NICE EXPANDS RECOMMENDATION FOR LYNPARZATM (OLAPARIB) TABLETS FOR WOMEN WITH RELAPSED, BRCA-MUTATED, ADVANCED OVARIAN CANCER[I]

• In the SOLO2 clinical trial, olaparib more than trebled the median length of time that patients had without disease progression compared to placebo, reducing the risk of disease progression or death by 70% (19.1 vs. 5.5 months; Hazard Ratio [HR] 0.30 [95% Confidence Interval 0.22-0.41], p<0.0001)[ii]
• Olaparib is now recommended by NICE as maintenance treatment for women with BRCA-mutated high grade epithelial advanced ovarian cancer, whose disease has responded to platinum-based chemotherapy, regardless of their line of treatment^1,[iii]^,[iv]
• Currently, approximately 70% of patients with advanced ovarian cancer will relapse within three years after treatment, including cytoreductive surgery and platinum-based chemotherapy[v]

Luton, UK, 29^th November 2019 – AstraZeneca and MSD today announced that olaparib is now recommended by the National Institute for Health and Care Excellence (NICE) for maintenance treatment of relapsed, platinum-sensitive high grade epithelial ovarian, fallopian tube or peritoneal cancer in adults whose disease has responded to platinum-based chemotherapy if they have a BRCA1 or BRCA2 mutation (BRCAm). It will be made available to patients within NHS England and Wales via routine commissioning if they have had three or more courses of platinum-based chemotherapy; and to patients within NHS England via the Cancer Drugs Fund (CDF) if they have had two courses of platinum-based chemotherapy.¹

Today’s decision was based on the results of the SOLO2 trial, which showed a statistically-significant and clinically-meaningful improvement in progression-free survival (PFS) for olaparib compared to placebo, improving the PFS to a median of 19.1 months vs. 5.5 months, respectively (HR 0.30 [95% Confidence Interval 0.22-0.41], p<0.0001).² Of those receiving olaparib, an estimated 43% remained progression-free at 24 months compared to 15% of patients in the placebo arm.²

Previously, olaparib was only available to relapsed BRCAm ovarian cancer patients if they have had three or more lines of chemotherapy, and they only had access to the capsule formulation (8 capsules twice daily). Today’s announcement means that all patients with BRCAm ovarian cancer have access to the tablet formulation (2 tablets twice daily), regardless of their line of therapy.

Professor Jonathan Ledermann, Professor of Medical Oncology at the University College London Cancer Institute, said: “This decision is positive news for patients because it means that we now have access to olaparib tablets for BRCA-mutated ovarian cancer across all lines of therapy. Not only does this mean that we have an additional treatment option that offers significant clinical benefits to patients, it also means that all patients currently being treated with olaparib can now access the tablet formulation instead of the capsules.”

In England, almost 60% of women with ovarian cancer are diagnosed with late stage disease[vi], and even after surgery and chemotherapy, 70% will relapse within three years.⁵ Every two hours a woman dies from ovarian cancer in the UK[vii]. Approximately 22% of ovarian cancer patients carry a BRCA mutation[viii], which can be identified via genetic testing upon referral by a healthcare professional.[ix]

Mohit Manrao, Business Unit Director, Oncology at AstraZeneca UK said: “We are delighted to have reached an arrangement with NICE to enable expanded access to olaparib tablets as maintenance treatment for women with advanced ovarian cancer who have had two or more lines of chemotherapy. As a UK-based company, it’s great to see this product of British science become more widely available, therefore helping more women across England and Wales.”

The NICE recommendation

The Final Appraisal Document by NICE states that the recommendation is as follows¹:

Olaparib is recommended as an option for the maintenance treatment of relapsed, platinum-sensitive, high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer in adults whose disease has responded to platinum-based chemotherapy only if:

• they have a BRCA1 or BRCA2 mutation
• they have had 3 or more courses of platinum-based chemotherapy and
• the company provides olaparib according to the commercial arrangement.

Olaparib is recommended for use within the Cancer Drugs Fund as an option for the maintenance treatment of relapsed, platinum-sensitive, high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer in adults whose disease has responded to platinum-based chemotherapy only if:

• they have a BRCA1 or BRCA2 mutation
• they have had 2 courses of platinum-based chemotherapy and
• the conditions in the managed access agreement for olaparib are followed.

[ii] Pujade-Lauraine et al. 2017. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncology. 18(9):1274-1284. doi: 10.1016/S1470-2045(17)30469-2.

[iii] NICE. 2019. Olaparib for maintenance treatment of newly diagnosed BRCA-mutated

advanced ovarian, fallopian tube or peritoneal cancer, after response to first-line platinum-based chemotherapy. Available at: https://www.nice.org.uk/guidance/ta598/chapter/1-Recommendations. [Accessed November 2019].

[iv] NICE. 2016. Olaparib for maintenance treatment of relapsed, platinum-sensitive, BRCA mutation-positive ovarian, fallopian tube and peritoneal cancer after response to second-line or subsequent platinum-based chemotherapy Technology appraisal guidance [TA381]. Available at: www.nice.org.uk/guidance/ta381/ifp/chapter/What-has-NICE-said [Accessed November 2019].

[v] Moore et al. 2018. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. New Eng J Med. 379(26):2495-2505. doi:10.1056/NEJMoa1810858.

[vi] Cancer Research UK. Ovarian cancer statistics: Ovarian cancer incidence. Available at: www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/ovarian-cancer#heading-Zero. [Accessed November 2019].

[vii] Ovarian Cancer Action. 2019. World Ovarian Cancer Day 2019. Available at: ovarian.org.uk/ovarian-cancer/world-ovarian-cancer-day-2019/ [Accessed November 2019].

[viii] Moschetta et al. 2016. BRCA somatic mutations and epigenetic BRCA modifications in serous ovarian cancer. Annals of Oncology. 27, 1449-55. doi: 10.1093/annonc/mdw142.

[ix] Cancer Research UK. Risks and causes: Risk factors for ovarian cancer. Available at: www.cancerresearchuk.org/about-cancer/ovarian-cancer/risks-causes. [Accessed November 2019].

About the SOLO2 Phase III trial

SOLO2 is a Phase III randomised, double-blinded, placebo-controlled, multicentre trial to evaluate the efficacy and safety of olaparib tablets (300 mg twice daily) as maintenance monotherapy compared with placebo, in BRCA mutation-positive, relapsed, platinum-sensitive high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer, that is in response to platinum-based chemotherapy in adults.² The trial randomised 295 patients with predicted deleterious or suspected deleterious BRCA1 or BRCA2 mutations based on either blood or tumour testing, who had received at least two lines of previous chemotherapy and were in clinical complete or partial response following platinum-based chemotherapy.² Patients were randomised (2:1) to receive olaparib or placebo until disease progression (at the investigator’s discretion).² The primary endpoint was PFS and key secondary endpoints included time to first subsequent therapy or death; time to study treatment discontinuation or death; time to second progression; time to second subsequent therapy or death; time to earliest progression or death, investigator assessment of overall survival; safety and tolerability; and health-related quality of life.²About ovarian cancer

In 2016, ovarian cancer was the 6th most common cancer in females in the UK.⁶ Every 2 hours a woman dies from ovarian cancer in the UK⁷, with six out of 10 cases of ovarian cancer diagnosed in England already at an advanced stage.⁶ Approximately 5-20% of women with  advanced (Stage III or IV) ovarian cancer will survive their disease for five years or more after they are diagnosed.[x] For newly-diagnosed advanced ovarian cancer, the primary aim of treatment is to delay progression of the disease for as long as possible and maintain the patient’s quality of life with the intent of achieving complete remission or cure.^5,[xi] Approximately 22% of ovarian cancer patients carry a BRCA mutation⁸, which can be identified via genetic testing upon referral by a healthcare professional.⁹

About olaparib

Olaparib is a PARP inhibitor and the first targeted treatment to block DNA damage response (DDR) in cells/tumours harbouring a deficiency in homologous recombination repair (HRR), such as mutations in BRCA1 and/or BRCA2. Inhibition of PARP with olaparib leads to the trapping of PARP bound to DNA single-strand breaks, stalling of replication forks, their collapse and the generation of DNA double-strand breaks and cancer cell death.

In ovarian cancer, olaparib is licensed as monotherapy for the[xii]:

• maintenance treatment of adult patients with advanced (FIGO stages III and IV) BRCA1/2-mutated (germline and/or somatic) high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer who are in response (complete or partial) following completion of first-line platinum-based chemotherapy
• maintenance treatment of adult patients with platinum-sensitive relapsed high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete or partial) to platinum-based chemotherapy.

Olaparib has been associated with adverse reactions generally of mild or moderate severity and generally not requiring treatment discontinuation. The most frequently observed adverse reactions across clinical trials in patients receiving olaparib monotherapy (≥ 10%) are nausea, vomiting, diarrhoea, dyspepsia, fatigue, headache, dysgeusia, decreased appetite, dizziness, upper abdominal pain, cough, dyspnoea, anaemia, neutropenia, thrombocytopenia and leukopenia.¹²

For further information about olaparib, including the complete list of licensed indications, side effects and adverse reactions, please refer to the summary of product characteristics.¹² https://www.medicines.org.uk/emc/product/9204/smpc

About BRCA mutations

BRCA1 and BRCA2 are human genes that produce proteins responsible for repairing damaged DNA and play an important role in maintaining the genetic stability of cells.[xiii] When either of these genes is mutated, or altered, such that its protein product either is not made or does not function correctly, DNA damage may not be repaired properly, and cells become unstable.¹³ As a result, cells are more likely to develop additional genetic alterations that can lead to cancer.¹³

About the AstraZeneca and MSD Strategic Oncology Collaboration

In July 2017, AstraZeneca and Merck & Co., Inc., Kenilworth, NJ, US, known as MSD outside the United States and Canada, announced a global strategic oncology collaboration to co-develop and co-commercialise olaparib and other medicines in development.

About AstraZeneca

AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialisation of prescription medicines, primarily for the treatment of diseases in three therapy areas - Oncology, Cardiovascular, Renal & Metabolism and Respiratory. The Company also is selectively active in the areas of autoimmunity, neuroscience and infection. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide.

AstraZeneca has five different sites in the UK, where around 6,500 employees work in research and development, manufacturing, supply, sales and marketing. We supply 40 different medicines to the NHS. The UK is also an important location for AstraZeneca’s clinical trials; in 2017, we undertook 191 trials in the UK, involving 340 centres and almost 9,000 patients.

For more information, please visit www.astrazeneca.co.uk

About MSD

For more than a century, MSD, a leading global biopharmaceutical company, has been inventing for life, bringing forward medicines and vaccines for the world’s most challenging diseases. MSD is a trade name of Merck & Co., Inc., with headquarters in Kenilworth, N.J., U.S.A. Through our prescription medicines, vaccines, biologic therapies and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to health care through far-reaching policies, programmes and partnerships. Today, MSD continues to be at the forefront of research to advance the prevention and treatment of diseases that threaten people and communities around the world.

For more information, please visit www.msd-UK.com and connect with us on Twitter @MSDintheUK

[x] Cancer Research UK. 2018. Survival. Available at: https://www.cancerresearchuk.org/about-cancer/ovarian-cancer/survival [Accessed November 2019].

[xi] NHS Choices, Ovarian Cancer. Available at: https://www.nhs.uk/conditions/ovarian-cancer/treatment/ [Accessed November 2019].

[xii] Lynparza 100mg Film-Coated Tablets Summary of Product Characteristics. 1^st October 2019. Available at: www.medicines.org.uk/emc/product/9204/smpc. [Accessed November 2019].

[xiii] NCI website. BRCA1 and BRCA 2: Cancer risk and Genetic testing. Available at: https://www.cancer.gov/about-cancer/causes-prevention/genetics/brca-fact-sheet. [Accessed November 2019].