Results from the final prespecified overall survival (OS) analysis of the PROpel Phase III trial in metastatic castration-resistant prostate cancer (mCRPC) showed AstraZeneca and MSD's Lynparza (olaparib) in combination with abiraterone and prednisone or prednisolone demonstrated median overall survival (OS) of 42.1 months versus 34.7 months for abiraterone plus placebo. This result represents a 7.4-month absolute difference in median OS versus a standard of care (47.9% maturity, hazard ratio [HR] of 0.81, 95% confidence interval [CI] 0.67-1.00; p=0.0544).

While this numerical increase in median OS did not achieve statistical significance, this clinical activity builds on the meaningful survival gains achieved for patients in this setting treated with abiraterone alone, a current standard of care. Results will be presented today in an oral presentation at the 2023 American Society of Clinical Oncology (ASCO) Genitourinary (GU) Cancers Symposium (#LBA16).

In the primary analysis presented at ASCO GU 2022, and published in The New England Journal of Medicine Evidence (https://evidence.nejm.org/doi/full/10.1056/EVIDoa2200043), PROpel met its primary endpoint of radiographic progression-free survival (rPFS), showing that Lynparza in combination with abiraterone significantly reduced the risk of disease progression or death by 34% versus abiraterone alone (HR 0.66; 95% CI 0.54-0.81; p<0.0001).

Noel Clarke, Urological Surgeon and Professor of Urological Oncology at Manchester's Christie/Salford Royal Hospitals and Manchester University, and a senior investigator in the PROpel trial, said: "From the primary radiographic progression-free survival analysis presented at ASCO GU last year to the updated overall survival data presented today, the data reinforce the therapeutic potential of olaparib plus abiraterone and prednisone for patients with metastatic castration-resistant prostate cancer in the overall trial population and across subgroups. The results of PROpel are important for patients and the oncology community alike, providing support for this combination as a potential and critically needed new treatment option in metastatic castration-resistant prostate cancer."

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: "Both PARP, the target of Lynparza, and the androgen receptor are important for providing DNA repair in prostate cancer. The results in the overall trial population from PROpel illustrate how the combination of Lynparza and abiraterone can exploit the dependency of the androgen receptor's role in DNA repair on PARP to provide greater anticancer activity than abiraterone alone. Based on the totality of the data, it is notable to see this combination delivering a meaningful benefit in a broad population of patients in this setting, which is further underscored by the recent indication approved in the EU."

Dr Eliav Barr, Head, Global Clinical Development and Chief Medical Officer, MSD Research Laboratories, said: "Prostate cancer is the second most commonly diagnosed cancer in patients assigned male at birth, and mortality is estimated to almost double over the next 20 years. With limited treatment options for these patients, we recognize the critical need for therapies that can delay disease progression. We are proud of our collaboration with AstraZeneca as we work together to advance pending regulatory reviews and bring a new treatment option to the prostate cancer community."

Summary of results on key secondary OS endpoint across subgroups

Lynparza + abiraterone Placebo + abiraterone
ITT
Number of patients (n) 399 397
Median OS in months 42.1 34.7
HR (95% CI) 0.81 (0.67, 1.00)
HRRm
Number of patients (n) 111 115
Median OS in months NR 28.5
HR (95% CI) 0.66 (0.45, 0.95)
Non-HRRm
Number of patients (n) 279 273
Median OS in months 42.1 38.9
HR (95% CI) 0.89 (0.70, 1.14)
BRCAm
Number of patients (n) 47 38
Median OS in months NR 23.0
HR (95% CI) 0.29 (0.14, 0.56)
Non-BRCAm
Number of patients (n) 343 350
Median OS in months 39.6 38.0
HR (95% CI) 0.91 (0.73, 1.13)

*18 patients with unknown HRRm status were excluded from subgroup analysis. NR, not reached

The safety and tolerability of Lynparza plus abiraterone was in line with that observed in prior clinical trials and the known profiles of the individual medicines. At the time of this updated analysis, there were no new long-term safety issues identified.

The most common adverse events (AEs) in the Lynparza plus abiraterone arm (greater than or equal to 20% of patients) were anaemia (49.7%), fatigue (38.7%), nausea (30.7%), back pain (21.6%) and diarrhoea (20.6%). Approximately 83% of patients treated with Lynparza plus abiraterone who experienced AEs remained on treatment at the time of data cut-off.

Lynparza in combination with abiraterone was approved by the European Commission in December 2022 (https://www.astrazeneca.com/media-centre/press-releases/2022/lynparza-approved-in-eu-for-prostate-cancer.html) for the treatment of mCRPC in adult men for whom chemotherapy is not clinically indicated and is currently undergoing regulatory review in other countries.

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 were 268,490 new cases and 34,500 deaths in 2022.[4,5] Overall survival for patients with mCRPC is approximately three years in clinical trial settings, and even shorter in the real-world.[6] Approximately half of patients with mCRPC may receive only one line of active treatment, with diminishing benefit of subsequent therapies.[7-12]

Metastatic castration-resistant prostate cancer

Metastatic prostate cancer is associated with a significant mortality rate.[14] Development of prostate cancer is often driven by male sex hormones called androgens, including testosterone.[15]

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.[16 ]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.[16] Of patients with no metastases at CRPC diagnosis, 33% are likely to develop metastases within two years.[16]

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.[16-19]

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 addition to 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 overall survival, 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.[20,21 ]In addition, the AR also plays a role in repairing DNA damage in prostate cancer cells, including damage not normally repaired by 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[ 22,23,24,26,27]. 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.[22,24]

For more information about the trial please visit ClinicalTrials.gov (https://clinicaltrials.gov/ct2/show/NCT03732820).

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; and HRR gene-mutated metastatic castration-resistant prostate cancer (BRCAm only in the EU and Japan). In China, Lynparza is approved for the treatment of BRCA-mutated metastatic castration-resistant prostate cancer as well as a 1st-line maintenance therapy in BRCA-mutated 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 (http://www.astrazeneca.com/) and follow the Company on Twitter @AstraZeneca (https://twitter.com/AstraZeneca).

Contacts

For details on how to contact the Investor Relations Team, please click here (https://www.astrazeneca.com/investor-relations.html#Contacts). For Media contacts, click here (https://www.astrazeneca.com/media-centre/contacts.html).

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