systematic literature review of prostate cancer

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Prostate Cancer Review: Genetics, Diagnosis, Treatment Options, and Alternative Approaches

Mamello sekhoacha.

1 Department of Pharmacology, University of the Free State, Bloemfontein 9300, South Africa

Keamogetswe Riet

2 Department of Health Sciences, Central University of Technology, Bloemfontein 9300, South Africa

Paballo Motloung

Lemohang gumenku, ayodeji adegoke.

3 Cancer Research and Molecular Biology Laboratories, Department of Biochemistry, College of Medicine, University of Ibadan, Ibadan 200005, Nigeria

Samson Mashele

Associated data.

Information was available in the public domain. Databases have been provided in Section 2 .

Simple Summary

Prostate cancer affects men of all racial and ethnic groups and leads to higher rates of mortality in those belonging to a lower socioeconomic status due to late detection of the disease. There is growing evidence that suggests the contribution of an individual’s genetic profile to prostate cancer. Currently used prostate cancer treatments have serious adverse effects; therefore, new research is focusing on alternative treatment options such as the use of genetic biomarkers for targeted gene therapy, nanotechnology for controlled targeted treatment, and further exploring medicinal plants for new anticancer agents. In this review, we describe the recent advances in prostate cancer research.

Prostate cancer is one of the malignancies that affects men and significantly contributes to increased mortality rates in men globally. Patients affected with prostate cancer present with either a localized or advanced disease. In this review, we aim to provide a holistic overview of prostate cancer, including the diagnosis of the disease, mutations leading to the onset and progression of the disease, and treatment options. Prostate cancer diagnoses include a digital rectal examination, prostate-specific antigen analysis, and prostate biopsies. Mutations in certain genes are linked to the onset, progression, and metastasis of the cancer. Treatment for localized prostate cancer encompasses active surveillance, ablative radiotherapy, and radical prostatectomy. Men who relapse or present metastatic prostate cancer receive androgen deprivation therapy (ADT), salvage radiotherapy, and chemotherapy. Currently, available treatment options are more effective when used as combination therapy; however, despite available treatment options, prostate cancer remains to be incurable. There has been ongoing research on finding and identifying other treatment approaches such as the use of traditional medicine, the application of nanotechnologies, and gene therapy to combat prostate cancer, drug resistance, as well as to reduce the adverse effects that come with current treatment options. In this article, we summarize the genes involved in prostate cancer, available treatment options, and current research on alternative treatment options.

1. Introduction

Prostate cancer affects middle-aged men between the ages of 45 and 60 and is the highest cause of cancer-associated mortalities in Western countries [ 1 ]. Many men with prostate cancer are diagnosed by prostate biopsy and analysis, prostate-specific antigen (PSA) testing, digital rectal examination, magnetic resonance imaging (MRI), or health screening. The risk factors related to prostate cancer include family risk, ethnicity, age, obesity, and other environmental factors. Prostate cancer is a heterogeneous disease both on the basis of epidemiology and genetics. The interplay among genetics, environmental influences, and social influences causes race-specific prostate cancer survival rate estimates to decrease, and thus, results in differences observed in the epidemiology of prostate cancer in different countries [ 2 ]. There is documented proof of a genetic contribution to prostate cancer. Hereditary prostate cancer and a genetic component predisposition to prostate cancer have been studied for years. One of the most predisposing genetic risk factors for prostate cancer is family inheritance. Twin studies and epidemiological studies have both proven the role of hereditary prostate cancer [ 3 ]. Many researchers have looked into the possible role of genetic variation in androgen biosynthesis and metabolism, as well as the role of androgens [ 4 , 5 ]. Genomics research has identified molecular processes that result in certain cancer developments, such as chromosomal rearrangements [ 2 ].

In general, gene mutations are a prevalent cause of cancer. Candidate genes for prostate cancer predisposition are genes that partake in the androgen pathway and metabolism of testosterone. The development of prostate epithelium and prostate cancer cells relies on the androgen receptor signaling pathway and testosterone [ 6 ]. The identification of cancer biomarkers and targeting of specific genetic mutations can be used for targeted treatment of prostate cancer. Biomarkers that can be used for targeted treatment are DNA tumor biomarkers, DNA biomarkers, and general biomarkers [ 7 ].

Prostate cancer can either be classified as androgen sensitive or androgen insensitive, which is an indicator of testosterone stimulation and the possible treatment option [ 8 ]. Treatment options available for prostate cancer are active surveillance, chemotherapy, radiation therapy, hormonal therapy, surgery, and cryotherapy. Treatment options delivered to a patient depend on the nature of the tumor, PSA level, grade and stage, and possible recurrence. For example, radical prostatectomy, a surgical option that involves the removal of the prostate and nearby tissues, is used in conjunction with radiation therapy for the treatment of low-risk prostate cancer [ 9 ]. For treating cancers that have spread beyond the prostate and have reoccurred, androgen-deprivation therapy, also called hormonal therapy, is recommended [ 1 ]. Each treatment is associated with severe side effects such as toxicity and reduced white and red blood cell counts, which lead to fatigue, hair loss, peripheral neuropathy, erectile incontinence and dysfunction, metastasis, and lastly, developing resistance to the initial treatment. Available treatment options are expensive and pose severe side effects. The discovery of new cost-effective chemotherapeutic agents with little or no side effects and higher efficacy is necessary [ 3 ]. In this review, we provide a holistic overview of prostate cancer, including the diagnosis of the disease, genes and mutations leading to the onset and progression of the disease, treatment options, and alternative treatment options.

2. Materials and Methods

In order to carry out the current review, in 2020, our team began to collect information and carry out a comprehensive search from different databases, i.e., Google Scholar, Pubmed, Springer, Elsevier ScienceDirect, and Web of Science, for studies published from 2010 to 2022, and older studies published as early as 2000 were included in this paper due to relevancy. The articles selected only utilized English texts, and searches were carried out for the following keywords and headings: ”prostate cancer”, ”prostate cancer genetics”, ”prostate cancer diagnosis and treatment”, ’ cancer statistics”, ”the prostate”, ”medicinal plants in prostate cancer treatment”, “traditional medicine”, “alternative therapy for prostate cancer”, ”nanomedicine in prostate cancer”, ”next generation sequencing”, “bioactive compounds in prostate cancer”, and ”drug repurposing in cancer”. Duplicate papers were eliminated, the data were screened, irrelevant works were factored out, and then full-text documents were screened. The inclusion criteria included several factors which involved original articles or review papers. The criteria for exclusion included articles with inadequate and irrelevant information and those without access to full text articles.

2.1. Epidemiology of Prostate Cancer

2.1.1. global scale.

Prostate cancer is one of the most common malignancies in men worldwide [ 10 ]. In 2018, GLOBOCAN reported approximately 1,276,106 new cases of prostate cancer resulting in about 358,989 deaths worldwide, with a higher prevalence in developed countries. On average, 190,000 new prostate cancer cases arise each year, with about 80,000 deaths occurring annually around the world [ 11 ]. The worldwide incidence of prostate cancer differs among various geographical regions and ethnic groups. Black men have the most reported incidence rates of prostate cancer in the world [ 12 ]. The incidence rates of Black Americans are approximately 60% higher than those of white men in America. The highest recorded incidence rates of prostate cancer are seen in developed countries where there is prostate cancer awareness and where prostate-specific antigen (PSA) testing is a prevalent screening practice [ 13 ]. The GLOBOCAN reports of PSA tests indicated high incidence rates in Australasia (111.6 per 100,000) and the USA (97.2 per 100,000) in the year 2012 [ 14 ]. Globally, prostate cancer is predicted to increase to approximately 1.7 million new cases and 499,000 deaths by the year 2030 because of the exponentially growing population and the large population of men who will be 65 years and older [ 15 ].

2.1.2. Local Scale

Little is known about prostate cancer in African countries. Prostate cancer screening using the PSA test or digital rectal examination is not a well-established practice in Africa. There is a higher incidence rate of prostate cancer among men in Southern Africa as compared with Northern Africa [ 16 ]. In South Africa, prostate cancer is one of the most diagnosed cancers in men across the country. As recorded by the South African National Cancer Registry, the incidence rate of prostate cancer in 2007 was 29.4 per 100,000 men. In 2012, the incidence increased to 67.9 per 100,000 men [ 15 ].

2.2. Screening and Diagnosis of Prostate Cancer

Prostate cancer diagnoses at mature stages of the disease and failure of therapy are the main factors leading to an increased mortality rate. There is no single, specific test for prostate cancer; however, it has conventionally been diagnosed by a digital rectal examination (DRE), where a gloved finger is inserted into the patient’s rectum to assess the size of the prostate gland and any abnormalities. However, the prostate-specific antigen (PSA) test remains to be the keystone for prostate cancer screening [ 17 ]. PSA is a glycoprotein secreted by the epithelial cells of the prostate gland. It is usually found in semen, but can also be found in the bloodstream [ 18 ]. During PSA testing, blood samples are taken to test the level of PSA. Then, the blood samples are analyzed at a PSA cut-off point of 4 ng/mL. PSA levels above 4 ng/mL suggest that the patient needs further testing [ 19 ]. Patients with PSA levels between 4 ng/mL and 10 ng/mL have an approximately one in four chance of having prostate cancer. If the PSA is more than 10 ng/mL the possibility of having prostate cancer is over 50% [ 20 ]. PSA is prostate gland specific and not prostate cancer specific; therefore, prostate-specific antigen levels can indicate benign pathologies such as benign prostatic hyperplasia (BPH) and prostatitis and not prostate cancer, and men who do not have prostate cancer have also been reported to have elevated PSA levels. A prostate tissue biopsy is usually performed to confirm the presence of cancer [ 21 ].

A biopsy is a medical procedure in which a thin hollow needle is used to collect small tissue samples from the prostate gland to be observed under a microscope. The biopsy can be performed through the skin between the anus and scrotum or through the rectal wall (known as a transrectal biopsy) [ 22 ]. During a biopsy, the prostate gland is usually located with devices such as magnetic resonance imaging (MRI) and transrectal ultrasound (TRUS). An MRI scanner creates detailed images of body tissue using a strong magnetic field and radio waves [ 23 ]. MRI positive results can be used for specifically targeting abnormal areas of the prostate gland during a biopsy [ 24 ]. A multiparametric MRI can also be a triage test performed without a biopsy if the results were negative for DRE, PSA test, and MRI. A TRUS is a small probe that is deposited into the rectum of a patient. The probe emits sound waves that go through the prostate gland and produce echoes. The probe then recognizes and reads the echoes, and a computer system turns them into a black and white image of the organ [ 25 ].

Biopsy analysis is one of the most reliable methods of prostate cancer diagnosis. Tissue samples of a biopsy are studied and analyzed in the laboratory using a microscope. The cells can also be analyzed to determine how quickly cancer will spread. The biopsy results are usually reported as follows:

• Negative for prostate cancer, there were no cancer cells detected in the biopsy samples.
• Positive for prostate cancer, there were cancer cells detected in the biopsy samples.
• Suspicious, abnormal cells present, but may not be cancer cells [ 26 ].

However, artificial intelligence (AI) and machine learning algorithms have recently advanced, resulting in new classifications for prostate cancer. In recent years, the availability of novel molecular markers, as well as the introduction of advanced imaging techniques such as multiparametric magnetic resonance imaging (mpMRI) and prostate-specific membrane antigen positron emission tomography (PSMA-PET) scans have shifted the paradigm of prostate cancer screening, diagnosis, and treatment to a more individualized approach [ 27 ]. According to the most recent guidelines, any man at risk of prostate cancer should have an MRI of the prostate performed before obtaining a prostate biopsy [ 28 ]. This serves to minimize complications such as lower urinary tract symptoms, hematuria, and temporary erectile dysfunction. Furthermore, the number of biopsy cores obtained is linked to a higher risk of complications such as rectal bleeding, hematospermia, bleeding problems, and acute urine retention [ 29 ]. Therefore, radiomics can help with prostate volume selection and segmentation; prostate cancer (PCa) screening, detection, and classification; and risk stratification, treatment, and prognosis ( Table 1 ).

Benefits and drawbacks of radiogenomics as compared with actual prostate cancer peril stratification management [ 30 ].

2.3. Prostate Cancer and Genetics

Genetic inheritance.

Close family lineage is the primary risk factor for prostate cancer. Men with close relatives diagnosed with prostate cancer are at a 50% risk of developing cancer as compared with men with no family history of prostate cancer [ 26 ]. First-degree relatives with successive generations of diagnosed prostate cancer usually have early onset prostate cancer [ 31 ]. Epidemiologic studies have shown the inheritance of prostate cancer susceptibility genes. Analyses of case-control, twin, and family studies have concluded that prostate cancer risk may be a result of heritable factors. Research has shown specific gene mutations in hereditary prostate cancer and has reported that patients with these mutations have an increased risk of the disease [ 4 ]. In the genetic evaluation of inheritance, scientists use multigene sequencing of men diagnosed with prostate cancer, as well as men at high risk of developing cancer. About 5.5% of these men had detectable mutations in DNA repair genes such as ATM , BRCA1 , and BRCA2 genes. African men have certain genetic mutations that predispose them to prostate cancer; therefore, race and environmental conditions such as migration and food diets are considered to be contributing factors [ 21 ].

Cancer occurs because of changes in the DNA sequence due to mutations such as point mutations, single nucleotide polymorphisms (SNPs), and somatic copy number alterations (SCNAs) [ 31 ]. Mutations can cause prostate cells to become cancerous by turning off tumor suppressor genes and turning on oncogenes [ 32 ]. This often leads to uncontrolled cell division. Mutations in genes can be passed on from generation to generation or be acquired by an individual. Acquired mutations usually occur during DNA replication in the nucleus [ 33 ]. The common genes used as biomarkers for prostate cancer are BRCA genes, HOX genes, the ATM gene, RNase L (HPC1, lq22), MSR1 (8p), and ELAC2/HPC2 (17p11). Table 2 shows most of the genes used as biomarkers for prostate cancer.

Prostate cancer genes used as biomarkers for the disease.

Biomarkers show the advantages of being used for diagnostic procedures, staging, assessing the aggressiveness of the disease, and evaluating the therapeutic process. Multiple advances have been achieved through profiling technologies, including novel biomarkers that guide diagnosis and precision medicine. Modern biological markers, such as the prostate health index (PHI), the TMPRSS2-ERG fusion gene, 4K tests, and PCA3, have proven to increase PSA specificity and sensitivity, resulting in patients avoiding biopsies and reducing over diagnosis [ 76 ]. Table 3 below shows different diagnostic biomarkers and their different tests and categories.

Examples of other diagnostic biomarkers classified as serum-based, urine-based, and tissue-based biomarkers used for prostate cancer [ 77 ].

Figure 1 depicts the developmental stages of prostate cancer [ 78 ].

A schematic depicting the development of prostate cancer. The stages of the cancer onset and progression are indicated by the molecular processes, genes, and signaling pathways which are important in different stages of cancer. The first sign of prostate cancer is an inflammation of the prostate gland as a result of uncontrollable cell division. This uncontrollable cell division is caused by mutations that arise due to damaged DNA. At a chromosomal level, the initiation of prostate cancer begins with the shortening of telomerase at the end of the chromosome. Oxidative stress from prostate gland inflammation can shorten prostatic telomeres [ 78 ]. Research on the Nkx3.1 homeobox gene has shown the impact of the gene on the prostate cancer initiation phase in mice. No tumor suppressor gene has been solely given a role in prostate cancer initiation or progression. However, several genes such as MYC , PTEN , NKX3.1 ., and TMPRSS2-ERG gene fusions are implicated in prostate cancer initiation. TMPRSS2-ERG gene fusions are responsible for the main molecular subtype of prostate cancer. The gene fusion activates the ERG oncogenic pathway, which contributes to the development of the disease. Metastasis of prostate cancer is conserved by the reactivation of pathways involved in cell division, which results in uncontrolled cell division and cell proliferation, leading to metastasis of the cancer [ 79 ]. Gene expression profiling results have indicated an overexpression in EZH2 mRNA and proteins present in metastatic prostate cancer. Due to the functions of EZH2 involving apoptosis and proliferation, EZH2 is a novel target for prostate cancer [ 80 ].

2.4. Precision Medicine for Prostate Cancer

Precision medicine is an emerging field that represents an alternative method, for some men with advanced cancer, to find gene-specific treatment for prostate cancer. It uses genetics as well as environmental biomarkers to determine diagnoses, prognosis therapeutic options for patients, and accurate dosing. Precision medicine classifies diseases using genome sequencing to identify patients who have tumors exhibiting actionable targets and promoting more informed and accurate treatment decisions [ 81 ]. Mutations in prostate cancer-related genes BRCA1 and BRCA2 render men with mCRPC suitable for treatment with either rucaparib or olaparib, and other prostate cancer genes that have responded well to olaparib treatment, which include ATM , CDK12 , CHECK2 , CHECK1 , PALB2 , PP2R2A, and RAD54L [ 82 ]. The influence of BRCA mutations on therapeutic outcomes in a study of 1302 patients with 67 BRCA mutation carriers was investigated. The results showed that patients who received prostatectomy or radiotherapy developed metastasis and had shorter survival as compared with patients who did not have mutations of the BRCA gene. This study also found that the BRCA1 gene was 12% more common than the BRCA2 gene, which was only 2% common. In a recent study, conducted in 2019, the mutation in the BRCA gene (c.4211C > G) was identified in a Chinese patient treated with radiotherapy and ADT for prostate cancer. The study indicated that prostate cancer patients with this specific mutation were sensitive to ADT as well as radiotherapy, making the treatment more effective [ 83 ]. Mutations that make it difficult to treat or design effective CRPC include the F876L mutation, which changes the binding ligand pocket in the AR. Similarly, the W741L/C mutation stimulates specific AR binding that is able to move AR into its active conformation. Such mutations create obstacles to designing effective treatment for CRPC [ 84 ].

2.5. Treatment and Management of Prostate Cancer

The prognostic factors consisting of initial PSA level, clinical TNM stage, and Gleason’s score have been considered together with other factors such as baseline urinary function, comorbidities, and age as a choice of treatment for prostate cancer [ 85 ]. Advances in prostate cancer diagnosis and treatment have enhanced clinicians’ capacities to classify patients by risk and propose therapy based on cancer prognosis and patient preference [ 86 ]. Surveillance, prostatectomy, and radiotherapy are recognized as the standard treatments for stage I–III prostate cancer patients. Androgen ablation by surgical or pharmacological castration can bring about lasting remission in all stage IV and high-risk stage III patients. In this case, first-generation antiandrogens such as flutamide and bicalutamide can aid. However, in stage IV, castration resistance, which is characterized by genomic mutations in the androgen receptor, invariably occurs, and the prognosis is poor [ 87 ]. Table 4 below summarizes prostate cancer treatment options and their adverse effects.

Common prostate cancer treatment options and potential adverse effects [ 88 ].

2.5.1. Active Surveillance

Active surveillance is a structured program that employs monitoring and expected intervention as the main techniques in the management of prostate cancer [ 89 ]. For patients who have low-risk cancers or those who have a short life expectancy, active surveillance has been recognized as the best option. The criteria for active surveillance have recommendations that are usually based on the following factors: disease characteristics, health conditions, life expectancy, side effects, and patient preference [ 90 ]. The PSA level, clinical progression, or histologic progression are used as prostate cancer trigger points [ 91 ].

The advantages of active surveillance are the preservation of erectile function, decreased costs of treatment, avoidance of needless treatment of inactive cancers, and sustaining life quality and normal activities. Its disadvantages include the likelihood of cancer metastasis before treatment, missed opportunity for a remedy, need for a complex therapy with side effects for larger and aggressive cancers, reduced chances of potency preservation mostly after surgery, chances of increased anxiety by patients, and frequent medical checks [ 92 ].

2.5.2. Radical Prostatectomy

Radical prostatectomy is the procedure of medically removing the prostate gland by open and/or laparoscopic surgery [ 93 ]. The procedure requires making small incisions on the abdomen or via the perineum.

Salvage radical prostatectomy is usually recommended to patients with local recurrence in the absence of metastases after undergoing external beam radiation therapy, brachytherapy, or cryotherapy. This may, however, lead to increased morbidity. Patients younger than age 70 with organ-confined prostate cancer, with a life expectancy higher than 10 years who have little to no comorbidities, are best suited for radical prostatectomy. However, there are a few complications associated with its use. These complications include incontinence and erectile dysfunction arising from surgical damage to the urinary sphincter and erectile nerves [ 94 ].

2.5.3. Cryotherapy

This method involves the use of surgical insertion of cryoprobes into the prostate under ultrasound guidance. It involves freezing of the prostate gland to a temperature from −100 °C to −200 °C for about 10 min. However, there are reports of complications associated with the use of this method, including urinary incontinence and urinary retention, erectile dysfunction, fistula, and rectal pain [ 95 ].

2.5.4. Radiation

Radiation therapy is regarded as one of the most effective therapies that kills prostate cancer cells using high radiations. Radiations are sent to cancerous cells through various techniques such as brachytherapy (the use of seeds placed in the body) and external beam (where the energy is projected through the skin) to the cancerous sites. Radiation therapy aims at specifically transferring high-energy rays or particle doses directly to the prostate without affecting the normal tissues. These doses are based on the level of prostate cancer. This treatment is considered to be an acceptable therapy for patients who are not suited for surgical procedures [ 96 ]. Various techniques of radiation therapy are discussed below.

Brachytherapy

Brachytherapy includes the direct placement of radioactive sources into the prostate gland with the aid of seeds, injections, or wires under the guidance of transrectal ultrasound. This often involves two techniques: low dose and high dose rates. The low dose rate refers to the permanent implantation of seeds in the prostate tissue, which loses radioactivity gradually [ 97 ], and the latter refers to the supply of a dose of radiation to the prostate tissues with significant risk of leakage to other surrounding organs. The advantage associated with brachytherapy is that it can be completed within a day or less. There is a minimal risk of incontinence in patients without a previous transurethral resection of the prostate (TURP). Erectile function is also not affected. Its disadvantages are usually a requirement for general anesthesia, acute urinary retention risks, and persistent irritative voiding symptoms [ 98 ].

External Beam Radiation Therapy

External beam radiation therapy (EBRT) is a commonly used treatment technique that involves emitting strong X-ray beams specifically targeting the prostate tissues. It radiates higher prostate radiation doses, with less emission to the surrounding tissues. Radiation therapy is considered to be an effective intermediate-risk and high-risk prostate cancer treatment when used together with androgen deprivation therapy (ADT) [ 80 ]. It is a suitable therapy for attenuating metastasizing cancer cells. This technique is more advantageous than surgical therapy. It can treat early stages of cancer, and it is associated with fewer risks such as bleeding, myocardial infarction, pulmonary embolus, urinary incontinence, and erectile dysfunction. It can also relieve symptoms such as bone and joint pain [ 93 ]. Side effects of radiation include urinary urgency and frequency, erectile dysfunction, dysuria, diarrhea, and proctitis [ 97 ].

2.5.5. Radium-223 Therapy

The radium-223 dichloride (Xofigo) technique makes use of a substance used for therapy in patients with metastatic prostate cancer that is resistant to hormone therapy. Its ability to mimic calcium makes radium-223 dichloride be selectively absorbed by the cancer cells in bone tissue. This technique has been reported to have a considerable impact on the survival and recovery of metastatic prostate cancer patients, leading to delayed onset of bone fracture and pain [ 85 ].

2.5.6. Hormonal Therapy

Hormonal therapy is also known as androgen deprivation therapy (ADT). This technique is applied in the treatment of advanced and/or metastasized prostate cancer. Its therapeutic mechanism is based on the blockage of testosterone production and other male hormones, preventing them from fueling prostate cancer cells. Therefore, significantly decreased male hormonal levels are responsible for inhibition of the action of androgen on the androgen receptor [ 99 ]. This is often achieved using bilateral orchiectomy or medical castration via administration of luteinizing hormone-releasing hormone (LHRH) analogs or antagonists. LHRH analog primarily elevates the luteinizing hormone (LH) and follicle-stimulating hormone (FSH) by stimulating hypophysis receptors, thus, enabling the drug to downregulate the hypophysis receptors with concomitant reduction of LH and FSH levels, leading to suppressed testosterone production. Leuprolide, goserelin, triptorelin, and histrelin are among the common LHRH agonists. The antagonists cause action by blocking the hypophysis receptors, thereby triggering the immediate inhibition of testosterone synthesis [ 100 ]. ADT has, however, been associated with acute and long-term side effects, such as hyperlipidemia, fatigue, hot flashes, flare effect, osteoporosis, insulin resistance, cardiovascular disease, anemia, and sexual dysfunction [ 101 ].

Flutamide is a type of drugnthat is nonsteroidal and pure antiandrogenic lacking hormonal agonist activity. Flutamide is antiandrogen at the androgen-dependent accessory genitals. Its biological activity is based on 2-hydroxyflutamide. Treating prostate cancer with flutamide and an (LHRH) agonist has produced promising results. In vivo studies of flutamide have shown certain antagonist at the ventral prostate and androgen-dependent seminal vesicles [ 102 , 103 ]. Flutamide is known to result in hepatic dysfunction; however, a study on antiandrogen therapy (AAT) in combination with flutamide indicated that flutamide could be successful when performing regular hepatic function testing during treatment periods [ 104 ]. Maximum androgen blockade (MAB) using flutamide as a second-line hormonal therapy can give a prostate-specific antigen response without side effects, making this a possible treatment option for patients with HRPC with no bone metastases or whose cancer has progressed more than a year following first-line therapy [ 105 ].

Chlormadinone acetate (CMA) is an oral steroidal antiandrogen. Chlormadinone has proven to have anticancer activity. Similar to progesterone used in maximum androgen blockade (MAB) therapy as well as monotherapy for prostate cancer in Japan [ 106 ]. To determine the success of the antiandrogen chlormadinone acetate in treating stage A prostate cancer, a study of 111 patients who received chlormadinone acetate was conducted. The progression rates linked to antiandrogen therapy for stage A1 and A2 patients were lesser in non-treatment receiving groups, concluding that antiandrogen treatment with chlormadinone acetate inhibited the progression [ 107 ]. Chlormadinone is also used to treat benign prostatic hyperplasia, it decreases testosterone level, prostate-specific antigen (PSA) level, and prostate volume, in benign prostatic hyperplasia slowing the progression of Prostate cancer [ 108 ].

2.5.7. Abiraterone

Abiraterone is a second-generation therapy targeted at adrenal and tumor androgen production. It is associated with the irreversible inhibition of the hydroxylase and lyase activities of CYP17A, AR pathways, and 3β-hydroxysteroid dehydrogenase activity, and is used to treat prostate cancer that has metastasized to other parts of the body [ 109 ]. Abiraterone has also been proven to be a potent inhibitor of other microsomal drug-metabolizing enzymes, including CYP1A2 and CYP2D6 [ 109 ]. Clinical data of abiraterone have indicated remarkable results, but there are reports of variable responses and concomitant increasing PSA levels. Abiraterone is correlated with high CYP17A upstream mineralocorticoids, with concomitant side effects including edema, hypertension, fatigue, and hypokalemia [ 110 ].

Immunotherapy or biological therapy is based on stimulating or suppressing the immune system. The treatment uses vaccines designed to work with the patient’s immune system to fight cancer cells. Sipuleucel-T (Provenge) is one of such vaccines, designed for advanced and metastatic prostate cancer cells that have developed resistance to hormone therapy. It is developed from the immune cells by collecting the white blood cells and activating them with prostatic acid phosphatase [ 109 ]. This is then associated with a protein that can trigger the immune system before infusing into the blood [ 99 ]. Sipuleucel-T (Provenge, Dendreon) is an autologous dendritic cell-based immunotherapy used in treating asymptomatic patients by assisting a patient’s immune system in fighting back cancer cells. It is intravenously administered in three doses over one month. Its lesser side effects make it more favorable compared to other chemotherapies. Its side effects include fever, nausea, chills, and muscle aches [ 111 ].

2.5.8. Chemotherapy

Chemotherapy uses anticancer drugs to kill or inhibit the growth of cancerous cells. There has been progress in treatment of prostate cancer after decades of learning and understanding genetics, diagnosis, and treatment. The most common chemotherapy drug for prostate cancer is docetaxel (Taxotere) [ 112 ].

Docetaxel is regarded as the first-line standard therapy for prostate cancer cells that are castration-resistant. It is an antimicrotubule agent which attaches to β-tubulin to inhibit microtubule depolymerization, thereby suppressing mitotic cell division and initiating apoptosis [ 113 ]. CYP3A is a major requirement for the activation of Docetaxel. The development of Docetaxel resistance has been associated with relapse. Docetaxel resistance has been attributed to increased upregulation of the multidrug resistance (MDR) 1 gene that encodes P-glycoprotein [ 114 ].

Cabazitaxel

Cabazitaxel is a novel antineoplastic semi-synthetic derived from the needles of various species of yew trees (Taxus). It is usually sold under the name Jevtana. Cabazitaxel is a second-generation therapy aimed at suppressing docetaxel resistance [ 99 ]. It has a low affinity for Pglycoprotein owing to its additional methyl groups. It is metabolized in the hepatic tissues by CYP3A4/5 and CYP2C8 (10–20%). Hypotension, bronchospasm, renal failure, neurotoxicity fatigue, alopecia, and generalized rash/erythema are among the common side effects associated with its use. There have also been reports of diarrheal deaths related to Cabazitaxel therapy resulting in electrolyte imbalances and dehydration [ 114 ].

Enzalutamide

Enzalutamide is a second-generation AR inhibitor that was recognized as one of the chemotherapeutic drugs for prostate cancer in 2012. This drug focuses on the androgen pathway and has functions such as (1) competitively inhibiting the binding of androgen to the androgen receptor, (2) inhibiting nuclear translocation and recruitment of cofactors, and (3) inhibiting the association of the activated androgen receptor. Enzalutamide targets androgens such as testosterone and dihydrotestosterone. Its therapeutic mechanism includes:

• Competitive inhibition of androgen binding to the androgen receptor;
• Inhibition of nuclear translocation and co-factor recruitment;
• Inhibition of the binding of DNA with activated androgen receptor.

The side effects of enzalutamide include fatigue, asthenia, diarrhea, and vomiting [ 115 ].

2.6. Combination Therapy

Combination therapy has been demonstrated as an effective strategy for prostate cancer treatment. Combination therapy is a strategy that was developed to treat castration-resistant prostate cancer and other forms of prostate cancer. There are no drugs to date that treat castration-resistant prostate cancer (CRPC), and currently approved treatment options either used alone or in combination therapy are useful in extending a patient’s lifespan by a few months [ 116 ]. Current treatment options used for the treatment of prostate cancer are not curative, and disease progresses to the castration-resistant phenotype over a period of time. Combination therapy with currently used treatment options for prostate cancer could successfully increase a patient’s lifespan and suppress tumors. Amongst all the available treatment strategies available for metastatic prostate cancer, androgen deprivation therapy (ADT) has more potential combination treatment compared to other therapeutic strategies for prostate cancer, and approved and currently ongoing clinical trials with ADT treatment include ADT with radiation therapy, which often treats high-risk patients to delay or prevent the disease from progressing to CRPC; (ii) ADT and chemotherapy, which in several clinical studies has shown to increase patient survival but results in adverse side effects and sometimes death; and (iii) immunotherapy and ADT, which has been reported to increase patient survival by 8.5 months [ 117 ]. Clinical trials are ongoing to analyze the effects of survival in ADT and the PSA-targeted poxviral vaccine, PROSTVAC-IF; a combination of radiation therapy with immunotherapy under ADT; a combination of chemotherapy with immunotherapy under ADT; and a combination of docetaxel under ADT [ 118 ]. There are a number of completed and ongoing clinical studies/trials for combination therapy of prostate cancer. Some of the clinical trials are listed in Table 5 and Table 6 .

Combination therapies for prostate cancer—completed clinical trials [ 116 ].

Combination therapies for prostate cancer—ongoing clinical trials [ 116 ].

2.7. Drug Repurposing

Drug repurposing, also known as drug repositioning, reprofiling, or retasking, is a way of identifying new uses for approved drugs [ 119 ]. The advantage of drug repurposing over de novo drug development (developing new drugs) is that repurposed drug candidates have undergone extensive research in animal models and clinical trials, testing the safety, optimization, and, in most cases, formulation development of the drug, as well as pharmacokinetic and pharmacodynamic properties. This advantage usually speeds up the research and development for new use of the drug and reduces the failure rate in later efficacy testing clinical trials [ 120 ]. These previously tested drugs can rapidly progress into phase II and phase III human clinical studies, which implies that the associated drug development cost could be drastically deceased. Researchers show great interest in this phenomenon because drug repurposing alleviates the dilemma of some challenges currently faced in clinical research for finding new cancer therapies, such as drug shortage. It can take a period of 10–17 years for a development of a new drug compared to 3–12 years for repurposed drugs. Technology advances play a major role in scanning large databases and detecting key molecular similarities in different diseases to identify drugs that can be repurposed. Androgen deprivation therapy (ADT) is used to treat advanced-stage prostate cancer patients. Metformin is a drug commonly used to treat type II diabetes, repurposed to treat prostate cancer. It can be utilized to sensitize prostate cancer to the currently used standard prostate cancer therapies and improve the efficacy of treatment. It is reported that Metformin is able to increase the effectiveness of ADT for the treatment of prostate cancer [ 121 ]. Here, we discuss three main categories of drug repurposing studies for PCa, classified by different discovery and validation categories, such as the knowledge and ability of the drug to be researched. For example, ormeloxifene, a selective estrogen receptor modulator, is known for its anticancer properties in several cancers such as breast and ovarian cancers, but ormeloxifene is reported to have mediated the inhibition of oncogenic β-catenin signaling and EMT progression in prostate cancer by significantly suppressing β-catenin/TCF-4 transcriptional activity, N-cadherin, MMPs, and triggering pGSK3β expression. The other category is drugs that have been tested in assays and classified in accordance with their activity. For example, Itraconazole, an antifungal drug responsible for preventing angiogenesis and the initiation of the Hedgehog signaling pathway, was experimented in phase II clinical trials and established to be effective in patients with metastatic CRPC [ 122 ]. Table 7 shows different drugs repositioning candidates in prostate cancer clinical trial studies.

Anticancer drug repositioning candidates under clinical investigation for the treatment of prostate cancer [ 32 ].

Other anticancer drugs that are currently being researched in vitro and in vivo for treatment of prostate cancer include naftopidil, an alpha blocker; niclosamide, an anti-helminthic agent; ormeloxifene, an estrogen receptor modulator; nelfinavir, an antiretroviral agent; glipizide, an antidiabetic agent; clofoctol, an antibacterial agent; and triclosan, an antibacterial agent [ 32 ]. Drug repurposing for prostate cancer presents an opportunity to address current treatment challenges. This strategy should be implemented using computational genomic and proteomic tools to assist and guide researchers in their decision making regarding patient treatment [ 122 ].

2.8. Treatment Challenges

Despite the various treatment options, mCRPC remains to be an incurable disease. Over time, the disease continues to develop resistance to different conventional treatment options [ 123 ]. This has led to continuous research on understanding the growth, metastasis, tumorigenesis, tumor microenvironment, and tumor environmental interactions that promote disease progression.

2.8.1. Drug Resistance

Castration resistance has been reported in prostate cancer that has reached advanced stages. Castration resistance allows for androgen signaling via amplification of the androgen receptor’s synthesis of the intra-tumoral hormone, while disrupting the androgen receptor’s coexpressors and coactivators [ 124 ]. Resistance to enzalutamide and abiraterone acetate, as well as gene mutation in metastatic prostate cancer, has been attributed to the overexpression of the active androgen receptor (AR) in patients. Prostate cancer often develops owing to androgens; thus, most treatments are targeted at blocking androgen hormones. This is beneficial to anticancer drug-resistant patients.

Mutations have also been shown to contribute to drug resistance in cancer cells, allowing for bypassing of the targeted pathways. Alterations in intrinsic pathways such as the AR signaling pathways, MAPK/ERK pathway, endothelin A receptor (EAR), and Akt/PI3K pathways as well as exacerbated expression of the androgen receptor have been shown to contribute to ADT resistance [ 46 ].

2.8.2. ABC Transporters

These transporters are expressed in the plasma membrane, where they serve as efflux pumps and are well-known triggers of multidrug resistance. They transport drugs and xenobiotics in and out of the cells [ 125 ]. Multidrug resistance protein (MRP) transporters MRP2, MRP3, MRP4, and MDR-1 protein (P-glycoprotein) have been reported in prostate cancer [ 110 ]. The exacerbated expression of these transporters has been implicated in the increased efflux of drugs, thereby leading to multidrug resistance. Of these transporters, MRP2 has been reported to exhibit the highest potency of resistance to natural product agents, MRP3 exhibits the lowest resistance to etoposide, and MRP4 and MRP5 are responsible for resistance to nucleoside analogs and transport cyclic nucleotides. MRP4 also influences resistance to chemotherapeutic agents such as camptothecins, cyclophosphamide, topotecan, methotrexate, and nucleoside analogs [ 126 ].

2.8.3. Cytochrome P450

Cytochromes P450 are a well-known multigene superfamily of heme-containing monooxygenases that are both constitutive and inducible. They catalyze the metabolism of a variety of xenobiotics and endocrine disruptors [ 127 ]. The family including CYP2C19, CYP4B1, CYP3A5, CYP2D6, CYP1A2, and CYP1B1, has been reported in human prostate cells [ 128 ]. CYP4B1′s main functions are the metabolism and activation of arylamines via N-hydroxylation, an activity that results in bladder tumor [ 129 ]. Exacerbated expression of CYP1B1 has been implicated in the advances of drug resistance in prostate cancers. This is often achieved by 2-hydroxylation of flutamide [ 130 ]. CYP17A speeds up the process of sequential hydroxylase and the lyase steps in the androgen biosynthetic pathway in humans, thus, making it a critical therapeutic marker for prostate cancer treatment [ 131 ].

2.8.4. Mutations in Androgen Receptors

Mutations in androgen receptors occur owing to a disorder in androgen sensitivity. Androgen receptor (AR) signaling plays an important role in the development, activity, and homeostasis of the prostate gland. It regulates the process of gene transcription via attaching to the androgen response elements on specific genes, as well as allowing nuclear translocation of the androgen receptor [ 132 ]. Gene changes in the AR signaling pathway ( Figure 2 ) have been reported in prostate cancers. AR mutations were first reported in an androgen-responsive cell line, LNCap. These mutations have been implicated in the development of AR resistance arising from AR-targeted therapy [ 133 ]. This has led to the use of androgen deprivation therapy (ADT) and antihormone therapy in the treatment of advanced prostate cancer. The majority of AR mutations result in single amino acid substitutions, which are mostly found in the AR androgen-binding domain. The mutation T877A, which has been found in roughly 30% of metastatic CRPC patients, is the most common [ 134 ]. Other mutations have resulted in enhanced AR binding to coregulators, resulting in higher AR transcriptional activity vis-à-vis H874Y and W435L mutations. These mutations have been implicated in the development of AR resistance arising from AR-targeted therapy [ 124 ]. Figure 3 illustrates the transcription activity of the androgen receptor gene [ 135 ].

The function of AR signaling in prostate cancer and development: ( A ) Prostate homeostasis is maintained in a healthy prostate via reciprocal signaling between the stromal and epithelial layers; ( B ) normal prostate cells are converted into cancer initiating cells by unknown mechanisms, histological evidence of prostatic intraepithelial neoplasia and early cancer lesions appears, cells at the basal layer express higher levels of AR in response to this event; ( C ) cellular and molecular alterations occur in prostate adenocarcinoma, resulting in luminal cells with the AR transcriptional pathway; ( D ) Prostate cancer cells in CRPC maintain AR activity through other mechanisms (including upregulation of AR and its splice variants, intra-tumoral androgen synthesis, cross communicate with other signal pathways, and increased/altered expression of AR cofactors) as the availability of androgen from the blood steam becomes limited [ 134 ].

The androgen receptor gene encodes a 110 kD protein composed of 919 amino acids that are classified by an androgen-binding domain (ABD), a conserved DNA-binding domain (DBD), and an N-terminal transactivation domain, which has two polymorphic trinucleotide repeat segments. These repeated segments, consisting of variable numbers of polyglycine repeats and polyglutamine, highly influence the androgen receptor transcription activity. The gene transcript consists of eight exons in total: exon 1 codes for the N-terminal domain, exons 2–3 code for the DBD, and exons 4–8 code for the ABD [ 135 ].

2.8.5. Tumor Microenvironment

The tumor microenvironment has a crucial role in the development and progression of prostate cancer to the advanced stage, as per recent studies. According to experimental research, the milieu and malignant tumor cells have a mutually reinforcing relationship in which early changes in the microenvironment of normal tissue can foster carcinogenesis and tumor cells can foster more protumor modifications in the microenvironment [ 136 ]. A tumor microenvironment comprises a wide interlinked niche encompassing the extracellular matrix and specialized cells such as neural cells, blood vessels, immune cells, and mesenchymal/stromal stem cells, all of which secrete factors such as chemokines, cytokines, and matrix-degrading enzymes. They interact with cancer cells through paracrine and autocrine mechanisms [ 137 , 138 ].

According to a tumor stage-specific histological investigation, high-grade PC is linked to enhanced stromal immune cell infiltrates with a variety of cellular types [ 139 ]. Chronic stresses such as direct infection, urine reflux, a high-fat diet, and estrogens affect the prostate’s ability to become inflamed on a long-term basis [ 140 ]. The stromal compartment experiences an inflow of several immune cells, including CD3+ T-cells, macrophages, and mast cells, amid ongoing inflammation [ 141 ]. High levels of cytokines and chemokines, primary tumor necrosis factor, nuclear factor kappa B, to mention a few, are produced by inflammatory cells. The regulation of angiogenesis, cellular proliferation, and inflammation involves these proteins among others. They control the PC’s shift to the malignant phenotype [ 136 ].

The surrounding stromal agents go through complex modifications as a result of the interaction between prostatic epithelial cells and the tumor microenvironment, and these changes control the severity of the disease, its capacity to spread, and its susceptibility to traditional treatments [ 142 , 143 ].

2.9. Role of Estrogen Receptors (ERs) in Prostate Cancer Etiology and Progression

Prostate cancer is often regarded as hormone dependent, since steroid hormones direct its initiation and progression. Earlier reports have emphasized the significance of steroid levels in the etiology of PCa [ 144 , 145 ]. Estrogen plays an indispensable role in the secretion of male sex hormones, and it also plays cardinal roles in the growth, differentiation, and homeostasis of prostate tissues. Estrogens also contribute to the development of prostate cancer [ 146 ]. In a report from Ellem and Risbridger using aromatase knockout (KO) mice, the knockout mice could not metabolize androgens to estrogens, and it was observed that high levels of testosterone led to the development of prostate gland enlargement (prostatic hyperplasia). Meanwhile, increased estrogen and decreased testosterone levels gave rise to inflammatory events and lesions [ 147 ]. Epidemiological studies have also proposed that the serum level of estradiol and the serum estradiol/testosterone (E/T) ratio influence the initiation of PC and its progression [ 148 ]. Estrogen activities are carried out by two receptors, which are estrogen receptor α (ERα) or β (ERβ); ERα and Erβ are expressed in prostate tissue [ 125 ]. ERα is confined to the prostatic stroma, and has an indirect effect on the epithelial cells, while ERβ is found to be expressed within the epithelial domain and regulates epithelial proliferation and differentiation [ 149 ]. No less than five ERβ homologues (ERβ1, -2, -3, -4, and -5) exist in humans [ 145 ]. ERβ1 plays a functional role, while the other isoforms control its activity. The role of ERβ may consequently depend on the ratio of expression of ERβ1 and ERβ isoforms. It is known that ERα brings about the adverse effects induced by estrogens, while ERβ directs the protective and anti-apoptotic effects of estrogen in PCa [ 149 ]. On the one hand, the expression of estradiol receptor α has been found to be remarkably linked with a high Gleason’s score and poor survival rate in patients with PCa [ 150 ]; on the other hand, ERβ expression was found to be decreased or lost in the examined PCa samples [ 151 ]. Furthermore, the expression of ERβ2 and ERβ5 together has been shown to constitute a marker for biochemical relapse, post-surgery spread/metastasis, and the period to spread after radical prostatectomy in PCa patients. Based on the aforementioned, the expression of ERβ1 decreased, and that of ERβ2 and ERβ5 increased with the progression of PCa. This expression pattern corresponded with the spreading and metastasis of PCa [ 152 ]. In PCa, on the one hand, ERα has an oncogenic role and directs the deleterious effects of estrogen, which include proliferation, inflammation, and prostate carcinogenesis. Erβ, on the other hand, may elicit antitumor activity (oncosuppressor) in PCa manipulation of ERβ by ligands. Novel drug candidates might be useful in the therapeutic strategies towards PCa, specifically during the earlier stages of the disease [ 145 ].

2.10. Experimental Work Exploring Alternative Treatments

Traditional medicine in prostate cancer medicine in prostate cancer treatment.

Traditional medicine plays a significant role in healthcare in developing countries, and such countries also have a long history of treating different diseases and ailments. The use of medicinal plants in cancer has gained substantial attention, and recently, research is ongoing, with the National Cancer Institute (NCI) playing a pivotal role in the research of traditional medicine to treat cancer [ 153 ]. Traditional medicine is used significantly by patients with cancer to minimize side effects or used entirely as a single treatment rather than conventional therapy. This is because plants are easily accessible, effective, and affordable. Plant-derived compounds and plant extracts have been widely used due to their anti-inflammatory, antioxidant, and antimicrobial properties [ 154 ]. Various anticancer agents used in therapy today are derived from plants, for example, paclitaxel and taxol are derived from Taxus brevifolia , docetaxel (Taxotere) from Taxus baccata , and vincristine and vinblastine from Catharanthus roseus [ 155 ].

There is considerable proof supporting the utilization of a plant-based diet for the prohibition of acute disorders. Consumption of plant-based food provides necessary nutritional supplements and phytochemicals that aid in growth and shield against the occurrence of various acute illnesses [ 156 ]. They also offer protection against oxidative stress related to chronic disorders such as cancer. Phenolic compounds serve protective roles including antibacterial, anti-inflammatory, and anticancer roles [ 157 ]. Plants containing organosulfur compounds have chemoprotective activity. Carotenoids and polyphenols have anti-inflammatory and antioxidant activity [ 158 ]. Consequently, medicinal plants are commonly used for the treatment of cancers [ 159 ]. Several flavonoids have shown anticancer activity in the treatment of prostate cancer. Flavonoids are polyphenolic compounds characterized by a benzene ring condensed with a six-member phenyl ring attached to the carbon 2 and carbon 3 (C2 and C3) carbon positions. Among flavonoids, flavonols which can be identified by a distinctive hydroxyl group at the carbon 3 carbon position, have been reported in a number of studies, both preclinical and clinical, for their anticancer activity in prostate cancer cell lines. Flavonols, myricetin, fisetin, and kaempferol are commonly found in several fruits and vegetables and display anti-inflammatory, antiviral, antineoplastic, antibacterial, and antioxidant activity, among many others, in different cells [ 160 ].

Several specific plants have been analyzed for their activity as anticancer agents for cancer treatment. Plant anticancer activity is linked to phytochemical constituents present in extracts. Table 8 summarizes various medicinal plants used in cancer treatment [ 161 ].

Summary of various medicinal plants used against different types of cancers [ 161 ].

2.11. Gene Therapy

The developments achieved in genetics, biotechnology, tumor biology, and immunology have facilitated new advancements in gene therapy. Gene therapy is a therapy that includes inserting or deleting a DNA sequence or base pair to rectify a genetic defect in a specific protein or to target a certain molecular pathway. A few gene editing technologies are currently being developed for gene therapy. Gene therapies usually involve the encapsulation of DNA nucleotides into viral and non-viral vectors that deliver the gene to a specific site, then, inserting the gene into the human genome to edit the DNA sequence and regulate cellular processes [ 162 ]. The main idea of gene therapy is to deliver exogenous nucleotides to specific DNA parts in the cells of various tissues. Viruses are well known for being efficient in transferring their genome into a host to infect it. The viral vector can be administered intravenously by injecting it directly into the targeted tissue. Non-viral vectors such as nanoparticles and polymers have also been studied for their use in gene therapy for the treatment of prostate cancer. These non-viral vectors usually condense DNA through electrostatic interactions, which also protects the genetic material from degrading. Gene therapies also explore the use of apoptosis. Failure of cells to undergo apoptosis can lead to uncontrolled cell division, which then leads to the development of cancer [ 163 ]. The suppression of apoptosis usually occurs as a result of the genetic mutations in cancerous cells. Gene therapy for prostate cancer targets apoptosis cellular pathways by introducing a gene that encodes a mediator or inducer of apoptosis in defective cells encoding an inducer, mediator, or executioner of apoptosis. Apoptosis-inducing genes, such as caspases, induce cell death in cancer cells [ 164 ]. Numerous challenges such as enhancing DNA transfer efficiency to cells, as well as immune responses that interfere with gene expression lie ahead for gene therapy. However, irrespective of the difficulties, it is definite that gene therapy will be the next up-and-coming medical technique used against prostate cancer in the future. Some clinical trial studies investigating prostate cancer therapy using gene therapy include various transgenes such as p53 and herpes simplex tk [ 165 ]. Recently used prostate cancer gene therapy procedures involve rectifying abnormal gene expression, utilizing programmed cell death mechanisms and biological pathways, specifically targeting important cell functions, initiating mutant or cell lytic suicide genes, strengthening the immune system anticancer response, and connecting treatment with radiation therapy or chemotherapy [ 166 ]. Animal studies in prostate cancer gene therapy have made use of intraprostatic administration of gene therapy delivery systems. This route of administration has been found to be more effective, as most of the dose was delivered directly to the prostate. This targeted delivery allowed the administered dose to reach prostate cancer metastasis. Lactoferrin and transferrin are multifunctional proteins that can bind to iron-binding proteins that are usually overexpressed on prostate cancer cells [ 167 ]. The proteins are responsible for regulating free iron levels. High iron levels have negative side effects such as increasing the risk of bacterial infections, as well generating free radicals and promoting the conversion of oxidation states ferrous ion (Fe2+) to ferric ion (Fe3+). Various studies in animals have used transferrin and lactoferrin for active targeting of prostate cancer cells. Prostate stem cell antigen (PSCA) is a cell surface antigen that is expressed in androgen-dependent and androgen-independent prostate cancer cells; therefore, it can be used as a marker for prostate cancer. Human epidermal growth factor receptor 2 (HER2) is another ligand that can be used as a marker for targeted treatment of prostate cancer due to mutations causing overexpression of tumor cells [ 168 ]. A study conducted on prostate cancer-induced xenograft mice models indicated that the inhibition of HER2 and epidermal growth factor receptor (EGFR) by specifically targeting tumor-initiating cells could highly improve the efficacy of the chemotherapy treatment for castration-resistant prostate cancer with activated STAT3, and could prevent metastasis EGF-induced STAT3 phosphorylation, which is responsible for enabling prostate cancer metastasis [ 169 , 170 ]. Various gene targeting systems have experimented on immune response treatment with a DAB-Lf dendriplex encoding IL12, which has demonstrated drastic tumor reduction in the PC3 and DU145 prostate tumors. MiRNA (miR)-205, miR-455-3p, miR-23b, miR-221, miR-222, miR-30c, miR-224, and miR-505 are downregulated in patients with prostate cancer and are known to be associated with tumor suppressors in prostate cancer cells, affecting proliferation, invasion, and aerobic glycolysis. MiR-663a and miR-1225-5p are linked to the development of prostate cancer, showing potential to be used as candidate markers. The specific functions of miR-663a and miR-1225-5p in stimulating prostate cancer growth and tumor progression are unclear [ 171 , 172 , 173 ].

2.12. CRISPR Cas9

The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) is a natural defense mechanism found in archaea and bacteria. This system is currently being extensively researched because of its simplicity and effectiveness [ 145 ]. The ability to target intraprostatic inoculation of specific gene therapy vectors is an advantage of immunotherapy-based and cytotoxic gene therapy approaches. Because changes in DNA sequences result in mutations that cause cancer, scientists have been interested in new approaches to correct such changes by manipulating DNA [ 174 ]. The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system uses single-guide RNA (sgRNA) to identify and bind to certain DNA sequences through Watson–Crick base pairing [ 175 ]. CRISPR and the CRISPR–Cas9 (CRISPR-associated 9) system have been extensively studied and have changed the study of biological systems. CRISPR allows the precise altering, inserting, or deleting of DNA nucleotides in the target DNA sequence by initiating double-strand breaks. A guide RNA binds to Cas9, leading it to a complementary DNA target sequence, where a double-strand break is inserted to repair or edit DNA nucleotides. CRISPR can also be used for detecting DNA from RNA from cancerous cells and cancer-causing viruses. CRISPR/Cas9 delivery in nanoparticle lipid-based vectors is safer to use and effective [ 176 ]. Liposomal vectors offer a wide range of advantages and modifications, giving direct control over the physico-chemical properties of the liposomal surface, and can accommodate the conjugation of targeting ligands. An antibody-targeted delivery system of lipid nanoparticles (LNPs) was initially developed and standardized for the targeted treatment with small interfering RNA (siRNA). Recently, LNPs were used in a proof-of-concept study to target disseminated ovarian cancer in mice with CRISPR/Cas9 [ 177 ]. A study by Ye et al., 2017, analyzed the function of GPRC6A in the progression of prostate cancer progression in vitro and in animal studies. The study indicated that GPRG6A was expressed in human prostate cancer cell lines, and also showed polymorphism that improved mTOR signaling. Clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated protein 9 nuclease (Cas9) (CRISPR/Cas9) were used to interrupt the GPRC6A gene in the PC-3 cell line. The results indicated that editing the GPRC6A gene using CRISPR/Cas9 stopped cell proliferation and migration in vitro, and also that osteocalcin activated the ERK, AKT, and mTOR signaling pathways. It was found that the GPRC6A gene mediated the progression of prostate cancer in animal studies mainly through assessing the response to osteocalcin in human prostate cancer xenograft models with cells expressing GPRC6A gene or the CRISPR/Cas9-mediated deletion of the gene. The findings of the study supported the use of CRISPR as a potential therapeutic target [ 178 ]. The first genome-scale CRISPRi screen in metastatic PCa models indicated that kinesin family member 4A (KIF4A) and WD repeat domain 62 (WDR62) initiate aggressive PCa. Novel targets for prostate cancer are also provided by CRISPR screen in prostate-specific cell lines, also suggesting the importance of assessing the results in other cancer cells, which may lead to the discovery of biomarkers for prostate cancer therapy [ 179 ].

2.13. Nanotechnology

Nanotechnology is an integrative field that combines pharmacology, biomedical science, and nanotechnology. Nanoparticles have characteristics that allow drug efficacy, can easily penetrate tumors, prevent drug degradation, and can be modified to target specific tissues [ 170 ]. Nanoparticles such as liposomes, polymers, metal nanomaterials, and porous silicon nanoparticles have been highly researched for application in prostate cancer treatment and prognosis. Active targeting nanoparticles have modified surfaces with attached antibodies, affibodies, peptides, or oligosaccharides. These targeting ligands target receptor cells on cancerous cells, such as the prostate-specific membrane antigen (PSMA) receptors on prostate cancer cells [ 180 ]. There is interest in developing nanoparticles for prostate cancer therapy due to challenges faced by currently used treatments. A study conducted at Mount Sinai New York on 16 patients used gold silica nanoparticles for localized prostate cancer. The gold silica nanoparticles absorbed infrared light at a wavelength that could penetrate biological tissues. The gold nanoparticles possessed plasmon resonance that could drastically decrease side effects related to the therapy. Patients were injected intravenously with gold nanoparticles with laser ablation. The growth of the tumor was analyzed using magnetic resonance imaging after 48 and 72 h of therapy. The results showed a decrease in tumor size with no side effects. While only a few studies have progressed to clinical trials, a study on targeted and controlled release for prostate cancer therapy has recently started clinical trials, which has led to the development of the BIND-014 docetaxel encapsulated nanoprototype [ 155 ]. The results of preclinical and clinical improvements linked to liposomal drug delivery in cancer treatment suggest that liposomal encapsulation signals a positive future for the treatment of prostate cancer. Nanocarriers have been demonstrated as useful in combination therapy, as they are able to overcome differences in pharmacokinetics in chemotherapeutic agents [ 173 ]. Combining nanotechnology and other therapeutic strategies can effectively enhance and improve the effectiveness of drugs. In prostate cancer, nanotechnology is used in diagnostics and therapeutic treatment. Not only are nanoparticles effective delivery systems, but they also improve the solubility of poorly soluble drugs, and multifunctional nanoparticles display adequate specificity toward urological cancers, bladder, renal, and prostate cancer. In a study conducted by Zhang et al., the encapsulation of docetaxel and doxorubicin in nanoparticles increased the observed cytotoxicity in prostate cancer cells [ 180 ]. Another study, conducted to assess the codelivery of doxorubicin (DOX) and docetaxel (DOC) by nanocarriers for synergistic activity, suggested that both anticancer agents DOX and DOC in the nanoparticles acted synergistically and promoted the curative effect of Dox and Doc in a xenograft mouse model, which acted on androgen-dependent and androgen-independent prostate cancer cell lines [ 181 ]. A multicenter phase II open-label clinical trial consisting of 42 patients with progressing mCRPC who received abiraterone acetate and/or enzalutamide treatment studied the safety and efficacy of a docetaxel-containing nanoparticle (BIND-014) targeting prostate-specific membrane antigen (PSMA) in metastatic castration-resistant prostate cancer. Targeted delivery of docetaxel by prostate-specific membrane antigen (PSMA)-conjugated nanoparticles was found to be clinically effective, drastically reducing circulating tumor cells [ 182 ]. A modern method of heating tumors after inoculation of magnetic nanoparticles has been extensively researched in prostate cancer clinical trials. The feasibility and tolerability were evaluated with the first prototype of an alternating magnetic field applicator in a study experimenting with magnetic nanoparticle thermotherapy alone or in combination with permanent seed brachytherapy. The results reported that magnetic nanoparticle thermotherapy had been shown to be hyperthermic and effective to thermoablative temperatures and could be achieved in the prostate at low magnetic field strengths of 4–5 kA/m [ 183 , 184 ].

2.14. Next-Generation Sequencing

Recently, the development of next-generation sequencing (NGS) technologies has proven to be a substantial advancement in the documentation of unique genetic alterations that have improved our understanding of cancer cell biology [ 185 ]. Precision medicine, also known as personalized medicine, strives to produce individualized treatment plans and do away with “one-size-fits-all” approaches to therapy [ 186 ]. The development of personalized treatment was supported by NGS, which not only increased our understanding of cancer but also gave oncologists a strong tool for understanding each patient’s disease and its distinct genetic characteristics and whole-genome mutational status [ 187 , 188 ]. NGS can identify tumor-specific alterations with single-nucleotide resolution [ 189 ]. The NGS technologies are whole-genome, whole-exome, RNA, reduced representation bisulfite, and chromatin immunoprecipitation sequencing. The three crucial phases in NGS are library preparation and amplification, sequencing, and data analysis [ 190 ]. Even though the Sanger sequencing and PCR methods have long been used to examine tumor biomarkers, the development of NGS has made it possible to screen more genes in a single test. Predictive biomarkers have subsequently been developed to assist in selecting the right patient populations for clinical investigations. Additionally, NGS enables researchers to identify the most prevalent known variants as well as the long tail of uncommon mutations that occur in less than 1% of patients and can offer helpful data on treatment sensitivity [ 187 ].

The application of NGS in PC genomics has significantly advanced the systematic cataloging of all DNA alterations occurring in cancer [ 188 ]. The identification and production of novel long non-coding RNAs and novel gene fusions in PC have been greatly aided by the use of RNA sequencing. This has resulted in the discovery of new recurrent alterations that have been identified, which are TMPRSS2-ERG translocation, SPOP and CHD1 mutations, and chromoplexy, and also the pathways that have been previously well-established have been validated (e.g., androgen receptor overexpression and mutations; PTEN, RB1, and TP53 loss/mutations) [ 189 , 190 ]. DNA sequencing is now far more sensitive and scaleable due to NGS [ 191 ]. PC continues to present a significant challenge in terms of diagnosis and prognosis due to its highly diverse nature [ 192 ]. To more accurately determine the cancer’s aggressiveness, clinicopathological and radiological data should be combined with the knowledge gathered from NGS investigations [ 193 , 194 ]. Despite having great hopes for NGS benefits, there are a number of limitations to the method that should be taken into consideration [ 194 ]. Firstly, there are valid arguments against NGS replacing established and thoroughly supported histopathological diagnoses. Although NGS can often be utilized to identify and subtype various cancer entities, an accurate pathological examination should always come first [ 195 ]. Second, NGS from tumor biopsies only provides limited temporal and geographical resolution of the entire tumor since it can only evaluate DNA and RNA changes in a small group of tumor cells at a particular timepoint [ 196 ]. This issue can be approached from a variety of angles, including improving spatial resolution through novel techniques, single-cell sequencing, serial analysis of circulating cell-free nucleic acids or tumor cells, or pragmatically focusing on the actionability of specific targets via functional studies [ 197 ]. Third, the creation of the software tools required for the analysis and clinical interpretation of the “big data” produced by NGS to support clinical decision making is still lagging behind the hardware infrastructure that is currently in place for its calculation, management, and storage [ 198 ]. Additionally, significant bioinformatical work is required to directly compare data obtained on various NGS platforms and evaluated by various bioinformatic pipelines and algorithms. Therefore, the success of NGS and precision oncology depends greatly on efficient communication and constructive teamwork among all parties [ 199 ].

3. Conclusions

Prostate cancer is one of the leading causes of death in men globally, after lung disease. Commonly mutated genes, proteins, and pathways associated with an increased risk of prostate cancer development can be used as biomarkers for the disease, which provide information on the stage and cause of cancer. Biomarkers can also give specifications on the type of treatment required for cancer. There is an urgent need for effective and targeted specific treatment for prostate cancer. The current treatments available for prostate cancer are beneficial to only a few patients, and present numerous side effects that eventually affect the quality of life of most patients. Chemotherapy, radiotherapy, and hormonal treatment have adverse side effects, including drug resistance, which remains a setback to anticancer treatment. Many medicinal plants, gene therapy, and the application of nanotechnology currently in research have proven to reduce side effects as well as restore chemosensitivity in resistant tumor cells. Medicinal plant fractions and compounds, genetic material encapsulated in target-specific nanocarriers with controlled release, and targeted therapies based on cellular pathways appear to be promising alternatives for prostate cancer treatment.

Funding Statement

Reference: TTK200415513610, NRF grant no 129891.

Author Contributions

M.S., supervision—oversight and leadership of the research, planning and execution, critical review and editing of the manuscript, funding acquisition; K.R., summary, introduction, abstract, genetics, diagnosis, treatment options, alternative approaches, conclusion and referencing, review and editing, project administration; P.M., summary, introduction, abstract, genetics, diagnosis, treatment options, alternative approaches, conclusion and referencing; L.G., summary, introduction, abstract, diagnosis, treatment options, alternative approaches, conclusion referencing; A.A., genetics, treatment options, critical review and editing of the manuscript; S.M., review and editing of the manuscript. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Data availability statement, conflicts of interest.

The authors declare that there are no conflicts of interest that could be perceived as prejudicing the impartiality of this review.

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

• Introduction
• Conclusions
• Article Information

The forest plot summarizes relative effect (hazard ratios [HRs]) of different comparisons by volume of disease and timing of metastatic presentation derived from mixed treatment comparisons. An HR greater than 1 indicates potential clinical harm with the treatment; an HR less than 1 indicates potential clinical benefit with the treatment. 95% CIs crossing 1 indicate statistically nonsignificant results. API indicates androgen pathway inhibitors.

a Triplet therapy is abiraterone or darolutamide plus docetaxel and androgen deprivation therapy (ADT) in overall patient population. Triplet therapy is abiraterone plus docetaxel and ADT in high and low volume of disease.

b Triplet therapy is abiraterone or darolutamide plus docetaxel and ADT in overall patient population and in synchronous (de novo) metastases. Triplet therapy is darolutamide plus docetaxel and ADT in metachronous (recurrent) metastases.

Summary of relative and absolute risks for mixed treatment comparisons derived from frequentist network meta-analysis using 4 levels of certainty: high (further research very unlikely to change confidence in estimate of effect), moderate (further research likely to have important association with confidence in estimate of effect and may change the estimate), low (further research very likely to have important association with confidence in estimate of effect and likely to change the estimate), and very low (very uncertain about the estimate). Values in cells indicate relative and absolute effect estimates for comparisons between triplet therapies (abiraterone and darolutamide triplet therapies) and other treatment options (androgen pathway inhibitor [API] doublet, docetaxel doublet, and androgen deprivation therapy [ADT]). Each comparison consists of absolute reduction in risk of events (upper cell) with triplet therapies compared with other treatments, relative effect hazard ratios (HRs; upper middle cell), sample size contributive to evidence (lower middle cell), and relative rank of treatment in a row (lower cell). AE indicates adverse event; NSAA, nonsteroidal antiandrogen; OS, overall survival; PFS, progression-free survival; RCTs, randomized clinical trials; RR, relative risk; and TAK, orteronel.

a Rated down 2 levels owing to very serious imprecision, considering null effect and wide 95% CIs indicating both potential benefit and harm.

b Rated down 1 level owing to serious imprecision, considering wide 95% CIs.

c Rated down 1 level owing to serious indirectness in definition of PFS used across trials; PFS may be an advantageous end point for APIs owing to fixed dosing schedule of docetaxel compared with most API trials that used an indefinite dosing until disease progression.

Summary of relative and absolute risks for mixed treatment comparisons derived from frequentist network meta-analysis using 4 levels of certainty: high (further research very unlikely to change confidence in the estimate of effect), moderate (further research likely to have important association with confidence in estimate of effect and may change the estimate), low (further research very likely to have important association with confidence in estimate of effect and likely to change the estimate), and very low (very uncertain about the estimate). Values in cells indicate relative and absolute effect estimates for comparisons between triplet therapy (abiraterone triplet) and other treatment options (androgen pathway inhibitor [API] doublet, docetaxel doublet, and androgen deprivation therapy [ADT]) by volume of disease. Each comparison consists of absolute reduction in risk of events (upper cell) with triplet therapy compared with other treatments, relative effect hazard ratios (HRs; upper middle cell), sample size contributive to evidence (lower middle cell), and relative rank of treatment in a row (lower cell). NSAA indicates nonsteroidal antiandrogen; OS, overall survival; PFS, progression-free survival; and RCTs, randomized clinical trials.

a Rated down 2 levels owing to very serious imprecision, considering null effect, wide 95% CIs indicating both potential benefit and harm, and low sample size of less than 1000.

b Rated down 1 level owing to serious indirectness in definition of PFS used across trials; PFS may be an advantageous end point for APIs owing to fixed dosing schedule of docetaxel compared with most API trials that used an indefinite dosing until disease progression.

c Rated down 1 level owing to wide 95% CI.

eAppendix. Detailed Search Strategy and Methodology

eFigure 1. PRISMA Flowchart Outlining the Process of Study Selection

eFigure 2. Risk of Bias for Included Trials Assessing Patient-Important Outcomes

eFigure 3. Forest Plot Showing Overall Survival in the Overall Patient Population

eFigure 4. Forest Plot Showing Progression-Free Survival in the Overall Patient Population

eFigure 5. Forest Plot Showing Adverse Events (Grade 3 or Higher)

eFigure 6. Forest Plot Showing Overall Survival in the Overall Patient Population (Excluding Patients Who Received Docetaxel in 3 Trials)

eFigure 7. Forest Plot Showing Progression-Free Survival in the Overall Patient Population (Excluding Patients Who Received Docetaxel in 3 Trials)

eFigure 8. Forest Plot Showing Overall Survival in Low-Volume Disease

eFigure 9. Forest Plot Showing Overall Survival in High-Volume Disease

eFigure 10. Forest Plot Showing Progression-Free Survival in Low-Volume Disease

eFigure 11. Forest Plot Showing Progression-Free Survival in High-Volume Disease

eFigure 12. Forest Plot Showing Overall Survival in Synchronous Disease

eFigure 13. Forest Plot Showing Overall Survival in Metachronous Disease

eFigure 14. Forest Plot Showing Progression-Free Survival in Synchronous Disease

eFigure 15. Forest Plot Showing Progression-Free Survival in Metachronous Disease

eFigure 16. Forest Plot Showing Overall Survival in Younger Patients

eFigure 17. Forest Plot Showing Overall Survival in Older Patients

eFigure 18. Forest Plot Showing Progression-Free Survival in Younger Patients

eFigure 19. Forest Plot Showing Progression-Free Survival in Older Patients

eFigure 20. Forest Plot Showing Overall Survival With Gleason Score 8 or Higher

eFigure 21. Forest Plot Showing Overall Survival With Gleason Score 8 or Lower

eFigure 22. Forest Plot Showing Progression-Free Survival With Gleason Score 8 or Higher

eFigure 23. Forest Plot Showing Progression-Free Survival With Gleason Score 8 or Lower

eFigure 24. Forest Plot Showing Overall Survival With Performance Status Score 0

eFigure 25. Forest Plot Showing Overall Survival With Performance Status Score ½

eFigure 26. Forest Plot Showing Progression-Free Survival With Performance Status Score 0

eFigure 27. Forest Plot Showing Progression-Free Survival With Performance Status Score ½

eFigure 28. Forest Plot Showing Sensitivity Analysis for Overall Survival Excluding GETUG Trial

eFigure 29. Forest Plot Showing Sensitivity Analysis for Progression-Free Survival Excluding GETUG Trial

eFigure 30. Subgroup Analysis for Overall Survival by Choice of Doublet Therapy

eFigure 31. Subgroup Analysis for Progression-Free Survival by Choice of Doublet Therapy

eFigure 32. Subgroup Analysis for Overall Survival by Volume of Disease

eFigure 33. Subgroup Analysis for Progression-Free Survival by Volume of Disease

eFigure 34. Subgroup Analysis for Overall Survival in Low Volume by Choice of Doublet Therapy

eFigure 35. Subgroup Analysis for Overall Survival in High Volume by Choice of Doublet Therapy

eFigure 36. Subgroup Analysis for Progression-Free Survival in Low Volume by Choice of Doublet Therapy

eFigure 37. Subgroup Analysis for Progression-Free Survival in High Volume by Choice of Doublet Therapy

eFigure 38. Subgroup Analysis for Overall Survival by Mode of Metastatic Presentation

eFigure 39. Subgroup Analysis for Overall Survival in Synchronous Metastases by Choice of Doublet Therapy

eFigure 40. Subgroup Analysis for Overall Survival in Metachronous Metastases by Choice of Doublet Therapy

eFigure 41. Subgroup Analysis for Progression-Free Survival by Mode of Metastatic Presentation

eFigure 42. Subgroup Analysis for Overall Survival With Docetaxel Doublet Between High-Volume and Low-Volume Synchronous Disease

eFigure 43. Subgroup Analysis for Overall Survival With Docetaxel Doublet Between High-Volume and Low-Volume Metachronous Disease

eFigure 44. Subgroup Analysis for Overall Survival by Gleason Score

eFigure 45. Subgroup Analysis for Progression-Free Survival by Gleason Score

eFigure 46. Subgroup Analysis for Overall Survival by Performance Status Score

eFigure 47. Subgroup Analysis for Progression-Free Survival by Performance Status Score

eFigure 48. Subgroup Analyses for Overall Survival Excluding GETUG Trial

eFigure 49. Subgroup Analyses for Progression-Free Survival Excluding GETUG Trial

eFigure 50. Network Plots for Patient-Important Outcomes in Overall Population and Contemporary Subgroups

eFigure 51. Mixed Treatment Comparisons for Overall Survival in the Overall Patient Population

eFigure 52. Mixed Treatment Comparisons for Progression-Free Survival in the Overall Patient Population

eFigure 53. Mixed Treatment Comparisons for Adverse Events (Grade 3 or Higher) in the Overall Patient Population

eFigure 54. Mixed Treatment Comparisons for Overall Survival in the Overall Patient Population (Excluding Patients Who Received Docetaxel in 3 Trials)

eFigure 55. Mixed Treatment Comparisons for Progression-Free Survival in the Overall Patient Population (Excluding Patients Who Received Docetaxel in 3 Trials)

eFigure 56. Mixed Treatment Comparisons for Overall Survival in Low-Volume Disease

eFigure 57. Mixed Treatment Comparisons for Overall Survival in High-Volume Disease

eFigure 58. Mixed Treatment Comparisons for Progression-Free Survival in Low-Volume Disease

eFigure 59. Mixed Treatment Comparisons for Progression-Free Survival in High-Volume Disease

eFigure 60. Mixed Treatment Comparisons for Overall Survival in Synchronous Disease

eFigure 61. Mixed Treatment Comparisons for Overall Survival in Metachronous Disease

eFigure 62. Mixed Treatment Comparisons for Progression-Free Survival in Synchronous Disease

eFigure 63. Mixed Treatment Comparisons for Progression-Free Survival in Metachronous Disease

eFigure 64. Mixed Treatment Comparisons for Overall Survival in Younger Patients

eFigure 65. Mixed Treatment Comparisons for Overall Survival in Older Patients

eFigure 66. Mixed Treatment Comparisons for Progression-Free Survival in Younger Patients

eFigure 67. Mixed Treatment Comparisons for Progression-Free Survival in Older Patients

eFigure 68. Mixed Treatment Comparisons for Overall Survival With Gleason Score 8 or Higher

eFigure 69. Mixed Treatment Comparisons for Overall Survival With Gleason Score 8 or Lower

eFigure 70. Mixed Treatment Comparisons for Progression-Free Survival With Gleason Score 8 or Higher

eFigure 71. Mixed Treatment Comparisons for Progression-Free Survival With Gleason Score 8 or Lower

eFigure 72. Mixed Treatment Comparisons for Overall Survival With Performance Status Score 0

eFigure 73. Mixed Treatment Comparisons for Overall Survival With Performance Status Score ½

eFigure 74. Mixed Treatment Comparisons for Progression-Free Survival With Performance Status Score 0

eFigure 75. Mixed Treatment Comparisons for Progression-Free Survival With Performance Status Score ½

eFigure 76. Mixed Treatment Comparisons for Overall Survival in the Overall Population and High and Low Volume of Disease Excluding the GETUG Trial

eFigure 77. Mixed Treatment Comparisons for Overall Survival in Older and Younger Patients and Gleason Score 8 or Higher and Lower Than 8 Excluding the GETUG Trial

eFigure 78. Mixed Treatment Comparisons for Progression-Free Survival in the Overall Population and High and Low Volume of Disease Excluding the GETUG Trial

eFigure 79. Mixed Treatment Comparisons for Overall Survival Using Subgroup Data (Docetaxel and Nondocetaxel) From the PEACE-1 and ENZAMET Trials

eFigure 80. Mixed Treatment Comparisons for Progression-Free Survival Using Subgroup Data (Docetaxel and Nondocetaxel) From the PEACE-1 and ENZAMET Trials

eTable 1. Outcome Definitions in Included Clinical Trials

eTable 2. Overall Survival and Progression-Free Survival by Receipt of Docetaxel in the ENZAMET, ARCHES, and TITAN Trials

eTable 3. Proportions of Patients by Volume of Disease and Timing of Metastatic Presentation in Included Trials

eTable 4. Overall Survival Rate by Volume of Disease and Timing of Metastatic Presentation in Included Trials

eTable 5. Summary of Additional Trial and Population Characteristics

eTable 6. Summary of Subsequent Therapy Across the Included Trials

eTable 7. Overall Survival in Patients Receiving Doublet Therapy (API or Docetaxel) Stratified by Volume of Disease and Timing of Metastatic Presentation

eTable 8. Overall Survival With Docetaxel Doublet Therapy in Patients With High-Volume Disease and Low-Volume Synchronous and Metachronous Presentation

eTable 9. Progression-Free Survival With Doublet Therapy (API or Docetaxel) Compared With ADT by Clinically Relevant Subgroups

eTable 10. Survival Outcomes With Doublet Therapy (API or Docetaxel) Compared With ADT by Additional Subgroups of Interest

eTable 11. GRADE Summary of Findings Table Outlining Certainty of Evidence and Absolute Risks With Doublet Therapy Compared With ADT Alone in the Overall Patient Population

eTable 12. GRADE Summary of Findings Table Outlining Certainty of Evidence and Absolute Risks With Doublet Therapy Compared With ADT Alone in Clinically Relevant Prognostic Subgroups

eTable 13. GRADE Summary of Findings Table Outlining Certainty of Evidence and Absolute Risks With Triplet Therapy Compared With Other Treatments by Timing of Metastatic Presentation

eTable 14. Adverse Events and Patient-Level Considerations for Androgen Pathway Inhibitors (API) in Patients With mCSPC

eTable 15. Reporting Matrix Outlining the Heterogeneity in Health-Related Quality-of-Life Assessment in Included Trials

eTable 16. Summary of the Quality of Life With Contemporary Systemic Therapies in Patients With mCSPC

eTable 17. Reporting Matrix for Outcomes Assessed in Included Trials

eTable 18. Strengths

eTable 19. Limitations

Data Sharing Statement

• Triplet Therapy in Metastatic Hormone-Sensitive Prostate Cancer JAMA Oncology Editorial May 1, 2023 Deaglan J. McHugh, MD; Howard I. Scher, MD

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Riaz IB , Naqvi SAA , He H, et al. First-line Systemic Treatment Options for Metastatic Castration-Sensitive Prostate Cancer : A Living Systematic Review and Network Meta-analysis . JAMA Oncol. 2023;9(5):635–645. doi:10.1001/jamaoncol.2022.7762

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First-line Systemic Treatment Options for Metastatic Castration-Sensitive Prostate Cancer : A Living Systematic Review and Network Meta-analysis

• 1 Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
• 2 Division of Hematology and Oncology, Department of Internal Medicine, Mayo Clinic, Phoenix, Arizona
• 3 Department of Informatics, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
• 4 Department of Artificial Intelligence and Informatics, Mayo Clinic, Rochester, Minnesota
• 5 Department of Internal Medicine, Creighton University, Omaha, Nebraska
• 6 Department of Internal Medicine, University of Toledo, Toledo, Ohio
• 7 Department of Oncology and Metabolism, The University of Sheffield, Sheffield, United Kingdom
• 8 Division of Preventive, Occupational and Aerospace Medicine, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota
• 9 Department of Urology, Mayo Clinic, Rochester, Minnesota
• 10 Division of Population Sciences, Harvard Medical School, Boston, Massachusetts
• Editorial Triplet Therapy in Metastatic Hormone-Sensitive Prostate Cancer Deaglan J. McHugh, MD; Howard I. Scher, MD JAMA Oncology

Question   How can the most effective systemic treatment for heterogeneous metastatic castration-sensitive prostate cancer (mCSPC) be chosen?

Findings   In this living systematic review and network meta-analysis of 10 clinical trials with 11 043 patients with mCSPC, abiraterone triplet therapy was ranked potentially as the most efficacious treatment for high-volume disease and was associated with significant improvement in survival compared with doublet regimens. For low-volume and metachronous disease, androgen pathway inhibitor (API) doublet therapies were ranked potentially as the most efficacious treatment options and were not significantly different from triplet regimen.

Meaning   The results of this systematic review and meta-analysis found that triplet therapy may be preferred for synchronous (de novo) high-volume disease; API doublet therapies may be preferred for metachronous (recurrent) low-volume disease.

Importance   The effectiveness of triplet therapy compared with androgen pathway inhibitor (API) doublets in a heterogeneous patient population with metastatic castration-sensitive prostate cancer (mCSPC) is unknown.

Objective   To assess the comparative effectiveness of contemporary systemic treatment options for patients with mCSPC across clinically relevant subgroups.

Data Sources   For this systematic review and meta-analysis, Ovid MEDLINE and Embase were searched from each database’s inception (MEDLINE, 1946; Embase, 1974) through June 16, 2021. Subsequently, a “living” auto search was created with weekly updates to identify new evidence as it became available.

Study Selection   Phase 3 randomized clinical trials (RCTs) assessing first-line treatment options for mCSPC.

Data Extraction and Synthesis   Two independent reviewers extracted data from eligible RCTs. The comparative effectiveness of different treatment options was assessed with a fixed-effect network meta-analysis. Data were analyzed on July 10, 2022.

Main Outcomes and Measures   Outcomes of interest included overall survival (OS), progression-free survival (PFS), grade 3 or higher adverse events, and health-related quality of life.

Results   This report included 10 RCTs with 11 043 patients and 9 unique treatment groups. Median ages of the included population ranged from 63 to 70 years. Current evidence for the overall population suggests that the darolutamide (DARO) triplet (DARO + docetaxel [D] + androgen deprivation therapy [ADT]; hazard ratio [HR], 0.68; 95% CI, 0.57-0.81), as well as the abiraterone (AAP) triplet (AAP + D + ADT; HR, 0.75; 95% CI, 0.59-0.95), are associated with improved OS compared with D doublet (D + ADT) but not compared with API doublets. Among patients with high-volume disease, AAP + D + ADT may improve OS compared with D + ADT (HR, 0.72; 95% CI, 0.55-0.95) but not compared with AAP + ADT, enzalutamide (E) + ADT, and apalutamide (APA) + ADT. For patients with low-volume disease, AAP + D + ADT may not improve OS compared with APA + ADT, AAP + ADT, E + ADT, and D + ADT.

Conclusions and Relevance   The potential benefit observed with triplet therapy must be interpreted with careful accounting for the volume of disease and the choice of doublet comparisons used in the clinical trials. These findings suggest an equipoise to how triplet regimens compare with API doublet combinations and provide direction for future clinical trials.

Intensification of androgen deprivation therapy (ADT) with androgen pathway inhibitor (API) agents (abiraterone [AAP], apalutamide [APA], and enzalutamide [E]) 1 - 5 or chemotherapy (docetaxel [D]) 6 , 7 for patients with metastatic castration-sensitive prostate cancer (mCSPC) has been demonstrated to delay disease progression and prolong patient survival. Recently, the PEACE-1 trial 8 and the ARASENS trial 9 showed incremental benefit among patients with mCSPC with the further intensification of treatment using triplet therapy (API + D + ADT). The PEACE-1 trial found that the combination of AAP acetate and D caused a substantial delay in disease progression and a remarkable improvement in overall survival (OS; 25% risk reduction in death). 8 Similarly, the ARASENS trial showed that adding darolutamide (DARO) to D doublet resulted in a consistent delay in disease progression and survival benefit (32.5% risk reduction of death). 9 Both PEACE-1 (100%) and ARASENS (86%) primarily included patients at high risk with synchronous (de novo) presentation.

The availability of multiple effective therapies and the clinical heterogeneity of patients with mCSPC make the choice of optimal treatment complicated. First, available evidence indicates that the D treatment effect for patients with mCSPC may vary by volume of disease and timing of metastatic presentation. 10 - 12 Second, it is unknown how triplet therapy compares with API doublets. Thus, the absence of evidence comparing triplet therapy with API doublets together with the prognostic variability by volume of disease provides a compelling rationale to conduct a systematic review and assess the comparative effectiveness of current treatment options in the overall patient population with mCSPC and across clinically relevant subgroups.

Here, we reported the contemporary findings from a network meta-analysis, with a particular emphasis on triplet vs API doublet comparisons in the context of clinically relevant subgroups defined by volume of disease and timing of metastatic presentation. We also maintained a living evidence profile for systemic treatment options for patients with mCSPC patients, using the “living” interactive evidence synthesis framework. 13

This systematic review and meta-analysis is reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses ( PRISMA ) reporting guideline extension statement for systematic reviews, incorporating network meta-analyses for health care interventions. 14 This study is registered at the open science framework (OSF) registries. 15

Embase and Ovid MEDLINE were searched from each database’s inception (MEDLINE, 1946; Embase, 1974) through July 10, 2022, to retrieve published reports of mCSPC clinical trials. The detailed living search strategy and eligibility criteria are provided in the eAppendix in Supplement 1 .

Patient-important outcomes included OS, radiographic or clinical progression-free survival (PFS), grade 3 or higher adverse events, and health-related quality of life. These outcomes were defined in accordance with definitions in the included clinical trials (eTable 1 in Supplement 1 ). Clinically relevant subgroups were mainly defined by timing of metastatic presentation (synchronous [de novo] and metachronous [recurrent]) and volume of disease (high and low). In instances in which an eligible trial had multiple reports, data from most updated or longest follow-up were included in the analysis. The quality of included trials was assessed with the Cochrane Risk of Bias Tool, version 2. 16 This process of data extraction and quality assessment was carried out by 2 independent reviewers (I.B.R. and S.A.A.N.). Discrepancies in the process were resolved by consensus and input from a senior reviewer (A.H.B.).

A DerSimonian and Laird random-effects meta-analysis was conducted to make direct (pairwise) comparisons. The Cochran Q test was used to assess statistically significant heterogeneity not explained by chance, whereas I 2 was used to quantify the total observed variability due to between-study heterogeneity. Statistical significance was established with a 2-sided α level of .05 and .1 for primary and subgroup analyses, respectively. Details for pairwise meta-analysis are described in the eAppendix in Supplement 1 . Data were analyzed on July 10, 2022.

Direct evidence and indirect evidence were used to compute mixed treatment comparisons using a multivariate metaregression within the frequentist framework. 17 , 18 Both fixed-effect and random-effects models were fitted; however, the final choice of model was made according to a priori criteria, and the fixed-effect model was used if the network was open and sparse, given that the common between-study heterogeneity cannot be estimated reliably in such networks. 19 Relative treatment rankings for each outcome were assessed with a P score and were evaluated according to their congruence with pairwise estimates. 20 A higher relative treatment rank indicated potentially better efficacy and safety. Details are described in the eAppendix in Supplement 1 .

Secondary analyses were performed for prespecified subgroups of interest, which are described in the eAppendix in Supplement 1 . All statistical analyses were conducted in R, version 4.1.1 (R Foundation for Statistical Computing). Pairwise and network meta-analyses were conducted with meta version 5.1-1 and netmeta version 2.0-1, respectively.

The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess the certainty of evidence. 21 , 22 Details are described in the eAppendix in Supplement 1 .

This present report from a living systematic review includes data from 10 clinical trials (28 references) published as of July 10, 2022. 1 - 9 , 11 , 23 - 40 The process of study selection is shown in the PRISMA flowchart (eFigure 1 in Supplement 1 ). All results of this systematic review are available on the Living Interactive Systematic Reviews website. 13

A total of 11 043 patients and 9 unique treatment options were assessed. Median ages of the included population ranged from 63 to 70 years. Data for race and ethnicity were not collected because the published trials included in this meta-analysis did not consistently report outcomes by race and ethnicity. All included clinical trials followed a randomized phase 3 design; most were open-label trials, and only 4 were double-blinded trials. All trials included only patients with mCSPC except STAMPEDE, which included a small subset of patients with high-risk localized prostate cancer. 4 , 6 The PEACE-1 trial 8 reported data for both the overall population and patients who received D; however, only data for patients who received D were used for analysis. The overall risk of bias for OS outcome was low for all trials. Some concerns due to the open-label nature of the trials were raised for the assessment of PFS and grade 3 or higher adverse events. A detailed summary of the risk of bias is provided in eFigure 2 in Supplement 1 . Additional baseline trial and population characteristics are outlined in Table 1 1 - 9 , 24 , 27 and eTables 5 and 6 in Supplement 1 . Proportions of patients and clinical outcomes by volume of disease and timing of metastatic presentation are outlined in eTable 3 and eTable 4 in Supplement 1 , respectively.

Direct comparative meta-analysis was derived from 8 trials, 1 - 7 , 11 , 23 , 24 , 26 - 29 , 31 , 39 , 40 some with more than 1 published report, that assessed doublet regimens (either API or D as add-on treatments to ADT) vs ADT alone. The relative efficacy of the control group—nonsteroidal antiandrogen (including bicalutamide, flutamide, or nilutamide) and ADT—in 2 trials 3 , 24 was considered equivalent to ADT for the purpose of pooling studies. Doublet therapy was associated with statistically significant OS benefit compared with ADT alone in the overall population. Detailed results are shown in eFigures 3 to 7 in Supplement 1 .

Results by choice of doublet therapy, volume of disease, and timing of metastatic presentation are outlined in Table 2 3 , 4 , 6 , 8 , 9 (for OS, see eTables 7 and 8 in Supplement 1 ; for PFS outcome, see eTable 9 in Supplement 1 ). For patients with low-volume disease, API doublet was significantly associated with OS improvement compared with ADT alone (hazard ratio [HR], 0.58; 95% CI, 0.49-0.68; I 2  = 0%); however, no statistically significant association was observed with D doublet compared with ADT (HR, 0.91; 95% CI, 0.73-1.13; I 2  = 0%). There was a statistically significant effect modification by the choice of doublet therapy for patients with low-volume disease ( P  < .01 for heterogeneity). In contrast, there was no statistically significant effect modification by choice of doublet therapy for patients with high-volume disease in regard to OS benefit. The detailed results of additional analyses are shown in eFigures 8 to 49 and eTable 10 in Supplement 1 .

A total of 10 trials 1 - 9 , 11 , 23 - 29 , 31 , 39 , 40 contributed to the network for OS outcome, 9 trials 1 - 8 , 11 , 23 - 29 , 31 for PFS, and 8 trials 1 - 6 , 8 , 24 for grade 3 or higher adverse events (some trials had more than 1 published report). Network plots are shown in eFigure 50 in Supplement 1 . Results from the fixed-effect model are reported here considering the open network geometry with sparse direct evidence. Mixed treatment comparisons were also made with a random-effects model that indicated consistent direction of the results but wider 95% CIs.

In the overall population, mixed treatment comparisons showed a statistically significant improvement in OS with DARO + D + ADT (HR, 0.68; 95% CI, 0.57-0.81; rank 1) and AAP + D + ADT (HR, 0.75; 95% CI, 0.59-0.95; rank 2) compared with D + ADT (rank 6). However, no statistically significant association was observed with triplet regimens compared with APA + ADT (rank 3), E + ADT (rank 4), and AAP + ADT (rank 5) regarding OS improvement. The AAP + D + ADT treatment (rank 1) was associated with statistically significant PFS improvement compared with AAP + ADT (HR, 0.61; 95% CI, 0.41-0.91; rank 4) and D + ADT (HR, 0.50; 95% CI, 0.35-0.72; rank 6). However, no statistically significant association was observed with AAP + D + ADT compared with E + ADT (rank 2) and APA + ADT (rank 3). The PFS data for DARO + D + ADT are not available. 9 The results of mixed treatment comparisons for OS and PFS were consistent when patients who received D in ENZAMET, 3 ARCHES, 1 , 25 and TITAN 2 , 31 were excluded (eTable 2 in Supplement 1 ). In terms of safety, AAP + D + ADT (rank 8) was associated with an increased risk of grade 3 or higher adverse events compared with D + ADT (relative risk [RR], 1.22; 95% CI, 1.07-1.39; rank 6), AAP + ADT (RR, 1.23; 95% CI, 1.04-1.47; rank 5), APA + ADT (RR, 1.45; 95% CI, 1.18-1.78; rank 4), and E + ADT (RR, 1.80; 95% CI, 1.39-2.34; rank 2). The DARO + D + ADT treatment (rank 7) was also associated with an increased risk of grade 3 or higher adverse events compared with APA + ADT (RR, 1.23; 95% CI, 1.04-1.47) and E + ADT (RR, 1.55; 95% CI, 1.22-1.96) but not compared with D + ADT (RR, 1.04; 95% CI, 0.97-1.12). Detailed results of these analyses are shown in eFigures 51 to 55 in Supplement 1 .

Data were not available by volume of disease for DARO + D + ADT. For patients with high-volume disease, AAP + D + ADT (rank 1) was associated with a significant improvement in OS compared with D + ADT (HR, 0.72; 95% CI, 0.55-0.95; rank 5) but not compared with AAP + ADT (rank 2), E + ADT (rank 3), or APA + ADT (rank 4). The AAP + D + ADT treatment (rank 1) was associated with significant PFS improvement in patients with high-volume disease compared with APA + ADT (HR, 0.54; 95% CI, 0.32-0.90; rank 4) and D + ADT (HR, 0.47; 95% CI, 0.30-0.73; rank 5). However, no significant improvement was observed with AAP + D + ADT compared with E + ADT (HR, 0.66; 95% CI, 0.39-1.13; rank 2) and AAP + ADT (HR, 0.62; 95% CI, 0.38-1.00; rank 3).

For patients with low-volume disease, AAP + D + ADT (rank 4) was not associated with statistically significant OS improvement compared with APA + ADT (HR, 1.45; 95% CI, 0.73-2.89; rank 1), AAP + ADT (HR, 1.27; 95% CI, 0.68-2.33; rank 2), E + ADT (HR, 1.14; 95% CI, 0.56-2.32; rank 3), or D + ADT (HR, 0.83; 0.50-1.38; rank 5). Similar results were observed regarding PFS improvement. Efficacy by volume of disease was not available for DARO + D + ADT. A summary of clinically important comparisons by volume of disease and timing of metastatic presentation is shown in Figure 1 . The detailed results of these analyses are available in eFigures 56 to 80 in Supplement 1 .

Summaries of findings for pairwise comparisons between doublet therapy and ADT are provided in eTables 11 and 12 in Supplement 1 . A summary of findings for mixed treatment comparisons in the overall patient population is outlined in Figure 2 . Absolute estimates by volume of disease and timing of metastatic presentation were derived from subgroup data from trials and had low to moderate certainty of evidence ( Figure 3 ; eTable 13 in Supplement 1 ).

This report from a “living systematic” review presents the benefits and harms of contemporary treatment options with relative and absolute effect estimates across patient-important outcomes by volume of disease for patients with mCSPC. Using mixed treatment comparison methods, we provided the most up-to-date evidence for performance of triplet therapy compared with API-based doublets, a question not answered in clinical trials but paramount to clinical practice and design of future clinical trials. In the overall population, intensified treatment with triplet therapies improved OS compared with D + ADT but not compared with API doublets. These results remained consistent even after exclusion of patients who received D in the ENZAMET, 3 ARCHES, 1 , 25 and TITAN 2 , 31 trials. Although triplet regimens offer promising efficacy, they do so at the expense of increased toxicity. The API doublets were ranked the safest treatment options in terms of the risk of grade 3 or higher adverse events. Our analysis also suggests that volume of disease and timing of metastatic presentation (synchronous vs metachronous) may offer insights into treatment selection for patients with mCSPC until more sophisticated and validated biomarkers become available ( Figure 1 ).

The available evidence suggests that patients with high-volume disease appear to derive the greatest benefit from triplet therapy (AAP + D + ADT). Although data by volume of disease were not available from the ARASENS trial, 9 the present analysis showed that triplet therapy with AAP + D + ADT may delay disease progression compared with D + ADT and API doublets, such as APA + ADT. For patients with low-volume disease, triplet therapy with AAP + D + ADT did not show a survival benefit compared with D + ADT and may perform worse compared with API-based doublets. Patients with low-volume disease derived greater treatment benefit with API doublets compared with D + ADT ( Table 2 ; eFigure 34 in Supplement 1 ). The API-based doublets appear to be the most efficacious and least toxic treatment options in this patient population. Lack of benefit with D intensification in patients with low-volume disease is consistent with the combined analysis of the CHAARTED and GETUG-AFU15 trials, which showed that the addition of D to ADT had a consistent effect of improving survival among patients with high volume of disease but not among patients with low-volume disease. 10 It is possible that volume is an effective surrogate for the underlying disease biology, with high-volume disease containing a higher proportion of patients from androgen receptor–independent populations, thus explaining the heterogeneity of the treatment effect. Alternatively, the small sample size in the D subgroup may have precluded statistical significance and the potential OS benefit for patients with low volume of disease owing to insufficient power.

Our analysis also suggests that the timing of metastatic presentation may be particularly important for patients presenting with low-volume disease. Patients with low-volume metachronous (recurrent) presentation are less likely to benefit from D doublets (eTable 8 and eFigures 42 and 43 in Supplement 1 ). Similarly, the lack of D benefit observed in patients with low-volume disease from the combined CHAARTED and GETUG-AFU15 trials’ analysis may have been associated with metachronous (recurrent) metastases in one-fourth of patients. In contrast, a post hoc analysis of group C of the STAMPEDE trial, 28 which included 95% of the patients who had synchronous (de novo) metastases, found no evidence of a difference in survival between patients with high and patients with low metastatic volume. Taken together, these findings, along with the STOPCaP individual patient data meta-analysis, 41 suggest that although D has a modest benefit in synchronous (de novo) low-volume metastases, the lack of any PFS or OS benefit indicates that the risks outweigh the benefits in low-volume metachronous (recurrent) presentation.

It remains important to critically analyze toxicity when considering treatment escalation. Sixteen of 1774 treatment-related deaths (0.90%) were observed in trials assessing the addition of D to ADT, 6 , 7 , 27 and 34 of 1039 treatment-related deaths (3.27%) were observed in trials assessing the addition of D to API + ADT. 8 , 9 These findings suggest caution with the use of D for patients with a low volume of disease who tend to live naturally longer, especially those with metachronous presentation with a median OS of 8 years with ADT alone. 12 Our analysis showed that DARO + D + ADT, AAP + D + ADT, and D + ADT were ranked the least in terms of grade 3 or higher adverse events. Hence, it would be plausible to favor API doublets for older and less fit patients. However, the choice of an optimal API doublet may be guided by unique toxic effects and patient-level consideration (eTable 14 in Supplement 1 ). The reporting of health-related quality of life across the included trials is summarized in eTables 15 and 16 in Supplement 1 . Health-related quality-of-life data are still emerging and will offer further guidance on treatment selection for patients with mCSPC. As treatment moves toward intensification with triplet therapy, even the use of doublet agents remains suboptimal in actual clinical practice. More than two-thirds of patients are being prescribed ADT only. In fact, the use of API doublets in clinical practice has been decreasing. 42 , 43 This may be due to the cost and access to the intensified treatments. In terms of the US-based health care perspective, intensification with D is likely to be the most cost-effective treatment for the overall population with mCSPC. However, future cost-effectiveness analysis adjusting for volume of disease and timing of metastatic presentation is required and may offer additional insights.

Our approach to living systematic reviews represents the next generation of systematic reviews, enhanced by a semiautomated approach through a framework supported by advanced programming and artificial intelligence. Our website (not peer reviewed) is updated every Monday with the most contemporary evidence. The strengths of this study are highlighted in eTable 18 in Supplement 1 . The present study is limited by a small number of trials with sparse direct comparative evidence and an open network that did not allow us to assess incoherence for most comparisons and precluded formal assessment of publication bias. Patients in the trials assessing D doublet therapies were less likely to receive subsequent life-prolonging API therapies (eTable 6 in Supplement 1 ). Moreover, there was variability in PFS definitions and inconsistent reporting of other patient-important end points across the included trials (eTable 17 in Supplement 1 ), different follow-up durations for treatments, limited efficacy data by volume of disease for triplet therapy, use of post hoc subgroup analyses in the included trials, and a lack of patient-level data that could potentially offer more granular estimates. Detailed discussion on limitations is provided in eTable 19 in Supplement 1 .

The findings of this systematic review and meta-analysis indicate that the decision of treatment intensification with triplet therapy for patients with mCSPC must be considered carefully by accounting for the volume of disease, the timing of metastatic presentation, and API doublet options with significant survival benefit and fitness for chemotherapy. These findings provide direction for future clinical trials and suggest an equipoise to the question of how triplet regimens compare with API doublet combinations. In summary, triplet therapy may be preferred for fit patients with synchronous (de novo) high-volume disease. The API doublet combinations may be preferred for patients with metachronous (recurrent) low-volume disease ( Figure 1 ). The choice of treatment with metachronous (recurrent) high-volume disease and synchronous (de novo) low-volume disease requires an individualized risk-based approach, including consideration of patient comorbidities. Evidence in this regard is rapidly increasing, and the results of this living meta-analysis will be updated as new data are published.

Accepted for Publication: December 1, 2022.

Published Online: March 2, 2023. doi:10.1001/jamaoncol.2022.7762

Corresponding Author: Irbaz Bin Riaz, MD, PhD, Dana-Farber Cancer Institute, 450 Brookline Ave, Dana 1017, Boston, MA 02215 ( [email protected] ).

Author Contributions: Drs Riaz and Naqvi had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Van Allen and Bryce contributed equally as senior authors.

Concept and design: Riaz, Naqvi, He, Asghar, Singh, Murad, Sweeney, Van Allen, Bryce.

Acquisition, analysis, or interpretation of data: Riaz, Naqvi, He, Asghar, Siddiqi, Liu, Childs, Ravi, Hussain, Murad, Boorjian, Sweeney, Van Allen, Bryce.

Drafting of the manuscript: Riaz, Naqvi, He, Siddiqi, Singh, Sweeney.

Critical revision of the manuscript for important intellectual content: Naqvi, He, Asghar, Liu, Singh, Childs, Ravi, Hussain, Murad, Boorjian, Sweeney, Van Allen, Bryce.

Statistical analysis: Riaz, Naqvi, He, Sweeney.

Obtained funding: Liu, Bryce.

Administrative, technical, or material support: He, Liu, Hussain, Sweeney, Bryce.

Supervision: Asghar, Liu, Singh, Childs, Hussain, Murad, Boorjian, Sweeney, Van Allen, Bryce.

Conflict of Interest Disclosures: Dr Singh reported serving on advisory boards for Aveo Pharmaceuticals, Bayer Healthcare Pharmaceuticals, EMD Serono Inc, and Janssen Research & Development, LLC. Dr Childs reported receiving grants from Janssen Pharmaceuticals directed to his institution for research purposes and personal fees from IntrinsiQ Specialty Solutions and Targeted Oncology outside the submitted work. Dr Hussain reported receiving personal fees from Boehringer Ingelheim, Pierre Fabre, Bayer, Roche, Merck, Janssen, Bristol Myers Squibb, AstraZeneca, Pfizer, Gilead, Astellas, MSD, Eisai, GSK, and Ipsen; and grants from Boehringer Ingelheim, Pfizer, Cancer Research United Kingdom, Medical Research Council/National Institute for Health and Care Research, Roche, Pierre Fabre, and Janssen outside the submitted work. Dr Boorjian reported receiving consulting fees from Ferring, FerGene, ArTara, and Prokarium outside the submitted work. Dr Sweeney reported receiving personal fees from Janssen, Astellas, Pfizer, Bayer, Sanofi, Genentech, and Lilly outside the submitted work; receiving grants from Janssen, Astellas, Sanofi, Bayer, Sotio, and Dendreon; holding patents or receiving royalties from Indiana University, Exelixis, and Leuchemix; and owning stock in Leuchemix. Dr Van Allen reported receiving personal fees from Roche/Genentech, Tango Therapeutics, Genome Medical, Genomic Life, Monte Rosa Therapeutics, Manifold Bio, Illumina, Enara Bio, Novartis, Foaley & Hoag, Riva Therapeutics, and Janssen; receiving grants from Novartis, BMS, Janssen, and Sanofi outside the submitted work; holding an institutional patent on chromatin mutations and immunotherapy response and having a pending patent for methods for clinical interpretation; and serving on the editorial board for JCO Precision Oncology and Science Advances. Dr Bryce reported receiving grants from Janssen; funding to his institution from Janssen, AstraZeneca, and Gilead; receiving personal fees from AstraZeneca, Merck, Bayer, Elsevier, Fallon Medica, Horizon CME, PRIME Education, MJH Life Sciences, and Novartis outside the submitted work; and holding a patent for therapeutic targeting of cancer patients with NRG1 rearrangements. No other disclosures were reported.

Data Sharing Statement: See Supplement 2 .

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Potential Benefits of Green Tea in Prostate Cancer Prevention and Treatment: A Comprehensive Review

• Herbal and Botanical Review
• Published: 02 April 2024

Cite this article

• Gui-hong Liu 1 ,
• Ze-qin Yao 1 ,
• Guo-qiang Chen 1 ,
• Ya-lang Li 2 &
• Bing Liang 1  

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Prostate cancer is a prevalent and debilitating disease that necessitates effective prevention and treatment strategies. Green tea, a well-known beverage derived from the Camellia sinensis plant, contains bioactive compounds with potential health benefits, including catechins and polyphenols. This comprehensive review aims to explore the potential benefits of green tea in prostate cancer prevention and treatment by examining existing literature. Green tea possesses antioxidant, anti-inflammatory, and anti-carcinogenic properties attributed to its catechins, particularly epigallocatechin gallate. Epidemiological studies have reported an inverse association between green tea consumption and prostate cancer risk, with potential protection against aggressive forms of the disease. Laboratory studies demonstrate that green tea components inhibit tumor growth, induce apoptosis, and modulate signaling pathways critical to prostate cancer development and progression. Clinical trials and human studies further support the potential benefits of green tea. Green tea consumption has been found to be associated with a reduction in prostate-specific antigen levels, tumor markers, and played a potential role in slowing disease progression. However, challenges remain, including optimal dosage determination, formulation standardization, and conducting large-scale, long-term clinical trials. The review suggests future research should focus on combinatorial approaches with conventional therapies and personalized medicine strategies to identify patient subgroups most likely to benefit from green tea interventions.

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Liu, Gh., Yao, Zq., Chen, Gq. et al. Potential Benefits of Green Tea in Prostate Cancer Prevention and Treatment: A Comprehensive Review. Chin. J. Integr. Med. (2024). https://doi.org/10.1007/s11655-024-4100-2

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Functional Quality-of-Life Outcomes Reported by Men Treated for Localized Prostate Cancer: A Systematic Literature Review

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• 1 University College Hospital in London.
• 2 Churchill Hospital in Oxford.
• 3 Oxford Brookes University in Oxford.
• PMID: 26906131
• DOI: 10.1188/16.ONF.199-218

Problem identification: To systematically evaluate the literature for functional quality-of-life (QOL) outcomes following treatment for localized prostate cancer. .

Literature search: The MEDLINE®, CINAHL®, EMBASE, British Nursing Index, PsycINFO®, and Web of Science™ databases were searched using key words and synonyms for localized prostate cancer treatments. .

Data evaluation: Of the 2,191 articles screened for relevance and quality, 24 articles were reviewed. Extracted data were tabulated by treatment type and sorted by dysfunction using a data-driven approach. .

Synthesis: All treatments caused sexual dysfunction and urinary side effects. Radiation therapy caused bowel dysfunction, which could be long-term or resolved within a few years. Sexual function could take years to return. Urinary incontinence resolved within two years of surgery but worsened following radiation therapy. Fatigue was worse during treatment with adjuvant androgen-deprivation therapy, and some men experienced post-treatment fatigue for several years. .

Conclusions: This review identified that QOL outcomes reported by men following different treatments for localized prostate cancer are mostly recorded using standardized health-related QOL outcome measures. Such outcome measures collect data about body system functions but limit understanding of men's QOL following treatment for prostate cancer. Holistic outcome measures are needed to capture data about men's QOL for several years following the completion of treatment for localized prostate cancer. .

Implications for practice: Nurses need to work with men to facilitate information sharing, identify supportive care needs, and promote self-efficacy, and they should make referrals to specialist services, as appropriate.

Keywords: EBRT; androgen deprivation; brachytherapy; cancer; prostate; prostatectomy.

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• Research Support, Non-U.S. Gov't
• Systematic Review
• Aged, 80 and over
• Middle Aged
• Prostatectomy / adverse effects*
• Prostatic Neoplasms / complications
• Prostatic Neoplasms / psychology*
• Prostatic Neoplasms / therapy*
• Quality of Life / psychology*
• Sexual Dysfunction, Physiological / etiology
• Sexual Dysfunction, Physiological / psychology*
• United Kingdom
• Urinary Incontinence / etiology
• Urinary Incontinence / psychology*

Correlates of illness uncertainty in cancer survivors and family caregivers: a systematic review and meta-analysis

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• Other Affiliation: Syracuse University
• Affiliation: School of Social Work
• Other Affiliation: Johns Hopkins University
• Other Affiliation: Arizona State University
• Other Affiliation: UT Health San Antonio
• Purpose: Illness uncertainty is widely recognized as a psychosocial stressor for cancer survivors and their family caregivers. This systematic review and meta-analysis aimed to identify the sociodemographic, physical, and psychosocial correlates that are associated with illness uncertainty in adult cancer survivors and their family caregivers. Methods: Six scholarly databases were searched. Data synthesis was based on Mishel’s Uncertainty in Illness Theory. Person’s r was used as the effect size metric in the meta-analysis. Risk of bias was assessed using the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. Results: Of 1116 articles, 21 articles met the inclusion criteria. Of 21 reviewed studies, 18 focused on cancer survivors, one focused on family caregivers, and 2 included survivors and family caregivers. Findings identified distinct correlates for illness uncertainty in cancer survivors, including sociodemographic factors (e.g., age, gender, race), stimuli frame (e.g., symptom, family history of cancer), structure providers (e.g., education), coping, and adaptation. Notable effect sizes were observed in the correlations between illness uncertainty and social support, quality of life, depression, and anxiety. Caregivers’ illness uncertainty was associated with their race, general health, perception of influence, social support, quality of life, and survivors’ prostate-specific antigen levels. Insufficient data precluded examining effect size of correlates of illness uncertainty among family caregivers. Conclusion: This is the first systematic review and meta-analysis to summarize the literature on illness uncertainty among adult cancer survivors and family caregivers. Findings contribute to the growing literature on managing illness uncertainty among cancer survivors and family caregivers.
• Cancer survivors
• Meta-analysis
• Quality of life
• Illness uncertainty
• Systematic review
• Family caregiver
• https://doi.org/10.17615/q3k3-h157
• https://dx.doi.org/10.1007/s00520-023-07705-7
• Supportive Care in Cancer
• Springer Science and Business Media Deutschland GmbH

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• Published: 23 January 2024

Best of 2023 in Prostate Cancer and Prostatic Diseases

• Cosimo De Nunzio   ORCID: orcid.org/0000-0002-2190-512X 1 &
• Riccardo Lombardo   ORCID: orcid.org/0000-0003-2890-3159 1  

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In recent years, several authors have focused on the role of social determinants of health (SDOH) in prostate cancer (PCa), which may have a significant impact on access to treatment and survival rates. The notable advancements in surgical and medical treatments for PCa have, however, exacerbated disparities due to the high costs associated with new diagnostic pathways and therapies. The present clearly represents a gap which needs to be filled. As a result, urologist and oncologist are actively fighting to reduce these disparities and the emerging literature is identifying areas where the most significant discrepancies exist [ 1 , 2 ].

Regarding prostate cancer diagnosis, the best strategy to perform prostate biopsy is still a great matter of debate. Although we are slowly abandoning the transrectal (TR) route, the number of unnecessary biopsies and insignificant cancers detected still represent an unmet need. Consequently, an increasing interest in evaluating different biopsy schemes is clearly gaining momentum across the PCa panorama. However, for the time being the trans-perineal (TP) route including target and random biopsies still represents the gold standard [ 3 , 4 , 5 , 6 , 7 ].

Treatment of localized PCa involves several lacks which need to be addressed too. The efficacy of focal therapy in PCa treatment remains questionable. Despite various publications on the topic, its application is only advised within the context of well-designed clinical trials.

Besides, authors are focusing on identifying patients at risk of relapse after localized treatment in order to refine their management [ 8 , 9 , 10 ]. The introduction of genomic classifiers and new-generation imaging is clearly improving the ability to better classify and stage PCa patients; however, the absence of these diagnostic tools in historical clinical trials complicates their implementation.

In the past few years, the introduction of minimally invasive techniques (MISTs) has opened new scenario for the treatment of benign prostatic hyperplasia (BPH). Based on the current evidence, MISTs are a viable option between medical and definitive surgical treatment. The best candidates for each MIST still represent a great area of debate and studies are providing new evidence to tailor the right treatment to the right patient. Indeed, recent studies are proposing patient reported outcomes and perspectives as a proxy of surgical success [ 11 , 12 , 13 ].

Finally, the introduction of natural language processors has unlocked a new reality in the field of artificial intelligence. After an initial skepticism from the scientific community with the fear of being replaced by complex algorithms, several authors are exploring the millions of different applications of this new technology. Although the most recent evidence suggests that a fundamental landmark has been achieved, significant improvements are warranted before its clinical use [ 14 , 15 , 16 , 17 ].

In 2023 hundreds of manuscripts were evaluated by our editorial team. In this commentary, we present the best articles selected to highlight the hot topics of this year for “ Prostate cancer and prostatic diseases” .

Prostate cancer disparities

The impact of race on survival in the metastatic prostate cancer (mPCa) setting has been evaluated by Freedland et al. in a systematic review including 51 studies. Main results showed Black and White patients to have similar survival outcomes in terms of metastasis free survival (MFS) and overall survival (OS). A secondary analysis demonstrated a better OS for Black patients on mPCa treatments. Similarly, no differences were recorded when comparing White and Hispanic patients. Finally, the Asian cohort presented better survival outcomes when compared to White patients. Certainly, the most intriguing finding of this study is the lower degree of disparities observed in metastatic stages rather than in earlier stages of the disease. Overall, continuous efforts to minimize such disparities in localized PCa diagnosis and management are needed [ 18 ].

Prostate biopsies: where do we stand?

Novara et al. explored the role of perilesional biopsies in patients on active surveillance (AS). The authors enrolled 112 patients with very low and low risk PCa and evaluated the detection rate of random biopsies, targeted biopsies and perilesional biopsies. A detection rate of 19% for ISUP > 2 cancer was gained using only targeted biopsies. By adding 4 perilesional, 14 random or 24 random biopsies, the detection rate was 30%, 39% and 49% respectively. Hence, the present study adds further evidence to the field of targeted biopsies in patients on AS. At this stage, performing only target or target and perilesional biopsies represents a suboptimal strategy for the detection of clinically significant cancer. Although several different strategies to avoid unnecessary biopsies are available, the use of standard plus targeted biopsies still represents the gold standard in the management of patients at risk of PCa [ 19 ].

Biopsy’s approach was evaluated by Hogenhout et al. in a retrospective cohort of 712 men undergoing either the TR approach or the TP approach without antibiotic prophylaxis. The authors recorded no differences in terms of PCa detection while a higher risk of infectious complications was observed in the TR arm (5% vs 1%; p  < 0,05). In doing so, further evidence for the TREXIT movement was added. However, even though the TR approach should be avoided when possible, additional studies should confirm the safety of the TP approach without antibiotic prophylaxis and its clinical implementation outside of clinical trials [ 20 ].

Localized prostate cancer: how to define outcomes?

A systematic review on functional and patient reported outcomes was performed by Nicoletti et al. in patients undergoing focal therapy for PCa. The authors retrieved 107 studies including high intensity focal ultrasound, focal cryotherapy, irreversible electroporation, focal brachytherapy, focal laser ablation, photodynamic therapy, microwave ablation, robotic partial prostatectomy, bipolar radio frequency ablation and prostatic artery embolization. The most important outcome observed was pad-free rate which reached 92–100%. Overall erectile function results were very heterogeneous, ranging from 0% to 94%. Regarding complications, hematuria, infections, and urethral strictures were the most commonly reported issues. The present review clearly underlines the advantages of focal therapy in terms of patient reported outcomes. In any case, the key to success is selecting the appropriate patients for personalized treatment strategies. However, it still remains unclear which specific focal therapy technique is the most effective and moreover, how many different focal therapy approaches should be available in every center [ 21 ].

Sood et al. analyzed the oncological outcomes of patients undergoing radical prostatectomy (RP) in a PSA screened cohort. Overall, 1807 men with a median follow-up of 14 years were analyzed. The 15-year rates of biochemical failure, metastasis rate, adjuvant therapy adoption, positive surgical margin (PCSM), and OS were 28.1%, 4.0%, 16.3%, 2.5%, and 82.1%, respectively. These findings clearly differed based on the D’Amico classification and Diaz classification, confirming the strong role of these tools in predicting survival and oncological outcomes [ 22 ].

The role of genomic classifier in patients with localized PCa was analyzed by Boyer et al. More specifically, they assessed Decipher, GPS and Prolaris ability to predict biochemical recurrence, MFS and cancer specific mortality (CSM) compared to standard classification schemes. According to their results, all the new classifiers improved the accuracy of the standard schemes, although the benefit was modest and the certainty of evidence low. In the past years, the use of genomic classifiers has undoubtedly improved the management of PCa, particularly in the diagnostic setting. Nowadays, however, prognostic models are severely challenged by the introduction of different imaging modalities and treatment regimens. Therefore, integrating genomic classifiers with artificial intelligence models may be a possible path to streamline, reducing the complexity of predicting outcomes in localized PCa [ 23 ].

Recurrent prostate cancer: is next generation imaging changing the game?

Preisser et al. evaluated the importance of persistent PSA after salvage RP. The authors identified 580 patients undergoing salvage RP, of whom 42% presented a persistent PSA. At 84 months after salvage RP, BCR-free, MFS, and OS was 6.6% vs. 59%, 71% vs. 88% and 77% vs. 94%, respectively for patients with persistent vs. undetectable PSA (all p  < 0.01). At multivariable Cox models, persistent PSA was an independent predictor for BCR (HR: 5.47, p  < 0.001) and death (HR: 3.07, p  < 0.01). The present study, even using exclusively conventional imaging, represents one of the widest cohorts of patients undergoing salvage RP, opening new insights on the possible role of adjuvant treatments in these patients with poor prognosis [ 24 ].

The role of NGI in biochemically recurrent PCa was summarized in a systematic review by Moul et al., evaluating nuclear medicine imaging modalities and MRI. According to their analysis, the detection rates of these new imaging range between 46% and 50%. While International Guidelines suggest the use of NGI for detecting recurrences and metastatic disease only, this study remarks that not enough evidence exists up to date to define how NGI affects treatment choices and patient outcomes. Indeed, the primary limitation of introducing NGI is its application in clinical practice. In fact, clinical trials supporting the use of systemic therapies for PCa at various stages, even in this setting used conventional imaging methods. Hence, the impact of NGI on clinical use is still to be defined [ 25 ].

Bladder outlet obstruction: back to physiopathology

Cash et al. highlighted new perspectives on the physiopathology of bladder neck obstruction in men. In fact, a new model of obstruction involving inflammation was proposed. According to their findings, an initial prostatitis might lead to a chronic inflammation of the bladder neck and consequently to a sclerosis with collagen deposition, continuous inflammatory processes, and neuromuscular dysfunction. Overall, the possible different clinical scenarios associated with primary bladder neck obstruction clearly suggest a non-homogeneous and non-continuous remodeling of the bladder neck. Therefore, it is pivotal to investigate physiopathology to better understand different clinical conditions. The authors’ hypothesis should be confirmed through in vitro or in vivo studies to definitively rule out the idea of a direct consequence of anatomical dysfunction [ 26 ].

Zhu et al. performed a real-world analysis of functional and surgical outcomes of Rezum surgery comparing younger vs elderly patients. The authors enrolled 256 patients of whom 110 (43%) were defined as elderly patients (>65 years). No significant differences in terms of IPSS, QoL and Qmax improvements were observed between groups. Likewise, no differences in terms of AEs and regret scores were recorded. Retreatment rates at 4 years were comparable (between 4–4.4%). In summary, the present study offers new insights into the management of elderly patients and those with comorbidities [ 12 ].

Perspectives in basic research and artificial intelligence

Liang et al. investigated the possible role of omega 3 acid diet on PCa by using cancer mouse models. More specifically they evaluated the antitumoral effect on mice with GPR120 receptors. According to their results, only GPR120+ animals responded to omega 3 effects. Therefore, they concluded that host bone marrow cells with functional GPR120 are essential for the anticancer effects of dietary omega-3 fatty acids, and that a key target of the omega-3 diet are the M2-like CD206+ macrophages. This study confirms the role of lipid metabolism in PCa and possibly open new insights in evaluating the role of diet and metabolic factors in PCa management [ 27 ].

Cocci et al. evaluated the quality of information and appropriateness of ChatGPT outputs for urology patients. The authors retrieved case studies of 100 patients and asked ChatGPT to answer the question: “According to the patient data presented, what are the most likely diagnosis, what examinations do you propose, and what are the treatment suggestions?”. The authors assessed accuracy, comprehensiveness, and clarity of ChatGPT. According to their results, 52% of all responses were deemed appropriate. Indeed, ChatGPT provided more appropriate responses for non-oncology conditions (58.5%) compared to oncology (52.6%) and emergency urology cases (11.1%) ( p  = 0.03). Although ChatGPT’s enthusiasm is rapidly growing, the present study clearly focuses on the significant limitations of the 3.5 version. Artificial intelligence will likely change our practice and research capabilities; however, as physicians, urologists, and researchers, we still need to identify and investigate its capabilities and safety [ 28 ]. Future studies should evaluate the best strategy for AI training and its future applications.

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Cocci A, Pezzoli M, Lo Re M. Quality of Information and Appropriateness of ChatGPT Outputs for Urology Patients. Prostate Cancer Prostatic Dis. 2023. https://doi.org/10.1038/s41391-023-00705-y . In Press.

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De Nunzio, C., Lombardo, R. Best of 2023 in Prostate Cancer and Prostatic Diseases. Prostate Cancer Prostatic Dis (2024). https://doi.org/10.1038/s41391-024-00790-7

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Received : 01 January 2024

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Accepted : 10 January 2024

Published : 23 January 2024

DOI : https://doi.org/10.1038/s41391-024-00790-7

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