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JU Open Plus Apr 2024Management strategies for metastatic castration-resistant prostate cancer (mCRPC) have rapidly shifted in recent years. As novel imaging and therapeutic approaches have...
Expert Perspectives on Controversies in Metastatic Castration-Resistant Prostate Cancer Management: Narrative Review and Report of the First US Prostate Cancer Conference Part 2.
BACKGROUND
Management strategies for metastatic castration-resistant prostate cancer (mCRPC) have rapidly shifted in recent years. As novel imaging and therapeutic approaches have made their way to the clinic, providers are encountering increasingly challenging clinical scenarios, with limited guidance from the current literature.
MATERIALS AND METHODS
The US Prostate Cancer Conference (USPCC) is a multidisciplinary meeting of prostate cancer experts intended to address the many challenges of prostate cancer management. At the first annual USPCC meeting, areas of controversy and consensus were identified during a 2-day meeting that included expert presentations, full-panel discussions, and postdiscussion responses to questions developed by the USPCC cochairs and session moderators.
RESULTS
This narrative review covers the USPCC expert discussion and perspectives relevant to mCRPC, including neuroendocrine/aggressive-variant prostate cancer (NEPC/AVPC). Areas of broad agreement identified among USPCC experts include the benefits of poly (ADP-ribose) polymerase (PARP) inhibitors for patients with mutations, the use of radioligand therapy in patients with prostate-specific membrane antigen (PSMA)-positive mCRPC, and the need for clinical trials that address real-world clinical questions, including the performance of novel therapies when compared with modern standard-of-care treatment. Ongoing areas of controversy and uncertainty included the appropriateness of PARP inhibitors in patients with non- mutations, the optimal definition of PSMA positivity, and systemic therapies for patients with NEPC/AVPC after progression on platinum-based therapies.
CONCLUSIONS
The first annual USPCC meeting identified several areas of controversy in the management of mCRPC, highlighting the urgent need for clinical trials designed to facilitate treatment selection and sequencing in this heterogeneous disease state.
PubMed: 38774467
DOI: 10.1097/ju9.0000000000000138 -
Journal For Immunotherapy of Cancer May 2024Androgen deprivation therapy (ADT) is the primary treatment for recurrent and metastatic prostate cancer. In addition to direct antitumor effects, ADT has...
RATIONALE
Androgen deprivation therapy (ADT) is the primary treatment for recurrent and metastatic prostate cancer. In addition to direct antitumor effects, ADT has immunomodulatory effects such as promoting T-cell infiltration and enhancing antigen processing/presentation. Previous studies in our laboratory have demonstrated that ADT also leads to increased expression of the androgen receptor (AR) and increased recognition of prostate tumor cells by AR-specific CD8+T cells. We have also demonstrated that ADT combined with a DNA vaccine encoding the AR significantly slowed tumor growth and improved the survival of prostate tumor-bearing mice. The current study aimed to investigate the impact of the timing and sequencing of ADT with vaccination on the tumor immune microenvironment in murine prostate cancer models to further increase the antitumor efficacy of vaccines.
METHODS
Male FVB mice implanted with Myc-CaP tumor cells, or male C57BL/6 mice implanted with TRAMP-C1 prostate tumor cells, were treated with a DNA vaccine encoding AR (pTVG-AR) and ADT. The sequence of administration was evaluated for its effect on tumor growth, and tumor-infiltrating immune populations were characterized.
RESULTS
Vaccination prior to ADT (pTVG-AR → ADT) significantly enhanced antitumor responses and survival. This was associated with increased tumor infiltration by CD4+ and CD8+ T cells, including AR-specific CD8+T cells. Depletion of CD8+T cells prior to ADT significantly worsened overall survival. Following ADT treatment, however, Gr1+ myeloid-derived suppressor cells (MDSCs) increased, and this was associated with fewer infiltrating T cells and reduced tumor growth. Inhibiting Gr1+MDSCs recruitment, either by using a CXCR2 antagonist or by cycling androgen deprivation with testosterone replacement, improved antitumor responses and overall survival.
CONCLUSION
Vaccination prior to ADT significantly improved antitumor responses, mediated in part by increased infiltration of CD8+T cells following ADT. Targeting MDSC recruitment following ADT further enhanced antitumor responses. These findings suggest logical directions for future clinical trials to improve the efficacy of prostate cancer vaccines.
Topics: Male; Animals; Mice; Prostatic Neoplasms; Receptors, Androgen; Cancer Vaccines; Vaccines, DNA; Androgen Antagonists; Cell Line, Tumor; Mice, Inbred C57BL; Vaccination; Humans; Tumor Microenvironment; Disease Models, Animal; CD8-Positive T-Lymphocytes
PubMed: 38772685
DOI: 10.1136/jitc-2024-008848 -
Lancet (London, England) Jun 2024Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for... (Randomized Controlled Trial)
Randomized Controlled Trial Comparative Study
Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial.
BACKGROUND
Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear.
METHODS
RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047.
FINDINGS
Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61-69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1-10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688-1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4-82·5) in the no ADT group and 80·4% (76·6-83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths.
INTERPRETATION
Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population.
FUNDING
Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society.
Topics: Humans; Male; Prostatic Neoplasms; Androgen Antagonists; Prostatectomy; Aged; Tosyl Compounds; Anilides; Middle Aged; Nitriles; Oligopeptides; Gonadotropin-Releasing Hormone; Combined Modality Therapy; Prostate-Specific Antigen
PubMed: 38763154
DOI: 10.1016/S0140-6736(24)00548-8 -
Lancet (London, England) Jun 2024Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate... (Randomized Controlled Trial)
Randomized Controlled Trial Comparative Study
Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial.
BACKGROUND
Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain.
METHODS
RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047.
FINDINGS
Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60-69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0-10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612-0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6-75·7) in the short-course ADT group and 78·1% (74·2-81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths.
INTERPRETATION
Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy.
FUNDING
Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society.
Topics: Humans; Male; Prostatic Neoplasms; Androgen Antagonists; Prostatectomy; Aged; Tosyl Compounds; Middle Aged; Anilides; Nitriles; Oligopeptides; Gonadotropin-Releasing Hormone; Prostate-Specific Antigen; Combined Modality Therapy; Drug Administration Schedule
PubMed: 38763153
DOI: 10.1016/S0140-6736(24)00549-X -
Free Radical Biology & Medicine Aug 2024Androgen receptor (AR)-targeting therapy induces oxidative stress in prostate cancer. However, the mechanism of oxidative stress induction by AR-targeting therapy...
Oxidative stress in peroxisomes induced by androgen receptor inhibition through peroxisome proliferator-activated receptor promotes enzalutamide resistance in prostate cancer.
Androgen receptor (AR)-targeting therapy induces oxidative stress in prostate cancer. However, the mechanism of oxidative stress induction by AR-targeting therapy remains unclear. This study investigated the mechanism of oxidative stress induction by AR-targeting therapy, with the aim to develop novel therapeutics targeting oxidative stress induced by AR-targeting therapy. Intracellular reactive oxygen species (ROS) was examined by fluorescence microscopy and flow cytometry analysis. The effects of silencing gene expression and small molecule inhibitors on gene expression and cytotoxic effects were examined by quantitative real-time PCR and cell proliferation assay. ROS induced by androgen depletion co-localized with peroxisomes in prostate cancer cells. Among peroxisome-related genes, PPARA was commonly induced by AR inhibition and involved in ROS production via PKC signaling. Inhibition of PPARα by specific siRNA and a small molecule inhibitor suppressed cell proliferation and increased cellular sensitivity to the antiandrogen enzalutamide in prostate cancer cells. This study revealed a novel pathway by which AR inhibition induced intracellular ROS mainly in peroxisomes through PPARα activation in prostate cancer. This pathway is a promising target for the development of novel therapeutics for prostate cancer in combination with AR-targeting therapy such as antiandrogen enzalutamide.
Topics: Male; Humans; Phenylthiohydantoin; Nitriles; Peroxisomes; Oxidative Stress; Drug Resistance, Neoplasm; Benzamides; Receptors, Androgen; Reactive Oxygen Species; PPAR alpha; Cell Proliferation; Prostatic Neoplasms; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Signal Transduction; Androgen Receptor Antagonists; RNA, Small Interfering
PubMed: 38762061
DOI: 10.1016/j.freeradbiomed.2024.05.030 -
Lipids in Health and Disease May 2024There is insufficient research on how gender-affirming hormone therapy (GAHT) affects body fat modifications in transwomen from China. It is unclear whether hormone...
BACKGROUND
There is insufficient research on how gender-affirming hormone therapy (GAHT) affects body fat modifications in transwomen from China. It is unclear whether hormone therapy affects the prevalence of obesity and blood lipid levels within this population. The current research aimed to assess how GAHT and treatment duration had an impact on the change in and redistribution of body fat in Chinese transwomen.
METHODS
This study included 40 transwomen who had not received GAHT and 59 who had. Body fat, blood lipid, and blood glucose levels were measured. GAHT is mainly a pharmacologic (estrogen and anti-androgen) treatment. The study also stratified participants based on the duration of GAHT to assess its impact on body fat distribution. The duration of GAHT was within one year, one to two years, two to three years, or more than three years.
RESULTS
After receiving GAHT, total body fat increased by 19.65%, and the percentage of body fat increased by 17.63%. The arm, corrected leg, and leg regions showed significant increases in fat content (+ 24.02%, + 50.69%, and + 41.47%, respectively) and percentage (+ 25.19%, + 34.90%, and + 30.39%, respectively). The total visceral fat content decreased (-37.49%). Based on the diagnostic standards for a body mass index ≥ 28 or total body fat percentage ≥ 25% or 30%, the chance of developing obesity did not change significantly. Blood glucose levels significantly increased (+ 12.31%). Total cholesterol levels (-10.45%) decreased significantly. Fat changes in those who received GAHT for one to two years were significantly different from those who did not receive GAHT.
CONCLUSION
After receiving GAHT, total body fat and regional fat increased in Chinese transwomen, and the body fat distribution changed from masculine to feminine, especially during the first two years. However, neither the increase in total body fat percentage nor the decrease in visceral fat content didn't bring about significant changes in the incidence of obesity, nor did triglycerides or low-density lipoprotein-cholesterol.
Topics: Adult; Female; Humans; Male; Adipose Tissue; Asian People; Blood Glucose; Body Fat Distribution; Body Mass Index; Case-Control Studies; China; East Asian People; Estrogens; Intra-Abdominal Fat; Obesity; Retrospective Studies; Sex Reassignment Procedures; Transgender Persons; Transsexualism
PubMed: 38760846
DOI: 10.1186/s12944-024-02131-y -
Cancers Apr 2024Advanced localized prostate cancers (PC) recur despite chemotherapy, radiotherapy and/or androgen deprivation therapy. We recently reported HOXB13 lysine (K)13...
Advanced localized prostate cancers (PC) recur despite chemotherapy, radiotherapy and/or androgen deprivation therapy. We recently reported HOXB13 lysine (K)13 acetylation as a gain-of-function modification that regulates interaction with the SWI/SNF chromatin remodeling complex and is critical for anti-androgen resistance. However, whether acetylated HOXB13 promotes PC cell survival following treatment with genotoxic agents is not known. Herein, we show that K13-acetylated HOXB13 is induced rapidly in PC cells in response to DNA damage induced by irradiation (IR). It colocalizes with the histone variant γH2AX at sites of double strand breaks (DSBs). Treatment of PCs with the Androgen Receptor (AR) antagonist Enzalutamide (ENZ) did not suppress DNA-damage-induced HOXB13 acetylation. In contrast, HOXB13 depletion or loss of acetylation overcame resistance of PC cells to ENZ and synergized with IR. mutants show diminished replication fork progression, impaired G2/M arrest with significant cell death following DNA damage. Mechanistically, we found that amino terminus regulates HOXB13 nuclear puncta formation that is essential for proper DNA damage response. Therefore, targeting HOXB13 acetylation with CBP/p300 inhibitors in combination with DNA damaging therapy may be an effective strategy to overcome anti-androgen resistance of PCs.
PubMed: 38730575
DOI: 10.3390/cancers16091622 -
Cureus Apr 2024Acne vulgaris, commonly called acne, is a skin condition affecting many individuals globally. It is a chronic condition characterized by developing pimples, blackheads... (Review)
Review
Acne vulgaris, commonly called acne, is a skin condition affecting many individuals globally. It is a chronic condition characterized by developing pimples, blackheads (open comedones), whiteheads (closed comedones), and other skin lesions. Acne usually appears on the face, neck, chest, and back. It is commonly associated with puberty and adolescence but can also affect adults of all ages. Acne can be very frustrating and embarrassing, leading to low self-esteem and social isolation. The condition arises from various factors, including clogged pores, excessive sebum production, bacteria, and inflammation. This systematic review assesses the effectiveness of topical antibiotics, retinoids, niacinamide, azelaic acid, and clascoterone in treating mild-to-moderate acne vulgaris. A comprehensive search across PubMed, PubMed Central, and Google Scholar yielded 10 articles focused on topical antibiotics, with findings from 198 subjects indicating the efficacy of doxycycline against inflammatory lesions. Retinoids, such as tretinoin and adapalene, significantly improved both lesion types (open and closed comedones). Niacinamide, examined in a randomized controlled trial involving 41 participants, reduced sebum production. Another study with 60 patients revealed that azelaic acid effectively reduced both inflammatory and non-inflammatory lesions. Clascoterone emerged as a promising antiandrogenic treatment, supported by a randomized controlled trial involving 4,440 patients. It is essential that individualized therapy, incorporating patient preferences and considering adverse effects, is emphasized for optimizing acne management.
PubMed: 38725769
DOI: 10.7759/cureus.57909 -
Journal of Oncology Pharmacy Practice :... May 2024The objective of this review is to provide an overview of common drug-drug interactions (DDIs) associated with prostate cancer treatments and outline recommendations for... (Review)
Review
OBJECTIVE
The objective of this review is to provide an overview of common drug-drug interactions (DDIs) associated with prostate cancer treatments and outline recommendations for managing polypharmacy.
DATA SOURCES
A literature search of PubMed, Embase, and CINAHL was carried out to identify pharmacokinetic and pharmacodynamic changes caused by DDIs that are relevant for prostate cancer patients, DDIs between prostate cancer therapies and co-administered medications (both prescription and over-the-counter), and measures to prevent DDIs. Medication package inserts were used to identify the impact of DDI on the prostate cancer therapy and suggested interventions.
DATA SUMMARY
No DDIs are expected for the LHRH agonists leuprolide acetate, histrelin, goserelin, or leuprolide mesylate. However, DDIs have been reported for GnRH antagonists, anti-androgens, PARP inhibitors, and taxanes. Although there are no confirmed DDIs for sipuleucel-T to date, it is not generally recommended to use sipuleucel-T concurrently with immunosuppressive medications. Interventions to prevent DDIs include the use of software that can detect clinically significant DDIs, up-to-date medication reconciliation, the inclusion of dedicated clinical pharmacists in cancer treatment teams, and patient/caregiver education.
CONCLUSIONS
Prostate cancer patients have a high risk of potential DDIs due to numerous new anti-cancer therapies, the increased use of treatment combinations, and the likelihood of comorbid conditions also requiring drug therapy. Drug-drug interaction screening software, up-to-date medication reconciliation, inclusion of oncology pharmacists on healthcare teams, and patient/caregiver education will aid the development of treatment plans that focus on achieving an optimal risk-benefit profile whilst reducing the risk of DDIs.
PubMed: 38720547
DOI: 10.1177/10781552241238198 -
Archivos Espanoles de Urologia Apr 2024
Topics: Humans; Male; Prostatic Neoplasms; Androgen Antagonists; Radiosurgery; Combined Modality Therapy
PubMed: 38715173
DOI: 10.56434/j.arch.esp.urol.20247703.41