Lynparza reduced the risk of death by 31% in BRCA1/2 or ATM-mutated metastatic castration-resistant prostate cancer in PROfound Phase III trial

Lynparza is the only PARP inhibitor to demonstrate overall survival in metastatic castration-resistant prostate cancer

Final results from the PROfound Phase III trial showed AstraZeneca and MSD’s Lynparza (olaparib) demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS) versus enzalutamide or abiraterone in men with metastatic castration-resistant prostate cancer (mCRPC) with BRCA1/2 or ATM gene mutations, a subpopulation of homologous recombination repair (HRR) gene mutations.

Patients had progressed on prior treatment with new hormonal agent (NHA) treatments (i.e. enzalutamide and abiraterone). Prostate cancer is the second-most common type of cancer in men, with an estimated 1.3 million new patients diagnosed worldwide in 2018.¹ Approximately 20-30% of men with mCRPC have an HRR gene mutation.²

In the key secondary endpoint of OS, Lynparza reduced the risk of death by 31% versus enzalutamide or abiraterone (based on a hazard ratio [HR] of 0.69; 95% confidence interval [CI] 0.50-0.97; p=0.0175). Median OS was 19.1 months for Lynparza versus 14.7 months for enzalutamide or abiraterone, despite 66% of men on NHA treatments had crossed over to receive treatment with Lynparza following disease progression.

An exploratory analysis also showed a non-statistically significant improvement in OS in the overall trial population of men with HRR gene mutations (BRCA1/2, ATM, CDK12 and 11 other HRRm genes), reducing the risk of death by 21% with Lynparza versus enzalutamide or abiraterone (based on a HR of 0.79; 95% CI  0.61-1.03). Median OS was 17.3 months versus 14.0 months for enzalutamide or abiraterone.

Johann de Bono, one of the principal investigators of the PROfound Phase III trial, Head of Drug Development at The Institute for Cancer Research and The Royal Marsden NHS Foundation Trust, said: “Lynparza has demonstrated significant clinical benefit across key endpoints in PROfound and the final overall survival results reinforce its potential to change the treatment standard for men with metastatic castration-resistant prostate cancer. The PROfound trial shows that Lynparza can play an important role in this new era of precision medicine in prostate cancer, bringing a targeted therapy at a molecular level to patients with a historically poor prognosis and few treatment options.”

José Baselga, Executive Vice President, Oncology R&D, said: “These results help to transform the treatment landscape for certain men with metastatic castration-resistant prostate cancer, where overall survival has been very difficult to achieve. Lynparza is the only PARP inhibitor to demonstrate overall survival versus enzalutamide or abiraterone for men with BRCA or ATM mutations. We look forward to continuing to bring Lynparza to these patients around the world.”

Roy Baynes, Senior Vice President and Head of Global Clinical Development, Chief Medical Officer, MSD Research Laboratories, said: “The PROfound trial is the first positive Phase III trial using molecular biomarker testing to help identify treatment options for certain men with metastatic castration-resistant prostate cancer. These results further underpin the importance of genomic testing for HRR gene mutations to identify this at-risk patient population and help physicians make treatment decisions. These results demonstrate the potential of Lynparza for metastatic castration-resistant prostate cancer patients with certain HRR mutations.”

Final OS results from the PROfound Phase III trial were presented on Sunday 20 September during the Presidential Symposium at the 2020 European Society of Medical Oncology virtual congress, and published simultaneously in The New England Journal of Medicine.

Summary of OS results

OS data cut-off date was 20 March, 2020

The most common adverse events (AEs) ≥20% were anaemia (50%), nausea (43%), fatigue/asthenia (42%), decreased appetite (31%), diarrhoea (21%) and vomiting (20%). The most common ≥ grade 3 AEs were anaemia (23%), nausea (2%), fatigue/asthenia (3%), decreased appetite (2%), and diarrhoea (1%). Twenty percent of patients on Lynparza discontinued treatment due to AEs.

The PROfound Phase III trial met its primary endpoint in August 2019, showing Lynparza significantly improved radiographic progression-free survival (rPFS) in men with BRCA1/2 or ATM genes, and met a key secondary endpoint of rPFS in the overall HRRm population, which formed the basis of the US approval in May 2020. Regulatory reviews are ongoing in the EU and other countries.  

AstraZeneca and MSD are exploring additional trials in metastatic prostate cancer including the ongoing PROpel Phase III trial testing Lynparza as a 1st-line medicine for patients with mCRPC in combination with abiraterone versus abiraterone alone. Data are anticipated in 2021.

Metastatic castration-resistant prostate cancer (mCRPC)

Prostate cancer is associated with a significant mortality rate.¹ Development of prostate cancer is often driven by male sex hormones called androgens, including testosterone.³ 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.³ Approximately 10-20% of men with advanced prostate cancer will develop CRPC within five years, and at least 84% of these men will have metastases at the time of CRPC diagnosis.⁴ Of men with no metastases at CRPC diagnosis, 33% are likely to develop metastases within two years.⁴ Despite advances in treatment for men with mCRPC, five-year survival is low and extending survival remains a key treatment goal.⁴

HRR gene mutations

HRR genes allow for accurate repair of damaged DNA in normal cells.^5,6 HRR deficiency (HRD) means the DNA damage cannot be repaired, and can result in normal cell death.⁶ This is different in cancer cells, where a mutation in HRR pathways leads to abnormal cell growth and therefore cancer.⁶ HRD is a well-documented target for PARP inhibitors, such as Lynparza. PARP inhibitors block a rescue DNA damage repair mechanism by trapping PARP bound to DNA single-strand breaks which leads to replication fork stalling causing their collapse and the generation of DNA double-strand breaks, which in turn lead to cancer cell death.⁶

PROfound

PROfound is a prospective, multicentre, randomized, open-label, Phase III trial testing the efficacy and safety of Lynparza versus enzalutamide or abiraterone in patients with mCRPC who have progressed on prior treatment with NHA treatments (abiraterone or enzalutamide) and have a qualifying tumour mutation in BRCA1/2, ATM or one of 12 other genes involved in the HRR pathway.

The trial was designed to analyse patients with HRRm genes in two cohorts: the primary endpoint was rPFS in those with mutations in BRCA1/2 or ATM genes and then, if Lynparza showed clinical benefit, a formal analysis was performed of the overall trial population of patients with HRRm genes (BRCA1/2, ATM, CDK12 and 11 other HRRm genes; a key secondary endpoint).

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 mutations in BRCA1 and/or BRCA2. 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 being tested in a range of PARP-dependent tumour types with defects and dependencies in the DDR pathway.

Lynparza is currently approved in a number of countries, including those in the EU, for the maintenance treatment of platinum-sensitive relapsed ovarian cancer. It is approved in the US, the EU, Japan, China, and several other countries as 1st-line maintenance treatment of BRCA-mutated advanced ovarian cancer following response to platinum-based chemotherapy. It is also approved in the US as a 1st-line maintenance treatment with bevacizumab for patients with homologous recombination deficiency (HRD)-positive advanced ovarian cancer. Lynparza is approved in the US, Japan, and a number of other countries for germline BRCA-mutated, HER2-negative, metastatic breast cancer, previously treated with chemotherapy; in the EU, this includes locally advanced breast cancer. It is also approved in the US and several other countries for the treatment of germline BRCA-mutated metastatic pancreatic cancer. Lynparza is approved in the US for HRR gene-mutated metastatic castration-resistant prostate cancer. Regulatory reviews are underway in several countries for ovarian, breast, pancreatic and prostate cancers.

Lynparza, which is being jointly developed and commercialised by AstraZeneca and MSD, has been used to treat over 30,000 patients worldwide. Lynparza has the broadest and most advanced clinical trial development programme of any PARP inhibitor, 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 MEK inhibitor, for multiple cancer types. Working together, the companies will develop Lynparza and Koselugo in combination with other potential new medicines and as monotherapies. Independently, the companies will develop Lynparza and Koselugo in combination with their respective PD-L1 and PD-1 medicines.

AstraZeneca in oncology

AstraZeneca has a deep-rooted heritage in oncology and offers a quickly growing portfolio ofnew medicines that has the potential to transform patients’ lives and the Company’s future. With seven new medicines launched between 2014 and 2020, and a broad pipelineof small molecules and biologics in development, the Company is committed to advance oncology as a key growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers.

By harnessing the power of four scientific platforms – Immuno-Oncology, Tumour Drivers and Resistance, DNA Damage Response and Antibody Drug Conjugates – and by championing the development of personalised combinations, AstraZeneca has the vision to redefine cancer treatment and, one day, eliminate cancer as a cause of death.

AstraZeneca

AstraZeneca (LSE/STO/NYSE: AZN) 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 & 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.

References

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2. Mateo, J, et al (2015). DNA-repair defects and olaparib in metastatic prostate cancer. New England Journal of Medicine, 373(18), pp.1697 - 1708.

3. Cancer.Net. (2019). Treatment of metastatic castration-resistant prostate cancer.

www.cancer.net/research-and-advocacy/asco-care-and-treatment-recommendations-patients/treatment-metastatic-castration-resistant-prostate-cancer [Last Accessed: September 2020].

4. Kirby, M. (2011). Characterising the castration-resistant prostate cancer population: a systematic review. International Journal of Clinical Practice, 65(11), pp.1180-1192.

5. Li et al. (2008). Homologous recombination in DNA repair and DNA damage tolerance. Cell Research, 18(1), pp.99-113.

6. Ledermann et al. (2016). Homologous recombination deficiency and ovarian cancer. European Journal of Cancer, 60, pp.49-58.