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Update on US regulatory review of Lynparza in combination with abiraterone for metastatic castration-resistant prostate cancer

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AstraZeneca and MSD today announced that the US Food and Drug Administration (FDA) will convene a meeting of the Oncologic Drugs Advisory Committee (ODAC) to discuss the supplemental new drug application (sNDA) for Lynparza (olaparib) in combination with abiraterone and prednisone or prednisolone for the treatment of adult patients with metastatic castration-resistant prostate cancer (mCRPC).

The ODAC meeting is scheduled for 28 April 2023. AstraZeneca and MSD are committed to working with the FDA to bring Lynparza in combination with abiraterone to patients with mCRPC.

The efficacy and safety of Lynparza in combination with abiraterone and prednisone or prednisolone have been demonstrated in the PROpel Phase III trial, first presented at the 2022 American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU), and subsequently published in the New England Journal of Medicine Evidence. Further results from the final prespecified overall survival (OS) analysis were presented at ASCO GU 2023.

Lynparza in combination with abiraterone and prednisone or prednisolone is approved in the EU and several other countries for the treatment of adult patients with mCRPC based on the PROpel trial.

Notes

Prostate cancer

Prostate cancer is the second most commonly diagnosed cancer in men and the fifth leading cause of cancer death in men globally, with an incidence of 1.4 million and 375,000 deaths in 2020.1,2,3 In the United States, it is estimated that there will be 288,300 new cases and 34,700 deaths in 2023.4 Overall survival for patients with mCRPC is approximately three years in clinical trial settings, and even shorter in the real-world.5 Approximately half of patients with mCRPC may receive only one line of active treatment, and those that go on to receive further treatment often have diminishing benefit of subsequent therapies.6-11

Metastatic castration-resistant prostate cancer

Metastatic prostate cancer is associated with a significant mortality rate.12 Development of prostate cancer is often driven by male sex hormones called androgens, including testosterone.13

In patients with mCRPC, their prostate cancer grows and spreads to other parts of the body despite the use of androgen-deprivation therapy to block the action of male sex hormones.14 Approximately 10-20% of men with advanced prostate cancer will develop castration-resistant prostate cancer (CRPC) within five years, and at least 84% of these men will have metastases at the time of CRPC diagnosis.14 Of patients with no metastases at CRPC diagnosis, 33% are likely to develop metastases within two years.14

Despite the advances in mCRPC treatment in the past decade with taxane and new hormonal agent (NHA) treatment, there is high unmet need in this population.14-17

PROpel

PROpel is a randomised, double-blind, multi-centre Phase III trial testing the efficacy, safety, and tolerability of Lynparza versus placebo when given in combination with abiraterone, as well as prednisone or prednisolone, in men with mCRPC who had not received prior chemotherapy or NHAs in the mCRPC setting.

The primary endpoint is rPFS and secondary endpoints include OS, time to secondary progression or death, and time to first subsequent therapy.

In the PROpel Phase III trial, Lynparza is combined with abiraterone, an NHA which targets the androgen receptor (AR) pathway. AR signalling engages a transcriptional programme that is critical for tumour cell growth and survival in prostate cancer.18,19 In addition, the AR also plays a role in repairing DNA damage in prostate cancer cells, including damage not normally repaired by homologous recombination repair (HRR). Preclinical models have suggested a number of potential mechanisms that could account for increased combination efficacy in both HRR deficient and HRR proficient prostate cancer.20-26 Recent data provide evidence that PARP facilitates AR-DNA binding in the presence of DNA damage (AZ internal data on file) and that combined inhibition of PARP with olaparib and AR activity with an NHA results in enhanced DNA damage and anti-tumour activity in non-HRRm prostate cancer models.21,24,26,27,28

For more information about the trial please visit ClinicalTrials.gov.

Lynparza

Lynparza (olaparib) is a first-in-class PARP inhibitor and the first targeted treatment to block DNA damage response (DDR) in cells/tumours harbouring a deficiency in HRR, such as those with mutations in BRCA1 and/or BRCA2, or those where deficiency is induced by other agents (such as NHAs).

Inhibition of PARP with Lynparza 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.

Lynparza is currently approved in a number of countries across multiple tumour types including maintenance treatment of platinum-sensitive relapsed ovarian cancer and as both monotherapy and in combination with bevacizumab for the 1st-line maintenance treatment of BRCA-mutated (BRCAm) and homologous recombination repair deficient (HRD)-positive advanced ovarian cancer, respectively; for gBRCAm, HER2-negative metastatic breast cancer (in the EU and Japan this includes locally advanced breast cancer); for gBRCAm, HER2-negative high-risk early breast cancer (in Japan this includes all BRCAm HER2-negative high-risk early breast cancer); for gBRCAm metastatic pancreatic cancer; in combination with abiraterone for the treatment of metastatic castration resistant prostate cancer in whom chemotherapy is not clinically indicated (EU) and as monotherapy in HRR gene-mutated metastatic castration-resistant prostate cancer in patients who have progressed on prior NHA treatment (BRCAm only in the EU and Japan). In China, Lynparza is approved for the treatment of BRCA-mutated metastatic castration-resistant prostate cancer, as a 1st-line maintenance therapy in BRCA-mutated advanced ovarian cancer as well as 1st-line maintenance treatment with bevacizumab for HRD-positive advanced ovarian cancer.

Lynparza, which is being jointly developed and commercialised by AstraZeneca and MSD, has been used to treat over 75,000 patients worldwide. Lynparza has a broad clinical trial development programme, and AstraZeneca and MSD are working together to understand how it may affect multiple PARP-dependent tumours as a monotherapy and in combination across multiple cancer types. Lynparza is the foundation of AstraZeneca's industry-leading portfolio of potential new medicines targeting DDR mechanisms in cancer cells.

The AstraZeneca and MSD strategic oncology collaboration

In July 2017, AstraZeneca and Merck & Co., Inc., Kenilworth, NJ, US, known as MSD outside the US and Canada, announced a global strategic oncology collaboration to co-develop and co-commercialise Lynparza, the world’s first PARP inhibitor, and Koselugo (selumetinib), a mitogen-activated protein kinase (MEK) inhibitor, for multiple cancer types.

Working together, the companies will develop Lynparza and Koselugo and other potential new medicines as monotherapies and as combinations. The companies will also develop Lynparza and Koselugo in combination with their respective PD-L1 and PD-1 medicines independently.

AstraZeneca in oncology

AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients.

The Company's focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyse changes in the practice of medicine and transform the patient experience.

AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death.

AstraZeneca
AstraZeneca (LSE/STO/Nasdaq: AZN) is a global, science-led biopharmaceutical company that focuses on the discovery, development, and commercialisation of prescription medicines in Oncology, Rare Diseases, and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. Please visit astrazeneca.com and follow the Company on Twitter @AstraZeneca.

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