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Missouri Medicine 2018Advanced prostate cancer is a heterogenous disease with multiple treatment options. Patients with advanced disease are stratified based evidence of metastasis and... (Review)
Review
Advanced prostate cancer is a heterogenous disease with multiple treatment options. Patients with advanced disease are stratified based evidence of metastasis and sensitivity to hormone therapy. Men with hormone sensitive disease are treated with androgen deprivation therapy and possibly chemotherapy. The treatment options for men with castrate resistant disease are rapidly evolving with multiple recently approved treatment options. Determining the proper sequence and combination of these therapies remains a work in progress.
Topics: Androgen Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Humans; Male; Prostatic Neoplasms
PubMed: 30228709
DOI: No ID Found -
The FEBS Journal Nov 2021Prostate cancer (PCa) is a very complex disease that is a major cause of death in men worldwide. Currently, PCa dependence on the androgen receptor (AR) has resulted in... (Review)
Review
Prostate cancer (PCa) is a very complex disease that is a major cause of death in men worldwide. Currently, PCa dependence on the androgen receptor (AR) has resulted in use of AR antagonists and antiandrogen therapies that reduce endogenous steroid hormone production. However, within two to three years of receiving first-line androgen deprivation therapy, the majority of patients diagnosed with PCa progress to castration-resistant prostate cancer (CRPC). There is an urgent need for therapies that are more durable than antagonism of the AR axis. Studies of runt-related transcription factors (RUNX) and their heterodimerization partner, core-binding factor subunit b (CBFβ), are revealing that the RUNX family are drivers of CRPC. In this review, we describe what is presently understood about RUNX members in PCa, including what regulates and is regulated by RUNX proteins, and the role of RUNX proteins in the tumor microenvironment and AR signaling. We discuss the implications for therapeutically targeting RUNX, the potential for RUNX as PCa biomarkers, and the current pressing questions in the field.
Topics: Androgen Antagonists; Core Binding Factor alpha Subunits; Humans; Male; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Transcription Factors
PubMed: 33682350
DOI: 10.1111/febs.15804 -
Current Oncology (Toronto, Ont.) Oct 2019Prostate cancer (pca) is the most common non-dermatologic cancer and the 3rd leading cause of male cancer mortality in Canada. In patients with high-risk localized or... (Review)
Review
BACKGROUND
Prostate cancer (pca) is the most common non-dermatologic cancer and the 3rd leading cause of male cancer mortality in Canada. In patients with high-risk localized or recurrent pca, management typically includes the combination of long-term androgen deprivation therapy (adt) and radiotherapy (rt). New androgen-receptor-axis targeted therapies (arats), which await validation, offer an option to intensify therapy.
METHODS
In this narrative review, we report the relevant history that has supported combining adt with rt. The literature in PubMed was searched for studies involving pca and novel arats (abiraterone acetate, enzalutamide, apalutamide, darolutamide) published between 1995 and 2019. Literature discussing clinical trials in which those modalities were combined was extracted and synthesized into a combined molecular and clinical discussion. Potential treatment intensification mechanisms and rationales are explored.
RESULTS
Early results from three phase i/ii trials demonstrated that concurrent abiraterone acetate, adt, and rt is safe, improves the extent of chemical castration, and is associated with limited treatment failures. A single study implies synergy for radiosensitization beyond that facilitated by conventional adt. Studies investigating the combination of other arats with rt are under way, including multiple phase iii trials, but short-term results are not yet available.
Topics: Abiraterone Acetate; Androgen Antagonists; Benzamides; Combined Modality Therapy; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Pyrazoles; Randomized Controlled Trials as Topic; Thiohydantoins
PubMed: 31708657
DOI: 10.3747/co.26.5005 -
Cancer Treatment Reviews Jul 2018Triple negative breast cancer (TNBC) represents the 15-20% of all breast cancers (BC) and is characterized by a very aggressive behavior. Recent data suggest that TNBC... (Review)
Review
Triple negative breast cancer (TNBC) represents the 15-20% of all breast cancers (BC) and is characterized by a very aggressive behavior. Recent data suggest that TNBC is not a single disease, but it is rather an umbrella for different ontology-profiles such as basal like 1 and 2, mesenchymal, and the luminal androgen receptor (LAR). The LAR subtype is characterized by the expression of the Androgen Receptor (AR) and its downstream effects. Notwithstanding the role of the AR in several signaling pathways, its impact on a biological and clinical standpoint is still controversial. The LAR subtype has been associated with better prognosis, less chemotherapy responsiveness and lower pathologic complete response after neoadjuvant treatment. Clinical evidence suggests a role for anti-androgen therapies such as bicalutamide, enzalutamide and abiraterone, offering an interesting chemo-free alternative for chemo-unresponsive patients, and therefore potentially shifting current treatment strategies.
Topics: Androgen Antagonists; Animals; Female; Humans; Receptors, Androgen; Triple Negative Breast Neoplasms
PubMed: 29940524
DOI: 10.1016/j.ctrv.2018.06.005 -
Acta Clinica Croatica Oct 2022For many years, androgen deprivation therapy (ADT) as monotherapy has been the gold standard for metastatic hormone-sensitive prostate cancer (mHSPC) treatment. Several... (Review)
Review
For many years, androgen deprivation therapy (ADT) as monotherapy has been the gold standard for metastatic hormone-sensitive prostate cancer (mHSPC) treatment. Several studies have been published within the last decade demonstrating a significant survival advantage resulting from combining the treatment with standard ADT plus docetaxel or androgen receptor targeted therapy (ARTA) compared to ADT monotherapy. Recently published data of the PEACE-1 and ARASENS trials suggest that in the future, triple therapy might be a treatment option for patients with mHSPC.
Topics: Humans; Male; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Hormones; Prostatic Neoplasms
PubMed: 36938560
DOI: 10.20471/acc.2022.61.s3.12 -
Annals of Oncology : Official Journal... Sep 2014The therapeutic landscape of metastatic castration-resistant prostate cancer (mCRPC) has been revolutionized by the arrival of multiple novel agents in the past 2 years.... (Review)
Review
The therapeutic landscape of metastatic castration-resistant prostate cancer (mCRPC) has been revolutionized by the arrival of multiple novel agents in the past 2 years. Immunotherapy in the form of sipuleucel-T, androgen axis inhibitors, including abiraterone acetate and enzalutamide, a chemotherapeutic agent, cabazitaxel, and a radiopharmaceutical, radium-223, have all yielded incremental extensions of survival and have been recently approved. A number of other agents appear promising in early studies, suggesting that the armamentarium against castrate-resistant prostate cancer is likely to continue to expand. Emerging androgen pathway inhibitors include androgen synthesis inhibitors (TAK700), androgen receptor inhibitors (ARN-509, ODM-201), AR DNA binding domain inhibitors (EPI-001), selective AR downregulators or SARDs (AZD-3514), and agents that inhibit both androgen synthesis and receptor binding (TOK-001/galeterone). Promising immunotherapeutic agents include poxvirus vaccines and CTLA-4 inhibitor (ipilimumab). Biologic agents targeting the molecular drivers of disease are also being investigated as single agents, including cabozantinib (Met and VEGFR2 inhibitor) and tasquinimod (angiogenesis and immune modulatory agent). Despite the disappointing results seen from studies evaluating docetaxel in combination with other agents, including GVAX, anti-angiogentic agents (bevacizumab, aflibercept, lenalinomide), a SRC kinase inhibitor (dasatinib), endothelin receptor antagonists (atrasentan, zibotentan), and high-dose calcitriol (DN-101), the results from the trial evaluating docetaxel in combination with the clusterin antagonist, custirsen, are eagerly awaited. New therapeutic hurdles consist of discovering new targets, understanding resistance mechanisms, the optimal sequencing and combinations of available agents, as well as biomarkers predictive for benefit. Novel agents targeting bone metastases are being developed following the success of zoledronic acid and denosumab. Finally, all of these modalities do not appear curative, suggesting that clinical trial enrollment and a better understanding of biology remain of paramount importance.
Topics: Androgen Antagonists; Androgen Receptor Antagonists; Angiogenesis Inhibitors; Antineoplastic Agents; Cancer Vaccines; Drug Discovery; Endothelin Receptor Antagonists; Humans; Immunotherapy; Male; Prostatic Neoplasms, Castration-Resistant; Steroid Synthesis Inhibitors
PubMed: 24658665
DOI: 10.1093/annonc/mdu038 -
The Oncologist Mar 2024In the ARASENS trial (NCT02799602), darolutamide in combination with androgen-deprivation therapy (ADT) and docetaxel significantly reduced the risk of death by 32.5%...
BACKGROUND
In the ARASENS trial (NCT02799602), darolutamide in combination with androgen-deprivation therapy (ADT) and docetaxel significantly reduced the risk of death by 32.5% (HR, 0.68; 95% CI, 0.57-0.80; P < .0001) compared with placebo plus ADT with docetaxel in patients with metastatic hormone-sensitive prostate cancer (mHSPC). We present efficacy and safety of darolutamide versus placebo in Black patients from ARASENS.
PATIENTS AND METHODS
Patients with mHSPC were randomized 1:1 to darolutamide 600 mg or placebo twice daily in combination with ADT and docetaxel. The primary endpoint was overall survival. Key secondary endpoints included time to castration-resistant prostate cancer (CRPC) and safety.
RESULTS
In ARASENS, 54 Black patients received darolutamide (n = 26) or placebo (n = 28) plus ADT and docetaxel. In Black patients, overall survival favored darolutamide versus placebo (median, not reached vs. 38.7 months; stratified HR, 0.41; 95% CI, 0.17-1.02), with 4-year survival rates of 62% versus 41%. The darolutamide group also had longer time to CRPC compared with the placebo group (median, not reached vs .12.6 months; HR, 0.09; 95% CI, 0.02-0.30). The safety profile of darolutamide in Black patients was consistent with that observed for the overall ARASENS population (grade 3/4 treatment-emergent adverse events, TEAEs: 61.5% vs. 66.1%; serious TEAEs: 42.3% vs. 44.8%).
CONCLUSION
In this small population of Black patients with mHSPC from the ARASENS trial, darolutamide was associated with an improvement in survival and time to CRPC and was well tolerated. Efficacy and safety findings in Black patients were consistent with the overall ARASENS population.
Topics: Humans; Male; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Pyrazoles; Randomized Controlled Trials as Topic
PubMed: 37812679
DOI: 10.1093/oncolo/oyad254 -
Frontiers in Endocrinology 2022Prostate cancer is the second most frequently diagnosed cancer in men and several therapeutic approaches are currently available for patient's care. Although the... (Review)
Review
Prostate cancer is the second most frequently diagnosed cancer in men and several therapeutic approaches are currently available for patient's care. Although the androgen receptor status represents a good predictor of response to androgen deprivation therapy, prostate cancer frequently becomes resistant to this approach and spreads. The molecular mechanisms that contribute to progression and drug-resistance of this cancer remain still debated. However, few therapeutic options are available for patient's management, at this stage. Recent years have seen a great expansion of the studies concerning the role of stromal-epithelial interactions and tumor microenvironment in prostate cancer progression. The findings so far collected have provided new insights into diagnostic and clinical management of prostate cancer patients. Further, new fascinating aspects concerning the intersection of the androgen receptor with survival factors as well as calcium channels have been reported in cultured prostate cancer cells and mouse models. The results of these researches have opened the way for a better understanding of the basic mechanisms involved in prostate cancer invasion and drug-resistance. They have also significantly expanded the list of new biomarkers and druggable targets in prostate cancer. The primary aim of this manuscript is to provide an update of these issues, together with their translational aspects. Exploiting the power of novel promising therapeutics would increase the success rate in the diagnostic path and clinical management of patients with advanced disease.
Topics: Androgen Antagonists; Animals; Humans; Male; Mice; Prostate; Prostatic Neoplasms; Tumor Microenvironment
PubMed: 35222290
DOI: 10.3389/fendo.2022.840787 -
Acta Clinica Croatica Oct 2022Anti-androgen therapy continues to be a basic pilar of treatment for both localized and metastatic prostate cancer. The advent of new generation of androgen receptor... (Review)
Review
Anti-androgen therapy continues to be a basic pilar of treatment for both localized and metastatic prostate cancer. The advent of new generation of androgen receptor targeted agents (ARTA) transformed the care of patients with advanced disease. After such a success, the steps were taken to incorporate a new generation of ARTAs into the treatment landscape of localized prostate cancer. High-risk prostate cancer represents the most aggressive form of localized disease with significant metastatic potential and poor outcome. Here, the impact of novel therapies will likely be profound and transforming. This clinical space has already been a showcase for multidisciplinary treatment where the combination of local therapies with systemic treatment gradually improved patient outcomes and the chances of cure. The most recent step in redefining the treatment of localized disease is the adoption of novel ARTAs moving forward the multidisciplinary platform. In this narrative review, we discuss current clinical evidence supporting the use of novel ARTAs in patients with localized high-risk prostate cancer and cover recent developments in biomarker-driven strategies for treatment individualization in this clinical context.
Topics: Male; Humans; Receptors, Androgen; Prostatic Neoplasms, Castration-Resistant; Androgen Antagonists; Antineoplastic Agents; Prostatic Neoplasms
PubMed: 36938555
DOI: 10.20471/acc.2022.61.s3.7 -
Prostate Cancer and Prostatic Diseases Mar 2019Androgen deprivation therapy (ADT) is foundational in the management of advanced prostate cancer (PCa) and has benefitted from a recent explosion in scientific advances.... (Review)
Review
BACKGROUND
Androgen deprivation therapy (ADT) is foundational in the management of advanced prostate cancer (PCa) and has benefitted from a recent explosion in scientific advances. These include approval of new therapies that suppress testosterone (T) levels or inactivate its function, improvements in diagnostic and assay technologies, identification of lower therapeutic targets for T, discovery of the relevance of germline genetic mutations and identification of the benefits of sequential and combination therapies.
METHODS
This review discusses the clinical profiles of the most up-to-date options for ADT, best practices for managing patients with advanced PCa and future directions in therapy.
RESULTS AND CONCLUSIONS
Modern assay technologies reveal that bilateral orchiectomy results in a serum T level of approximately 15 ng/dL as compared to the historical definition of castration of T < 50 ng/dL. Evidence shows that lowering T levels to <20 ng/dL improves patient survival and delays disease progression. Routine monitoring of T in addition to prostate-specific antigen throughout treatment is important to ensure continuing efficacy of T suppression. New drugs that inhibit androgen signaling in combination with traditional ADT suppress T activity to near zero and have significantly improved patient survival. When personalizing ADT regimens physicians should consider a number of factors including initiation and duration of ADT, monitoring of T levels and PSA, the possibility of switching monotherapies if a patient does not achieve adequate T suppression, and consideration of intermittent vs. continuous ADT according to patients' lifestyles, comorbidities, risk factors and tolerance to treatment.
Topics: Androgen Antagonists; Androgen Receptor Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Drug Discovery; Humans; Male; Molecular Targeted Therapy; Prostatic Neoplasms; Receptors, Androgen; Signal Transduction; Testosterone; Treatment Outcome
PubMed: 30131604
DOI: 10.1038/s41391-018-0079-0