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Cancer Journal (Sudbury, Mass.) 2020Patients with high-risk localized prostate cancer benefit from multimodality therapy of curative intent. Androgen-deprivation therapy (ADT) combined with radiation... (Review)
Review
Patients with high-risk localized prostate cancer benefit from multimodality therapy of curative intent. Androgen-deprivation therapy (ADT) combined with radiation improves survival in this population. However, prior clinical trials of neoadjuvant ADT and surgery failed to consistently demonstrate a survival advantage. The development of novel, more potent hormonal agents presents an opportunity to revisit the potential for neoadjuvant therapy to improve long-term outcomes for patients with localized prostate cancer. We review recent advances in neoadjuvant approaches for prostate cancer and emerging clinical trials data supporting the use of neoadjuvant therapy prior to radical prostatectomy.
Topics: Androgen Antagonists; Antineoplastic Agents, Hormonal; Chemoradiotherapy, Adjuvant; Clinical Trials as Topic; Disease Progression; Humans; Male; Neoadjuvant Therapy; Progression-Free Survival; Prostate; Prostatectomy; Prostatic Neoplasms; Risk Assessment
PubMed: 31977379
DOI: 10.1097/PPO.0000000000000424 -
Acta Oncologica (Stockholm, Sweden) Sep 2023We compared the effectiveness of currently available systemic therapies for high-volume metastatic hormone-sensitive prostate cancer (mHSPC) and aimed to establish the... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
We compared the effectiveness of currently available systemic therapies for high-volume metastatic hormone-sensitive prostate cancer (mHSPC) and aimed to establish the optimal treatment regimen.
MATERIAL AND METHODS
We searched multiple databases for randomized controlled trials (RCTs) that evaluated the efficacy of systemic therapy in patients with high-volume mHSPC. Bayesian network meta-analysis was used to indirectly compare overall survival (OS) and progression-free survival (PFS) of various systemic therapies.
RESULTS
Eleven RCTs (6708 participants) finally met the eligibility criteria. Compared with androgen deprivation therapy (ADT) alone, rezvilutamide (REZ) [hazard ratio (HR) = 0.58, 95% confidence interval (CI): 0.44-0.77], abiraterone (ABI) (HR = 0.61, 95% CI: 0.53-0.71), apalutamide (APA) (HR = 0.70, 95% CI: 0.56-0.88), enzalutamide (ENZ) (HR = 0.65, 95% CI: 0.53-0.80), docetaxel (DOC) (HR = 0.72, 95% CI: 0.63-0.84), darolutamide (DAR) + DOC (HR = 0.49, 95% CI: 0.39-0.62), and ABI + DOC (HR = 0.52, 95% CI: 0.38-0.71) significantly improved OS in patients with high-volume mHSPC. Compared with DOC, no advantages were observed for doublet therapies, including REZ, ABI, APA, and ENZ on the basis of ADT, whereas DAR + DOC (HR = 0.68, 95% CI: 0.57-0.82) and ABI + DOC (HR = 0.72, 95% CI: 0.55-0.95) was associated with better OS. The ranking analysis showed that triplet therapy (DAR + DOC + ADT and ABI + DOC + ADT) had the greatest improvement in OS, followed by REZ + ADT. All the regimens showed improved PFS in patients with high-volume mHSPC. Compared with DOC, significant differences were detected for DAR + DOC, ABI + DOC, ENZ + DOC, REZ, and ENZ. According to the ranking analysis, triplet therapy ranked first, followed by ENZ and REZ.
CONCLUSIONS
REZ + ADT were the highest ranked doublet therapy for improvement in OS of patients with high-volume mHSPC, second only to triplet therapy (DAR + DOC + ADT and ABI + DOC + ADT).
Topics: Male; Humans; Network Meta-Analysis; Treatment Outcome; Prostatic Neoplasms; Docetaxel; Androgen Antagonists; Hormones; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37548225
DOI: 10.1080/0284186X.2023.2241985 -
Current Opinion in Supportive and... Dec 2022The landscape of metastatic hormone sensitive prostate cancer (mHSPC) has evolved rapidly in recent years with new data from landmark trials supporting upfront treatment... (Review)
Review
PURPOSE OF REVIEW
The landscape of metastatic hormone sensitive prostate cancer (mHSPC) has evolved rapidly in recent years with new data from landmark trials supporting upfront treatment intensification. The developments come not only on the fronts of systemic agents but also in area of therapy to primary tumour and metastases.
RECENT FINDINGS
More recently, the ARASENS and PEACE trials have taken the concept of treatment intensification further by demonstrating survival benefit from combination of chemotherapy (docetaxel) and androgen receptor pathway inhibitors (abiraterone and darolutamide) in addition to backbone therapy of androgen deprivation therapy (ADT). Intensification of treatment has also seen evidence supporting local therapy to the primary tumour with overall survival and biochemical recurrence-free survival although only evident in low volume synchronous metastases. There is emerging evidence for metastases-directed therapy as well with pooled data suggesting improved biochemical-free and ADT-free survival.
SUMMARY
Robust clinical data has demonstrated survival benefits with treatment intensification and this should be the new standard of care. Subgroup analysis has highlighted the importance of tailoring mHSPC treatment for patients with high- and low-volume metastatic disease. However, defining the volume of disease is becoming increasingly controversial due to heterogeneity of trial patient populations and next generation molecular imaging.
Topics: Male; Humans; Androgen Antagonists; Prostatic Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Treatment Outcome; Hormones
PubMed: 36239736
DOI: 10.1097/SPC.0000000000000622 -
Current Opinion in Urology May 2022To summarize the role of chemotherapy and offer some guidance regarding the selection of chemotherapy in mPC. (Review)
Review
PURPOSE OF REVIEW
To summarize the role of chemotherapy and offer some guidance regarding the selection of chemotherapy in mPC.
RECENT FINDINGS
Patients with mHSPC have varied prognoses with testosterone suppression alone (androgen deprivation therapy, ADT) and differential responses to docetaxel with ADT. Patients with de novo and metachronous high-volume disease have a robust survival benefit with the addition of docetaxel to hormonal therapies. Patients with synchronous low-volume disease have a more modest survival benefit from docetaxel and there is no evidence of survival benefit with docetaxel in patients with metachronous low-volume disease. Integration of biomarkers may refine treatment selection regardless of volume of disease. Docetaxel and cabazitaxel also impart an OS benefit in patients with metastatic castration-resistant prostate cancer (mCRPC). The choice of chemotherapy in mCRPC depends on treatment received in mHSPC setting. Docetaxel remains the first line chemotherapy in castration-resistant patients who have not received it in mHSPC followed by cabazitaxel, otherwise cabazitaxel can be deployed without docetaxel retreatment.
SUMMARY
Chemotherapy is a key class of therapy for selected patients with mHSPC and mCRPC.
Topics: Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Treatment Outcome
PubMed: 35552310
DOI: 10.1097/MOU.0000000000000985 -
Journal of Medicinal Chemistry Jul 2022The androgen receptor (AR) plays a key role in the maintenance of muscle and bone and the support of male sexual-related functions, as well as in the progression of... (Review)
Review
The androgen receptor (AR) plays a key role in the maintenance of muscle and bone and the support of male sexual-related functions, as well as in the progression of prostate cancer. Accordingly, AR-targeted therapies have been developed for the treatment of related human diseases and conditions. AR agonists are an important class of drugs in the treatment of bone loss and muscle atrophy. AR antagonists have also been developed for the treatment of prostate cancer, including metastatic castration-resistant prostate cancer (mCRPC). Additionally, selective AR degraders (SARDs) have been reported. More recently, heterobifunctional degrader molecules of AR have been developed, and four such compounds are now in clinical development for the treatment of human prostate cancer. This review attempts to summarize the different types of compounds designed to target AR and the current frontiers of research on this important therapeutic target.
Topics: Androgen Antagonists; Androgen Receptor Antagonists; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen
PubMed: 35786895
DOI: 10.1021/acs.jmedchem.2c00716 -
International Journal of Clinical... Mar 2020From the primary care perspective, many urologists and oncologists appear to be ignoring an FDA warning to assess patients' cardiovascular (CV) risk before instituting... (Review)
Review
BACKGROUND
From the primary care perspective, many urologists and oncologists appear to be ignoring an FDA warning to assess patients' cardiovascular (CV) risk before instituting androgen deprivation therapy (ADT) with gonadotropin-releasing hormone (GnRH) agonists. A growing body of data suggest an association between ADT and CV/cardiometabolic risk, particularly for GnRH agonists.
METHODOLOGY
The author examined available evidence regarding CV side effects with GnRH agonists and antagonists to determine what urologists, medical oncologists, primary care physicians (PCPs) and patients need to know about these risks.
RESULTS
Data are inconclusive and somewhat conflicting-for example, both low testosterone and testosterone replacement have been associated with elevated CV risk. But the distinction between GnRH agonists and antagonists is becoming clearer, as agonists appear to be more strongly linked with CV risk, perhaps due to the transient testosterone surge they cause upon administration. Moreover, adverse CV events associated with GnRH agonists can emerge relatively quickly, within weeks to months. Conversely, two studies show that GnRH antagonists may significantly reduce CV risk compared to GnRH agonists.
CONCLUSIONS
Both GnRH agonists and antagonists carry some degree of CV risk. Although the risk appears to be lower with GnRH antagonists, urologists and oncologists should communicate with PCPs to determine patients' baseline CV risk levels before implementing ADT with either type of agent.
Topics: Androgen Antagonists; Cardiovascular Diseases; Evidence-Based Medicine; Gonadotropin-Releasing Hormone; Hormone Replacement Therapy; Humans; Male; Prostatic Neoplasms; Risk Assessment; Risk Factors
PubMed: 31755635
DOI: 10.1111/ijcp.13449 -
Seminars in Radiation Oncology Jan 2022Androgen receptor signaling blockade is perhaps the first example of targeted therapy in the treatment of cancer. Since the initial observations that prostate cancers... (Review)
Review
Androgen receptor signaling blockade is perhaps the first example of targeted therapy in the treatment of cancer. Since the initial observations that prostate cancers depend on hormone signaling, hormonal therapies remain a cornerstone in the treatment of metastatic prostate cancer. Androgen deprivation therapy has been shown to improve outcomes involving treatment of prostate cancers with radiotherapy, though a mechanistic understanding into the optimal sequencing of androgen deprivation therapy and radiotherapy remains incomplete. In this review we highlight key clinical trials designed to study combinations of hormonal and radiotherapies and introduce recent discoveries into the complex biology of androgen receptor signaling and DNA damage and repair. These emerging mechanistic and translational studies may have profound implications on both our understanding of hormonal therapy and radiotherapy combinations and the development of novel treatment strategies for locally-advanced and metastatic castrate resistant prostate cancer.
Topics: Androgen Antagonists; Androgen Receptor Antagonists; Antineoplastic Agents, Hormonal; Humans; Male; Prostatic Neoplasms
PubMed: 34861998
DOI: 10.1016/j.semradonc.2021.09.003 -
Handbook of Experimental Pharmacology 2020In both sexes, estrogen is one of the most essential hormones for maintaining bone integrity. Also, especially in men, androgen has beneficial effects on bone...
In both sexes, estrogen is one of the most essential hormones for maintaining bone integrity. Also, especially in men, androgen has beneficial effects on bone independent of estrogen. However, estrogen replacement therapy for postmenopausal women increases the risk of developing breast cancer and endometrial cancer, and androgen replacement therapy for partial androgen deficiency of the aging male increases the risk of developing prostate cancer. Various mechanisms have been proposed on the effects of gonadal hormones on bone, such as effects through cytokines including IL-6 and effects on the OPG/RANKL ratio. In addition, large amounts of new information deriving from high-throughput gene expression analysis raise the possibility of multiple other effects on bone cells. Both estrogen and androgen exert their effects via the estrogen receptor (ER) or the androgen receptor (AR), which belongs to the nuclear receptor superfamily. Compounds such as selective estrogen receptor modulators (SERMs) and selective androgen receptor modulators (SARMs) also bind ER and AR, respectively. However, SERMs and SARMs alter the ER or AR structure differently from estrogen or androgen, resulting in other downstream gene responses. As a result they can exert favorable effects on bone while suppressing the undesirable actions of estrogen and androgen. Elucidation of ER and AR ligand-specific and tissue-specific gene regulation mechanisms will also provide information on the signal transduction mechanisms of other nuclear receptors and will be valuable for the development of new therapeutic agents.
Topics: Androgen Antagonists; Bone and Bones; Female; Gonadal Hormones; Humans; Male; Receptors, Androgen; Receptors, Estrogen; Selective Estrogen Receptor Modulators
PubMed: 31820173
DOI: 10.1007/164_2019_327 -
Current Opinion in Oncology May 2023This review is designed to highlight recent research examining treatment progress in advanced prostate cancer while identifying ongoing challenges to clinical outcomes. (Review)
Review
PURPOSE OF REVIEW
This review is designed to highlight recent research examining treatment progress in advanced prostate cancer while identifying ongoing challenges to clinical outcomes.
RECENT FINDINGS
Recent randomized trials suggest an overall survival advantage to treating some men with newly identified metastatic prostate cancer with a "triplet" of androgen deprivation therapy, docetaxel, and an androgen receptor axis-targeted agent. Questions remain about which men are best served by these combinations. Additional treatment success is being identified with prostate-specific membrane antigen positron emission tomography (PSMA)-radiopharmaceuticals, combinations involving targeted therapies, and novel manipulations of the androgen receptor axis. Challenges remain in selecting between available therapies, harnessing immune therapies, and treating tumors with emergent neuroendocrine differentiation.
SUMMARY
An expanding number of therapeutics are becoming available for men with advanced prostate cancer improving outcomes but at the same time making treatment selection more demanding. Ongoing research will be required to continue to hone treatment paradigms.
Topics: Male; Humans; Prostatic Neoplasms; Receptors, Androgen; Prostatic Neoplasms, Castration-Resistant; Androgen Antagonists; Docetaxel; Antineoplastic Agents
PubMed: 36966494
DOI: 10.1097/CCO.0000000000000938 -
Targeted Oncology Sep 2023Darolutamide (NUBEQA) is an oral androgen receptor inhibitor (ARi) that is approved for the treatment of metastatic hormone-sensitive prostate cancer (mHSPC) in... (Review)
Review
Darolutamide (NUBEQA) is an oral androgen receptor inhibitor (ARi) that is approved for the treatment of metastatic hormone-sensitive prostate cancer (mHSPC) in combination with androgen deprivation therapy (ADT) and docetaxel. In a pivotal trial, darolutamide plus ADT and docetaxel was superior to placebo plus ADT and docetaxel in prolonging the primary endpoint of overall survival, with improvements also reported in most secondary endpoints. Treatment with darolutamide plus ADT and docetaxel was associated with a manageable tolerability profile. Furthermore, the adverse events reported with darolutamide plus ADT and docetaxel were generally consistent with the safety profiles previously reported for ADT and docetaxel. Darolutamide expands the availability of treatment options in mHSPC and may be useful as a treatment for high-volume disease (typically defined as ≥ 4 bone metastases with spread outside of the pelvis and vertebral column).
Topics: Male; Humans; Prostatic Neoplasms; Docetaxel; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Hormones
PubMed: 37542594
DOI: 10.1007/s11523-023-00984-4