Horizon Scanning Centre March 2013

Orteronel for metastatic hormone- relapsed following chemotherapy

SUMMARY NIHR HSC ID: 4870

Orteronel is intended to be used as therapy for the treatment of hormone- relapsed prostate cancer following progression despite docetaxel-containing chemotherapy. If licensed, it will provide an additional treatment option for this patient group. Orteronel is a reversible, non-steroidal biosynthesis inhibitor that selectively inhibits the 17,20 lyase enzyme, This briefing is suppressing the production of . based on

information Prostate cancer is the most common cancer in men in the UK, accounting for available at the time 25% of all male cancers. The main risk factor is increasing age, with an of research and a average of 75% of cases diagnosed in men aged 65 years and over. In 2010, limited literature there were 37,354 new diagnoses registered in England and Wales and in search. It is not 2011, there were 9,671 deaths. intended to be a definitive statement Current treatment options include hormonal therapies, (glucocorticoids, low- on the safety, dose oestrogens, selective 17,20 lyase inhibitors, or novel efficacy or antagonists), chemotherapies (docetaxel, mitoxantrone) and effectiveness of the immunotherapies (sipuleucel-T). Orteronel is currently in phase III clinical health technology trials comparing its effect on overall survival and event-free survival against covered and should treatment with placebo. These trials are expected to complete in 2013 and not be used for 2015. 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 Centre, University of Birmingham Email: [email protected] Web: http://www.hsc.nihr.ac.uk NIHR Horizon Scanning Centre

TARGET GROUP

• Prostate cancer: metastatic; hormone-relapsed (mHRPC) - in combination with prednisolone, following disease progression during or after docetaxel-based therapy.

TECHNOLOGY

DESCRIPTION

Orteronel (TAK-700) is a reversible, non-steroidal androgen biosynthesis inhibitor that selectively inhibits the 17,20 lyase enzyme, suppressing the production of testosterone. The progression and growth of prostate cancer cells are initially driven by testosterone via a signalling cascade that begins with the secretion of -releasing hormone and luteinising hormone in the pituitary gland. Orteronel targets the testes and the adrenal cortex where testosterone is synthesised in the mitochondrial membrane by a series of enzymes, including 17-alpha-hydroxylase. Previous agents known to inhibit this pathway have blocked other key enzymatic pathways in the adrenal glands, affecting the synthesis of cortisol. Selective blockade of the 17,20 lyase enzyme, but not the synthesis of cortisol, has the potential to offer a benefit over less selective agents. Orteronel is administered orally, twice daily, in combination with prednisolone.

Orteronel is in phase III clinical trials for the treatment of mHRPC pre-chemotherapy, and in phase II trials for non-metastatic HRPC.

INNOVATION and/or ADVANTAGES

If licensed, orteronel will provide an additional treatment option for this patient group.

DEVELOPER

Takeda UK Ltd.

AVAILABILITY, LAUNCH OR MARKETING

In phase III clinical trials.

PATIENT GROUP

BACKGROUND

HRPC is defined clinically as a failure of medical or surgical castration to prevent an increase in circulating hormones which are associated with worsening prostate cancer1. The mainstay of prostate cancer treatment is hormone therapy, which aims to suppress endogenous and thus slow tumour growth1. Most men eventually become resistant to this therapy and the cancer will progress and metastasise, which is variously termed HRPC, castration-resistant prostate cancer (CRPC), or androgen-resistant prostate cancer1.

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NHS or GOVERNMENT PRIORITY AREA

This topic is relevant to Improving Outcomes: A Strategy for Cancer (2011).

CLINICAL NEED and BURDEN OF DISEASE

Prostate cancer is the most common cancer in men in the UK, accounting for 25% of all male cancers2. The lifetime risk of being diagnosed with prostate cancer is approximately 1 in 8 for men in the UK3. The main risk factor is increasing age, with an average of 75% of cases diagnosed in men aged 65 years and over2. In 2010, there were 37,354 new cases registered in England and Wales, resulting in an age-standardised incidence rate of around 110 per 100,000 population3. Estimates suggest that most prostate cancer deaths occur in men with metastatic disease4, which develops in approximately 55-65% of patients5. In 2011-12, there were 56,027 hospital admissions in England due to prostate cancer (ICD-10 C61), accounting for 60,650 finished consultant episodes and 118,393 bed days6. In 2011, 9,671 deaths were registered in England and Wales7.

PATIENT PATHWAY

RELEVANT GUIDANCE

NICE Guidance • NICE technology appraisal in development. Sipuleucel-T for the first line treatment of metastatic hormone relapsed prostate cancer. Expected February 20148. • NICE technology appraisal in development. Radium-223 for the treatment of bone metastases in hormone relapsed prostate cancer. Expected January 20149. • NICE technology appraisal in development. Bone metastases (hormone refractory prostate cancer) – denosumab (ID405). Expected November 201310. • NICE technology appraisal in development. for the treatment of metastatic castration-resistant prostate cancer not previously treated with chemotherapy (ID503). Expected November 201311. • NICE technology appraisal. Abiraterone for castration-resistant metastatic prostate cancer previously treated with a docetaxel-containing regimen (TA259). June 201212. • NICE technology appraisal. Cabazitaxel for hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing regimen (TA255). May 201213. • NICE technology appraisal. Docetaxel for the treatment of hormone-refractory metastatic prostate cancer (TA101). June 200614.

• NICE clinical guideline in development. Prostate cancer: diagnosis and management (CG58). Expected January 201415. • NICE clinical guideline. Prostate cancer: diagnosis and treatment (CG58). 200816.

• NICE interventional procedure guidance. Focal therapy using cryoablation for localised prostate cancer (IPG423). April 201217. • NICE interventional procedure guidance. Focal therapy using high-intensity focused ultrasound for localised prostate cancer (IPG424). April 201218. • NICE interventional procedure guidance. Transperineal template biopsy and mapping of the prostate (IPG364). October 201019. • NICE interventional procedure guidance. High dose rate brachytherapy in combination with external-beam radiotherapy for localised prostate cancer (IPG174). May 200620.

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• NICE interventional procedure guidance. Cryotherapy as a primary treatment for prostate cancer (IPG145). November 200521. • NICE interventional procedure guidance. Low dose rate brachytherapy for localised prostate cancer (IPG132). July 200522. • NICE interventional procedure guidance. Cryotherapy for recurrent prostate cancer (IPG119). May 200523. • NICE interventional procedure guidance. High-intensity focused ultrasound for prostate cancer (IPG118). March 200524.

• NICE cancer service guidance. Improving outcomes in urological cancers (CSGUC). September 200225.

Other Guidance • National Comprehensive Cancer Network. NCCN guideline prostate cancer. 201326. • European Association of Urology. Guidelines on prostate cancer. 201227. • European Society for Medical Oncology. Prostate cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. 201028. • American Society of Clinical Oncology. American Society of Clinical Oncology endorsement of the cancer care Ontario practice guideline on nonhormonal therapy for men with metastatic hormone-refractory (castration-resistant) prostate cancer. 200729.

EXISTING COMPARATORS and TREATMENTS

Hormone relapsed disease generally develops around 18-24 months from the start of hormone therapy30. Treatment options for HRPC include14,15,25,30,a: • Additional hormonal therapy o Non-steroidal anti-androgens, i.e. , . o Glucocorticoids, i.e. dexamethasone, prednisolone o Low dose oestrogens, i.e. diethylstilboestrol o Non-selective adrenal inhibitors, i.e. o Selective 17,20-lyase inhibitors, i.e. abiraterone (Zytiga) in minimally symptomatic chemotherapy naïve paitents with low burden or slowly progressive disease, or after progression on docetaxel. o Novel androgen receptor antagonists, i.e. – second line after progression on docetaxel (not yet licensed for this indication). • Chemotherapy o Docetaxel in combination with prednisolone. o Mitoxantrone with prednisolone – second line after progression on docetaxel (not licensed for this indication). o Cabazitaxel (Jevtana) – second line after progression on docetaxel. • Immunotherapy o Sipuleucel-T, asymptomatic chemotherapy naïve patients, or after progression on docetaxel (not yet licensed for these indications). • Supportive care, given in combination with the above o External beam radiotherapy. o Bisphosphonates. o Systemic radioisotopes, i.e. radium-223 (Alpharadin) – chemotherapy naive patients, after progression on docetaxel, or symptomatic patients with bone metastases (not yet licensed for this indication) - samarium-153 or - 89.

a Expert personal communication.

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EFFICACY and SAFETY

Trial NCT01193257, C21005, NCT01707966, SAKK NCT01193244, C21004, 2010-018662-23; orteronel 08/11, 2011-002965-39; 2010-018661-35; orteronel vs placebo, both in orteronel vs placebo; vs placebo, both in combination with phase III. combination with prednisolone; phase III. prednisolone; phase III. Sponsor Millenium Swiss Group for Clinical Millenium Pharmaceuticals, Inc. Cancer Research. Pharmaceuticals, Inc. Status Ongoing. Ongoing. Ongoing. Source of Trial registry31. Trial registry32. Trial registry33. information Location EU, USA, Canada and EU (incl UK). EU, USA, Canada and other countries. other countries. Design Randomised, placebo- Randomised, placebo- Randomised, placebo- controlled. controlled. controlled. Participants n=1,083 (planned); aged n=192 (planned); aged 18 n=1,454 (planned); aged 18 years and older; males; years and older; males; 18 years and older; males; prostate cancer; prostate cancer; prostate cancer; metastatic; prior surgical metastatic; castration metastatic; progressive; castration or concurrent resistant, tumour prior surgical castration or use of an agent for progression following concurrent use of an agent medical castration; orchiectomy or during for medical castration; no progressive disease treatment with pain or pain not requiring during or following 1 or 2 gonadotropin-releasing use of any opioid or cytotoxic chemotherapy hormone (GnRH) narcotic analgesia in 2 regimens, 1 of which must analogues; non- weeks prior to entry. have included docetaxel. progressive disease following first line treatment with docetaxel. Schedule Randomised to orteronel, Randomised to orteronal, Randomised to orteronel, oral, twice daily, or oral, 300mg twice daily, or oral, twice daily; or placebo, oral, twice daily; placebo, twice daily; both placebo, twice daily; both both in combination with with best supportive care. in combination with prednisolone. prednisolone and concomitant GnRH analogue therapy unless previously undergone orchiectomy and have testosterone concentration of <50ng/dL. Follow-up Active treatment until Active treatment until Active treatment until disease progression, disease progression; disease progression, unacceptable toxicity, or follow-up until death. unacceptable toxicity or death; follow-up until 80% death; follow-up until 80% of participants have died of participants have died or lost to follow-up. or lost to follow-up. Primary Overall survival (OS). Event free survival (EFS). rPFS; OS. outcome Secondary Prostate specific antigen AEs; PSA response; rPFS; PSA response; circulating outcomes (PSA) response; pain QoL and pain response; tumour cell counts; time to response; radiographic OS; FACT-Pb. pain progressionc; progression-free survival HRQoL. (rPFS); health-related b FACT-P: Functional Assessment of Cancer Therapy-Prostate, a questionnaire measuring health-related quality of life in men with prostate cancer. c Measured by Brief Pain Inventory-Short Form (BPI-SF), a validated questionnaire to measure pain.

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quality of life (HRQoL). Expected Estimated 2013. Estimated 2015. Estimated 2014. reporting date

ESTIMATED COST and IMPACT

COST

The cost of orteronel is not yet known. The costs of selected treatments for HRPC are summarised belowd:

Drug Dose Unit cost34 Abiraterone (Zytiga) 1g, oral, once daily (taken as 250mg tabs, £2930.00 per 120-tab pack with prednisolone) Docetaxel 75mg/m2 , IV, once every 3 weeks (with £1,069.50 per cycle prednisolone) Prednisolone 5mg, oral, twice daily £9.65 per 30-tab pack

IMPACT - SPECULATIVE

Impact on Patients and Carers

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

 Other:  No impact identified

Impact on Services

 Increased use of existing services: additional  Decreased use of existing services: oral therapeutic option administration

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

 Other:  None identified

Impact on Costs

 Increased drug treatment costs  Reduced drug treatment costs

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

 Other: uncertain unit cost compared to  None identified existing treatments

Other Issues

 Clinical uncertainty or other research question  None identified identified: Expert opinion highlights that trials will not currently address the relative efficacy of different agents acting on the same hormonal axis, whether this agent may be active following failure of new agents, or has potential synergies with other newer agents. Future work should consider the optimal agent for individual patients.

d Based on an average adult surface area of 1.88m2, assumes wastage.

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REFERENCES

1 Hirst CJ, Cabrera C, Kirby M. Epidemiology of castration resistant prostate cancer: A longitudinal analysis using a UK primary care database. Cancer Epidemiology 2012;36(6):e349-e353. 2 Cancer Research UK. Prostate cancer key facts. http://www.cancerresearchuk.org/cancer- info/cancerstats/keyfacts/prostate-cancer/ Accessed 1 February 2013. 3 Cancer Research UK. Prostate cancer incidence statistics. http://www.cancerresearchuk.org/cancer-info/cancerstats/types/prostate/incidence/ Accessed 1 February 2013. 4 National Institute for Health and Clinical Excellence. Prostate Cancer: diagnosis and treatment. Clinical guideline CG58. London: NICE; February 2008. 5 National Institute for Health and Clinical Excellence. Draft scope for the proposed appraisal of abiraterone for the treatment of chemotherapy naïve metastatic castration-resistant prostate cancer. London: NICE; July 2011. 6 NHS Hospital episode statistics. NHS England 2007-08 HES data. 2013. www.hesonline.nhs.uk 7 Office for National Statistics. Mortality statistics: deaths registered in England and Wales (series DR), 2011. www.ons.gov.uk 8 National Institute for Health and Clinical Excellence. Sipuleucel-T for the first line treatment of metastatic hormone relapsed prostate cancer. Technology appraisal in development. Expected February 2014. 9 National Institute for Health and Clinical Excellence. Radium-223 for the treatment of bone metastases in hormone relapsed prostate cancer. Technology appraisal in development. Expected January 2014. 10 National Institute for Health and Clinical Excellence. Bone metastases (hormone refractory prostate cancer) – denosumab. Technology appraisal in development ID405. Expected November 2013. 11 National Institute for Health and Clinical Excellence. Abiraterone acetate for the treatment of metastatic castration-resistant prostate cancer not previously treated with chemotherapy. Technology appraisal in development ID503. Expected November 2013. 12 National Institute for Health and Clinical Excellence. Abiraterone for castration-resistant metastatic prostate cancer previously treated with a docetaxel-containing regimen. Technology appraisal TA259. London: NICE; June 2012. 13 National Institute for Health and Clinical Excellence. Cabazitaxel for hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing regimen. Technology appraisal TA255. London: NICE; May 2012. 14 National Institute for Health and Clinical Excellence. Docetaxel for the treatment of hormone- refractory metastatic prostate cancer. Technology appraisal TA101. London: NICE; June 2006. 15 National Institute for Health and Clinical Excellence. Prostate cancer: diagnosis and management. Clinical guideline in development (CG58). Expected January 2014. 16 National Institute for Health and Clinical Excellence. Prostate cancer: diagnosis and treatment. Clinical Guideline CG58. London: NICE; February 2008. 17 National Institute for Health and Clinical Excellence. Focal therapy using cryoablation for localised prostate cancer. Interventional procedure guidance IPG423. London: NICE; April 2012. 18 National Institute for Health and Clinical Excellence. Focal therapy using high-intensity focused ultrasound for localised prostate cancer. Interventional procedure IPG424. London: NICE; April 2012. 19 National Institute for Health and Clinical Excellence. Transperineal template biopsy and mapping of the prostate. Interventional procedure guidance IPG364. London: NICE; October 2010. 20 National Institute for Health and Clinical Excellence. High dose rate brachytherapy in combination with external-beam radiotherapy for localised prostate cancer. Interventional procedure guidance IPG174. London: NICE; May 2006. 21 National Institute for Health and Clinical Excellence. Cryotherapy as a primary treatment for prostate cancer. Interventional procedure guidance IPG145. London: NICE; November 2005. 22 National Institute for Health and Clinical Excellence. Low dose rate brachytherapy for localised prostate cancer. Interventional procedure guidance IPG132. London: NICE; July 2005.

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23 National Institute for Health and Clinical Excellence. Cryotherapy for recurrent prostate cancer. Interventional procedure guidance IPG119. London: NICE; May 2005. 24 National Institute for Health and Clinical Excellence. High-intensity focused ultrasound for prostate cancer. Interventional procedure guidance IPG118. London: NICE; March 2005. 25 National Institute for Health and Clinical Excellence. Improving outcomes in urological cancer. Cancer service guidance CSGUC. London: NICE; September 2002. 26 National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology (NCCN guideline) prostate cancer. http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf Accessed 19 February 2013. 27 Haidenreich A, Bastian PJ, Bellmunt J et al. Guidelines on prostate cancer. http://www.uroweb.org/gls/pdf/08%20Prostate%20Cancer_LR%20March%2013th%202012.pdf Accessed 20 February 2013. 28 Horwich A, Parker C, Bangma C et al. Prostate cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Annals of Oncology 2010;21(suppl 5):v129-v133. 29 Basch EM, Somerfield MR, Beer TM et al. American Society of Clinical Oncology endorsement of the Cancer Care Ontario Practice Guideline on nonhormonal therapy for men with metastatic hormone-refractory (castration resistant) prostate cancer. Journal of Clinical Oncology 2007;25(33):5313-5318. 30 National Institute for Health Research Horizon Scanning Centre. Enzalutamide for chemotherapy naïve castration-resistant prostate cancer. http://www.hsc.nihr.ac.uk/topics/enzalutamide-for- chemotherapy-naive-castration-res/ Accessed 20 February 2013. 31 ClinicalTrials.gov. Study comparing orteronel plus prednisolone in patients with metastatic castration-resistant prostate cancer. http://clinicaltrials.gov/show/NCT01193257 Accessed 20 February 2013. 32 ClinicalTrials.gov. Orteronel maintenance therapy in patients with metastatic castration resistant prostate cancer and non-progressive disease after first-line docetaxel therapy. http://clinicaltrials.gov/ct2/show/NCT01707966?term=orteronel+AND+prostate&rank=1 Accessed 20 February 2013. 33 ClinicalTrials.gov. Study comparing orteronel plus prednisolone in patients with chemotherapy- naïve metastatic castration-resistant prostate cancer. http://www.clinicaltrials.gov/ct2/show?term=orteronel+AND+prostate+cancer&rank=4 Accessed 21 February 2013. 34 British Medical Association and Royal Pharmaceutical Society of Great Britaicn. British National Formulary. BNF 64. London: BMJ Group and RPS Publishing, September 2012.

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