LYNPARZA (OLAPARIB) APPROVED IN THE UK AS COMBINATION THERAPY FOR TREATMENT OF METASTATIC CASTRATION-RESISTANT PROSTATE CANCER WHEN CHEMOTHERAPY IS NOT CLINICALLY INDICATED

• Approval from the MHRA is based on positive data from the PROpel Phase III trial and olaparib is the first PARP inhibitor to demonstrate clinical benefit in combination with a new hormonal agent in first-line metastatic castration-resistant prostate cancer (mCRPC).^[1]
• Combination therapy of olaparib with abiraterone and prednisone or prednisolone showed a 34% reduction in risk of disease progression or death versus abiraterone and prednisone or prednisolone in patients with mCRPC with or without homologous recombination repair (HRR) gene mutations.^[1]
• Approximately 140 men are diagnosed with prostate cancer each day in the UK, and around 10-20% of patients with advanced prostate cancer will develop castration-resistant prostate cancer (CRPC) within five years, and at least 84% of these patients will have metastases at the time of CRPC diagnosis.^[2],[3]

London, UK, Monday 20 March 2023 – AstraZeneca and MSD (tradename of Merck & Co., Inc., Rahway, N.J., USA [NYSE: MRK]) today announced that the Medicines and Healthcare products Regulatory Agency (MHRA) has granted marketing authorisation for olaparib in the United Kingdom for use as combination therapy with abiraterone and prednisone or prednisolone, for the treatment of adult patients with metastatic castration-resistant prostate cancer (mCRPC) in whom chemotherapy is not clinically indicated.^[4]

Prostate cancer is a major cause of disease and mortality among men and the fifth most common cause of cancer death globally.^[5] In the UK, more than 52,000 men are diagnosed with prostate cancer every year, accounting for more than 140 cases per day.² Around 10-20% of patients with advanced prostate cancer will develop castration-resistant prostate cancer (CRPC) within five years which occurs when prostate cancer evolves to resist standard treatment with androgen deprivation therapy (ADT).³ Most CRPCs are metastatic (mCRPC), meaning the cancer has spread to a site distant from the prostate.^[6]

Professor Noel Clarke, Professor of Urological Oncology at The Christie, and Salford Royal Hospitals, said: “This approval by the MHRA is an important next step for healthcare professionals and their patients in the UK with this specific type of prostate cancer. These data from the PROpel Phase III trial underline the therapeutic potential of new first-line treatment options for patients with metastatic castration-resistant prostate cancer, especially given that many have a much-shortened life-span when their disease becomes castrate resistant.”

The decision from the MHRA was based on results from the PROpel Phase III trial which showed that AstraZeneca and MSD’s olaparib in combination with abiraterone significantly improved radiographic progression-free survival (rPFS) versus abiraterone alone as a first-line treatment for patients with mCRPC regardless of their biomarker status.¹

Results also show that combination therapy reduced the risk of disease progression or death by 34% versus abiraterone alone (median PFS 24.8 months vs 16.6 months; based on a hazard ratio [HR] of 0.66; 95% confidence interval [CI] 0.54-0.81; p<0.0001).¹ At the time of data cut off, analysis of overall survival (OS) was at 40% maturity, the trial will continue to assess OS as a key secondary endpoint.^[7]

Ed Piper, Medical and Scientific Affairs Director, AstraZeneca UK, said: “We are delighted that olaparib has been authorised by the MHRA today, opening a new chapter in prostate cancer treatment. This additional therapy option supports our overall ambition to reduce the national burden of prostate cancer and we are continuing to work with NICE and NHS England to secure access as quickly as possible for patients. Medical advances like these offer hope of further progressing the UK as a leader in life science.”

David Long, Head of Oncology at MSD UK, said: “Prostate cancer is the most common cancer in men in the UK and advanced prostate cancer is associated with a significant mortality rate. This approval from the MHRA marks important progress in advancing a new treatment option to address the significant unmet need of patients with metastatic castration-resistant prostate cancer.”

Results from additional unpowered exploratory efficacy endpoints are consistent with the treatment benefit of olaparib and abiraterone compared to monotherapy with abiraterone alone in the overall trial population, including objective response rate (ORR) (odds ratio, 1.60; 95% CI,1.02-2.53), time to first subsequent therapy (TFST) (HR, 0.74; 95% CI, 0.61-0.90), second progression-free survival (PFS2) (HR, 0.69; 95% CI, 0.51-0.94), as well as prostate-specific antigen levels and circulating-tumour-cell counts.¹

Olaparib has been associated with adverse reactions generally of mild or moderate severity (CTCAE grade 1 or 2) and generally not requiring treatment discontinuation.⁴

The most frequently observed adverse reactions across clinical trials in patients receiving Lynparza monotherapy (≥ 10%) were nausea, fatigue/asthenia, anaemia, vomiting, diarrhoea, decreased appetite, headache, neutropenia, dysgeusia, cough, leukopenia, dizziness, dyspnoea and dyspepsia.⁴ The Grade ≥ 3 adverse reactions occurring in > 2% of patients were anaemia (15%), neutropenia (5%), fatigue/asthenia (4%), leukopenia (3%) and thrombocytopenia (2%).⁴

[1] Clarke NW, et al. Abiraterone and Olaparib for Metastatic Castration-Resistant Prostate Cancer. NEJM Evidence 2022;1(9).

[2] About Prostate Cancer. Prostate Cancer UK. Available at: https://prostatecanceruk.org/prostate-information/about-prostate-cancer. Last accessed: March 2023.

[3] Kirby M, et al. Characterising the castration-resistant prostate cancer population: a systematic review. International Journal of Clinical Practice. 2021;65(11):1180-1192.

[4] Electronic Medicines Compendium (EMC). Lynparza 100 mg film-coated tablets – Summary of Product Characteristics (SmPC). Available at: https://www.medicines.org.uk/emc/product/9204/smpc#gref. Last accessed: March 2023.

[5] Pernar CH et al. The Epidemiology of Prostate Cancer. Cold Spring Harb Perspect Med 2018; 8(12).

[6] Advanced Prostate Cancer. Urology Care Foundation. Available at: https://www.urologyhealth.org/urology-a-z/a_/advanced-prostate-cancer. Last accessed: March 2023

[7] Saad F, et al. Biomarker analysis and updated results from the Phase III PROpel trial of abiraterone (abi) and olaparib (ola) vs abi and placebo (pbo) as first-line (1L) therapy for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). Poster 13570. Presented at the 2022 ESMO Virtual Plenary Session, 16–18 March 2022.