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Current Oncology (Toronto, Ont.) Apr 2023The treatment paradigm for metastatic castrate-sensitive prostate cancer (mCSPC) has evolved rapidly in the past decade with the approval of several life-prolonging... (Review)
Review
The treatment paradigm for metastatic castrate-sensitive prostate cancer (mCSPC) has evolved rapidly in the past decade with the approval of several life-prolonging therapies including docetaxel chemotherapy and multiple androgen receptor pathway inhibitors (ARPI) in combination with androgen deprivation therapy (ADT). Recently reported phase-three trials have demonstrated a survival benefit of upfront triplet therapy with ADT, docetaxel plus either abiraterone acetate or darolutamide when compared to ADT plus docetaxel alone. However, multiple questions including the incremental benefit of docetaxel to a combination of ADT and ARPI, the timing of ARPI, optimal patient selection for triplet therapy and clinical and genomic biomarkers still remain to be answered. Moreover, real-world data suggest suboptimal treatment intensification with many patients treated with ADT alone highlighting challenges in implementation. In this article, we review the phase-three data associated with triplet therapy in mCSPC. We also discuss the knowledge gaps that exist despite the completion of these studies and how ongoing studies are likely to change the paradigm in the near future. Finally, we provide a simple algorithm based on current data that clinicians can use in daily practice to select patients for appropriate treatment strategies.
Topics: Male; Humans; Prostatic Neoplasms; Docetaxel; Androgen Antagonists; Standard of Care; Abiraterone Acetate
PubMed: 37185445
DOI: 10.3390/curroncol30040332 -
Best Practice & Research. Clinical... Sep 2022Cachexia is a complex wasting syndrome, accompanying a variety of end-stage chronic diseases, such as cancer, heart failure and human immunodeficiency virus (HIV)... (Review)
Review
Cachexia is a complex wasting syndrome, accompanying a variety of end-stage chronic diseases, such as cancer, heart failure and human immunodeficiency virus (HIV) infection/acquired immunodeficiency syndrome (AIDS). It significantly affects patients' quality of life and survival. Multiple therapeutic approaches have been studied over time. However, despite promising results, no drug has been approved to date. In this review, we examine and discuss the available data on the therapeutic effects of androgens and selective androgen receptor modulators (SARMs) for cachexia.
Topics: Androgen Antagonists; Androgens; Cachexia; Humans; Quality of Life; Receptors, Androgen
PubMed: 34801415
DOI: 10.1016/j.beem.2021.101598 -
Medical Sciences (Basel, Switzerland) Apr 2022Prostate cancer therapy for locally advanced and metastatic diseases includes androgen deprivation therapy (ADT). Second-generation antiandrogens have a role in... (Review)
Review
Prostate cancer therapy for locally advanced and metastatic diseases includes androgen deprivation therapy (ADT). Second-generation antiandrogens have a role in castration-resistant prostate cancer. Nevertheless, some patients do not respond to this therapy, and eventually all the patients became resistant. This is due to modifications to intracellular signaling pathways, genomic alteration, cytokines production, metabolic switches, constitutional receptor activation, overexpression of some proteins, and regulation of gene expression. The aim of this review is to define the most important mechanisms that drive this resistance and the newest discoveries in this field, specifically for enzalutamide and abiraterone, with potential implications for future therapeutic targets. Furthermore, apalutamide and darolutamide share some resistance mechanisms with abiraterone and enzalutamide and could be useful in some resistance settings.
Topics: Androgen Antagonists; Disease Progression; Humans; Male; Prostatic Neoplasms, Castration-Resistant
PubMed: 35645241
DOI: 10.3390/medsci10020025 -
Expert Opinion on Pharmacotherapy 2023Prostate cancer is the most common malignancy in the male. Androgen-deprivation therapy (ADT) has been the mainstay in the treatment of metastatic prostate cancer... (Review)
Review
INTRODUCTION
Prostate cancer is the most common malignancy in the male. Androgen-deprivation therapy (ADT) has been the mainstay in the treatment of metastatic prostate cancer however, due to the outgrowth of castration-resistant cell population the disease inevitably progresses to an aggressive, difficult to handle stage.
AREAS COVERED
We have reviewed the literature regarding hormonal-directed therapy prostate cancer. New agents, namely abiraterone acetate, combined with prednisone, and next generation antiandrogens (enzalutamide, apalutamide and darolutamide) have shown considerable efficacy, not only in patients with metastatic but also in those with non-metastatic disease, either castration resistant (CRPC) or hormone sensitive (HSPC).
EXPERT OPINION
The addition of abiraterone and of the second-generation antiandrogens to our therapeutic armamentarium has improved prognosis ofprostate cancer in the last decade. Abiraterone is a viable option in patients with metastatic disease (hormone-sensitive and castration-resistant), whereas all next-generation antiandrogens have demonstrated efficacy in terms of metastasis-free and overall survival in non-metastatic CRPC. In addition, enzalutamide has also been found efficacious in mCRPC and mHSPC, while apalutamide in mHSPC. Currently there are no reliable data to indicate a potential superiority of one of these agents over the others in CRPC or HSPC as there are no relevant head to head studies . Sequencing hormone treatment modalities, chemotherapies and immunotherapies have not reached a consensus as yet. Randomized controlled trials are warranted to clearly define the role of novel antiandrogens in the treatment of prostate cancer. The choice of treatment should be individualized following discussion with the patient .
Topics: Humans; Male; Prostatic Neoplasms, Castration-Resistant; Androgen Antagonists; Treatment Outcome; Hormones
PubMed: 37545430
DOI: 10.1080/14656566.2023.2244415 -
Seminars in Oncology Nursing Aug 2020To review the indications for and side effects of androgen deprivation therapy (ADT) in men affected by prostate cancer. (Review)
Review
OBJECTIVE
To review the indications for and side effects of androgen deprivation therapy (ADT) in men affected by prostate cancer.
DATA SOURCES
National guidelines, evidence-based summaries, peer-reviewed studies, and websites.
CONCLUSION
Indications for ADT include men with (1) intermediate- to high-risk localised prostate cancer undergoing radiation therapy, (2) biochemical recurrence after radical prostatectomy treated with salvage radiation therapy, or (3) metastatic prostate cancer. Several forms of ADT are available. To support self-management, body weight, diet, physical activity, alcohol consumption, and smoking should be discussed during clinical consultations. Important side effects of ADT may include flare-up phenomena of GnRH analogues, local reactions at injection sites, cardiovascular events, bone loss/fractures, drug-drug interactions, urinary tract dysfunction, hot flashes, cognitive impairment, seizure falls, and liver impairment.
IMPLICATIONS FOR NURSING PRACTICE
Nurses have a role in personalized cancer care and should be familiar with indications, side effects, and interventions to optimize quality of life for men affected by prostate cancer receiving ADT.
Topics: Androgen Antagonists; Bone Density; Hot Flashes; Humans; Male; Oncology Nursing; Prostatic Neoplasms; Quality of Life
PubMed: 32773255
DOI: 10.1016/j.soncn.2020.151042 -
The Oncologist Mar 2022The second-generation antiandrogens have achieved an ever-growing list of approvals and indications in subsets of prostate cancer. Here, we provide an overview of...
The second-generation antiandrogens have achieved an ever-growing list of approvals and indications in subsets of prostate cancer. Here, we provide an overview of second-generation antiandrogen trials and FDA approvals and outline a rational sequencing approach for the use of these agents as they relate to chemotherapy and other available treatment modalities in advanced prostate cancer. All published phase II-III randomized controlled trials reporting outcomes with the use of second-generation antiandrogens in prostate cancer are included as well as all published trials and retrospective studies of second-generation antiandrogen sequencing and/or combinations. Complete tabular and graphical representation of all available evidence is provided regarding the use and sequencing of second-generation antiandrogens in prostate cancer. In metastatic castration-resistant prostate cancer, evidence suggests prioritization of abiraterone before chemotherapy, chemotherapy after second-generation antiandrogen failure, and postchemotherapy enzalutamide in select patients to maximize agent efficacy and tolerability. We conclude that a rational, optimized sequencing of second-generation antiandrogens with other treatment options is feasible with present data.
Topics: Androgen Antagonists; Humans; Male; Prostatic Neoplasms; Retrospective Studies
PubMed: 35641216
DOI: 10.1093/oncolo/oyab045 -
International Journal of Radiation... Apr 2023Using the primary endpoint of time to biochemical progression (TTP), Androgen Suppression Combined with Elective Nodal and Dose Escalated Radiation Therapy (ASCENDE-RT)... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Using the primary endpoint of time to biochemical progression (TTP), Androgen Suppression Combined with Elective Nodal and Dose Escalated Radiation Therapy (ASCENDE-RT) randomized National Comprehensive Cancer Network patients with intermediate and high-risk prostate cancer to low-dose-rate brachytherapy boost (LDR-PB) or dose-escalated external beam boost (DE-EBRT). Randomization to the LDR-PB arm resulted in a 2-fold reduction in biochemical progression compared with the DE-EBRT group at a median follow-up of 6.5 years (P < .001). Herein, the primary endpoint and secondary survival endpoints of the ASCENDE-RT trial are updated at a 10-year median follow-up.
METHODS
Patients were randomly assigned to either the LDR-PB or the DE-EBRT arm (1:1). All patients received 1 year of androgen deprivation therapy and 46 Gy in 23 fractions of pelvic RT. Patients in the DE-EBRT arm received an additional 32 Gy in 16 fractions, and those in the LDR-PB arm received an I implant prescribed to a minimum peripheral dose of 115 Gy. Two hundred patients were randomized to the DE-EBRT arm and 198 to the LDR-PB arm.
RESULTS
The 10-year Kaplan-Meier TTP estimate was 85% ± 5% for LDR-PB compared with 67% ± 7% for DE-EBRT (log rank P < .001). Ten-year time to distant metastasis (DM) was 88% ± 5% for the LDR-PB arm and 86% ± 6% for the DE-EBRT arm (P = .56). There were 117 (29%) deaths. Ten-year overall survival (OS) estimates were 80% ± 6% for the LDR-PB arm and 75% ± 7% for the DE-EBRT arm (P = .51). There were 30 (8%) patients who died of prostate cancer: 12 (6%) in the LDR-PB arm, including 2 treatment-related deaths, and 18 (9%) in the DE-EBRT arm.
CONCLUSIONS
Men randomized to the LDR-PB boost arm of the ASCENDE-RT trial continue to experience a large advantage in TTP compared with those randomized to the DE-EBRT arm. ASCENDE-RT was not powered to detect differences in its secondary survival endpoints (OS, DM, and time to prostate cancer-specific death) and none are apparent.
Topics: Male; Humans; Prostatic Neoplasms; Androgen Antagonists; Androgens; Pelvis; Kaplan-Meier Estimate; Brachytherapy
PubMed: 36528488
DOI: 10.1016/j.ijrobp.2022.11.005 -
Clinical Genitourinary Cancer Jun 2023Androgen deprivation therapy (ADT) has been considered for years the standard initial treatment for patients with metastatic prostate cancer (mPC). Recently published... (Review)
Review
Androgen deprivation therapy (ADT) has been considered for years the standard initial treatment for patients with metastatic prostate cancer (mPC). Recently published results support the use of taxanes, second-generation antiandrogens or radiotherapy to the primary tumor as part of the treatment in these patients, considering ADT alone as suboptimal. Metastasis-directed therapy (MDT) is used as part of the treatment for oligometastatic patients in different tumor types. In oligometastatic hormone-sensitive prostate cancer the role of MDT is being studied with promising results. In the present review we assess the available evidence for radiotherapy to the primary tumor in newly diagnosed mPC and for MDT in oligometastatic prostate cancer, as well as future directions in this clinical setting.
Topics: Male; Humans; Prostatic Neoplasms; Androgen Antagonists; Hormones
PubMed: 36456467
DOI: 10.1016/j.clgc.2022.10.015 -
Proceedings of the National Academy of... May 2022Antiandrogen strategies remain the prostate cancer treatment backbone, but drug resistance develops. We show that androgen blockade in prostate cancer leads to...
Antiandrogen strategies remain the prostate cancer treatment backbone, but drug resistance develops. We show that androgen blockade in prostate cancer leads to derepression of retroelements (REs) followed by a double-stranded RNA (dsRNA)-stimulated interferon response that blocks tumor growth. A forward genetic approach identified H3K9 trimethylation (H3K9me3) as an essential epigenetic adaptation to antiandrogens, which enabled transcriptional silencing of REs that otherwise stimulate interferon signaling and glucocorticoid receptor expression. Elevated expression of terminal H3K9me3 writers was associated with poor patient hormonal therapy outcomes. Forced expression of H3K9me3 writers conferred resistance, whereas inhibiting H3K9-trimethylation writers and readers restored RE expression, blocking antiandrogen resistance. Our work reveals a drug resistance axis that integrates multiple cellular signaling elements and identifies potential pharmacologic vulnerabilities.
Topics: Androgen Antagonists; Androgen Receptor Antagonists; Androgens; DNA Methylation; Drug Resistance, Neoplasm; Gene Silencing; Humans; Interferons; Male; Methylation; Nitriles; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen
PubMed: 35584120
DOI: 10.1073/pnas.2114324119 -
The Journal of Clinical Investigation Nov 2023Half of all men with advanced prostate cancer (PCa) inherit at least 1 copy of an adrenal-permissive HSD3B1 (1245C) allele, which increases levels of 3β-hydroxysteroid...
Half of all men with advanced prostate cancer (PCa) inherit at least 1 copy of an adrenal-permissive HSD3B1 (1245C) allele, which increases levels of 3β-hydroxysteroid dehydrogenase 1 (3βHSD1) and promotes intracellular androgen biosynthesis. Germline inheritance of the adrenally permissive allele confers worse outcomes in men with advanced PCa. We investigated whether HSD3B1 (1245C) drives resistance to combined androgen deprivation and radiotherapy. Adrenally permissive 3βHSD1 enhanced resistance to radiotherapy in PCa cell lines and xenograft models engineered to mimic the human adrenal/gonadal axis during androgen deprivation. The allele-specific effects on radiosensitivity were dependent on availability of DHEA, the substrate for 3βHSD1. In lines expressing the HSD3B1 (1245C) allele, enhanced expression of DNA damage response (DDR) genes and more rapid DNA double-strand break (DSB) resolution were observed. A correlation between androgen receptor (AR) expression and increased DDR gene expression was confirmed in 680 radical prostatectomy specimens. Treatment with the nonsteroidal antiandrogen enzalutamide reversed the resistant phenotype of HSD3B1 (1245C) PCa in vitro and in vivo. In conclusion, 3βHSD1 promotes prostate cancer resistance to combined androgen deprivation and radiotherapy by upregulating DNA DSB repair. This work supports prospective validation of early combined androgen blockade for high-risk men harboring the HSD3B1 (1245C) allele.
Topics: Humans; Male; Androgen Antagonists; Androgens; DNA; Genotype; Hydroxysteroid Dehydrogenases; Multienzyme Complexes; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen
PubMed: 37966114
DOI: 10.1172/JCI165718