Horizon Scanning Research January 2016 & Intelligence Centre

Rucaparib for advanced BRCA- mutated

LAY SUMMARY

Ovarian cancer is the fifth most common cancer for women in the UK. Symptoms of ovarian cancer are often vague early on and many women are not diagnosed until after the cancer has grown and spread to other parts of the body. Less than half of women with ovarian This briefing is based on cancer survive five years from diagnosis with many not responding to information current treatments. available at the time of research and a Ovarian, fallopian tube, and primary peritoneal cancer all begin in the limited literature same part of the ovary or fallopian tube. is a new drug for search. It is not the treatment of ovarian, fallopian tube, or primary peritoneal cancer. It intended to be a is taken as a , twice daily with water. definitive statement on the safety, If rucaparib is licensed for use in the UK, it could be a new treatment efficacy or option for patients with ovarian, fallopian tube, or primary peritoneal effectiveness of the cancer. This may improve survival when current treatments have health technology stopped working. covered and should not be used for commercial NIHR HSRIC ID: 4201 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

Ovarian, fallopian tube and peritoneal cancer: advanced; deleterious or suspected deleterious BRCA-mutated tumour (inclusive of both germline BRCA and somatic BRCA mutations) – treated with three or more prior lines of .

TECHNOLOGY

DESCRIPTION

Rucaparib (PF-1367338, AG-014699 PARP) is an oral, small molecule poly ADP-ribose polymerase (PARP) inhibitor that has potent activity against PARP-1, PARP-2, PARP-3 and tankyrases. Rucaparib is intended for the treatment of ovarian cancer associated with homologous recombination DNA repair deficiency. In a phase II , rucaparib is administered orally at 600mg twice daily on a continuous basis1.

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

Rucaparib is currently in phase II trials for breast and pancreatic cancer.

INNOVATION and/or ADVANTAGES

If licensed, rucaparib will provide an additional oral treatment option for patients with BRCA- mutated ovarian cancer.

DEVELOPER

Clovis Oncology.

AVAILABILITY, LAUNCH OR MARKETING

In phase II clinical trials.

PATIENT GROUP

BACKGROUND

Ovarian, fallopian and primary peritoneal cancers arise from the epithelial tissues of the ovary or fallopian tube. Almost 90% of adult ovarian tumours are epithelial cancers. The serous sub-type of ovarian epithelial carcinoma accounts for approximately 60-80% of ovarian cancer cases and has the most aggressive histology2. Symptoms can be vague and non-specific initially, but may include: abdominal distension; feeling full and/or loss of appetite; pelvic or abdominal pain; irregular periods or vaginal bleeding; and increased urinary urgency and/or frequency3,4. For patients with advanced (stage III or IV) disease, initial treatment results are generally favourable, but the clinical course commonly involves relapse, which is ultimately fatal5.

Several risk factors have been associated with the development of ovarian cancer, such as obesity, infertility, poor reproductive history, and duration of reproductive career6. Genetic predisposition is also a risk factor for ovarian cancer; in particular, women who carry BRCA1

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mutations have an estimated lifetime risk of between 26% and 54% of developing ovarian cancer, and women who carry BRCA2 mutations have an estimated lifetime risk of between 10% and 23%7. BRCA-associated ovarian carcinomas are usually high-grade, poorly differentiated, serous adenocarcinomas7.

NHS or GOVERNMENT PRIORITY AREA

This topic is relevant to: • Improving Outcomes: A Strategy for Cancer (2011). • NHS England. Clinical Commissioning Policy: Genetic Testing for BRCA1 and BRCA2 Mutations. E01/P/b. • NHS England. 2013/14 NHS Standard Contract for Medical Genetics (All Ages). E01/S/a. • NHS England. 2013/14 NHS Standard Contract for Complex Gynaecology - Special Gynaecological Cancers. E10/S/f. • NHS England. 2013/14 NHS Standard Contract for Cancer: Chemotherapy (Adult). B15/S/a. • NHS England. 2013/14 NHS Standard Contract for Cancer: Chemotherapy (Children, Teenagers and Young Adults). B12/S/b. • NHS England. 2013/14 NHS Standard Contract for Cancer: Radiotherapy (All Ages). B01/S/a.

CLINICAL NEED and BURDEN OF DISEASE

Ovarian cancer is the fifth most common cancer in women in the UK, and has an overall 5- year survival rate of 46%8. Approximately 10% of ovarian cancers occur in women with mutations in the genes BRCA 1 or 29. Approximately 70% of women present with advanced disease and undergo a combination of debulking surgery and six cycles of platinum-based chemotherapy6,10,11,12. Approximately 75% of tumours are sensitive to first line platinum- based chemotherapy, however this falls to 50% on recurrence if the duration of the platinum- free interval is greater than 12 months5. Although most patients respond to initial treatment, 70-80% with advanced stage ovarian cancer subsequently develop recurrent disease5,6,13. Most patients receive platinum-based therapy for a second or third time before developing resistance5. The cure rate for stage III disease is approximately 30% while treatments for stage IV are usually palliative6. The median time to progression after primary treatment (surgery and chemotherapy) is 15-18 months5. Patients who progress within six months of primary treatment typically experience a short overall survival, usually less than 12 months5.

The annual incidence of ovarian cancer in England is around 5,500. It is estimated that around 82% of these women have stage IIIB to IV ovarian cancer; chemotherapy will be unsuitable for about 10% of these patients14. Between 2009 and 2011, in the UK an average 54% of cases were diagnosed in women aged 65 years and over, and three-quarters were diagnosed in those aged 55 years and over15. In 2014-15, there were 39,088 admissions for ovarian cancer and other unspecified female genital organ cancers (ICD-10 C56-C57) resulting in 62,616 bed days and 41,678 finished consultant episodes in England16. There were 3,695 deaths due to ovarian cancer (ICD-10 C56-C57) registered in England and Wales in 201417.

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PATIENT PATHWAY

RELEVANT GUIDANCE

NICE Guidance

• NICE technology appraisal in development. , pegylated liposomal hydrochloride, , and for advanced ovarian cancer (for recurrent disease only) (review of TA91 & TA222) (ID469). Expected date of issue to be confirmed. • NICE technology appraisal in development. Ovarian, fallopian tube and peritoneal cancer (BRCA 1 or 2, mutated, relapsed, platinum-sensitive) – (maintenance) (ID735). Expected January 2016. • NICE technology appraisal. Bevacizumab in combination with paclitaxel and for first-line treatment of advanced ovarian cancer (TA284). May 2013. • NICE technology appraisal. Bevacizumab in combination with gemcitabine and carboplatin for treating the first recurrence of platinum-sensitive advanced ovarian cancer (TA285). May 2013. • NICE technology appraisal. Trabectedin for the treatment of relapsed ovarian cancer (TA222). April 2011. • NICE technology appraisal. Paclitaxel, pegylated liposomal doxorubicin hydrochloride and topotecan for second-line or subsequent treatment of advanced ovarian cancer (TA91). May 2005. • NICE technology appraisal. Guidance on the use of paclitaxel in the treatment of ovarian cancer (TA55). January 2003.

• NICE clinical guideline. The recognition and initial management of ovarian cancer (CG122). April 2011. • NICE quality standard. Quality standard for ovarian cancer (QS18). May 2012.

Other Guidance

• National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Ovarian cancer including fallopian tube cancer and primary peritoneal cancer (Version 3.2014). 201418. • European Society for Medical Oncology. Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. 20136. • Scottish Intercollegiate Guidelines Network. Epithelial ovarian cancer (SIGN 75). 201319. • European Society for Medical Oncology. Non-epithelial ovarian cancer: ESMO Clinical Practice guidelines for diagnosis, treatment and follow-up. 201220.

CURRENT TREATMENT OPTIONS

For platinum-sensitive patients where relapse has occurred more than six months after initial platinum-based treatment, guidelines recommend the retreatment of patients with a platinum-based combination chemotherapy regime. Where patients are too frail to tolerate combination therapy, single-agent therapy is recommended. Treatment options include6,21,22,23,24,25,26: • Primary surgery – complete resection before or after chemotherapy. • Olaparib – maintenance treatment of adult patients with platinum-sensitive relapsed BRCA-mutated high-grade, serous epithelium ovarian, fallopian tube or primary peritoneal

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cancer who have responded to platinum-based chemotherapy (NICE technology appraisal in progress). • Pegylated liposomal doxorubicin (PLD) and carboplatin, or PLD single-agent – second line (or subsequent) treatment of women with partially platinum-sensitive, or platinum- refractory advanced ovarian cancer, and for women who are allergic to platinum-based compounds. • Paclitaxel – in combination with a platinum-based compound (carboplatin or ), or as single agent in women who are allergic to platinum-based compounds. • Bevacizumab – in combination with gemcitabine and carboplatin for patients at first relapse, followed by use as a maintenance therapy in those who have not received prior therapy with bevacizumab or other VEGF inhibitors or VEGF receptor-targeted agents (not recommended by NICE). • Topotecan – in women for whom PLD and single-agent paclitaxel are considered inappropriate. • Tamoxifen or an aromatase inhibitor may be considered in patients for whom chemotherapy is not appropriate; however this is unlicensed for this indication.

EFFICACY and SAFETY

Trial CO-338-010, NCT01482715; rucaparib; CO-338-017, ARIEL2, NCT01891344; phase I/II. rucaparib; phase II. Sponsor Clovis Oncology. Clovis Oncology. Status Ongoing. Ongoing. Source of Trial registry1, manufacturer. Trial registry27, manufacturer. information Location EU (incl UK), USA, Canada and Israel. EU (incl UK), USA, Canada and Australia. Design Non-randomised, open label. Non-randomised, open label. Participants n=160 (planned); ≥18 years; histologically n=480 (planned); ≥18 years; histologically confirmed diagnosis of high-grade confirmed diagnosis of high grade serous epithelial ovarian, fallopian tube, or or grade 2 or grade 3 endometrioid primary peritoneal cancer; received ≥3 epithelial ovarian, fallopian tube, or prior chemotherapy regimens and have primary peritoneal cancer; have sufficient relapsed disease confirmed by radiologic archival formalin-fixed paraffin-embedded assessment; known deleterious germline (FFPE) tumour tissue available for BRCA mutation as determined by a local planned analyses. laboratory; evidence of measurable Part 1: received ≥1 prior platinum disease as defined by RECIST Version regimen and were platinum-sensitive to 1.1. the most recent platinum-regimen. Part 2: received ≥3 prior chemotherapy regimens. Relapsed/progressive disease as confirmed by CT scan; biopsiable and measurable disease. Schedule Rucaparib 600mg orally twice daily with Rucaparib 600mg orally twice daily with 240ml of water. 240ml of water. Follow-up Patients continue with continuous dosing Patients continue with continuous dosing until one of the following occur: until one of the following occur: • Withdrawal of consent • Withdrawal of consent • Progression of patient’s underlying • Progression of patient’s underlying disease disease • Any event, adverse or otherwise, that, in • Any event, adverse or otherwise, that, in the opinion of the investigator, would the opinion of the investigator, would pose an unacceptable safety risk to the pose an unacceptable safety risk to the patient patient

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• An intercurrent illness that, in the • An intercurrent illness that, in the opinion of the Investigator, would affect opinion of the Investigator, would affect assessments of the clinical status to a assessments of the clinical status to a significant degree and requires significant degree and requires discontinuation of therapy discontinuation of therapy • A positive pregnancy test at any time • A positive pregnancy test at any time during the study during the study

Once dosing stops, there is a 28 day Once dosing stops, there is a 28 day follow-up. follow-up. All patients who come off study for reasons other than disease progression continue to have disease assessments until progression and the patients in Part 2, are also followed for survival Primary Objective response rate (ORR). Part 1: progression-free survival (PFS); outcomes part 2: ORR. Secondary Adverse events (AEs); ; Part 1: ORR; part 2: PFS; AEs; outcomes response per RECIST version 1.1; overall pharmacokinetics. survival. Expected Estimated completion date reported as Estimated completion date reported as reporting April 2017. March 2017. date

ESTIMATED COST and IMPACT

COST

The cost of rucaparib 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:  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 cost compared to  None identified existing treatments

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Other Issues

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

REFERENCES

1 ClinicalTrials.gov. A study of oral rucaparib in patients with a solid tumor (phase I) or with gBRCA mutation ovarian cancer (phase II) clinicaltrials.gov/ct2/show/NCT01482715 Accessed 04 December 2015 2 Levanon K, Crum C and Drapkin R. New insights into the pathogenesis of serous ovarian cancer and its clinical impact. Journal of Clinical Oncology 2008;26:5284-5293. 3 National Institute for Health and Clinical Excellence. The recognition and initial management of ovarian cancer. Clinical guideline CG122. London: NICE; April 2011. 4 Cancer Research UK. Ovarian cancer symptoms www.cancerresearchuk.org/cancer- help/type/ovarian-cancer/about/ovarian-cancer-symptoms Accessed 04 December 2015. 5 NIHR Horizon Scanning Centre. Bevacizumab (Avastin) for relapsed platinum-resistant ovarian cancer – second line. University of Birmingham, January 2013. www.hsric.nihr.ac.uk 6 Ledermann JA, Raja FA, Fotopoulou C et al. Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Annals of Oncology 2013;24(6):vi24-32. 7 Banerjee S, Kaye SB and Ashworth A. Making the best of PARP inhibitors in ovarian cancer. Nature Reviews Clinical Oncology 2010;7:508-519. 8 Cancer Research UK. Ovarian cancer key facts info.cancerresearchuk.org/cancerstats/types/ovary/uk-ovarian-cancer-statistics Accessed 04 December 2015. 9 National Institute for Health and Care Excellence. Draft scope for he proposed appraisal of olaparib for maintenance treatment of relapsed, platinum-sensitive ovarian, fallopian tube and peritoneal cancer in people who have tested positive for BRCA 1 or 2 mutations, following response to prior platinum-based chemotherapy. London: NICE; November 2014. 10 Martinek IE and Kehoe S. When should cytoreduction in advanced ovarian cancer take place? Journal of Oncology 2010; Article ID 852028;doi:10.1155/2010/852028. 11 Morgan Jr RJ, Alvarez RD, Armstrong DK et al. Ovarian cancer. Clinical practice guidelines in oncology. Journal of the National Comprehensive Cancer Network 2008;6:766-794. 12 NIHR Horizon Scanning Centre. Cediranib for ovarian cancer – second line. University of Birmingham, March 2014. www.hsric.nihr.ac.uk 13 Herzog TJ and Pothuri B. Ovarian cancer: a focus on management of recurrent disease. Nature Clinical Practice Oncology 2006;3:604-611. 14 National Institute for Health and Care Excellence. Costing statement. Bevacizumab in combination with paclitaxel and carboplatin for first-line treatment of advanced ovarian cancer. Technology appraisal TA284. London: NICE; May 2013. 15 Cancer Research UK. Ovarian cancer – UK incidence statistics info.cancerresearchuk.org/cancerstats/types/ovary/incidence/ Accessed 04 December 2015. 16 Health & Social Care Information Centre. Hospital episode statistics for England. Inpatient statistics, 2014-15. www.hscic.gov.uk 17 Office for National Statistics. Mortality statistics: deaths registered in England and Wales, series DR, 2014. www.ons.gov.uk 18 National Comprehensive Cancer Network. NCCN Clinical practice guidelines in oncology: Ovarian Cancer including fallopian tube cancer and primary peritoneal cancer – Version 3.2014. Philadelphia: NCCN; May 2014. 19 Scottish Intercollegiate Guidelines Network. Management of epithelial ovarian cancer. National clinical guideline 135. Edinburgh: SIGN; November 2013. 20 Colombo N, Peiretti M, Garbi A et al. Non-epithelial ovarian cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Annals of Oncology 2012;23(suppl7):vii20-vii26. 21 National Institute for Health and Clinical Excellence. Trabectedin for the treatment of relapsed ovarian cancer. Technology appraisal TA222. London: NICE; April 2011.

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22 National Institute for Health and Clinical Excellence. Paclitaxel, pegylated liposomal doxorubicin hydrochloride and topotecan for second-line or subsequent treatment of advanced ovarian cancer. Technology appraisal TA91. London: NICE; May 2005. 23 National Institute for Health and Care Excellence. Bevacizumab in combination with paclitaxel and carboplatin for first-line treatment of advanced ovarian cancer. Technology appraisal TA284. London: NICE; May 2013. 24 NIHR Horizon Scanning Centre. Paclitaxel poliglumex (Xyotax) for advanced ovarian cancer – maintenance therapy. University of Birmingham, January 2014. www.hsric.nihr.ac.uk 25 National Institute for Health and Care Excellence. NICE Pathways: ovarian cancer. London: NICE; August 2015. 26 electronic Medicines Compendium. Lynparza 50mg hard capsules www.medicines.org.uk/emc/medicine/30359 Accessed 04 December 2015. 27 ClinicalTrials.gov. A study of rucaparib in patients with platinum-sensitive, relapsed, high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer (ARIEL2). clinicaltrials.gov/ct2/show/NCT01891344 Accessed 04 December 2015.

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