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Cancer Treatment Reviews Apr 2017Since 2010, five new antineoplastic therapies have been FDA approved for the treatment of metastatic prostate cancer. With additional treatment options, questions arose... (Review)
Review
Since 2010, five new antineoplastic therapies have been FDA approved for the treatment of metastatic prostate cancer. With additional treatment options, questions arose about the optimal sequence of these agents. Until recently, chemotherapy has been deferred until later in the disease course in favor of next-generation androgen deprivation therapy. Prior to the development of abiraterone acetate and enzalutamide, clinical trials were opened investigating the combination of chemotherapy with androgen deprivation therapy in patients with metastatic hormone-sensitive disease. With the development of new oral therapies used to treat castration-resistant disease, these trials were largely forgotten or felt to be obsolete. Recently, two trials have been reported showing an overall survival benefit of the early use of chemotherapy in patients with hormone-naive prostate cancer, changing the treatment paradigm for metastatic disease. Here we review the history of chemotherapy in treating prostate cancer and the emerging evidence favoring its use as first-line therapy against metastatic hormone-sensitive disease.
Topics: Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; History, 20th Century; History, 21st Century; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Randomized Controlled Trials as Topic; Survival Rate; Taxoids; Time Factors
PubMed: 27720577
DOI: 10.1016/j.ctrv.2016.09.017 -
F1000Research 2021Although intermittent androgen deprivation therapy was introduced many years ago to improve patients' quality of life with the same carcinologic efficiency as...
Although intermittent androgen deprivation therapy was introduced many years ago to improve patients' quality of life with the same carcinologic efficiency as continuous hormonal therapy, recent data suggest that intermittency could be underutilised. This study aims to estimate the prevalence of prostate cancer patients receiving intermittent androgen deprivation therapy in Spain. A retrospective, longitudinal study was conducted using electronic drug dispensation data from four Spanish autonomous communities, which encompass 17.23 million inhabitants (36.22% of the total population in Spain). We estimated intermittent androgen therapy use (%IAD) and the prevalence of patients under intermittent androgen therapy in reference to the total number of PC patients using hormonal therapy (P ) and stratified by region. Other outcome variables included the pharmaceutical forms dispensed and the total direct annual expenditure on androgen deprivation therapy-associated medications. A total of 863,005 dispensations corresponding to a total of 65,752 men were identified, treated with either luteinizing hormone-releasing hormone (LHRH) analogues (353,162) administered alone or in combination with anti-androgens (509,843). Overall, the mean (±SD) age of the patients was 76.9 (±10.4) years. Results revealed that the mean annual P along the study was 6.6% in the total population studied, and the overall %IAD during the five-year study period was 5.6%. The mean cost of hormonal therapy per year was 25 million euros for LHRH analogues and 6.3 million euros for anti-androgens. Few prostate cancer patients in Spain use the intermittent androgen deprivation therapy suggesting underutilization of a perfectly valid option for a significant proportion of patients, missing the opportunity to improve their quality of life and to reduce costs for the National Health Service with comparable overall survival rates than continuous therapy.
Topics: Male; Humans; Aged; Aged, 80 and over; Androgen Antagonists; Prostatic Neoplasms; Antineoplastic Agents, Hormonal; Quality of Life; Spain; Cross-Sectional Studies; Retrospective Studies; Longitudinal Studies; State Medicine; Gonadotropin-Releasing Hormone
PubMed: 36330533
DOI: 10.12688/f1000research.53875.2 -
Cancer Sep 2014There remains no standard of care for patients with a rising prostate-specific antigen level after radical prostatectomy or radiotherapy but who have no radiographic... (Review)
Review
There remains no standard of care for patients with a rising prostate-specific antigen level after radical prostatectomy or radiotherapy but who have no radiographic metastases, even though this is the second largest group of patients with prostate cancer (CaP) in the United States. Androgen deprivation therapy (ADT) may cure some men with advanced CaP based on single-institution series and a randomized clinical trial of immediate versus delayed ADT for men found to have pelvic lymph node metastasis at the time of radical prostatectomy. ADT may be more effective when initiated for minimal disease burden, which can be detected using PSA after radical prostatectomy or radiotherapy, and if more complete disruption of the androgen axis using newer agents decreases the chance that androgen-sensitive cells survive to adapt to a low-androgen environment. Androgens may be "annihilated" simultaneously using a luteinizing hormone-releasing hormone antagonist or agonist to inhibit testicular production of testosterone, a P45017A1 (CYP17A1) inhibitor to diminish metabolism of testosterone via the adrenal pathway and dihydrotestosterone (DHT) via the backdoor pathway, a 5α-reductase (SRD5A) inhibitor to diminish testosterone reduction to DHT and backdoor metabolism of progesterone substrates to DHT, and a newer antiandrogen to compete better with DHT for the androgen receptor ligand-binding domain. Early initiation of androgen annihilation for induction as part of planned intermittent ADT should be safe, may reduce tumor burden below a threshold that allows eradication by the immune system, and may cure many men who have failed definitive local therapy.
Topics: Androgen Antagonists; Animals; Antineoplastic Agents, Hormonal; Humans; Male; Orchiectomy; Prostatic Neoplasms; Tumor Burden
PubMed: 24771515
DOI: 10.1002/cncr.28675 -
Cell Death & Disease Jul 2022Prostate cancer is a hormone-dependent malignancy, whose onset and progression are closely related to the activity of the androgen receptor (AR) signaling pathway. Due... (Review)
Review
Prostate cancer is a hormone-dependent malignancy, whose onset and progression are closely related to the activity of the androgen receptor (AR) signaling pathway. Due to this critical role of AR signaling in driving prostate cancer, therapy targeting the AR pathway has been the mainstay strategy for metastatic prostate cancer treatment. The utility of these agents has expanded with the emergence of second-generation AR antagonists, which began with the approval of enzalutamide in 2012 by the United States Food and Drug Administration (FDA). Together with apalutamide and darolutamide, which were approved in 2018 and 2019, respectively, these agents have improved the survival of patients with prostate cancer, with applications for both androgen-dependent and castration-resistant disease. While patients receiving these drugs receive a benefit in the form of prolonged survival, they are not cured and ultimately progress to lethal neuroendocrine prostate cancer (NEPC). Here we summarize the current state of AR antagonist development and highlight the emerging challenges of their clinical application and the potential resistance mechanisms, which might be addressed by combination therapies or the development of novel AR-targeted therapies.
Topics: Androgen Antagonists; Androgen Receptor Antagonists; Androgens; Drug Resistance, Neoplasm; Humans; Male; Nitriles; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen
PubMed: 35864113
DOI: 10.1038/s41419-022-05084-1 -
Cell Reports Feb 2022Androgen receptor (AR) signaling is the central driver of prostate cancer across disease states. While androgen deprivation therapy (ADT) is effective in the initial...
Androgen receptor (AR) signaling is the central driver of prostate cancer across disease states. While androgen deprivation therapy (ADT) is effective in the initial treatment of prostate cancer, resistance to ADT or to next-generation androgen pathway inhibitors invariably arises, most commonly through the re-activation of the AR axis. Thus, orthogonal approaches to inhibit AR signaling in advanced prostate cancer are essential. Here, via genome-scale CRISPR-Cas9 screening, we identify protein arginine methyltransferase 1 (PRMT1) as a critical mediator of AR expression and signaling. PRMT1 regulates the recruitment of AR to genomic target sites and the inhibition of PRMT1 impairs AR binding at lineage-specific enhancers, leading to decreased expression of key oncogenes, including AR itself. In addition, AR-driven prostate cancer cells are uniquely susceptible to combined AR and PRMT1 inhibition. Our findings implicate PRMT1 as a key regulator of AR output and provide a preclinical framework for co-targeting of AR and PRMT1 in advanced prostate cancer.
Topics: Androgen Antagonists; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Humans; Male; Prostate; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Protein-Arginine N-Methyltransferases; Receptors, Androgen; Repressor Proteins; Signal Transduction
PubMed: 35196489
DOI: 10.1016/j.celrep.2022.110417 -
Strahlentherapie Und Onkologie : Organ... Jun 2023To describe a local radio-oncological treatment for patients with prostate cancer that metastasized to either the lymph nodes or distant regions.
PURPOSE
To describe a local radio-oncological treatment for patients with prostate cancer that metastasized to either the lymph nodes or distant regions.
METHODS AND MATERIALS
We included 133 patients with prostate cancer that displayed either distant metastases (DM) or lymph node metastases alone (NM) and were treated between 2004 and 2019. All patients underwent computed tomography and a bone scan or 18F- or prostate-specific membrane antigen-targeted positron emission tomography. Patients received local external beam radiation therapy to the prostate to achieve local control (60-81.4 Gy to the prostate, and 45-50.4 Gy to pelvic lymph nodes), with either the 3D conformal (4-field box) or volumetric modulated arc therapy technique. A urologist prescribed additional therapy.
RESULTS
We included 51 patients with DM and 82 patients with NM. The mean follow-up was 42 months for all patients. The groups were similar in T stage, initial prostate-specific antigen, histology, androgen deprivation therapy, age, treatment techniques, and prescribed doses, but different in lymph node inclusion and follow-up times. In the NM and DM groups, the 5‑year biochemical recurrence-free rates were 52% and 24%, respectively (p < 0.0001); the 5‑year disease-specific survival rates were 92% and 61%, respectively (p = 0.001); and the 5‑year OS rates were 77% and 48%, respectively (p = 0.01). The groups had similar acute and late gastrointestinal and genitourinary side effects, except that late genitourinary side effects occurred significantly more frequently in the NM group (p = 0.01).
CONCLUSIONS
DM was associated with significantly worse outcomes than NM. The long-term survival of patients with metastatic prostate cancer was low.
Topics: Male; Humans; Prostatic Neoplasms; Androgen Antagonists; Radiotherapy, Intensity-Modulated; Prostate-Specific Antigen; Urogenital System
PubMed: 35953611
DOI: 10.1007/s00066-022-01993-4 -
The Prostate Oct 2022Androgen deprivation therapy (ADT) is a standard treatment modality for locally advanced, high-risk, and metastatic hormone-sensitive prostate cancer. Long-term ADT...
BACKGROUND
Androgen deprivation therapy (ADT) is a standard treatment modality for locally advanced, high-risk, and metastatic hormone-sensitive prostate cancer. Long-term ADT treatment likely develops side-effects that include changes in cognition or onset of dementia. However, the molecular understanding of this effect remains elusive. We attempt to establish a link between ADT and changes in cognitive function using patient databases and bioinformatics analyses.
METHODS
Gene expression profiling was performed using RNA sequencing data from Alzheimer patient cohort and compared with the data from advanced-stage prostate cancer patients receiving neoadjuvant antiandrogen therapy. Differentially expressed genes (DEGs) were analyzed using the Ingenuity knowledge database.
RESULTS
A total of 1952 DEGs in the Alzheimer patient cohort and 101 DEGs were identified in ADT treated prostate cancer patients. Comparing both data sets provided a subset of 33 commonly expressed genes involving cytokine-cytokine signaling with an over representation of cytokine-cytokine receptor interaction, inflammatory cytokines, signaling by interleukins together with alterations in the circulating lymphocyte repertoire, adaptive immune responses, regulation of cytokine production, and changes in T-cell subsets. Additionally, lipopolysaccharide, tumor necrosis factor, and toll-like receptors were identified as upstream transcriptional regulators of these pathways. The most commonly expressed genes viz. IL-17A, CCL2, IL-10, IL-6, IL-1RN, LIF/LIFR were further validated by quantitative RT-PCR exhibited higher expression in antiandrogen treated neuronal, glial, and androgen-responsive prostate cancer cells, compared to no-androgen antagonist treatment.
CONCLUSIONS
Our findings suggest that changes in cytokine signaling under the influence of ADT in prostate cancer patients may be linked with cognitive impairment presenting new avenues for diagnostic and therapeutic development in combating brain deficits.
Topics: Alzheimer Disease; Androgen Antagonists; Cognition; Cytokines; Gene Expression; Humans; Male; Prostatic Neoplasms
PubMed: 35821621
DOI: 10.1002/pros.24411 -
Minerva Urologica E Nefrologica = the... Aug 2018Androgen-deprivation therapy (ADT) administered in neoadjuvant setting before radical prostatectomy (RP) represents an ideal in vivo human model to test the efficacy of... (Review)
Review
INTRODUCTION
Androgen-deprivation therapy (ADT) administered in neoadjuvant setting before radical prostatectomy (RP) represents an ideal in vivo human model to test the efficacy of hormonal treatments in prostate cancer (PCa). This review summarizes the findings from published studies specifically focused on the biological effects of ADT assessed on specimens from RP. The aim is to provide a base of knowledge that might be used to design future studies on neoadjuvant therapy for PCa.
EVIDENCE ACQUISITION
A systematic review of the literature was performed according to the PRISMA statements. Search protocol identified published studies including a detailed analysis on specimen from RP to assess the biological effects of neoadjuvant ADT. In November 2017, Medline, Embase, and Scopus databases were searched using the terms "neoadjuvant" AND ("hormone therapy" OR "androgen deprivation therapy") AND "prostate cancer" in the "Title/Abstract" fields. Effects of ADT were classified according to four pathways - suppression of cellular proliferation, induction of apoptosis, alteration of immune response and onset of hormonal refractoriness - and relative markers of response were identified.
EVIDENCE SYNTHESIS
From 1856 papers initially retrieved, 19 studies were finally selected and included into the present review. ADT was constituted by luteinizing hormone-releasing hormone (LH-RH) agonist alone in two, peripheral anti-androgen alone in one, both in 10, abiraterone acetate in one, unspecified in five. According to the above-mentioned four pathways, the following markers of response were identified: transcription of the oncogene TMPRSS2:ERG, translation of Aurora-A, coding of β1C integrin gene, translation of Ki-67, expression of nerve growth factors TrkA and p75NGFR, anti-angiogenic activity and micro-vessel density were involved into suppression of proliferation; mRNA transcription of bcl-2, expression of cleaved caspase-3 and translation of insulin growth factor binding protein 3, into induction of apoptosis; expression of IL-7 gene, programmed death-ligand 1, and increase of intra-prostatic T-cell population were related to alteration of immune response; finally, expression of heat shock protein 27 and de-differentiation of PCa to neuroendocrine cells, influenced the onset of hormonal refractoriness.
CONCLUSIONS
Despite a potential high interest, unexpectedly, only 19 heterogeneous studies investigated the effects of ADT through the analysis of specimens from RP. The present review summarizes the available evidences on this topic showing that ADT interferes on PCa at different levels that can be investigated by specific biological markers.
Topics: Androgen Antagonists; Humans; Male; Neoadjuvant Therapy; Orchiectomy; Prostate; Prostatectomy; Prostatic Neoplasms; Treatment Outcome
PubMed: 29392925
DOI: 10.23736/S0393-2249.18.03022-9 -
Human Cell Jan 2021The androgen receptor (AR) is a validated therapeutic target for prostate cancer and has been a focus for drug development for more than six decades. Currently approved...
The androgen receptor (AR) is a validated therapeutic target for prostate cancer and has been a focus for drug development for more than six decades. Currently approved therapies that inhibit AR signaling, such as enzalutamide, rely solely on targeting the AR ligand-binding domain and, therefore, have limited efficacy on prostate cancer cells that express truncated, constitutively active AR splice variants (AR-Vs). The LNCaP95 cell line is a human prostate cancer cell line that expresses both functional full-length AR and AR-V7. LNCaP95 is a heterogeneous cell population that is resistant to enzalutamide, with its proliferation dependent on transcriptionally active AR-V7. The purpose of this study was to identify a LNCaP95 clone that would be useful for evaluating therapies for their effectiveness against enzalutamide-resistant prostate cancer cells. Seven clones from the LNCaP95 cell line were isolated and characterized using morphology, in vitro growth rate, and response to ralaniten (AR N-terminal domain inhibitor) and enzalutamide (antiandrogen). In vivo growth of the clones as subcutaneous xenografts was evaluated in castrated immunodeficient mice. All of the clones maintained the expression of full-length AR and AR-V7. Cell proliferation of the clones was insensitive to androgen and enzalutamide but importantly was inhibited by ralaniten, which is consistent with AR-Vs driving the proliferation of parental LNCaP95 cells. In castrated immunodeficient animals, the growth of subcutaneous xenografts of the D3 clone was the most reproducible compared to the parental cell line and other clones. These data support that the enzalutamide-resistant LNCaP95-D3 subline may be suitable as a xenograft tumor model for preclinical drug development with improved reproducibility.
Topics: Androgen Antagonists; Animals; Antineoplastic Agents; Benzamides; Castration; Cell Line, Tumor; Clone Cells; Disease Models, Animal; Drug Resistance, Neoplasm; Heterografts; Humans; Male; Mice; Mice, Inbred NOD; Neoplasm Transplantation; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Receptors, Androgen
PubMed: 32954481
DOI: 10.1007/s13577-020-00435-6 -
Endocrine-related Cancer Jan 2018Antiandrogen withdrawal syndrome is an unpredictable event diagnosed in patients with hormone-sensitive prostate cancer treated with combined androgen blockade therapy.... (Review)
Review
Antiandrogen withdrawal syndrome is an unpredictable event diagnosed in patients with hormone-sensitive prostate cancer treated with combined androgen blockade therapy. It is defined by prostate-specific antigen value reduction, occasionally associated with a radiological response, that occurs 4-6 weeks after first-generation antiandrogen therapy discontinuation. New-generation hormonal therapies, such as enzalutamide and abiraterone acetate, improved the overall survival in patients with metastatic castration-resistant prostate cancer, and recent trials have also shown the efficacy of abiraterone in hormone-sensitive disease. In the last few years, several case reports and retrospective studies suggested that the withdrawal syndrome may also occur with these new drugs. This review summarizes literature data and hypothesis about the biological rationale underlying the syndrome and its potential clinical relevance, focusing mainly on new-generation hormonal therapies. Several studies suggest that androgen receptor gain-of-function mutations are involved in this syndrome, shifting the antiandrogen activity from antagonist to agonist. Several different drug-specific point mutations have been reported. The association of the withdrawal syndrome for enzalutamide and abiraterone needs confirmation by additional investigations. However, new-generation hormonal therapies being increasingly used in all stages of disease, more patients may experience the syndrome when stopping the treatment at the time of disease progression, although the clinical relevance of this phenomenon in the management of metastatic castration-resistant prostate cancer remains to be defined.
Topics: Androgen Antagonists; Humans; Male; Prostatic Neoplasms; Receptors, Androgen; Substance Withdrawal Syndrome
PubMed: 28971898
DOI: 10.1530/ERC-17-0355