Transforming long-term outcomes in prostate cancer

Prostate cancer is the second most commonly diagnosed cancer amongst men^* and is the fifth leading cause of cancer death worldwide, with an incidence of 1.4 million, and 375,000 deaths globally in 2020.^1,2
 
Despite an increase in the number of available therapies, the problem isn’t going away, with the number of patients predicted to die from prostate cancer expected to almost double over the next 20 years.^1,2,3,4 At AstraZeneca our aim is to help improve the lives of these patients with the ambition to one day help eliminate prostate cancer as a cause of death.

Understanding the role of the prostate throughout someone’s life helps to understand why it is vulnerable to cancer. The prostate is a gland within the male genitourinary system which, upon reaching puberty, helps to produce semen to protect and nourish sperm.^5,6 This gland also produces prostate-specific antigen (PSA) to control sperm motility.^7,8 As more of the growth hormone testosterone is produced, the prostate gradually enlarges and continues to grow with age.⁹ Although this is initially part of a normal process, if this growth becomes uncontrollable, cancer can form.⁶ The number of patients diagnosed with prostate cancer is increasing, in part due to population ageing and increases in screening.¹ Many patients present with early (localised) prostate cancer, but approximately 20-30% will unfortunately see their disease progress to advanced (metastatic) disease.^,9,10,11,12 At AstraZeneca we are dedicated to helping improve the outcomes for patients affected by prostate cancer and our aim is to support the identification of this disease at the earliest stages in order to optimise the potential of therapeutic approaches.

Early diagnosis can lead to benefits in survival if made when the disease is at an early more treatable stage. When comparing survival rates following diagnosis, there is a significant difference between an early (localised) diagnosis and a late (advanced/metastatic) diagnosis. The five-year survival rate for most patients with local prostate cancer is nearly 100%, whereas for patients with advanced prostate cancer, the five-year survival rate falls to 31%.^6,13 By striving for early diagnosis, we have a critical opportunity to reduce the chance of patients developing advanced disease, help them maintain a good quality of life and reduce the risk of morbidity.¹

Prostate cancer is inherently sensitive to hormonal stimulation by male sex hormones. Therefore, being able to control hormone levels is of critical importance during treatment.¹⁴ Unfortunately, prostate cancer can become unresponsive to hormonal agents and alternative treatment 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 disease progression, and extend life as much as possible.^19,20,21

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 and no longer responds effectively to testosterone-lowering treatments. Most patients with mCRPC unfortunately succumb to this aggressive disease within two to three years, demonstrating the critical unmet need for therapy advancements in this area.^23,24

Prostate cancers have been recognised to be biologically heterogeneous – meaning that they are not all the same.²⁵ Historically in the treatment of mCRPC, hormonal therapy has been used to control growth hormone levels, with chemotherapy also provided as an option.^23,22, 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.²⁶ By determining the genomic profile and assessing the alteration of specific DNA repair genes associated with a patient’s tumour, it may be possible to consider novel approaches to treatment.²⁸ One such approach and class of potential targeted mCRPC therapies are PARP (poly-ADP ribose polymerase) inhibitors, which block the activity of the DNA repair protein PARP. While PARP is needed by ‘healthy’ cells to repair DNA damage, it can be disrupted in cancer cells with PARP inhibitors, preventing DNA repair and causing cell death.^27,28

Every day, DNA strands in cells are repeatedly damaged and then repaired so they can function normally again. Many genes are involved in this DNA damage response (DDR) process – including BRCA1, BRCA2 and ATM.^28,29 These genes act as tumour suppressors and are part of one of the repair pathways known as ‘homologous recombination repair’ (HRR). Mutations in such genes result in impaired 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.³⁰ 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.³¹

To learn more about the DDR process, the proteins included in the repair pathway and how we can exploit deficiencies in homologous recombination deficiency (HRD), click here.
 

To date, traditional approaches to treatments for advanced prostate cancer have been limited, with little consideration given to the genomic make-up of the tumour and how it could inform treatment decisions to better personalise care and improve outcomes.^32,33

Genomic profiling or molecular testing can assess the presence of germline and somatic gene mutations. A germline mutation is hereditary and can be identified using a blood or saliva test to compare the sample against our known genome. Somatic mutations are acquired during natural cell division or from exposure to environmental factors throughout someone’s life. As these somatic mutations will only be present in cells arising from the original mutated cell, they are usually only tested once a tumour has formed, by taking a tissue sample from the tumour and testing for gene alterations.^32,34

Testing for DNA repair gene alterations is important to identify patients who may benefit from targeted treatment approaches and is clinically important for prognostic and risk purposes, such as to assess the risk of other family members, or to assess an increased risk of other cancers associated with the same genetic profile.³⁵

The way we treat cancer is changing to a more ‘personalised’ targeted approach, and prostate cancer is no exception. While genetic mutations fuel cancer development, they can also help us to understand and exploit deficiencies in the repair pathways of certain cancers

At AstraZeneca we remain wholly committed to innovative research that allows us to build on our long-standing oncology history and help as many patients living with prostate cancer as possible.

We will continue to research personalised treatment options for people with mCRPC, as already seen in ovarian, breast and pancreatic cancer, so we can one day achieve our ambition to eliminate prostate cancer as a cause of death.

Reference

1.Rawla P, et al. Epidemiology of prostate cancer. World J Oncol. 2019;10(2):63-89.

2.Sung H, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209-249.

3.Globocan. Prostate. Estimated number of deaths from 2020 to 2040, Both sexes, age [0-85+]. Available at http://gco.iarc.fr/tomorrow/en/dataviz/bars?types=1&sexes=0&mode=population&group_populations=0&multiple_populations=1&multiple_cancers=1&cancers=27&populations=903_904_905_908_909_935&apc=cat_ca20v1.5_ca23v-1.5&group_cancers=1&bar_mode=grouped. Accessed May 2022.

4.World Health Organization. IARC. 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 2022.

5.Male Contraceptive Initiative. n.d. What Is The Prostate? - Blog - Male Contraceptive Initiative. Available at www.malecontraceptive.org/what-is-the-prostate/. Accessed May 2022.

6.Prostate Cancer UK. About Prostate Cancer. Available at www.prostatecanceruk.org/prostate-information/about-prostate-cancer Accessed May 2022.

7.Prostate Cancer UK. PSA Test. Available at www.prostatecanceruk.org/prostate-information/prostate-tests/psa-test. Accessed May 2022.

8.Gupta N, et al. Mutations in the prostate specific antigen (PSA/KLK3) correlate with male infertility. Scientific Reports. 2017;7(1).

9.Prostate Cancer UK. Where Are The Increased Prostate Cancer Deaths Coming From? Available at prostatecanceruk.org/about-us/news-and-views/2018/2/where-are-the-increased-prostate-cancer-deaths-coming-from. Accessed May 2022.

10.Droz J, et al. Management of prostate cancer in older men: recommendations of a working group of the International Society of Geriatric Oncology. BJU International. 2020;106(4), pp.462-469.

11.World Cancer Research Fund. Prostate Cancer Statistics. Available at www.wcrf.org/dietandcancer/cancer-trends/prostate-cancer-statistics. Accessed May 2022.

12.Holm M, et al. Quality of life in men with metastatic prostate cancer in their final years before death – a retrospective analysis of prospective data. BMC Palliative Care. 2018;17(126).

13.Chowdhury S, et al. Real-world outcomes in first-line treatment of metastatic castration-resistant prostate cancer: the prostate cancer registry. Targeted Oncology. 2020; 15(3):301-315.

14.Cancer.Net. Prostate Cancer - Types Of Treatment. Available at www.cancer.net/cancer-types/prostate-cancer/types-treatment Accessed May 2022.

15.Di Zazzo E, et al. Estrogens and Their Receptors in Prostate Cancer: Therapeutic Implications. Frontiers in Oncology. 2018;8(2).

16.Cancer.Net. Treatment Of Metastatic Castration-Resistant Prostate Cancer. Available at www.cancer.net/research-and-advocacy/asco-care-and-treatment-recommendations-patients/treatment-metastatic-castration-resistant-prostate-cancer. Accessed May 2022.

17.Everyday Health. Diagnosed With Metastatic Castration-Resistant Prostate Cancer: What’s Next? Available at www.everydayhealth.com/hs/advanced-prostate-cancer-what-is-crpc/ Accessed May 2022.

18.Prostate Cancer UK. Advanced Prostate Cancer. Available at www.prostatecanceruk.org/prostate-information/just-diagnosed/advanced-prostate-cancer. Accessed May 2022.

19.Urologyhealth.org. Advanced Prostate Cancer: Symptoms, Diagnosis & Treatment - Urology Care Foundation. Available at www.urologyhealth.org/urologic-conditions/advanced-prostate-cancer. Accessed May 2022.

20.Cancer.Net. Treatment Of Metastatic Castration-Resistant Prostate Cancer. Available at www.cancer.net/research-and-advocacy/asco-care-and-treatment-recommendations-patients/treatment-metastatic-castration-resistant-prostate-cancer. Accessed May 2022.

21.NHS.uk. Prostate Cancer - Treatment. Available at www.nhs.uk/conditions/prostate-cancer/treatment/. Accessed May 2022.

22.Crawford E.D. et al. Navigating the evolving therapeutic landscape in advanced prostate cancer. Urol Oncol. 2017 May;35S:S1-S13.

23.Teo M, et al. Treatment of Advanced Prostate Cancer. Annual Review of Medicine. 2019;70, pp.479-499.

24.Moreira, D, et al. Predicting Time From Metastasis to Overall Survival in Castration-Resistant Prostate Cancer: Results From SEARCH. Clinical Genitourinary Cancer. 2017;15(1), pp.60-66.e2.

25.Haffner M.C. et al. Genomic and phenotypic heterogeneity in prostate cancer. Nat Rev Urol. 2021; 18(2): 79–92.

26.Nombela P, et al. BRCA2 and Other DDR Genes in Prostate Cancer. Cancers. 2019;11(3), p.352.

27.Li H, et al. PARP inhibitor resistance: the underlying mechanisms and clinical implications. Mol Cancer. 2020 Jun 20;19(1):107.

28.Rose M, et al. PARP Inhibitors: Clinical Relevance, Mechanisms of Action and Tumor Resistance. Front Cell Dev Biol. 2020 Sep 9;8:564601.

29.Harvard Health Blog. Researchers Urge Prostate Cancer Screening For Men With BRCA Gene Defects - Harvard Health Blog. Available at www.health.harvard.edu/blog/researchers-urge-prostate-cancer-screening-for-men-with-brca-gene-defects-2019122018615. Accessed May 2022.

30.Keung, M, et al. PARP Inhibitors as a Therapeutic Agent for Homologous Recombination Deficiency in Breast Cancers. Journal of Clinical Medicine. 2019; 8(4):435.

31.Cancerresearchuk.org. PARP Inhibitors. Available at www.cancerresearchuk.org/about-cancer/cancer-in-general/treatment/targeted-cancer-drugs/types/PARP-inhibitors. Accessed May 2022.

32.National Cancer Institute. Biomarker Testing for Cancer Treatment. Available at http://www.cancer.gov/about-cancer/treatment/types/biomarker-testing-cancer-treatment. Accessed March 2022.

33.Babu D, et al. Personalised Management of Prostate Cancer. EMJ Urol. 2018;6(1]:67-73.

34.NCCN.org. NCCN Guidelines For Patients - Prostate Cancer. Available at http://www.nccn.org/patients/guidelines/content/PDF/prostate-patient.pdf. Accessed May 2022.

35.Prostate Cancer UK. 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 2022.