioMarin Pharmaceutical Inc.

Medivation, Inca.

AVAILABILITY, LAUNCH OR MARKETING

Talazoparib is in a phase III clinical trial.

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+) breast cancer includes disease in which tumour cells express either oestrogen receptors (ER+) or progesterone receptors (PR+)3. Approximately 80% of breast cancers in postmenopausal women are HR+3 and around two-thirds of breast cancers are ER+. Human epidermal growth factor receptors (HER2) are overexpressed in around 15-25% of women with breast cancer and promote tumour growth4. HER2-negative

a Medivation Inc bought worldwide rights to talazoparib in Aug 2015.

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breast cancer refers to disease that does not overexpress HER24. Both HR+ 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. BRCA2, BRCA1 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 30% of all cancers in women6. 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 patients present with metastatic breast cancer, and around 30% of people who present with localised disease will later develop metastases3.

Breast cancer that is negative for ER, PR and HER2 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,c whereas those with germline BRCA2 mutations develop breast cancers more in line with the proportions seen in sporadic casesb. Patients with triple negative breast cancer frequently are young or premenopausal women and often have worse outcome than other breast cancer subtypes11. A woman’s lifetime risk of developing breast and/or ovarian cancer is greatly increased if the BRCA1 or BRCA2 mutation is

b Expert personal communication.

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inherited13. 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 years14,15. Around 1 in 20 (5%) people diagnosed with breast cancer may have inherited a BRCA mutation, accounting for 2,500 of the 50,000 cases diagnosed each year in the UK16. 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 BRCA1/2 mutation may be overestimatedc.

In 2013-14, there were 188,103 hospital admissions for breast cancer (ICD-10:C50) in England, accounting for 191,337 finished consultant episodes and 106,988 bed days17. In 2013, 10,230 deaths from breast cancer were registered in England and Wales18.

PATIENT PATHWAY

RELEVANT GUIDANCE

NICE Guidance

• NICE technology appraisal in development. Breast cancer (HER2 positive, metastatic) - pertuzumab (with trastuzumab and docetaxel) [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. Bevacizumab in combination with capecitabine 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. Eribulin for the treatment of locally advanced or metastatic breast cancer (TA250). April 2012.

• 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. Gemcitabine 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.

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• 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). 201419. • 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. 201520. • European Society for Medical Oncology. Primary breast cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. 201321. • Scottish Intercollegiate Guidelines Network. Treatment of primary breast cancer (134). 201322. • European Society for Medical Oncology. BRCA in Breast Cancer: ESMO Clinical Practice Guidelines. 201123.

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 chemotherapy regimen recommended for BRCA breast cancer nor any approved treatments specifically for patients with breast cancer harbouring a deleterious BRCA mutation. Treatment may include12, 23: • Chemotherapy – anthracycline (such as doxorubicin or epirubicin) or taxane-based regimens (such as docetaxel or paclitaxel). A retrospective study found that cisplatin treatment in the neoadjuvant setting demonstrated a high pathological complete response in BRCA1 breast cancer patients compared with other chemotherapies (cyclophosphamide, methotrexate and fluorouracil, and taxane based therapies). • Targeted therapy: Poly (ADP-ribose) polymerase (PARP) inhibitors are being developed as single therapeutic agents against BRCA breast and ovarian cancers. • 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 EMBRACA, NCT01945775, 673-301, ABRAZO, NCT02034916, 673-201; U1111-1155-7579; talazoparib vs talazoparib; phase II. protocol specific physician’s choice; phase III. Sponsor BioMarin Pharmaceutical. BioMarin Pharmaceutical. Status Ongoing. Ongoing. Source of Trial registry1. Trial registry24. information Location EU (incl. UK), USA and other countries. EU (incl. UK) and USA. Design Randomised, active-controlled. Uncontrolled, open-label.

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Participants n=429 (planned); aged ≥18 years; breast n=140 (planned); aged ≥18 years; breast cancer; locally advanced and/or cancer; locally advanced and/or metastatic; deleterious or pathogenic metastatic; deleterious or pathogenic BRCA1 or BRCA2 mutation; up to 2 prior BRCA1 or BRCA2 mutation; prior chemotherapy therapies for platinum containing regimen for advanced/metastatic disease; prior metastatic disease with disease treatment with a taxane and/or progression >8 weeks following the last anthracycline in the adjuvant or dose of platinum (cohort 1), or up to 2 metastatic setting; Eastern Cooperative prior chemotherapy therapies for Oncology Group (ECOG) performance metastatic disease but no platinum status ≤1. therapy (cohort 2); ECOG performance status ≤1. Schedule Randomised to talazoparib 1.0mg, oral, Patients receive talazoparib 1.0mg, oral, once daily for 21 continuous days or once daily for 21 continuous days. physician’s choice of capecitabine, eribulin, gemcitabine or vinorelbine.

Follow-up Patients followed up to 30 months from Patients followed up to 30 months from enrolment. Treatment given until disease first patient enrolment. progression or unacceptable toxicity. Primary Progression free survival (PFS). ORR. outcome/s Secondary Overall survival (OS); objective response OS; PFS; clinical benefit rate; DOR; outcome/s rate (ORR); duration of response (DOR); health-related quality of life. and health-related quality of life. Expected Primary study enrolment completion date Primary completion date reported as Q4 reporting reported as second half of 2016. 2015. date

ESTIMATED COST and IMPACT

COST

The cost of talazoparib 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  Decreased use of existing services

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

 Other: as long as metastatic breast cancer  None identified remains an incurable disease, there will be a clinical need for additional treatments. PARP- inhibitors have a potential role in improving response, progression-free survival and possibly overall survival. However, there is a question about where limited resources are best utilised. It could be argued that there is

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greater need in investment at earlier stages, including widening availability of genetic testing, and improving screening and preventative optionsc.

Impact on Costs and Other Resource Use

 Increased drug treatment costs  Reduced drug treatment costs

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

 Other: some patients with metastatic breast  None identified cancer are likely to obtain moderate benefit from inclusion of PARP-inhibitors such as talazoparib in the treatment pathway. This ideally means a response to treatment, with a measurable reduction in volume of disease, improvement in symptoms and possibly improvement in duration of survival. Talazoparib would need to be shown to be cost-effective in the proposed setting. If 10,000 patients develop metastatic breast cancer each year and 2% of these were ascertained as having a BRCA mutation, this would mean about 200 eligible patients per year - assuming fit enough for further treatment after standard first-line therapy. However, talazoparib in not the only PARP- inhibitor for which these patients may be eligibled.

Other Issues

 Clinical uncertainty or other research question  None identified identified: more data are required from studies of PARP-inhibitors in earlier stages of disease e.g. the adjuvant setting. If patients have already received a PARP-inhibitor in an adjuvant setting research study and then develop metastatic disease, there will be a question about benefit of re-treatment for the metastatic disease.

Cross-resistance of PARP-inhibitors is another area of uncertainty. If a patient has already responded to one PARP-inhibitor and then progresses, will there be any benefit in subsequent treatment with a different PARP- inhibitor? Due to cost of these drugs and lack of evidence, it is likely patients would only be eligible for one line of treatment with one of the drugs (if any) in the metastatic setting through the NHS.

It is expected that germline genetic testing availability will continue to increase. Ultimately, all patients with breast cancer are likely to be offered a gene test. However, the time-frame for this being widely implemented

c Expert personal communication.

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is uncertain. Testing is likely to also include other genes linked with an increased risk of breast cancer. There is also an expectation that genetic testing of affected patients will be more frequently arranged through oncology clinics, rather than as currently through clinical genetics services. The NHS financial climate will have an impact on if, and when, these changes can be implemented.

For the use of PARP-inhibitors, testing of the tumour may be more relevant than germline genetic testing. Breast cancers may contain BRCA mutations or features of “BRCAness” due to other mutations, without the patient carrying a germline BRCA mutation. If tumour testing is performed, it is possible that more patients could be identified who would benefit from treatment. However, this would need to be supported by trial evidence and there are limited resources and expertise currently in NHS laboratories for such testingd.

REFERENCES

1 ClinicalTrials.gov. A study evaluating talazoparib (BMN 673), a PARP inhibitor, in advanced and/or metastatic breast cancer patients with BRCA mutation (EMBRACA Study). https://clinicaltrials.gov/ct2/show/NCT01945775 Accessed 11 August 2015. 2 Breast Cancer Care. Breast cancer facts. http://www.breastcancercare.org.uk/breast-cancerinformation/about-breast-cancer/breast-cancer-facts Accessed 29 July 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 July 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 July 2015. 6 Cancer Research UK. Cancer incidence statistics in the UK in 2011. January 2014. www.cancerresearchuk.org 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 April 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. 12 Macmillan. Triple negative breast cancer. http://www.macmillan.org.uk/Cancerinformation/Cancertypes/Breast/Aboutbreastcancer/Typesan drelatedconditions/Triplenegativebreastcancer.aspx Accessed 24 August 2015.

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13 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 08 June 2015. 14 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. 15 Chen S and Parmigiani G. Meta-analysis of BRCA1 and BRCA2 penetrance. Journal of Clinical Oncology 2007; 25(11):1329–1333. 16 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 08 June 2015. 17 Health & Social Care Information Centre. Hospital Episode Statistics for England. Admitted Patient Care, 2013-14. www.hscic.gov.uk 18 Office for National Statistics. Deaths registered in England and Wales (series DR), 2013. www.ons.gov.uk 19 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. 20 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. 21 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. 22 Scottish Intercollegiate Guidelines Network. Treatment of primary breast cancer. National Clinical Guideline 134. Edinburgh: SIGN; September 2013. 23 Balmana J, Diez O, Rubio IT et al. BRCA in breast cancer: ESMO Clinical Practice Guidelines. Annals Oncology 2011;22(Suppl 6):vi31-vi34. 24 ClinicalTrials.gov. A phase 2, 2-stage, 2-cohort study of talazoparib (BMN 673), in locally advanced and/or metastatic breast cancer patients with BRCA mutation (ABRAZO Study). https://clinicaltrials.gov/ct2/show/NCT02034916 Accessed 11 August 2015.