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Current Problems in Cancer 2016Triple-negative breast cancer represents approximately 15%-20% of all newly diagnosed breast cancers, but it accounts for a disproportionate number of breast... (Review)
Review
Triple-negative breast cancer represents approximately 15%-20% of all newly diagnosed breast cancers, but it accounts for a disproportionate number of breast cancer-related deaths each year. Owing to the lack of estrogen, progesterone, and human epidermal growth factor receptor 2 expression, patients with triple-negative breast cancer do not benefit from generally well-tolerated and effective therapies targeting the estrogen and human epidermal growth factor receptor 2 signaling pathways and are faced with an increased risk of disease progression and poorer overall survival. The heterogeneity of triple-negative breast cancer has been increasingly recognized and this may lead to therapeutic opportunities because of newly defined oncogenic drivers and targets. A subset of triple-negative breast tumors expresses the androgen receptor (AR) and this may benefit from treatments that inhibit the AR-signaling pathway. The first proof-of-concept trial established activity of the AR antagonist, bicalutamide, in patients with advanced AR+ triple-negative breast cancer. Since that time, evidence further supports the activity of other next-generation AR-targeted agents such as enzalutamide. Not unlike in estrogen receptor-positive breast cancer, mechanisms of resistance are being investigated and rationale exists for thoughtful, well-designed combination regimens such as AR antagonism with CDK4/6 pathway inhibitors or PI3K inhibitors. Furthermore, novel agents developed for the treatment of prostate cancer, which reduce androgen production such as abiraterone acetate and seviteronel, are being tested as well. This review summarizes the underlying biology of AR signaling in breast cancer development and the available clinical trial data for the use of anti-androgen therapy in the treatment of AR+ triple-negative breast cancer.
Topics: Androgen Antagonists; Antineoplastic Agents; Humans; Molecular Targeted Therapy; Receptors, Androgen; Triple Negative Breast Neoplasms
PubMed: 27816190
DOI: 10.1016/j.currproblcancer.2016.09.004 -
Cancer Journal (Sudbury, Mass.) 2020Our understanding of metastatic disease is rapidly advancing, with recent evidence supporting an oligometastatic state currently defined by patients having a limited... (Review)
Review
Our understanding of metastatic disease is rapidly advancing, with recent evidence supporting an oligometastatic state currently defined by patients having a limited (typically ≤5) number of metastatic deposits. The optimal management of these patients is also shifting toward increased integration of local therapies, with emerging evidence suggesting metastasis-directed therapy can improve overall survival. Additionally, the use of stereotactic ablative radiation therapy within castration-sensitive oligometastatic prostate cancer cohorts appears to forestall the need to initiate systemic therapy, which has unfavorable side effect profiles, such as androgen deprivation therapy, while itself being associated with little toxicity. We review the literature surrounding the use of metastasis-directed therapy in the treatment of oligometastatic prostate cancer by reviewing the evidence for its use within 3 subgroups: de novo synchronous, oligorecurrent, and oligoprogressive disease.
Topics: Ablation Techniques; Androgen Antagonists; Chemoradiotherapy; Disease Progression; Disease-Free Survival; Evidence-Based Medicine; Humans; Male; Medical Oncology; Neoplasm Metastasis; Patient Selection; Progression-Free Survival; Prostate; Prostatic Neoplasms; Radiosurgery; Randomized Controlled Trials as Topic
PubMed: 32205538
DOI: 10.1097/PPO.0000000000000432 -
Medicinal Research Reviews Sep 2023The androgen receptor (AR) has been shown to be a key determinant in the pathogenesis of castration-resistant prostate cancer (CRPC). The current standard of care... (Review)
Review
The androgen receptor (AR) has been shown to be a key determinant in the pathogenesis of castration-resistant prostate cancer (CRPC). The current standard of care therapies targets the ligand-binding domain of the receptor and can afford improvements to life expectancy often only in the order of months before resistance occurs. Emerging preclinical and clinical compounds that inhibit receptor activity via differentiated mechanisms of action which are orthogonal to current antiandrogens show promise for overcoming treatment resistance. In this review, we present an authoritative summary of molecules that noncompetitively target the AR. Emerging small molecule strategies for targeting alternative domains of the AR represent a promising area of research that shows significant potential for future therapies. The overall quality of lead candidates in the area of noncompetitive AR inhibition is discussed, and it identifies the key chemotypes and associated properties which are likely to be, or are currently, positioned to be first in human applications.
Topics: Male; Humans; Receptors, Androgen; Prostatic Neoplasms, Castration-Resistant; Androgen Antagonists; Cell Line, Tumor
PubMed: 37062876
DOI: 10.1002/med.21961 -
International Journal of Molecular... Feb 2023Prostate cancer (PCa) is today the second most common cancer in the world, with almost 400,000 deaths annually. Multiple factors are involved in the etiology of PCa,... (Review)
Review
Prostate cancer (PCa) is today the second most common cancer in the world, with almost 400,000 deaths annually. Multiple factors are involved in the etiology of PCa, such as older age, genetic mutations, ethnicity, diet, or inflammation. Modern treatment of PCa involves radical surgical treatment or radiation therapy in the stages when the tumor is limited to the prostate. When metastases develop, the standard procedure is androgen deprivation therapy, which aims to reduce the level of circulating testosterone, which is achieved by surgical or medical castration. However, when the level of testosterone decreases to the castration level, the tumor cells adapt to the new conditions through different mechanisms, which enable their unhindered growth and survival, despite the therapy. New knowledge about the biology of the so-called of castration-resistant PCa and the way it adapts to therapy will enable the development of new drugs, whose goal is to prolong the survival of patients with this stage of the disease, which will be discussed in this review.
Topics: Male; Humans; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Androgen Antagonists; Testosterone; Prostate; Orchiectomy; Receptors, Androgen
PubMed: 36769263
DOI: 10.3390/ijms24032939 -
Medicine Jul 2022Glucocorticoids act through the glucocorticoid receptor (GR) and exert pleiotropic effects in different cancer types. In prostate cancer cells, GR and androgen receptor... (Review)
Review
Glucocorticoids act through the glucocorticoid receptor (GR) and exert pleiotropic effects in different cancer types. In prostate cancer cells, GR and androgen receptor (AR) share overlapping transcriptomes and cistromes. Under enzalutamide treatment, GR signaling can bypass AR activation and promote castration resistance via the expression of a subset of AR-target genes. However, GR-dependent growth under enhanced antiandrogen inhibition occurs only in a subset of primed cells. On the other hand, glucocorticoids have been used successfully in the treatment of prostate cancer for many years. In the context of AR signaling, GR competes with AR for DNA-binding and has the potential to halt the proliferation rate of prostate cancer cells. Their target genes overlap by <50% and they execute unique functions in vivo. In addition, even when AR and GR upregulate the same transcriptional target gene, the effect might not be identical in magnitude. Besides being able to drive tumor proliferation, GR is also a key player in prostate cancer cell survival. Stimulation of GR activity can undermine the effects of enhanced antiandrogen treatment, chemotherapy and radiotherapy. GR activation in prostate cancer can increase prosurvival gene expression. Identifying the full spectrum of GR activity will inform the optimal use of glucocorticosteroids in prostate cancer. It will also determine the best strategies to target the protumorigenic effects of GR.
Topics: Androgen Antagonists; Androgen Receptor Antagonists; Cell Line, Tumor; Humans; Male; Nitriles; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Receptors, Glucocorticoid
PubMed: 35866830
DOI: 10.1097/MD.0000000000029716 -
Journal For Immunotherapy of Cancer Mar 2023This phase 1 study evaluated PF-06753512, a vaccine-based immunotherapy regimen (PrCa VBIR), in two clinical states of prostate cancer (PC), metastatic...
First-in-human, phase 1 study of PF-06753512, a vaccine-based immunotherapy regimen (VBIR), in non-metastatic hormone-sensitive biochemical recurrence and metastatic castration-resistant prostate cancer (mCRPC).
BACKGROUND
This phase 1 study evaluated PF-06753512, a vaccine-based immunotherapy regimen (PrCa VBIR), in two clinical states of prostate cancer (PC), metastatic castration-resistant PC (mCRPC) and biochemical recurrence (BCR).
METHODS
For dose escalation, patients with mCRPC received intramuscular PrCa VBIR (adenovirus vector and plasmid DNA expressing prostate-specific membrane antigen (PSMA), prostate-specific antigen (PSA), and prostate stem cell antigen (PSCA)) with or without immune checkpoint inhibitors (ICIs, tremelimumab 40 or 80 mg with or without sasanlimab 130 or 300 mg, both subcutaneous). For dose expansion, patients with mCRPC received recommended phase 2 dose (RP2D) of PrCa VBIR plus tremelimumab 80 mg and sasanlimab 300 mg; patients with BCR received PrCa VBIR plus tremelimumab 80 mg (Cohort 1B-BCR) or tremelimumab 80 mg plus sasanlimab 130 mg (Cohort 5B-BCR) without androgen deprivation therapy (ADT). The primary endpoint was safety.
RESULTS
Ninety-one patients were treated in dose escalation (mCRPC=38) and expansion (BCR=35, mCRPC=18). Overall, treatment-related and immune-related adverse events occurred in 64 (70.3%) and 39 (42.9%) patients, with fatigue (40.7%), influenza-like illness (30.8%), diarrhea (23.1%), and immune-related thyroid dysfunction (19.8%) and rash (15.4%), as the most common. In patients with mCRPC, the objective response rate (ORR, 95% CI) was 5.6% (1.2% to 15.4%) and the median radiographic progression-free survival (rPFS) was 5.6 (3.5 to not estimable) months for all; the ORR was 16.7% (3.6% to 41.4%) and 6-month rPFS rate was 45.5% (24.9% to 64.1%) for those who received RP2D with measurable disease (n=18). 7.4% of patients with mCRPC achieved a ≥50% decline in baseline PSA (PSA-50), with a median duration of 4.6 (1.2-45.2) months. In patients with BCR, 9 (25.7%) achieved PSA-50; the median duration of PSA response was 3.9 (1.9-4.2) and 10.1 (6.9-28.8) months for Cohorts 5B-BCR and 1B-BCR. Overall, antigen specific T-cell response was 88.0% to PSMA, 84.0% to PSA, and 80.0% to PSCA.
CONCLUSIONS
PrCa VBIR overall demonstrated safety signals similar to other ICI combination trials; significant side effects were seen in some patients with BCR. It stimulated antigen-specific immunity across all cohorts and resulted in modest antitumor activity in patients with BCR without using ADT.
TRIAL REGISTRATION NUMBER
NCT02616185.
Topics: Male; Humans; Prostatic Neoplasms, Castration-Resistant; Docetaxel; Prostate-Specific Antigen; Androgen Antagonists; Vaccines; Immunotherapy; Hormones
PubMed: 36948505
DOI: 10.1136/jitc-2022-005702 -
European Journal of Pharmaceutical... Sep 2022Current guidelines suggest radiotherapy as a first-line treatment for prostate cancer, along with prostatectomy, and androgen deprivation therapy. Abiraterone is a... (Review)
Review
Current guidelines suggest radiotherapy as a first-line treatment for prostate cancer, along with prostatectomy, and androgen deprivation therapy. Abiraterone is a first-in-class medicinal product recommended in the treatment of metastatic castration resistant prostate cancer (mCRPC) that targets androgen receptors and inhibits systemic synthesis. However, successful therapy with this drug may pose some challenges. It has to be administered as an inactive prodrug - abiraterone acetate. It is also dissolved and absorbed poorly with large interindividual variability and exhibits considerable food effects. Additionally, the recommended daily dose of the drug is high (1000 mg abiraterone acetate), and the cost of the therapy is burdensome. The following review focuses on the strategies to optimize therapy with abiraterone acetate. First, it summarizes current findings on abiraterone pharmacokinetics and accentuates the need for utilizing therapeutic monitoring in clinical practice. Next, it extensively describes the options for improving the low bioavailability of the drug. The two major approaches are the utilization of the positive food effect to increase the exposure and development of supergenerics. The review emphasizes how different formulation approaches lead to increased solubility and impact the outcomes of pre-clinical and clinical trials. The review concludes with a discussion on possible future directions that may lead to the increase of the therapeutic efficacy of abiraterone.
Topics: Abiraterone Acetate; Androgen Antagonists; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Drug Monitoring; Humans; Male; Pharmaceutical Preparations; Prostatic Neoplasms, Castration-Resistant
PubMed: 35793751
DOI: 10.1016/j.ejps.2022.106254 -
Endocrinology Aug 2021Coronavirus disease 2019 (COVID-19) is characterized by a gender disparity in severity, with men exhibiting higher hospitalization and mortality rates than women. Severe...
Coronavirus disease 2019 (COVID-19) is characterized by a gender disparity in severity, with men exhibiting higher hospitalization and mortality rates than women. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, infects cells following recognition and attachment of the viral spike glycoprotein to the angiotensin-converting enzyme 2 transmembrane protein, followed by spike protein cleavage and activation by cell surface transmembrane protease serine 2 (TMPRSS2). In prostate cancer cells, androgen acting on the androgen receptor increases TMPRSS2 expression, which has led to the hypothesis that androgen-dependent expression of TMPRSS2 in the lung may increase men's susceptibility to severe COVID-19 and that, accordingly, suppressing androgen production or action may mitigate COVID-19 severity by reducing SARS-CoV-2 amplification. Several ongoing clinical trials are testing the ability of androgen deprivation therapies or anti-androgens to mitigate COVID-19. This perspective discusses clinical and molecular advances on the rapidly evolving field of androgen receptor (AR) action on cell surface transmembrane protease serine 2 (TMPRSS2) expression and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and the potential effect of anti-androgens on coronavirus disease 2019 (COVID-19) severity in male patients. It discusses limitations of current studies and offers insight for future directions.
Topics: Androgen Antagonists; Animals; Gene Expression; Humans; Lung; Male; Mice; Prostatic Neoplasms; Receptors, Androgen; SARS-CoV-2; Serine Endopeptidases; Sex Factors; COVID-19 Drug Treatment
PubMed: 34089595
DOI: 10.1210/endocr/bqab114 -
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 -
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