Horizon Scanning Research January 2016 & Intelligence Centre Rucaparib for advanced BRCA- mutated ovarian cancer 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. Rucaparib 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 tablet, 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 chemotherapy. 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 clinical trial, 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 2 Horizon Scanning Research & Intelligence Centre 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. 3 Horizon Scanning Research & Intelligence Centre PATIENT PATHWAY RELEVANT GUIDANCE NICE Guidance • NICE technology appraisal in development. Topotecan, pegylated liposomal doxorubicin hydrochloride, paclitaxel, trabectedin and gemcitabine 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) – olaparib (maintenance) (ID735). Expected January 2016. • NICE technology appraisal. Bevacizumab in combination with paclitaxel and carboplatin 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