A personalised approach in prostate cancer
Prostate cancer remains the most common form of cancer in men worldwide and despite an increase in the number of available therapies, the 5-year survival for advanced prostate cancer is only ~31%.1,2 At AstraZeneca our aim is to help transform the lives of these men with the ambition to one day help eliminate prostate cancer as a cause of death.
Why is such a small gland vulnerable to cancer?
Understanding the role of the prostate throughout a man’s life will help to understand why it is vulnerable to cancer. The prostate is a gland within the male genitourinary system which, after reaching puberty, helps to produce semen to protect and nourish sperm.3,4 It also produces prostate-specific antigen (PSA) to control the sperm motility.5,6 At this stage in life, more testosterone is developed which, being a growth hormone, gradually enlarges the prostate. This process doesn’t stop with time and instead, the prostate continues to grow throughout a man’s life.7 Although normal, if this growth becomes uncontrollable then cancer can form.4 The number of men diagnosed with prostate cancer is increasing, largely due to an increasing and ageing population as well as increased screening. Many men present with early (localised) prostate cancer, however ~20-30% will unfortunately see their disease progress to advanced (metastatic) disease.8,9,10,11,12 At AstraZeneca we are dedicated to helping improve the outcomes of men affected by prostate cancer. Our aim is to help identify men at early stages of the disease and optimise approaches to therapy.
Timing is everything! But why?
Early diagnosis could lead to benefits in survival if it involves the diagnosis at an earlier, more treatable stage, and that treatment options for the disease exist. On comparison of survival rates 5-years after diagnosis, there is a significant difference between an early (localised) diagnosis and a late (advanced/metastatic) diagnosis. The 5-year survival rate for most men with local prostate cancer is nearly 100%, whereas for men with advanced prostate cancer, the 5-year survival rate is ~31%.2 By diagnosing early, there is a critical opportunity to reduce the chance of a patient developing advanced disease, maintain good quality of life and reduce risk of morbidity.13
Prostate cancer is inherently sensitive to hormonal stimulation by male sex hormones. Therefore, being able to control hormone levels is of upmost importance during treatment.14 Unfortunately, prostate cancer can become unresponsive to these agents and alternative options need to be considered to control the disease.15 If the cancer becomes resistant to treatment, it may progress further locally and spread to other parts of the body.16,17,18 At this stage of the disease, it is important to control symptoms, delay progression of disease and extend life as much as possible.17,19,20,21
What is Metastatic Castration-Resistant Prostate Cancer?
Approximately 10-20% of patients with advanced prostate cancer will develop castration-resistant prostate cancer within approximately 5 years of diagnosis.22 Metastatic Castration-Resistant Prostate Cancer (mCRPC) occurs when prostate cancer grows and spreads to other parts of the body despite control of the male hormone levels which were previously driving the cancer growth. The outlook is poor, with most men unfortunately succumbing to the aggressive disease within two years, demonstrating the critical unmet need for therapy advancements in this area.23,24
Prostate cancers have been recognised to be biologically heterogeneous – they are not all the same.25 Historically in the treatment of mCRPC, hormonal therapy has been used to control growth hormone levels and chemotherapy has also been an option.18,26 Scientific studies have shown that approximately 25% of mCRPC is associated with defects of the signalling pathway associated with the key repair mechanisms involved when DNA is damaged.27 By determining the genomic profile and assessing the alteration of DNA repair genes associated with a patient’s tumour, it may be possible to consider novel approaches to treatment.22 PARP (poly-ADP ribose polymerase) is a protein found in cells which helps damaged cells to repair themselves. As a targeted treatment for cancer, PARPI work by stopping PARP from repairing cancer cells, leading to cell death.28,29
The role of DDR and genetic repair pathways
Every day, DNA in cells are repeatedly damaged and repaired to function normally. Many genes are involved in this DNA damage response (DDR) process – including BRCA1, BRCA2, ATM.26,30 These genes act as tumour suppressors and are part of just one of the repair pathways, homologous recombination repair (HRR). Mutations in such genes result in mutated HRR and a compromised ability for the cell to repair its DNA. Mutations in other HRR genes (HRRm) can also influence cancer development. Through a highly targeted approach, PARP inhibitors may be used to target the family of enzymes (PARPs) involved in DDR.31 By inhibiting their action, a cell must rely on alternative DNA repair pathways to survive. In the case of cancer cells, there are fewer functional pathways and the overwhelming level of DNA damage causes cell death.32
To learn more about the DDR process, the proteins included in the repair pathway and how we can exploit deficiencies in HRR (HRD), click here.
The importance of genetic and biomarker testing
To date traditional approaches to treatments for advanced prostate cancer have been limited and the genomic make-up of the tumour and how it could inform treatment decisions to better personalise care and impact outcomes were not considered as part of routine patient assessment.33,34
Genomic profiling or molecular testing can assess for the presence of germline and somatic mutations. A blood or saliva test can assess only for germline mutations. A germline mutation is inherited whereas a somatic mutation is not inherited. For tumour testing, a tissue sample is taken from the tumour and tested for gene alterations.27,35
Testing for DNA repair gene alterations is important to identify patients who may benefit from targeted treatment approaches. It is also important to assess the risk of other family members, as well as an increased risk of other cancers associated with the same genetic profile.36
The way that we treat cancer is changing to a more ‘personalised’ targeted approach, and prostate cancer is no exception. Whilst genetic mutations fuel cancer development, they can also help us to understand and exploit the HRD seen in cancer cells.
At AstraZeneca we remain wholly committed to innovative research that allows us to build on our long-standing oncology history in order to help as many men suffering from prostate cancer as possible.
We will continue to research personalised treatment options for men with mCRPC, as already seen in ovarian, breast and pancreatic cancer, to one day help eliminate prostate cancer as a cause of death.
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2. Cancer.Net. (2020). Prostate Cancer - Statistics. Available at: www.cancer.net/cancer-types/prostate-cancer/statistics [Accessed May 2020].
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8. World Health Organization. IARC. (2018). Estimated number of incident cases from 2018 to 2040, prostate, males, all ages. Available at: gco.iarc.fr/tomorrow/graphic-bar?type=0&type_sex=0&mode=population&sex=1&populations=900&cancers=27&age_group=value&apc_male=0&apc_female=0&single_unit=500000&print=0 [Accessed May 2020].
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23. Frieling et al. (2015). Current and Emerging Therapies for Bone Metastatic Castration-Resistant Prostate Cancer. Cancer Control, 22(1), pp.109-120.
24. Moreira et al. (2017). Predicting Time From Metastasis to Overall Survival in Castration-Resistant Prostate Cancer. Clinical Genitourinary Cancer, 15(1), pp.60-66.
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30. Harvard Health Blog (2019). Researchers Urge Prostate Cancer Screening For Men With BRCA Gene. Available at: www.health.harvard.edu/blog/researchers-urge-prostate-cancer-screening-for-men-with-brca-gene-defects-2019122018615 [Accessed May 2020].
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34. Babu et al. (2018). Personalised Management of Prostate Cancer. EMJ Urol, 6(1], pp.67-73.
35. Nccn.org. (2019). NCCN Guidelines For Patients - Prostate Cancer. Available at: https://www.nccn.org/patients/guidelines/content/PDF/prostate-patient.pdf [Accessed May 2020].
36. Prostate Cancer UK. (2019). Behind The Headlines: Genetic Testing And Prostate Cancer Risk. Available at: www.prostatecanceruk.org/about-us/news-and-views/2019/3/behind-the-headlines-genetic-testing-and-prostate-cancer-risk [Accessed May 2020].
Veeva ID: Z4-24620
Date of Prep: 28/05/2020