Tala Elremmash
Glossary: Brachytherapy, BRCA genes, Digital Rectal Examination (DRE), External Beam Radiation Therapy (EBRT), ExoDx Prostate (EPI), 68Ga-PSMA-11, Gleason Score, High Intensity Focused Ultrasound (HIFU), Intensity Modulated Radiation Therapy (IMRT), 4Kscore Test, Multiparametric Magnetic Resonance Imaging (mpMRI), PCA3, Prostatic Intraepithelial Neoplasia (PIN), Prostate-Specific Antigen (PSA), Prostate-specific Membrane Antigen Positron Emission Tomography (PSMA-PET), Stereotactic ablative radiotherapy (SBRT), SelectMDx Test, TNM
Abbreviations: Adoptive Cellular Immunotherapy (ACT); American Joint Committee on Cancer (AJCC); Antigen Presenting Cell (APC); Atypical Small Acinar Proliferation (ASAP); Chimeric Antigen Receptor T cell (CAR-T);Committee for Medicinal Products (CHMP); Cambridge Prognostic Groups (CPG); Digital Rectal Exam (DRE); External Beam Radiotherapy (EBRT); Food and Drug Administration (FDA); Gonadotrophin-releasing hormone (GnRH); High Intensity Focused Ultrasound (HIFU); Homologous Recombinant Repair (HRR); Intensity Modulated Radiation Therapy (IMRT); Low-dose rate (LDR); Luteinizing Hormone-Releasing Hormone (LHRH); Medicine and Healthcare products Regulatory Agency (MHRA); Multiparametric Magnetic Resonance Imaging (mpMRI); National Comprehensive Cancer Network (NCCN); Prostatic Acid Phosphatase (PAP);Programmed Cell Death (PD-1); Prostate Health Index (PHI); Proliferative Inflammatory Atrophy (PIA); Prostatic Intraepithelial Neoplasia (PIN); poly ADP-Ribose Polymerase (PARP); Prostate-specific Antigen (PSA); Prostate Screening EpiSwitch (PSE); Prostate-specific Membrane Antigen Positron Emission Tomography (PSMA-PET); Stereotactic ablative radiotherapy (SBRT); Transrectal Ultrasound (TRUS)
Introduction
Prostate cancer is a globally significant disease that affects men of all ethnicities. The prevalence of prostate cancer is higher in older men and in those with previous family history of the disease. Over the years, various screening and diagnosing approaches have become available for the early detection of prostate cancer. The digital rectal examination (DRE), prostate-specific antigen (PSA) test, multiparametric MRIs, and prostate biopsies are the most commonly used tests for confirming the presence of the disease. Combining these tests enables physicians to grade the cancer according to the appearance of biopsied cells under a microscope and to stage the cancer according to its size. This information helps doctors to determine the most appropriate treatment for each patient. Some of the currently available treatment alternatives include surgery, radiotherapy, and chemotherapy.
What is the prostate gland?
The prostate gland is a walnut-sized gland that is located in front of the rectum and below the bladder (Figure 1). The urethra, which is responsible for urine excretion, passes from the bladder through the prostate gland and the penis. The prostate gland contributes to the production of semen by secreting fluids (together with the seminal vesicles) into the urethra during ejaculation for the protection and nourishment of sperm cells [1].
Figure 1 Anatomy of male reproductive system
The structure of the male reproductive system consists of the prostate gland, seminal vesicle, bladder, and urethra, testes, and epididymis. Sperm are mainly produced in the testes and their maturation is supported by the surrounding epididymis. The prostate gland and seminal vesicles release fluids that are mixed with sperm released from the testes. The urethra is responsible for secreting the seminal fluid out of the body during ejaculation.
What is prostate cancer?
Cancers are characterized by the uncontrolled growth of cells anywhere in the body. Some cancer cells may exhibit the ability to spread from their original site to other organs and tissues, in a process known as metastasis. Prostate cancer is thought to be the most prevalent non-skin cancer among men globally [2]. It is a clinically heterogenous disease, meaning that different patients can have different clinical presentations. Prostate cancer can be either localized indolent (only inside the prostate gland), locally advanced (cancer spread to nearby tissues), or fatal metastatic disease, where the cancer has spread to other parts of the body such as the bones [3]. Prostate cancer is considered to be the second leading cause of cancer deaths in men in the UK [4] and the US [2] after lung cancer.
Symptoms, risk factors, and prevention
During the early stages of prostate cancer, there may not be any apparent signs or symptoms. The symptoms that are observed in patients with more advanced prostate cancers include the frequent need to urinate (especially at night), difficult and painful urination, blood in urine or semen, erectile dysfunction and painful ejaculation, and feeling that the bladder has not emptied fully. It should be kept in mind that these symptoms are not specific to only prostate cancer and may be present in other medical conditions [5, 6].
The chance of experiencing one or more of these symptoms and of developing prostate cancer increases as men age, especially after the age 50 [7]. The risk of contracting prostate cancer has also been observed to increase in men with African ancestry, familial history of prostate cancer [7, 8], and lifestyle factors such as obesity [9]. As most of these risk factors are difficult or impossible to control, there are no known preventative measures against prostate cancer. However, adopting a healthy diet and lifestyles can help to reduce the chance of high-risk patients developing prostate cancer [10, 11].
Screening tests
Digital Rectal Exam (DRE)
This exam requires the Doctor to insert a gloved finger into the rectum and examine the prostate (as well as its surroundings) for any abnormal signs, such as lumps, hard areas, or anything that seems unusual. Abnormal findings may be due to health problems other than prostate cancer, such as colorectal cancer, an abscess in the anal/rectal region, hemorrhoids, or bleeding in the digestive tract [12].
Prostate-specific Antigen (PSA) test
PSA is a protein that is secreted by the prostate gland. PSA levels can become elevated after performing vigorous exercise, but can also indicate the presence of abnormal prostate conditions, including prostate cancer [4]. In 1994, the US Food and Drug Administration approved the use of PSA screening test for the early detection of prostate cancer and recommended that patients with PSA serum levels ≥4 nanograms per milliliter (ng/ml) be referred for biopsies [13].
Diagnostic tests
Multiparametric Magnetic Resonance Imaging (mpMRI)
Multiparametric Magnetic Resonance Imaging (mpMRI) is an advanced type of magnetic resonance imaging (MRI) that combines two anatomical and two functional images of the prostate, creating more detailed prostate images than the ones that are produced using standard MRI [14]. Gadolinium-based contrast agents (GBCA) are intravenous drugs that are used to improve the quality of mpMRI images by changing the contrast of the MRI scans, thereby enhancing the quality of the images [15, 16]. It also improves the visibility of the images, allowing doctors to determine whether a biopsy may be required for further diagnosis [17].
Prostate Biopsies
A prostate biopsy involves taking small samples from the prostate tissue using a thin needle. The samples are viewed under a microscope, and the images obtained are used to determine the stage and grade of the cancer. The biopsy results may also indicate how aggressive the cancer is and whether it has spread to nearby tissues. The two types of prostate biopsies (Figure 2) are the transrectal ultrasound (TRUS)-guided biopsy (sample obtained by inserting the needle through the rectum) and transperineal biopsy (samples obtained by inserting the needle through the perineum) [18].
Figure 2 Types of Prostate Biopsies A TRUS-guided biopsy requires the passing of a biopsy needle through the rectum into the prostate, while a transperineal biopsy is done by passing the needle through the perineal skin into the prostate. Both methods are guided using an ultrasound [19].
Prostate-specific Membrane Antigen (PSMA)-Positron Emission Tomography (PET) test
Prostate-specific Membrane Antigen (PSMA) is a membrane glycoprotein that is overexpressed on the surface of prostate cancer cells [20]. Following intravenous injection of 68Ga-PSMA-11, it binds to prostate cancer cells. This allows the cancer cells to be visualized using a Positron Emission Tomography (PET) scan. The 68Ga-PSMA-11 PET scan is approved for clinical diagnosis of prostate cancer by the Medicine and Healthcare products Regulatory Agency (MHRA) in the UK, the Food and Drug Administration (FDA) in the US, and the Committee for Medicinal Products for Human Use (CHMP) in Europe [21]. Current uses of a PSMA PET test include intraprostatic localization of cancer cells, primary staging, and recurrence of cancer following therapy [20].
Grading system of prostate cancer
Following the diagnosis of prostate cancer from a biopsy, the cancer is graded based on the appearance of the cells under a microscope. The higher the grade, the more abnormal and aggressive the cancer is and the more likely it is to spread. The main prostate cancer grading systems that are used currently are described below.
Gleason score – This is the most common global prostate cancer grading system. A score on a scale of 3 to 5 is assigned according to the main pattern of cellular growth from two different locations in a prostate biopsy sample. The scores from both regions are then added together in order to arrive at an overall score between 6 and 10. A prostate cancer with a Gleason score of 6 is low-grade, 7 is medium-grade, and 8, 9, and 10 are high-grade (Table 1) [22].Grade groups – Recently, it has been concluded that Gleason scores may not be sufficiently descriptive of the cancer grade. This is because prostate cancer outcomes can be divided into more groups than the previously mentioned grades (low, medium, and high). Furthermore, Gleason scores may be misleading in some cases, as a patient with a Gleason score of 6 may assume that their cancer is advanced and that it will spread quickly, and this is likely to affect their treatment decisions. For this reason, Grade Groups have been developed (Table 1). A biopsy pathology report may include Gleason scores, Grade Groups, or both [23].
| Gleason Score | Grade Group | Cancer Grade | Other Comments |
| Gleason 6 or less | Group 1 | – | Gleason score cannot be determined – These scores are discarded |
| Gleason 3+ 4= 7 | Group 2 | Low-grade | Well-differentiated cells (resembling healthy cells) |
| Gleason 4+ 3= 7 | Group 3 | Medium grade | Moderately differentiated cells (somewhat similar to healthy cells) |
| Gleason 8 | Group 4 | High-grade | Poorly differentiated or undifferentiated cells that are very different from healthy cells |
| Gleason 9 and 10 | Group 5 | High-grade | Poorly differentiated or undifferentiated cells that are very different from healthy cells |
Table 1 Prostate Cancer Grading Systems A description of the Gleason score system and grade groups used to grade patients’ prostate cancer. Gleason scores below 6 or grade group 1 are disregarded, while scores above 6 are classified into low, medium, and high-grade groups [24].
Staging system of prostate cancer
A widely used staging system for determining the size and spread of prostate cancer is the American Joint Committee on Cancer (AJCC) TNM system. This system requires answering the following question:
- What is the size and location of the primary Tumor?
- Has the tumor spread to the nearby Lymph Nodes?
- Did the tumor spread/Metastasize to other parts of the body?
The answers to the above questions, the PSA level at the time of diagnosis, and Gleason score/grade group are combined to describe the type of cancer. Therefore, prostate cancer is classified as TNM stage I if the cancer is too small, stage II if the cancer is completely localized in the prostate, stage III if the cancer breaks through the prostatic capsule, and stage IV if the cancer has metastasized into nearby organs.
Current treatments for prostate cancer
Surgery
A Radical Prostatectomy is a surgical procedure to remove the entire prostate gland and seminal vesicles (nearby lymph nodes may be removed) in cases where the cancer is localized in the prostate gland and has not spread yet. The different current surgical approaches include open radical prostatectomy, Laparoscope radical prostatectomy, and robot-assisted radical prostatectomy [25, 26].
External Beam Radiotherapy (EBRT)
External beam radiotherapy (EBRT) causes damage to DNA within the nuclei of prostate cancer cells, inhibiting their growth and preventing their spread. This is achieved by directing high-energy photon beams (a type of X-rays), proton beams, or electron beams to the specific area where the tumor is located without the need to carry out any invasive procedures. EBRT is recommended for patients for whom a radical prostatectomy is not possible [27]. Some of the variations of EBRT available globally include Stereotactic Body Radiation Therapy (SBRT) and Intensity Modulated Radiation Therapy (IMRT) [28, 29].
The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London, recently performed a randomized trial (PACE-A) comparing the long-term side effects of SBRT and surgery. Their results were presented in the 2023 ASCO Genitourinary Cancers Symposium, reporting that patients treated with 20 sessions of SBRT carried out on CyberKnife® robotic radiation delivery system, over a period of four weeks are less likely to suffer from incontinence and impotence compared to prostate cancer patients treated surgically. “It’s great to see that using SBRT for early-stage prostate cancer can help people avoid sexual and urinary side effects that are commonly associated with surgery, and I hope these findings will help men decide, with their clinician, the best course of treatment for them”, says Professor Emma Hall who is managing the PACE-A trial [30].
Brachytherapy
According to the guidelines of the American Brachytherapy Society and the European Urologic Association, brachytherapy is a type of internal radiotherapy that can be used for treating all types of prostate cancer [31]. Low-dose rate (LDR) brachytherapy, also known as permanent seed brachytherapy, is a type of radiotherapy in which small radioactive metal (Iodine-125 or Palladium-103) seeds, each the size of a grain of rice, are surgically implanted into the prostate gland where they release photon beam radiation directly into the cancer cells destroying them with minimal effects on nearby healthy cells [32].
Hormone therapy
Testosterone is an androgen hormone that can increase the growth rate and development of prostate cancer cells. Hormone therapy (also called androgen deprivation therapy) decreases testosterone levels or activity, leading to the reduction of many of the symptoms of low-grade prostate cancer as well as shrinkage of the prostate tumor. Hormone therapy is usually recommended for localized prostate cancers and is combined with other treatments, including EBRT, brachytherapy, and High-intensity focused ultrasound (HIFU). Hormone therapy may also be used to treat locally advanced prostate cancers, advanced (metastatic) prostate cancer, and recurrent prostate cancer. Currently available hormone therapies include injections/ implants [33], tablets [34], and orchidectomy (surgical removal of the testicles) [33].
Chemotherapy
The use of drugs to inhibit the growth and development of cancer cells by destroying them is referred to as chemotherapy. Chemotherapy may be recommended for the treatment of advanced and castration-resistant prostate cancers. The standard chemotherapy regimen is to administer Docetaxel®, a chemotherapeutic drug that leads to the death of prostate cancer cells. Cabazitaxel® is another chemotherapeutic drug that was approved by the US FDA in 2010 for clinical use for the treatment of Docetaxel-resistant prostate cancers [35].
Focal therapy
High-intensity focused ultrasound (HIFU) is a type of focal therapy that uses high-frequency ultrasound energy to destroy prostate cancer cells. Although HIFU has been approved by FDA for use in the US in 2015 [36], it remains a relatively new approach for treating prostate cancer. Therefore, it is currently only available at a few specialist clinics or clinical trials being conducted in the UK [37]. Cryotherapy, which is also referred to as cryosurgery or cryoablation, is an alternative type of focal therapy that involves the freezing of prostate cancer cells in order to destroy them. Similarly to HIFU, cryotherapy is only available at specialized clinics or clinical trials in the UK, [38] but was approved for clinical use in the US as of January, 2018 [36].
Medical advances in prostate cancer research
New prostate cancer screening & early detection approaches
Due to the limitations of PSA screening tests to differentiate between prostate cancer and non-cancerous prostate abnormalities, further screening may be required for better diagnosis of clinically significant prostate cancers. Accordingly, new prostate-specific biomarkers are being discovered. For instance, the PCA3 is a non-coding RNA biomarker that is overexpressed by prostate cancer cells. Elevated levels of PCA3 RNA in urine following a DRE test may indicate the presence of prostate cancer and the urgency of performing a prostate biopsy for further confirmation. The Progensa® PCA3 Assay was been approved for clinical use by the US FDA in February, 2012 [39].
The National Comprehensive Cancer Network (NCCN) approved SelectMDx biomarker test is another simple urine-based test that measures the levels of prostate cancer biomarkers (other than PCA3), including HOXC6 and DLX1 genes [38]. It provides another reliable, non-invasive predictive method for detecting prostate cancer and its aggressiveness. The results are clinically correlated with factors including age, DRE test findings, previous biopsy results, and family history [40]. This test is starting to become more widely available in the UK due to its high predictive accuracy and its benefits with regards to avoiding unnecessary biopsies [41, 42]
Another non-invasive, simple urine test for identifying clinically significant prostate cancers is the ExoDx Prostate (EPI) test. An EPI test is capable of isolating and measuring levels of exosomes in urine, which are small vesicles containing PCA3, ERG, and SPDEF biomarkers shed from prostate cancer cells. Accordingly, without the need to perform a DRE test, an EPI test enables the determination of a patient’s risk of having a clinically significant prostate cancer and potentially reducing the conduction of unnecessary prostate biopsies [43].
Protein biomarkers other than PSA have also been targeted as indicators of aggressive prostate cancers and were combined in a simple blood 4Kscore test that was approved by the US FDA in December 2021 [44]. The 4Kscore test measures the levels of four proteins (total PSA, free PSA, bound PSA, and kallikrein 2) and correlates the findings with age, DRE test, and previous biopsy results [45].
Prostate Health Index (PHI) is another simple blood test that was approved by the US FDA in 2012 [45]. The PHI test uses a mathematical formula by combining the values of the total PSA, free PSA, and proPSA in the serum to calculate a PHI score. This score may be used for detecting prostate cancer by differentiating whether the elevated levels of PSA in the serum are due to cancerous or benign prostate gland abnormalities. Despite its approval, the European Association of Urology and the American Urological Association suggest that further data is essential for confirming the reliability of the PHI screening tests for detecting prostate cancer [46].
Pylarify® (Piflufolastat F 18), is a new radioactive drug agent approved by the US FDA for use in PSMA-PET tests to detect prostate cancers. It is anticipated that the Pylarify test will become more available than the 68Ga-PSMA-11 tests. Similar to 68Ga-PSMA-11, Pylarify is injected intravenously and binds to PSMA. It then emits positrons, enabling PET imaging to detect the presence of PSMA-positive prostate cancer cells [47].
A new 94% accurate Prostate Screening EpiSwitch (PSE) blood test for detecting prostate cancer was developed recently by researchers at Oxford Biodynamics, University of East Anglia, Imperial College London, and Imperial College NHS Trust. Their PSE test combines the traditional PSA test with an epigenetic (EpiSwitch) test. Professor Dmitry Pshezhetskiy from the University of East Anglia commented, “When tested in the context of screening a population at risk, the PSE test yields a rapid and minimally invasive prostate cancer diagnosis with impressive performance. This suggests a real benefit for both diagnostic and screening purposes.” [48].
New prostate cancer treatments
Hormone Therapy
Despite the availability of numerous treatments for prostate cancer, it is necessary to continue to develop new approaches for treatment. This is because some of the currently available treatments are not effective in certain patients. The androgen receptor blocker, Enzalutamide (Xtandi), blocks testosterone from reaching the prostate gland, thereby inhibiting further growth and development of prostate cancer. Enzalutamide was first approved by the US FDA in 2012, for the treatment of prostate cancers that fail to respond to hormone therapies, but that have not metastasized. These are also known as castration-resistant prostate cancers. In 2019, this drug was further approved for clinical use for patients with metastatic castration-sensitive prostate cancer [49].
Abiraterone (Zytiga) is another hormone therapeutic that blocks testosterone production [50]. It was approved by the US FDA in 2011 for clinical use in the treatment of castration-resistant prostate cancer. However, following the LATITUDE-controlled international clinical trial, Abiraterone’s clinical usage approval was expanded to include the treatment of metastatic high-risk castration-sensitive prostate cancer [51]. Similarly, based on the results of the ARASENS clinical trial, it was concluded at the 2022 Genitourinary Cancers Symposium that the androgen receptor blocker drug, Darulotamide (Nubeqa), should be implemented as a standard therapy for treating metastatic hormone-sensitive prostate cancers [52]. Darulotamide was later approved for clinical use by the US FDA in August 2022 for use in combination with Docetaxel to improve the survival of patients with metastatic hormone-sensitive prostate cancers [53].
Targeted Radiotherapy
As of March 2022, the US FDA approved Pluvicto™ (Lutetium-177-PSMA-617) as a new promising pharmaceutical for treating patients with PSMA-positive castration-resistant prostate cancers [54]. The results of the Vision clinical trial, which was published in The New England Journal of Medicine, showed that Pluvicto slows the progression and further development of prostate cancer [55]. Its mode of action (Figure 3) relies on identifying and binding to PSMA-expressing prostate cancer cells, entering the cells, and releasing radiation that would result in damaging and killing the cells [56].
Figure 3 PluvictoTM mechanism of action PSMA proteins are overexpressed on the surface of prostate cancer cells. Using its PSMA617 ligand, Pluvicto targets PSMA proteins. Once bound, Pluvicto is internalized by the PSMA-positive cancer cells. There, it releases its Lutetium-177 cytotoxic radionuclide, which emits radiation within the cell, thereby inducing DNA damage that leads to the death of the cancer cell [57]. Figure created with BioRender.com
Immunotherapy Vaccines
Scientists are also developing novel immunotherapies that aid the immune system in destroying cancer cells. In 2010, the Provenge® (Sipuleucel-T) vaccine became the first and only prostate cancer vaccine to be approved for clinical use by the US FDA and is currently only available in the US [58]. Provenge is an active immunotherapeutic vaccine that induces a patient’s immune system to target cancer cells for treating metastatic hormone-resistant prostate cancer. It does so by filtering out the patient’s immune cells, engineering the cells to target the cancer cells, and reinfusing them back into the patient (Figure 4). The engineered immune cells are able to target and destroy the prostate cancer cells [59]. Another immunotherapeutic vaccine that is currently undergoing phase III clinical trials is the Prostvac-VF vaccine [60]. It is a viral vector vaccine that contains a benign virus that has been engineered to encode and produce PSA. Prostvac-VF initiates an immune response that leads to the destruction of PSA and viral proteins, which subsequently destroys the PSA-secreting virus and any PSA-secreting tumor cells [61].
Figure 4 Provenge® active immunotherapeutic vaccine mechanism of action Provenge immunotherapy vaccine is produced by collecting blood from a prostate cancer patient and then isolating immune cells from that blood using a leukapheresis machine. The patient’s immune cells, (mainly antigen presenting cells (APCs), are isolated and incubated with the prostatic acid phosphatase (PAP) antigen. Following intracellular uptake of PAP, the antigen is expressed by APCs and these PAP-expressing cells are subsequently collected and infused into the patient. The modified PAP-expressing APCs can activate T-cells, mediating the destruction of prostate cancer cells thereby eliminating them from the body [62] Figure created with BioRender.com
Immunotherapy: Immune checkpoint inhibitors
Prostate cancer is a solid tumor that is described as a “cold” tumor which is surrounded by cells that fail to elicit a T-cell (a type of immune cells) response, thereby inhibiting the detection and clearance of tumor cells [63]. For this reason, many unsuccessful clinical trials have reported prostate cancer failing to respond to immune checkpoint inhibitor therapies. However, a recent research has identified Keytruda® (Pembrolizumab) as a new immune checkpoint inhibitor that is effective in treating various adult and childhood solid cancers. In 2017, the US FDA granted approval for the application of Pembrolizumab to treat metastatic and unresectable solid tumors. However, Pembrolizumab does not have a prostate cancer-specific FDA approval yet [64]. As an immune checkpoint inhibitor, Pembrolizumab activates a patient’s immune response by binding to programmed cell death (PD-1) receptors on the surface of T-cells, inhibiting their interaction with their corresponding ligands (PD-1L and PD-2L). This results in initiating an immune response where T-cells are activated and can identify and destroy tumor cells (Figure 5) [65]. Pembrolizumab is approved for clinical use in advanced prostate cancer treatment making it a promising new option for immunotherapy.
Figure 5 Pembrolizumab immune checkpoint inhibitor activity The interaction between PD-1L on the surface of cancer cells and PD-1 receptors on T cells results in the deactivation of T cells, preventing them from attacking and killing the cancer cells. The immune checkpoint inhibitor Pembrolizumab, blocks the PD-1 receptor expressed by T cells from interacting with PD-1L on cancer cells, meaning that T cells are able to elicit an immune response leading to the destruction of the cancer cells [66]. Figure created with BioRender.com
Immunotherapy: Chimeric Antigen Receptor T cell (CAR-T) therapy
The Chimeric Antigen Receptor T cell (CAR-T) therapy is a type of Adoptive Cellular Immunotherapy (ACT) that elicits an immune response targeting specific tumor cells using genetically engineered T-cells. The success of CAR-T therapy over the last few years in treating hematological malignancies has encouraged investigations of its application to solid tumors, including prostate cancer. Current research focuses on genetically modifying T-cells to target prostate-specific tumor-associated antigens such as PSA and PSMA [67].
Poly (ADP-Ribose) Polymerase (PARP) inhibitors
A number of different genetic alterations have been detected in prostate cancer patients. The Homologous Recombinant Repair (HRR) genes, including BRCA1 and BRCA2, are commonly mutated in metastatic castration-resistant prostate cancers. These genes normally function in repairing damaged double-stranded DNA, thereby when mutated, the tumor cells fail to repair the damaged DNA and would most likely die [68]. However, prostate cancer cells can overcome this by expressing the poly (ADP-Ribose) Polymerase (PARP) enzyme to repair the damaged DNA and ensure their survival [69].
Lynparza® (Olaparib) and Rubraca® (Rucaparib) are PARP inhibitors that were approved by the US FDA in 2020 for treating patients with HRR-mutated castration-resistant cancer patients who stopped responding to hormone therapy [70]. In the UK, Olaparib is currently only available for use in Scotland [71]. These novel therapeutics act by inhibiting the PARP enzyme from repairing damaged DNA in tumor cells, thereby leading to their death (Figure 6) [72].
Figure 6 Poly (ADP-Ribose) Polymerase (PARP) inhibitor for treatment of prostate cancer Prostate cancer cells with single-stranded DNA breaks can continue to survive by repairing DNA damage using PARP proteins. A PARP inhibitor can be used to block the interaction of PARP proteins with damaged DNA, thereby inhibiting its repair, and leading to the death of the cancer cells [72]. Figure created with BioRender.com
Conclusion
Despite the development of new diagnostic methods and treatments, prostate cancer continues to be a global public health issue affecting males from different backgrounds. In fact, it is the second leading cause of cancer-related morbidities and mortalities in both the US and the UK. Since its approval for early detection in 1994, PSA tests remain as the primary screening component for prostate cancer. However, as a result of its inability to differentiate between non-cancerous and cancerous abnormal prostate conditions, novel research has discovered new prostate cancer screening and detection approaches. These include the 68Ga-PSMA-11 tests, 4Kscore tests, and PHI tests. These are becoming more available globally due to their high predictive accuracy and benefits with regard to avoiding unnecessary biopsies. Once detected, further diagnostic tests must be performed to classify prostate cancer patients into different risk groups by grading and staging the cancer according to the cellular morphologies and metastatic status. The most commonly used grading and staging systems are the Gleason scores and TNM systems, respectively. Current treatments for prostate cancer include surgical prostatectomy, radiation therapy, chemotherapy, hormonal therapy, and focal therapy. Due to the heterogeneous nature of prostate cancer and observed resistance to current treatments, continued research into the development of more personalized and targeted prostate cancer treatment alternatives is still very much needed.
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Useful Links
Guides
1. Prostate Cancer Guide
2. What is Prostate Cancer?
3. Prostate Cancer-Patient Version
4. Mayo Clinic Explains Prostate Cancer
5. Prostate Cancer Treatment
6. Understanding your Prostate Cancer
Charities
1. Cancer Research UK
2. Prostate Cancer UK
3. American Cancer Society
4. Prostate Cancer Foundation
Clinical Trials that are currently recruiting: Screening & Diagnosis
1. PRISMA-PET Primary Staging of Prostate Cancer with PSMA
2. 68Ga-PSMA PET-CT scan for Diagnosis and Management of Prostate Cancer
3. Early Detection of Prostate Cancer (PROLIPSY)
4. UK Genetic Prostate Cancer Study: Epidemiology and Molecular Genetics Studies (UKGPCS)
5. The BARCODE 1 Study (Full Study): The Use of Genetic Profiling to Guide Prostate Cancer Targeted Screening
Clinical Trials that are currently recruiting: Treatment
1. A Pilot Study of 68-Ga PSMA 11 PET/MRI and 68-Ga RM2 PET/MRI for Evaluation of Prostate Cancer Response to HIFU or HDR Therapy
2. Hyperfractioned Image Guided Proton Therapy For Low and Intermediate Risk Prostate Cancer
3. Randomized Trial of Five or Two MRI-Guided Adaptive Radiotherapy Treatments for Prostate Cancer (FORT)
4. Safety of Prodencel in the Treatment of Metastatic Castration-resistant Prostate Cancer
5. Fluzoparib and Abiraterone in the preSurgery Treatment of Prostate Cancer: FAST Trial
6. Additional Treatments to Local Tumour for Metastatic Prostate Cancer: Assessment of Novel Treatment Algorithms (IP2-ATLANTA)
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