Prostate Cancer

Epidemiology

Globally, prostate cancer is estimated to be the second most common cancer in males and the fifth most common cause of male deaths¹

Prevalence, incidence and mortality

Prostate cancer is estimated to be the second most common cancer in males globally, estimated at 1,276,106 new cases in 2018, and the fifth most common cause of male cancer-related deaths, estimated at 358,989 deaths¹. There are considerable differences in incidence rates (189.1/100,000 in Guadeloupe and 1.0/100,000 in Bhutan at the extremes); however, incidence rates do not correlate with mortality rates, which varies less^1,2. Both genetic and environmental factors impact on prostate cancer incidence, including rate of diagnosis, differences in screening and access to healthcare².

The estimates for Europe for the same period show that prostate cancer is the most common male cancer, forming an estimated 21.8% of all new male cancers diagnosed in 2018 (Figure 1)³. This places prostate cancer as the third most common cause of cancer mortality in men in Europe at 10% of male cancer deaths, following lung (24.8%) and colorectum cancers (12.0%) (Figure 1)³.

Figure 1. Estimated incidence and mortality rates for the top 5 cancers in males across European countries in 2018. Adapted from Ferlay et al., 2018³.

The 2018 age-standardised incidence rates of prostate cancer vary by more than 5-fold (37–189.3 per 100,000) across European countries (Figure 2)³.

Figure 2. Estimated 2018 age-standardised incidence and mortality rates (per 100,000) for prostate cancer by area and country in Europe. Adapted from Ferlay et al., 2018³.

The highest incidence rates are in Northern European countries and the lowest in Central and Eastern European countries. The fold difference is an improvement on the greatest (7.7-fold) difference recorded in 2012 and likely reflects improvements in prostate cancer screening programs in Central and Eastern European countries⁴. In comparison with incidence, mortality rates vary less across Europe (3.5-fold difference)³. These figures likely reflect variability in national health system policies (for example, organised screening for prostate cancer), differences in risk factors between countries and regions, and disparities in the delivery of cancer management measures. The variation in incidence and mortality is much lower for the EU-5 countries (United Kingdom, France, Germany, Spain and Italy) (Figure 3)³.

Figure 3. Estimated number of new cases and deaths for prostate cancer in 2018 for the EU5 countries. Adapted from Ferlay et al, 2018³.

Prostate cancer survival

Overall prostate cancer survival has been steadily increasing over the past 50 years (Figure 4)⁵. This increase in survival is partly explained by early detection and treatment, however other factors are likely to be involved⁶.

Figure 4. Age-standardised one, five and ten–year net survival in England and Wales between 1971 and 2011. Adapted from CRUK Prostate Cancer Statistics⁵.

Clinical outcome is dependent on many factors, including clinical stage at diagnosis. If detected at an early stage (Stages I–II), prostate cancer patients are likely to live beyond 5 years from diagnosis (Figure 5)⁵. Stage III prostate cancer patients have an approximately 93% chance of surviving beyond 5 years, whilst Stage IV patients who have incurable metastatic disease have only a 30% five-year relative survival based on data from 2002–2006⁵.

Figure 5. Five–year relative survival (%) by prostate cancer stage in adults aged 15–99, 2002–2006 data from the National Cancer Registration Service, East Office. Adapted from CRUK Prostate Cancer Statistics⁵.

Risk factors

The risk of prostate cancer is higher in older men, men of African-American descent and men with a family history of cancer⁶

Unmodifiable risks of prostate cancer include increasing age, race and a family history of prostate and other cancers, whereas modifiable risks factors include obesity and smoking⁶.

Age

Prostate cancer risk increases with age, with incidence rates peaking in men who are in their seventies (Figure 6)⁵.  

Figure 6. Average number of new cases per year and age-specific incidence rates per 100,000 males, UK. Adapted from CRUK Prostate Cancer Statistics⁵.

Race

Differences in prostate cancer incidence and mortality exist between racial and ethnic groups. In the USA, African-American men are nearly twice as likely to be diagnosed with prostate cancer compared to Caucasian men, and three times as likely compared to Asian men⁶. African-American men are also more likely to die from the disease than Caucasian and Asian men^6,7. The reason for the difference in incidence and mortality rates between racial and ethnic groups is not clear; however, this may be impacted by differences in access to care, stage at diagnosis and genetic predisposition^2,8,9.

Family risk

Genome-wide association studies have identified more than 180 genetic risk loci, indicating that predisposition genes may also impact on prostate cancer risk⁶. Indeed, studies in twins found a high heritability rate of up to 57%^10,11. Family association studies also found that men who have a brother or a father diagnosed with prostate cancer have a two to three-fold increased risk of developing and dying of the disease themselves^12,13. If both a brother and a father have been diagnosed, the risk is further increased¹⁴. Prostate cancer patients who have a first-degree family history of any cancer are also more likely to develop and die from secondary primary cancers such as lung and colorectal cancers¹⁵.

Men who have a family history of hereditary breast and ovarian cancer (HBOC) syndrome that is caused by germline mutations in homologous recombination repair (HRR) genes such as BRCA1 and BRCA2 are at an increased risk of prostate cancer^16–18. Initial findings of the IMPACT study that followed up male subjects who had germline mutations in BRCA1 or BRCA2 found that BRCA2 carriers had a higher prostate cancer incidence rate per 1000 patient years compared to noncarriers (19.4 vs 12.0; P=0.03)¹⁹. This study also found that BRCA2 carriers were diagnosed at a younger age and were more likely to have clinically significant disease¹⁹. The role for BRCA1 remains unclear, and more data is needed to understand it’s role in prostate cancer risk¹⁹.

To find out more about the cellular role for BRCA2 in DNA damage repair, its prevalence in prostate cancer, and its impact on clinical practice, please visit the DNA repair section.

Find out more on the techniques for molecular testing of BRCA2 in prostate cancer here.

Modifiable risks of prostate cancer

Obesity has been associated with increased mortality and recurrence of prostate cancer in multiple studies, even when normalising to the prostate cancer stage and PSA readings at diagnosis⁶. Smoking is also suggested to increase the risk of death from prostate cancer, advanced stage disease and poorly differentiated cancer⁶. Smokers were found to have an approximately 60% increased risk of prostate cancer mortality following adjustment of potential confounding factors compared to men who never smoked⁶.

Detection and Classification

Based on data from 2002–2006, stage IV prostate cancer has a 5–year survival rate of approximately 30% compared to early stage disease which has a 5–year survival rate of 95–100%⁵. Prostate cancer staging is therefore key to ensuring the best chance of survival

Major international guidelines do not currently recommend routine screening for prostate cancer²⁰. The diagnosis of prostate cancer therefore typically follows a patient requesting examination or following investigation for clinical symptoms. Local symptoms for prostate cancer start arising once the cancer is large enough to affect the urethra²¹. Subsequently, a lot of the symptoms involve problems with urinating such as frequent urination, difficulty in urinating and weak flow²². Patients may also experience blood in semen, erectile dysfunction and discomfort in the pelvic area²². Metastatic prostate cancer further present symptoms according to the organ affected and symptoms can include bone pain, a loss of appetite, and unexplained weight loss²¹.

Detection

A patient is assessed to determine if they have prostate cancer using detection techniques that typically involve²³:

• Digital rectal exam (DRE)
• Prostate-specific antigen (PSA) levels in blood
• Imaging tests
• Biopsy

Digital rectal exam (DRE)

Digital rectal exam (DRE) is a partial physical exam used to screen for prostate cancer, and measure prostate size for the purposes of grading. Since the prostate can be felt through the rectal wall, DRE involves the insertion of a finger into the rectum to feel the prostate. Prostate cancers are mostly located in the peripheral zone of the prostate and can be detected by DRE when the volume is ≥0.2 mL²³.

Prostate-specific antigen (PSA)

The most common type of prostate cancer is acinar adenocarcinoma which arises from glandular epithelial cells that line the prostate²⁴. These cells secrete prostate-specific antigen (PSA), high blood levels of which may indicate the presence of a prostate cancer²⁵. Some measurements for PSA include²³:

• PSA level is measurable in blood samples as ng/mL blood
• PSA density is the level of serum PSA divided by the TRUS-determined prostate volume
• PSA velocity describes the change in PSA levels over time
• PSA doubling time is the time it takes the PSA level to double

Major international guidelines do not recommend routine PSA screening due to the high false positive rate²⁰. Additionally, poorly differentiated prostate cancers and rarer types of prostate cancer that do not secrete PSA may be missed²⁴. These include ductal adenocarcinomas and some neuroendocrine and basal cell prostate cancers that most often present normal levels of PSA²⁴.

To overcome the challenges of PSA sensitivity and cancer specificity, other measurements and biomarkers of prostate cancer are being explored to be used in conjunction with PSA testing.

Imaging

Imaging is recommended to some patients to stage the disease and guide treatment planning²⁶. Imaging is also used to inform on metastatic relapse, to monitor response to therapy, assess for disease progression and to investigate new symptoms potentially associated with the disease²⁷.

Imaging techniques used to assess prostate cancer include transrectal ultrasound (TRUS) imaging, computed tomography (CT), magnetic resonance imaging (MRI), radionucleotide bone scan, and positron emission tomography (PET) in combination with CT or MRI (Figure 7)²⁶. 

Figure 7. Summary of imaging techniques used for prostate cancer detection, staging and assessing treatment response^27–34.

Ultrasound imaging: Ultrasound imaging is used to guide the retrieval of primary prostate cancer samples, known as transrectal ultrasound guided (TRUS) biopsy³⁵. TRUS is carried out if a patient displays a high PSA level and abnormal DRE findings. Typically, ten to twelve cores are taken which are used to measure Gleason scores³⁵. Since biopsy retrieval is based on estimation, high-grade cancers that require urgent treatment are often missed²⁸. New techniques to distinguish between low and high-grade tumours are currently being explored.

Magnetic resonance imaging (MRI): An MRI scan uses magnetism and radio waves to create images from multiple angles to show soft tissue clearly³⁶. Multi-parametric MRI (mpMRI) is a more recent technique which provides more information than standard MRI by combining multiple images^26,30. Alongside tissue anatomy, it provides information on prostate volume, cellularity and vascularity³⁰. Whilst not yet routine, recent studies show that mpMRI may help in stratifying patients for TRUS biopsy and reduce overdiagnosis of clinically insignificant disease, whilst improving the detection of clinically significant cancer³⁰.

Computed tomography (CT): A CT scan uses X-rays to create cross-sectional images of the body. CT scans are used primarily for staging at base-line to assess for any suspected locally advanced or metastatic disease²⁹. CT scans are also used for planning radiation delivery and assessing treatment response in advanced disease³⁴.

Positron emission tomography (PET): PET scans are typically used to assess metastatic disease for staging and more recently, for treatment planning in patients who require salvage therapy^31,37. PET is often carried out together with a CT scan to provide more detailed images (PET/CT scan)^27,32. PET can identify specific cells using labelled radiotracers that are attached to a biologically active molecule³². Common radiotracers include ¹¹C and ¹⁸F choline and more recently, ⁶⁸Ga- or ¹⁸F-labelled prostate specific membrane antigen (PMSA) that has higher sensitivity, specificity and target-to-background ratio^32,38. PSMA-PET/CT has a high positive detection rate since PSMA is over-expressed in 95% of primary prostate cancers; however, its expression is not limited to prostate tissue and can be overexpressed in other tumours^31,38. PSMA PET/CT is highly sensitive and can detect prostate cancers, even when PSA levels are less than 1ng/mL^31,37. This sensitivity has proven to be useful in planning salvage radiotherapy treatments for cancers with biochemical recurrence^31,37.

Bone scan: More than 80% of patients with metastatic castration resistant prostate cancer (mCRPC) present with bone metastasis that is associated with greater morbidity²⁷. A standard bone scan involves a planar whole body imager³³. A radiotracer is used to mark regions of bone deposition, indicative of bone metastasis³³.

Biopsy

A biopsy confirms diagnosis, gives more detail on the type of cancer and contributes to risk scoring²³. Prostate cancer clinical staging informs on the extent of disease progression and is used alongside risk assessment to determine the best management option for the patient²³. Using imaging results and biopsy samples, staging involves^23,39:

• Gleason scoring of the primary tumour
• Tumour, node, metastasis (TNM) scoring

Prostate cancer staging

Prostate cancer can be broadly described as localised, locally advanced or advanced prostate cancer.

• Localised prostate cancer is sometimes referred to as ‘early’ or ‘organ-confined’ since it describes prostate cancer that hasn’t spread from inside the prostate to other parts of the body⁴⁰. It is often slow-growing and poses a low risk of spreading
• Locally advanced prostate cancer, describes prostate cancer that has breached the prostate capsule and potentially invaded local structures including seminal vesicles, pelvic lymph nodes, bladder and rectum⁴¹
• Advanced prostate cancer, or metastatic prostate cancer has spread to other parts of the body via the blood or lymphatic system⁴²

The International Society of Urologic Pathology (2005) (ISUP) Gleason grade that is based on histological analysis of biopsy samples is used together with tumour, node, metastasis (TNM) scores to stage prostate cancer²³.   

ISUP Gleason grade

The International Society of Urologic Pathology (2005) Gleason grade is based on patterns from core biopsy and operative specimens of the primary tumour²³. Gleason patterns of the prostate gland are graded 1–5 (Figure 8). The Gleason score, which ranges from 2–10, is the sum of the most common pattern and the second most common pattern, or is doubled if only one pattern is present²³. If there are more than 2 patterns, the score is the sum of the most common pattern, and that for the highest grade, irrespective of its extent (Table 1)²³.

Figure 8. Gleason patterns and associated grades for glandular structures of the prostate. Adapted from NCI SEER training module⁴³.

Table 1. Gleason score descriptions. Adapted from Cancer Research UK⁴⁴.

The Gleason scores are further sub-divided into International Society of Urological Pathology (ISUP) Gleason grades (also referred to as Gleason groups) (Table 2), that are used together with tumour node metastasis (TNM) scores and PSA levels for tumour staging²³.

Table 2. International Society of Urological Pathology (ISUP) 2014 Gleason grade. Adapted from the EAU-ESTRO-ESUR-SIOG Guidelines on Prostate Cancer, 2020²³.

TNM scores

The tumour, node and metastasis (TNM) score describes tumour locality (Table 3)²³. The locations are primary tumour site (T), lymph nodes (N) and distant sites (M). Prostate cancer spreads most frequently to the internal and external iliac and obturator lymph nodes³⁸. Distant metastatic sites are most frequently lymph nodes, bone, then the lungs and liver³⁸.

Table 3. Tumour Node Metastasis (TNM) classification (2017). Adapted from the EAU-ESTRO-ESUR-SIOG Guidelines on Prostate Cancer, 2020²³.

Stage Groups

The TNM classification is used alongside PSA levels and ISUP Grade/Gleason group to determine the prostate cancer stage group (Table 4)²³.

Stage I describes a tumour that is slow growing, cannot be felt and occupies one side of the prostate or less⁴⁵. Stage II describes a tumour that is small and found only in the prostate but has an increasing risk of growing and spreading⁴⁵. Stage III describes a tumour that is locally advanced, growing and likely to spread whereas Stage IV describes a tumour that has spread beyond the prostate⁴⁵.

There is increasing evidence that patients with oligometastatic disease (presence of 3–5 metastatic sites) respond better to some metastatic-directed therapies⁴⁶. Staging of low versus high volume disease using sensitive imaging techniques may help to identify these patients who may be managed differently in the future⁴⁶.

Table 4. Parameters for the stages of prostate cancer. Adapted from the American Cancer Society⁴⁷.

Treatment Planning

Treatment planning is informed by prostate cancer stage and risk group, as well as the patients health status and life expectancy²³. Risk assessments can involve^23,26:

• Risk stratification that involves assigning the patient to a risk group
• Nomograms
• Molecular testing

Risk stratification

Risk stratification is used to describe the likelihood of a patient’s prostate cancer progressing to an advanced stage²³. An understanding of the risk of developing advanced disease helps to guide treatment decisions at an earlier stage. The European Association of Urology prostate cancer risk stratification group guide considers the patients TNM score, Gleason score/ISUP Gleason grade and PSA levels (Table 5)²³.

Table 5. Risk group stratification criteria. Adapted from the EAU-ESTRO-ESUR-SIOG Guidelines on Prostate Cancer, 2020; Parker et al., 2020^23,48.

Nomograms

Nomograms are powerful tools that use data from large studies to provide either predictive or prognostic information based on relevant patient-specific variables²⁶. The Partin tables, the first of its kind, uses cancer stage, Gleason score and PSA levels to establish the probability that a patient with localised disease will progress to each pathologic stage²⁶. There are nomograms that predict outcome for various treatment options, including for active surveillance, radical prostatectomy or external beam radiotherapy, and those that assess prognostic probabilities such as biochemical progression-free survival (PFS)²⁶.

Testing for familial risk

Pathogenic alteration of homologous recombination repair (HRR) and mismatch repair (MMR) genes have been associated to an increased risk of prostate cancer, and can lead to hereditary breast and ovarian cancer syndrome (HBOC) and Lynch syndrome, respectively^{16–18,49–51}. These are cancer predisposing syndromes that impact on prostate cancer risk, risk of prostate cancer patients developing secondary cancers, as well as overall family risk of cancer^{16–18,49–51}.

The V2.2020 NCCN Guidelines^® for Prostate Cancer recommends germline testing for DNA repair gene alterations in patients with high-risk, very-high-risk, regional or metastatic prostate cancer (Table 6)²⁶. The V2.2020 NCCN Guidelines for Prostate Cancer also recommends germline testing for low and intermediate risk patients with a positive family history, Ashkenazi Jewish ancestry or intraductal/cribriform histology²⁶. The DNA repair genes assessed should include at a minimum MLH1, MSH2, MSH6, and PMS2 (mismatch repair genes) and BRCA2, BRCA1, ATM, PALB2, and CHEK2 (homologous recombination repair genes)²⁶.

Table 6: The V2.2020 NCCN Guidelines for Prostate Cancer recommendations on germline testing, and molecular and biomarker tumour testing in prostate cancer. Adapted with permissions from V2.2020 NCCN Guidelines for Prostate Cancer²⁶.

Dr Alexander Wyatt, who leads a research group on prostate cancer genomics and diagnostics at the Vancouver Prostate Centre discusses how molecular diagnostics are now being applied in prostate cancer.

The ESMO Clinical Practice Guidelines for Prostate Cancer (2020) also recommends germline testing for BRCA2 and other DNA damage response (DDR) genes associated with predisposition syndromes in prostate cancer patients who have a family history of cancer⁴⁸. It also suggests to consider germline testing for these genes in patients with metastatic prostate cancer⁴⁸. The EAU guidelines (2020) do not currently provide any recommendations on molecular testing for DNA repair gene alterations in prostate cancer; however, the EAU guidelines recommend offering early PSA testing to men who have an elevated risk of prostate cancer, including men >40 years old who carry BRCA2 mutations²³.

Testing for prognostic biomarkers

There is a need for prognostic biomarkers to support treatment planning and to mitigate the risk of unnecessary and costly radical treatment for early disease⁵². Recent developments have led to the production of diagnostic testing kits that assess collective molecular signatures associated with progression to an advanced disease state⁵². Whilst not routinely used in the clinic, diagnostic testing kits are a major point of interest with emerging evidence that testing increases active surveillance and reduces the number of men referred for immediate treatment⁵². The V2.2020 NCCN Guidelines for Prostate Cancer suggest to consider tumour multigene molecular testing in patients with low, intermediate and high-risk prostate cancer, who have a life expectancy of 10 years or more (Table 6)²⁶. Indeed, an understanding of personal risk of aggressive disease may influence the patient choosing treatment instead of active surveillance.

Testing for predictive biomarkers

There is growing evidence that alterations to DNA repair genes may serve as predictive biomarkers of response to investigational treatments⁵³. The V2.2020 NCCN Guidelines for Prostate Cancer therefore recommend tumour testing for HHR gene mutations in patients with metastatic prostate cancer, and suggest to consider tumour testing for MSI or defective MMR in these patients²⁶. Tumour testing for HRR gene mutations, and MSI or defective MMR should also be considered in patients with regional disease²⁶. The ESMO Clinical Practice Guidelines for Prostate Cancer (2020) suggest to consider tumour testing for homologous recombination repair genes and mismatch repair defects in patients with metastatic castration-resistant prostate cancer (mCRPC)⁴⁸.

Visit the section on molecular diagnostics to learn more about germline and tumour testing for DNA repair gene alterations in prostate cancer.

The DNA repair section delves deep into the prevalence and the role for DNA repair genes in prostate cancer.

Management options

Multiple treatment options are available for both localised and metastatic prostate cancer disease states. Prostate cancer management involves a multidisciplinary approach to ensure the best treatment and outcome for the patient.

Multidisciplinary approach

The number and variety of treatment options for men with prostate cancer can be overwhelming for both the patient and his family. Decision making can be further complicated by the potential for poor outcomes and treatment regret⁵⁴.

Good communication between patients and the various members of the clinical team can help empower patients to commit to treatment plans⁵⁵

The European Association of Urology (2020) guidelines state that management decisions for prostate cancer should be made after all treatments have been discussed by a multidisciplinary team (Figure 9) and after the balance of benefits and side effects of each therapy modality has been considered by the patient with regard to their own individual circumstances²³.

Figure 9. Examples of members involved in the multi-disciplinary approach for prostate cancer patient management. Adapted from Murphy et al., 2019^23,56.

The specialists involved in the management of a patient with prostate cancer can include urologists, radiotherapists, oncologists, radiologists, pathologists, surgeons, clinical nurse specialists and psychologists^23,54,56. A multidisciplinary approach to cancer care has been associated with a decrease in time from diagnosis to treatment, shorter time to completion of pre-treatment consultations and improved adherence to guidelines supported by the literature^56,57.

Treatment options

Treatment options for prostate cancer vary based on disease severity and risk stratification²³. Table 7 gives a brief summary of treatment options available for the EAU risk groups and advanced disease that is based on disease severity and risk group²³. For exhaustive information on treatment guidelines, please refer to the European Association of Urologists prostate cancer guidelines (2020)²³.

Table 7. Summary of treatment options available to prostate cancer patients based on European Association of Urology (EAU) risk groups. Adapted from the EAU-ESTRO-ESUR-SIOG Guidelines on Prostate Cancer, 2020²³.

Deferred Treatment

Active surveillance and watchful waiting are conservative management strategies that aim to avoid unnecessary treatment that may lead to genitourinary adverse events (AEs) and decreased quality of life (QoL)²³.

Active surveillance aims to optimise the timing of curative intent treatment options in patients who have a life expectancy of greater than 10 years and includes an active decision not to treat the patient immediately²³. The patient remains under close surveillance using assessment markers (for example, using DRE and PSA levels), and treatment is prompted by predefined thresholds indicative of progressive disease²³.

Watchful waiting refers to symptom-guided palliative treatment that aims to minimise treatment-related toxicity²³. Watchful waiting can be considered as an option for treating patients with a limited life expectancy (< 10 years) regardless of prostate cancer stage²³.

Radical prostatectomy

Radical prostatectomy involves the removal of the entire prostate gland along with a margin of surrounding tissue⁵⁸. The procedure may be accompanied by bilateral pelvic lymph node dissection²³. Three radical prostatectomy approaches are currently used²³:

• open radical prostatectomy (RP)
• laparoscopic radical prostatectomy (LRP)
• robotic assisted laparoscopic prostatectomy (RALP).

Extended pelvic lymph node dissection (eLND) involves the removal of the lymph nodes closely associated with the prostate (overlying the external iliac artery and vein, within the obturator fossa located cranially and caudally to the obturator nerve, and nodes medial and lateral to the internal iliac artery) and provides important information for staging and prognosis²³.

Urinary incontinence and erectile dysfunction are extremely common following radical prostatectomy⁵⁹. Although generally transient, these can be long-term and risk increases significantly with increasing age⁵⁹.

Radiotherapy

Radiotherapy is an important and valid alternative to surgery alone for curative intent therapy²³. External beam radiotherapy (EBRT) and brachytherapy (internal radiotherapy) are the two treatment modalities commonly used as monotherapy or in combination with each other or androgen deprivation (hormonal therapy)^23,60.

External beam radiation therapy (EBRT) is directed at the prostate gland from outside the body to target cancer cells⁶⁰. EBRT may be used as a curative intent treatment in early stage disease, or to relieve symptoms in advanced disease⁶⁰. The use of three-dimensional conformal radiotherapy (3D-CRT) and intensity-modulated radiation therapy (IMRT) have improved the quality and precision of EBRT and allows for dose escalation⁶⁰. 3D-CRT uses imaging technologies to create a three-dimensional image of the tumour and nearby tissues and organs that is used for treatment planning to deliver concentrated radiation doses directly to the tumour whilst sparing healthy tissue⁶¹. IMRT uses multiple small radiation beams of varying intensities to precisely radiate the tumour⁶⁰. The goal of IMRT is to bend the radiation dose to avoid or reduce exposure of healthy tissue and limit the side effects of treatment^23,60.

Brachytherapy (also known as interstitial radiation) is an internal radiotherapy, which involves inserting radioactive ‘seeds’ close to the tumour cells^60,62. Either permanent or temporary radioactive source implantation can be used in brachytherapy for patients with prostate cancer⁶².

Common side effects of EBRT and brachytherapy include bowel problems, urinary problems and erectile dysfunction⁶⁰. Unlike with prostatectomy, erectile dysfunction and urinary issues may develop several years after radiation therapy⁶⁰.

Less common options for clinically localised prostate cancer

Cryotherapy and high-intensity focused ultrasound (HIFU) have been developed as minimally invasive procedures aiming to provide equivalent treatment compared to radical prostatectomy, EBRT and brachytherapy, but with reduced toxicity²³.

Hormonal therapies

Normal prostate cells are dependent on androgens such as testosterone to stimulate growth and tumour growth is similarly dependent on androgens⁶³. If tumour cells are deprived of androgenic stimulation, they undergo apoptosis (programmed cell death)⁶⁴. Hormone therapy for prostate cancer therefore aims to suppress androgen activity and is also referred to as androgen suppression therapy⁶⁵. Therapies with differing modes of action may also be combined to achieve a complete (maximal or total) androgen blockade (CAB)²³.

Androgen suppression can be achieved by⁶⁵:

• lowering testicular androgen levels
• lowering androgen levels from the adrenal glands
• stopping androgens from working

Lowering testicular androgen levels

Androgen deprivation therapy (ADT) aims to lower testicular androgen levels⁶⁵. Surgical castration remains the primary treatment modality for androgen deprivation, against which all other treatments are rated²³. It leads to a considerable decline in testosterone to castrate levels defined by testosterone levels of less than 20 ng/dL²³.

Androgen deprivation can also be achieved through ADT drugs, including luteinizing hormone-releasing hormone (LHRH) agonists and antagonists (Table 8)⁶⁵.

Table 8. Mode of the action for prostate cancer hormone therapies^18,65.

LHRH, also known as gonadotropin-releasing hormone (GnRH), is secreted by the hypothalamus and binds to its receptor in the pituitary to stimulate the release of luteinising hormone (LH) and follicle stimulating hormone (FSH)⁶⁶. These hormones trigger the release of androgens (sex-steroids) to promote growth and development of both normal and tumour cells⁶⁶. LHRH antagonists induce a state of sex steroid deprivation by competitive blockade of pituitary LHRH receptors, whereas LHRH agonists achieve a similar effect by down regulating the pituitary receptors for LHRH⁶⁷. This reduces the levels of FSH and LH, and subsequently the levels of sex steroids.

Lowering androgen levels from the adrenal glands

Adrenal glands and prostate cancer cells can also produce androgens⁶⁵. Drugs such as ketoconazole and abiraterone can block the formation of androgens made in this way⁶⁵.

Abiraterone acetate is a new hormonal agent that aims to lower androgen levels produced by the adrenal glands⁶⁵. New hormonal agents (NHA) target the androgen axis and were originally developed to treat patients who no longer respond to androgen deprivation therapy (Table 9)²³.

Table 9. Mode of action of generic new hormonal agents (NHA) that target the androgen axis for prostate cancer treatment^63,65,68,69.

Abiraterone is a CYP17 inhibitor that significantly decreases the intracellular testosterone level by suppressing CYP17-mediated androgen biosynthesis⁶³. Abiraterone acetate must be used together with the corticosteroid prednisone/prednisolone and is indicated for the treatment of metastastic prostate cancer (mCRPC) and metastatic high-risk hormone sensitive prostate cancer (mHSPC)⁷⁰.

Stopping androgens from working

Anti-androgen drugs such as flutamide, bicalutamide and nilutamide bind to androgen receptors on prostate cancer cells, thereby preventing androgen binding and signalling for growth⁶⁵.

Enzalutamide is a NHA that is an AR signalling inhibitor with a high affinity for the androgen receptor (AR)⁶³. It blocks androgen binding to AR, inhibits AR translocation to the nucleus, and impairs AR binding to DNA⁶³. Enzalutamide is indicated for the treatment of high-risk nonmetastatic castration-resistant prostate cancer (nmCRPC) and metastatic castration-resistant prostate cancer (mCRPC)⁷¹.

Both apalutamide and darolutamide are more recently approved NHAs now indicated for nmCRPC^72–75. Apalutamide in combination with ADT is additionally indicated for the treatment of metastatic hormone-sensitive prostate cancer (mHSPC)^72,74. Both apalutamide and darolutamide bind to the ligand binding domain of AR to prevent its nuclear translocation, thereby preventing DNA binding and AR-mediated transcription^68,69.

Chemotherapy

Cytotoxic chemotherapy agents such as docetaxel or cabazitaxel can delay progression and improve survival for patients with advanced prostate cancer⁷⁶. The mode of action for both docetaxel and cabazitaxel are as anti-mitotic agents^77,78. Docetaxel is indicated for mHSPC and mCRPC. Cabazitaxel is indicated as a therapy for mCRPC patients previously exposed to docetaxel^77,78.

Radium-223

Radium-223 (Ra-223) is a bone-seeking alpha particle–emitting radiopharmaceutical that mimics calcium uptake at osteoblastic lesions where it leads to DNA damage and tumour death⁷⁹. Ra-223 can be considered as a treatment option for patients with CRPC and symptomatic bone metastases²³. This targeted treatment also possesses a short tissue-penetration range that altogether allows for a low toxicity profile⁸⁰.

Bone protection therapies

The most common site for metastatic spread in prostate cancer is bone^81,82. Complications associated with this include bone pain, hypercalcaemia, fractures and spinal cord compression^81,82. Complications may be compounded further by issues with bone mineral density (BMD) due to long term use of ADT⁸³. 

Bisphosphonates such as zoledronic acid are often used to increase bone mineral density⁸¹. They do this by preventing bone breakdown by osteoclasts and can encourage osteoblast-mediated growth of new bone tissue⁸¹. Zoledronic acid is also used to prevent complications from bone metastases and to treat hypercalcaemia associated with cancer⁸⁴. Denosumab is a human monoclonal antibody that is indicated for the prevention of skeletal related events in patients with advances malignancies involving bone^83,85. Osteoclast formation, activity and survival is driven by RANKL (receptor activator of nuclear factor κB ligand)²³. Denosumab inhibits RANKL, thereby reducing osteoclast formation and bone deterioration²³.

Palliative care

Advanced prostate cancer can be a debilitating disease. A multidisciplinary approach is important for the optimal management of symptoms impacting on quality of life including pain, constipation, anorexia, nausea, fatigue and depression²³. Palliative treatments such as external beam radiation therapy (EBRT), palliative surgery and bone protection therapies may be used alone or as adjuncts to systemic therapies for advanced disease²³.

Clinical trials

The introduction of abiraterone and enzalutamide for treating metastatic CRPC signalled a paradigm shift in the management of advanced prostate cancer. Recent clinical trials on these new hormonal agents have furthermore led to approvals for abiraterone and apalutamide in mHSPC, and for enzalutamide, apalutamide and darolutamide in nonmetastatic castration resistant disease (nmCRPC)^70–72,75. Despite these advances, metastatic prostate cancer remains incurable⁸⁶. To this end, new sequences for existing treatments are being explored in clinical trials, as well as novel therapeutic compounds that may be suitable for patients who understand the risks involved in partaking in clinical trials. 

Treatment pathways

The treatment journey for patients with prostate cancer is complex and dependent on the clinical state of the disease at diagnosis and how it progresses over time⁸⁷. Multiple clinical states have been defined in prostate cancer based on the status of the primary tumour, presence or absence of detectable metastases, prior and current treatment, and serum testosterone levels (non-castrate/castrate)⁸⁸.

Broadly, prostate cancer disease states include⁸⁸:

• Localised prostate cancer
• Locally advanced prostate cancer
• Biochemically recurrent disease
• Nonmetastatic castration-resistant prostate cancer (nmCRPC)
• Metastatic hormone sensitive prostate cancer (mHSPC)
• Metastatic castration-resistant prostate cancer (mCRPC)

Metastatic prostate cancer is incurable and represents the unmet need in prostate cancer care⁸⁶. The approval of multiple life-extending treatments over the past decade has transformed the treatment landscape and ongoing clinical trials indicate that this change is set to continue⁸⁷

The evolving prostate cancer treatment landscape

Androgen receptor (AR) signalling is the primary driver of prostate cancer progression and androgen deprivation therapy (ADT) has been the backbone of care⁶³. ADT aims to lower testosterone to castration levels of <20 ng/dL which can be achieved either through surgery or using hormone therapies²³. Prostate cancers that respond to ADT are described as hormone sensitive prostate cancer (HSPC), whereas those that progress despite castrate levels of testosterone are known as castration-resistant prostate cancers (CRPC)⁸⁸.

Figure 10. Alterations in androgen signalling associated with progression to castration resistant prostate cancer (CRPC). Adapted from Attard et al., 2016⁸⁹. The key targets for the new hormonal agents are highlighted. AR, androgen receptor; ARE, androgen receptor element; CRPC, castration-resistant prostate cancer; CYP17A1, cytochrome P450 17A1; GR, growth hormone receptor; PI3K, phosphoinositide 3-kinase; PSA, prostate specific antigen; TMPRSS2-ERG, transmembrane protease, serine 2-ETS-related gene fusion.

The onset of castration resistance is complex and can involve multiple mechanisms (Figure 10). High intracellular androgen levels have been observed in CRPC cells compared to androgen sensitive cells, as well as an overexpression of the androgen receptor^23,90. This observation led to the development of new hormonal agents (NHA; for example, abiraterone and enzalutamide) that target the androgen axis, thereby providing a treatment option for patients with castration resistant disease²³. For instance, abiraterone inhibits the CYP17 enzyme that is necessary for de novo androgen synthesis whereas enzalutamide has three-fold inhibitor activity; it inhibits androgen binding to the androgen receptor, androgen entry into the nucleus and androgen receptor binding to DNA⁶³. Both abiraterone and enzalutamide were initially approved for treating mCRPC patients; however, increasing clinical trial evidence has led to approvals for their use earlier on in the patient’s treatment journey (Figure 11)^70,71. Two recently approved NHAs, apalutamide and darolutamide, are now indicated for nmCRPC^69,72,73,91. Apalutamide is also EMA and FDA approved for the treatment of mHSPC^72,74. Alternative treatments that do not target the androgen axis have also been integrated into clinical practice. They include docetaxel and cabazitaxel which are both anti-mitotic taxane chemotherapy agents^77,78.

Please refer to the European Association of Urology (EAU) and European Society for Medical Oncology (ESMO) guidelines on prostate cancer for comprehensive details on treatment options^23,48.  

Figure 11. Prostate cancer treatment journey based on changing disease states^{70–73,77,78,92,93}. Existing standard of care treatments according to ESMO and EAU guidelines^23,48. *Approved for use post-docetaxel treatment. †Indicated for patients with symptomatic bone metastases and no known visceral metastases, in progression after at least two prior lines of systemic therapy for mCRPC. ADT, androgen deprivation therapy; mHSPC, metastatic hormone-sensitive prostate cancer; mCRPC, metastatic castration-resistant prostate cancer; nmCRPC, nonmetastatic castration-resistant prostate cancer; PSA, prostate-specific antigen.

Metastatic castration-resistant prostate cancer

Metastatic castration-resistant prostate cancer (mCRPC) is currently incurable, with some improvement in overall survival since the introduction of systemic drugs compared to non-systemic treatment (2.8 years versus 2.2 years)⁹⁴. Currently, approved treatments for mCRPC include abiraterone, enzalutamide, docetaxel, cabazitaxel and radium-223^{23,48,70,71,77,78,93}. 

First-line clinical trials

The key clinical trial studies that led to the approvals for NHAs and taxanes in the first-line treatment of mCRPC are highlighted in Table 10^95–98.

Table 10. Key first-line clinical trials for metastatic castration-resistant prostate cancer (mCRPC)^95–98.

The TAX 327 clinical trial found that docetaxel in the first-line setting led to a modest increase in overall survival with adverse events including fatigue, nausea, vomiting, alopecia and diarrhoea⁹⁵. NHA in the first-line setting with either enzalutamide or abiraterone led to improvements in overall survival^96,97. Common adverse events for abiraterone were fatigue, arthralgia, peripheral oedema and hepatotoxicity whereas fatigue, back pain, arthralgia and hypertension were reported for enzalutamide^96,97.

Second-line clinical trials

In the key second-line clinical trials post-docetaxel treatment for mCRPC, improvements in overall survival were observed for mCRPC patients treated with abiraterone, enzalutamide, cabazitaxel and radium-223 (Table 11)^99–102. The most common Grade 3–4 adverse events observed for abiraterone were fatigue and anaemia⁹⁹. For enzalutamide, the most common Grade 3-4 adverse events observed included fatigue and diarrhoea, and for cabazitaxel, this was neutropenia and diarrhoea^100,101.

Table 11: Key second-line clinical trials post-docetaxel treatment for metastatic castration-resistant prostate cancer (mCRPC)^99–102.

Sequencing therapies for mCRPC

Currently, docetaxel, abiraterone and enzalutamide are used to treat mCRPC patients, both as first- and second-line therapies (Figure 11). There is currently no clear evidence for, or guidance on, the optimal treatment sequence for mCRPC. Alternate sequential treatment for enzalutamide and abiraterone shows limited additional benefit as indicated by modest differences in overall PSA responses, though abiraterone followed by enzalutamide may be slightly better^103,104. In the Phase III CARD trial, cabazitaxel was compared with NHA treatment (abiraterone or enzalutamide) in mCRPC patients previously treated with docetaxel who progressed ≤12 months while receiving the alternative NHA¹⁰⁵. This trial found that these patients had longer progression-free and overall survival when treated with cabazitaxel than when treated with the alternative NHA¹⁰⁵. 

A key issue that complicates sequencing of treatments is the possibility of intra cross-resistance (resistance shared between agents in the same class of drug) and inter cross-resistance (between agents in different classes)¹⁰⁶. For the latter, there is some evidence that docetaxel may have reduced efficacy when given following NHA treatments; however, more evidence is needed to better understand cross-resistance¹⁰³.

Nonmetastatic castration-resistant prostate cancer (nmCRPC)

It is customary practice to continue using androgen deprivation therapy (ADT) to treat nmCRPC, despite the onset of castration resistance¹⁰⁷. Three recent Phase III double-blind studies (SPARTAN, PROSPER and ARAMIS) investigated the use of new hormonal agents in nmCRPC (Table 12)^69,91,108. In these studies, ADT alone was compared to ADT plus apalutamide (SPARTAN), enzalutamide (PROSPER) or darolutamide (ARAMIS). Altogether the findings indicate that all three NHAs significantly increased metastasis-free survival (MFS) and median overall survival (final endpoint not yet reached in ARAMIS) with tolerable side effects^{69,91,108–111}. These findings have led to FDA and EMA approvals for apalutamide, enzalutamide and daroluatmide in nmCRPC^71–75,112.

Table 12. Key clinical trials for nonmetastatic castration-resistant prostate cancer (nmCRPC)^{69,91,108–111}.

Metastatic hormone sensitive prostate cancer (mHSPC)

Most mHSPC patients respond to the standard of care therapy, ADT; however, the majority will progress to mCRPC after 2–3 years¹¹³. Progression to metastatic disease most commonly follows biochemical recurrence; however, diagnosis of de novo mHSPC is also increasing, which is partly due to improved imaging and reduced PSA screening¹¹⁴. To date, there have been multiple clinical trials to assess agents used in the mCRPC setting for mHSPC (Table 13). This has led to recent approvals of alternative treatments for mHSPC, including docetaxel, abiraterone and apalutamide^70,72,78. Of note, de novo mHSPC patients tend to have a worse outcome compared to mHSPC patients who progress from localised or locally advanced disease¹¹⁵.

Table 13: Key clinical trials for metastatic hormone sensitive prostate cancer (mHSPC)^116–121.

Docetaxel

Three clinical trials have compared docetaxel plus ADT to ADT alone in mHSPC patients (Table 13)^116,117,120. The GETUG-AFU-15 study identified no significant difference in overall survival when docetaxel was added to ADT treatment compared to ADT alone¹¹⁶. However, the multi-stage STAMPEDE trial identified some benefit of docetaxel addition to ADT treatment for all patients, whereas the later Phase III study (CHAARTED) identified a benefit only in mHSPC patients who presented with high volume disease (51.2 months versus 34.4 months)^117,120. A follow-up report on STAMPEDE showed no difference based on metastatic burden as defined by the CHAARTED study¹²². A possible explanation for the difference in outcome between the two studies relate to differences in patient selection. Approximately 95% of patients enrolled on to the STAMPEDE trial had de novo mHSPC, versus only 25% of patients enrolled on the CHAARTED trial¹²². Based on these findings of the clinical trials, docetaxel is now approved for mHSPC⁷⁸. Adverse events were found to be consistently higher in patients receiving docetaxel compared to those treated with ADT throughout the studies^116,117,120.

New Hormonal Agents (NHAs)

In the STAMPEDE Phase III clinical trial, abiraterone in combination with prednisolone and ADT had a 3-year survival of 83% compared to 76% for mHSPC patients treated with ADT¹¹⁹. In the LATITUDE study, the likelihood of survival significantly improved by 38% when abiraterone and prednisone were added to ADT versus ADT alone¹¹⁸. Based on these findings, abiraterone with prednisone is now approved for mHSPC⁷⁰.

Apalutamide has also shown significant increases in overall survival and radiographic progression compared to ADT treatment alone for mHSPC in a Phase III double-blind clinical trial (Table 13)¹²¹. These findings have led to recent FDA and EMA approvals for apalutamide for mHSPC^71,72.

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