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Urologie (Heidelberg, Germany) Mar 2024Metastasis-directed therapy (MDT) in oligometastatic prostate cancer (omHSPC) is playing an increasingly important role in therapy with the aim of delaying disease... (Review)
Review
BACKGROUND
Metastasis-directed therapy (MDT) in oligometastatic prostate cancer (omHSPC) is playing an increasingly important role in therapy with the aim of delaying disease progression, the start of systemic treatment or switching systemic treatment to improve the patient's overall prognosis. Molecular imaging as prostate-specific membrane antigen positron emission tomography (PSMA-PET) imaging allows metastases to be detected with a higher sensitivity and specificity. This means that they can be detected early and made accessible for treatment.
RESULTS
The standard therapy for oligo-mHSPC is androgen deprivation (ADT), which is supplemented by novel hormonal therapeutics (NHT). A few small prospective trials have shown an extension of the ADT-free interval and progression-free survival (PFS), particularly in metachronous oligo-mHSPC, by MDT, usually radiotherapy. Additional ADT can further extend the PFS in particular. There are hardly any prospective data for synchronous oligo-mHSPC.
CONCLUSION
Despite the currently still poor evidence, MDT is playing an increasingly important role. The still unclear definition of oligometastasis and the large number of influencing factors make it difficult to compare current data. Large multicenter prospective data are still pending. It is also important to clarify the effect of limited ADT in combination with NHT in the treatment of synchronous and metachronous oligo-mHSPC with MDT. In synchronous oligo-mHSPC in particular, further benefit of additional local therapy of the primary in combination with MDT should also be investigated.
Topics: Male; Humans; Prostatic Neoplasms; Androgen Antagonists; Prospective Studies; Treatment Outcome; Tomography, X-Ray Computed; Multicenter Studies as Topic
PubMed: 38388789
DOI: 10.1007/s00120-024-02281-y -
Cancer Oct 2023Accurate information regarding real-world outcomes after contemporary radiation therapy for localized prostate cancer is important for shared decision-making. Clinically...
PURPOSE
Accurate information regarding real-world outcomes after contemporary radiation therapy for localized prostate cancer is important for shared decision-making. Clinically relevant end points at 10 years among men treated within a national health care delivery system were examined.
METHODS
National administrative, cancer registry, and electronic health record data were used for patients undergoing definitive radiation therapy with or without concurrent androgen deprivation therapy within the Veterans Health Administration from 2005 to 2015. National Death Index data were used through 2019 for overall and prostate cancer-specific survival and identified date of incident metastatic prostate cancer using a validated natural language processing algorithm. Metastasis-free, prostate cancer-specific, and overall survival using Kaplan-Meier methods were estimated.
RESULTS
Among 41,735 men treated with definitive radiation therapy, the median age at diagnosis was 65 years and median follow-up was 8.7 years. Most had intermediate (42%) and high-risk (33%) disease, with 40% receiving androgen deprivation therapy as part of initial therapy. Unadjusted 10-year metastasis-free survival was 96%, 92%, and 80% for low-, intermediate-, and high-risk disease. Similarly, unadjusted 10-year prostate cancer-specific survival was 98%, 97%, and 90% for low-, intermediate-, and high-risk disease. The unadjusted overall survival was lower across increasing disease risk categories at 77%, 71%, and 62% for low-, intermediate-, and high-risk disease (p < .001).
CONCLUSIONS
These data provide population-based 10-year benchmarks for clinically relevant end points, including metastasis-free survival, among patients with localized prostate cancer undergoing radiation therapy using contemporary techniques. The survival rates for high-risk disease in particular suggest that outcomes have recently improved.
Topics: Male; Humans; Prostatic Neoplasms; Androgen Antagonists; Androgens; Disease-Free Survival; Prostate-Specific Antigen; Delivery of Health Care; Treatment Outcome
PubMed: 37389814
DOI: 10.1002/cncr.34916 -
BMC Cancer Aug 2023Ultra-hypofractionated image-guided stereotactic body radiotherapy (SBRT) is increasingly used for definitive treatment of localized prostate cancer. Magnetic resonance... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Ultra-hypofractionated image-guided stereotactic body radiotherapy (SBRT) is increasingly used for definitive treatment of localized prostate cancer. Magnetic resonance imaging-guided radiotherapy (MRgRT) facilitates improved visualization, real-time tracking of targets and/or organs-at-risk (OAR), and capacity for adaptive planning which may translate to improved targeting and reduced toxicity to surrounding tissues. Given promising results from NRG-GU003 comparing conventional and moderate hypofractionation in the post-operative setting, there is growing interest in exploring ultra-hypofractionated post-operative regimens. It remains unclear whether this can be done safely and whether MRgRT may help mitigate potential toxicity. SHORTER (NCT04422132) is a phase II randomized trial prospectively evaluating whether salvage MRgRT delivered in 5 fractions versus 20 fractions is non-inferior with respect to gastrointestinal (GI) and genitourinary (GU) toxicities at 2-years post-treatment.
METHODS
A total of 136 patients will be randomized in a 1:1 ratio to salvage MRgRT in 5 fractions or 20 fractions using permuted block randomization. Patients will be stratified according to baseline Expanded Prostate Cancer Index Composite (EPIC) bowel and urinary domain scores as well as nodal treatment and androgen deprivation therapy (ADT). Patients undergoing 5 fractions will receive a total of 32.5 Gy over 2 weeks and patients undergoing 20 fractions will receive a total of 55 Gy over 4 weeks, with or without nodal coverage (25.5 Gy over 2 weeks and 42 Gy over 4 weeks) and ADT as per the investigator's discretion. The co-primary endpoints are change scores in the bowel and the urinary domains of the EPIC. The change scores will reflect the 2-year score minus the pre-treatment (baseline) score. The secondary endpoints include safety endpoints, including change in GI and GU symptoms at 3, 6, 12 and 60 months from completion of treatment, and efficacy endpoints, including time to progression, prostate cancer specific survival and overall survival.
DISCUSSION
The SHORTER trial is the first randomized phase II trial comparing toxicity of ultra-hypofractionated and hypofractionated MRgRT in the salvage setting. The primary hypothesis is that salvage MRgRT delivered in 5 fractions will not significantly increase GI and GU toxicities when compared to salvage MRgRT delivered in 20 fractions.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT04422132. Date of registration: June 9, 2020.
Topics: Male; Humans; Prostatic Neoplasms; Androgen Antagonists; Magnetic Resonance Imaging; Radiotherapy, Image-Guided; Prostate
PubMed: 37608258
DOI: 10.1186/s12885-023-11278-3 -
Biomedicine & Pharmacotherapy =... Dec 2023Androgen receptor (AR) signaling is essential in prostate cancer treatment. For many years, androgen deprivation therapy (ADT) has been primarily applied to manage... (Review)
Review
Androgen receptor (AR) signaling is essential in prostate cancer treatment. For many years, androgen deprivation therapy (ADT) has been primarily applied to manage advanced prostate cancer. However, most individuals with metastatic hormone-sensitive prostate cancer (mHSPC) administered ADT alone are at risk of developing metastatic castration-resistant prostate cancer (mCRPC) in less than two years. New approaches employing novel AR inhibitors (ARi) as intensified upfront systemic treatment in mHSPC have recently demonstrated substantial benefits in delaying disease progression and prolonging overall survival. Administration of novel ARi has become the new standard of care in mHSPC. The new landscape simultaneously makes treatment choice more challenging. This review provides comprehensive data on molecular structure, pharmaceutical properties, and efficacy and safety profiles reported by pivotal clinical trials. We also discuss future directions with ongoing Phase III trials of novel ARi in mHSPC. Considering these biological and clinical insights, this review aimed to provide a comprehensive understanding of differences in the development and applications of novel ARi for mHSPC, which may be helpful in designing strategies for first-line treatment choices.
Topics: Humans; Male; Androgen Receptor Antagonists; Hormones; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Treatment Outcome
PubMed: 37925933
DOI: 10.1016/j.biopha.2023.115806 -
World Journal of Urology Nov 2023Around 40% of men with intermediate-risk or high-risk prostate cancer will experience a biochemical recurrence after radical prostatectomy (RP). The aim of this review...
PURPOSE
Around 40% of men with intermediate-risk or high-risk prostate cancer will experience a biochemical recurrence after radical prostatectomy (RP). The aim of this review is to describe both toxicity and oncological outcomes following stereotactic body radiation therapy (SBRT) delivered to the prostate bed (PB).
METHOD
In april 2023, we performed a systematic review of studies published in MEDLINE or ClinicalTrials.gov according to Preferred Reporting Items for Systematic Reviews, using the keywords "stereotactic radiotherapy" AND "postoperative" AND "prostate cancer".
RESULTS
A total of 14 studies assessing either adjuvant or salvage SBRT to the whole PB or macroscopic local recurrence (MLR) within the PB, and SBRT on radiorecurrent MLR within the PB were included. Doses delivered to either whole PB or MLR between 30 to 40 Gy are associated with a low rate of late grade ≥ 2 genitourinary (GU) toxicity, ranging from 2.2 to 15.1%. Doses above 40 Gy are associated with increased rate of late GU toxicity, raising up to 38%. Oncological outcomes should be interpreted with caution, due to both short follow-up, heterogeneous populations and androgen deprivation therapy (ADT) use.
CONCLUSION
PB or MLR SBRT delivered at doses up to 40 Gy appears safe with relatively low late severe GU toxicity rates. Caution is needed with dose-escalated RT schedules above 40 Gy. Further prospective trials are eagerly awaited in this disease setting.
Topics: Male; Humans; Prostatic Neoplasms; Prostate; Radiosurgery; Androgen Antagonists; Prostatectomy; Salvage Therapy
PubMed: 37725131
DOI: 10.1007/s00345-023-04605-7 -
IU1 and enzalutamide combination yields synergistic effects on castration-resistant prostate cancer.The Prostate Nov 2023Androgen deprivation therapy (ADT) is one of the main treatment modalities for prostate cancer (PCa); however, almost all patients treated with ADT eventually progress...
BACKGROUND
Androgen deprivation therapy (ADT) is one of the main treatment modalities for prostate cancer (PCa); however, almost all patients treated with ADT eventually progress into castration-resistant PCa (CRPC). Although second-generation androgen receptor (AR) antagonists, such as enzalutamide, have been approved for CRPC treatment, AR signaling in CRPC cells is reactivated through multiple mechanisms, resulting in resistance to treatment and tumor progression with a very poor prognosis. The present study aimed to explore the anticancer effect of a treatment combining AR antagonist enzalutamide with AR degrader IU1 on PCa cells.
METHODS
The joint effects of enzalutamide and IU1 on PCa cell proliferation and apoptosis and associated cell signaling were evaluated in vitro. Mechanistically, the ubiquitination level and half-life of AR were examined under the combination treatment. The binding of IU1 and enzalutamide to AR was further verified using cellular thermal shift analysis and isothermal dose-response curve fingerprinting.
RESULTS
The combination of IU1 and three AR antagonists showed synergistic effects in different prostate cell lines. IU1 and enzalutamide synergistically promoted the degradation of AR and AR-V7 proteins, as well as suppressed the expression levels of AR and AR-V7 downstream target genes at the transcriptional and protein levels. The combination also synergistically blocked the PCa cell cycle and promoted apoptosis in PCa cell lines. Mechanistically, the combination promoted increased levels of AR ubiquitination. In CRPC cell lines and in the presence of increased androgen concentrations, enzalutamide was still able to bind AR competitively with androgens, reducing the stability of AR and thus promoting the degradation effect of IU1 on AR, synergistically producing an inhibitory effect on PCa cells.
CONCLUSION
Taken together, our findings suggest that the combination of AR degrader and enzalutamide potentially represents a new therapeutic strategy for CRPC.
Topics: Male; Humans; Prostatic Neoplasms, Castration-Resistant; Androgens; Androgen Antagonists; Receptors, Androgen; Benzamides; Nitriles; Androgen Receptor Antagonists; Cell Line, Tumor; Drug Resistance, Neoplasm
PubMed: 37545197
DOI: 10.1002/pros.24607 -
Clinical and Translational Medicine Oct 2023A growing number of studies have shown that Yin Yang 1 (YY1) promotes the development of multiple tumours. The purpose of the current study was to determine the...
BACKGROUND
A growing number of studies have shown that Yin Yang 1 (YY1) promotes the development of multiple tumours. The purpose of the current study was to determine the mechanism by which YY1 mediates neuroendocrine differentiation of prostate cancer (NEPC) cells undergoing cellular plasticity.
METHODS
Using the Cancer Genome Atlas and Gene Expression Omnibus (GEO) databases, we bioinformatically analyzed YY1 expression in prostate cancer (PCa). Aberrant YY1 expression was validated in different PCa tissues and cell lines via quantitative reverse transcription polymerase chain reaction, western blotting, and immunohistochemistry. In vivo and in vitro functional assays verified the oncogenicity of YY1 in PCa. Further functional assays showed that ectopic expression of YY1 promoted cellular plasticity in PCa cells via epithelial-mesenchymal transition induction and neuroendocrine differentiation.
RESULTS
Androgen deprivation therapy induced a decrease in YY1 protein ubiquitination, enhanced its stability, and thus enhanced the transcriptional activity of FZD8. Castration enhanced FZD8 binding to Wnt9A and mediated cellular plasticity by activating the non-canonical Wnt (FZD8/FYN/STAT3) pathway.
CONCLUSIONS
We identified YY1 as a novel dysregulated transcription factor that plays an important role in NEPC progression in this study. We believe that an in-depth investigation of the mechanism underlying YY1-mediated disease may lead to improved NEPC therapies.
Topics: Male; Humans; Prostatic Neoplasms; Wnt Signaling Pathway; Androgen Antagonists; Yin-Yang; Cell Differentiation; STAT3 Transcription Factor
PubMed: 37771187
DOI: 10.1002/ctm2.1422 -
Drug Resistance Updates : Reviews and... Sep 2023This study investigated cellular mechanisms in steroidogenesis responsible for treatment resistance to the novel antiandrogen agent darolutamide in prostate cancer....
This study investigated cellular mechanisms in steroidogenesis responsible for treatment resistance to the novel antiandrogen agent darolutamide in prostate cancer. HSD3B1 was overexpressed in darolutamide-resistant cells and induced by darolutamide treatment and AR knockdown. Inversely, HSD3B1 knockdown increased cellular sensitivity to darolutamide. Similarly, its upstream regulator NR5A2 was up-regulated in darolutamide-resistant cells and induced by darolutamide treatment and AR knockdown. Inversely, NR5A2 knockdown and NR5A2 inhibitor ML180 decreased expression of various steroidogenic enzymes including HSD3B1, leading to increased cellular sensitivity to darolutamide. The NR5A2/HSD3B1 pathway promoted cellular resistance to darolutamide and targeting NR5A2/HSD3B1 pathway is a promising therapeutic strategy to overcome darolutamide resistance.
Topics: Humans; Male; Androgen Antagonists; Androgen Receptor Antagonists; Multienzyme Complexes; Prostatic Neoplasms, Castration-Resistant; Receptors, Cytoplasmic and Nuclear
PubMed: 37478518
DOI: 10.1016/j.drup.2023.100990 -
Clinical Genitourinary Cancer Apr 2024Two randomized trials demonstrated a survival benefit of triplet therapy (androgen deprivation therapy [ADT]) plus androgen receptor pathway inhibitor [ARPI] plus...
INTRODUCTION
Two randomized trials demonstrated a survival benefit of triplet therapy (androgen deprivation therapy [ADT]) plus androgen receptor pathway inhibitor [ARPI] plus docetaxel) over doublet therapy (ADT plus docetaxel), thus changing treatment strategies in metastatic hormonesensitive prostate cancer (mHSPC).
PATIENTS AND METHODS
We conducted the first real-world analysis comprising 97 mHSPC patients from 16 Austrian medical centers, among them 79.4% of patients received abiraterone and 17.5% darolutamide treatment. Baseline characteristics and clinical parameters during triplet therapy were documented. Mann-Whitney U test for continuous or X²-test for categorical variables was used. Variables on progression were tested using logistic regression analysis and tabulated as hazard ratios (HR), 95% confidence interval (CI).
RESULTS
Of 83.5% patients with synchronous and 16.5% with metachronous disease were included. 83.5% had high-volume disease diagnosed by conventional imaging (48.9%) or PSMA PET-CT (51.1%). While docetaxel and ARPI were administered consistent with pivotal trials, prednisolone, prophylactic gCSF and osteoprotective agents were not applied guideline conform in 32.5%, 37%, and 24.3% of patients, respectively. Importantly, a nonsimultaneous onset of chemotherapy and ARPI, performed in 44.3% of patients, was associated with significantly worse treatment response (P = .015, HR 0.245). Starting ARPI before chemotherapy was associated with significantly higher probability for progression (P = .023, HR 15.781) than vice versa. Strikingly, 15.6% (abiraterone) and 25.5% (darolutamide) low-volume patients as well as 14.4% (abiraterone) and 17.6% (darolutamide) metachronous patients received triplet therapy. Adverse events (AE) occurred in 61.9% with grade 3 to 5 in 15% of patient without age-related differences. All patients achieved a PSA decline of 99% and imaging response was confirmed in 88% of abiraterone and 75% of darolutamide patients.
CONCLUSIONS
Triplet therapy arrived in clinical practice primarily for synchronous high-volume mHSPC. Regardless of selected therapy regimen, treatment is highly effective and tolerable. Preferably therapy should be administered simultaneously, however if not possible, chemotherapy should be started first.
Topics: Humans; Male; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Austria; Docetaxel; Hormones; Positron Emission Tomography Computed Tomography; Prostatic Neoplasms; Randomized Controlled Trials as Topic
PubMed: 38267304
DOI: 10.1016/j.clgc.2023.12.018 -
Archivos Espanoles de Urologia Dec 2023New-generation imaging techniques and the increasing use of surgery in high-risk prostate cancer (PCa) allow us to detect many cases of nodal disease at initial... (Review)
Review
BACKGROUND
New-generation imaging techniques and the increasing use of surgery in high-risk prostate cancer (PCa) allow us to detect many cases of nodal disease at initial diagnosis or after resection. The treatment of PCa with pathologic regional nodes has evolved from the exclusive use of systemic therapy to its combination with locoregional treatment. It can also represent a benefit in the overall survival. However, the evidence from randomised studies is limited. Thus, we review the most relevant results in this scenario.
MATERIALS AND METHODS
A literature search was conducted in MEDLINE, PubMed, EMBASE, Clinical-Trials.gov and Web of Science on January 2023 to review node-positive PCa by considering the relevant literature on this topic published with no restrictions on date and language. The search keywords used were "Prostatic Neoplasms" (MeSh) and "Node-positive" (Text Word) and "Radiotherapy" (MeSh) and ("Androgen Antagonists" (MeSh) or "Antineoplastic Agents, Hormonal" (MeSh)), which are indexed within the Medical Subject Headings database.
RESULTS
The management of node-positive PCa has no clear definitive consensus at the initial disease diagnosis or after surgery. However, in this review, we summarise the existing literature for the management of these patients in both scenarios, considering imaging tests, radiotherapy, hormone therapy and second-generation hormonal treatments.
CONCLUSIONS
The combination of radiotherapy and androgen-deprivation therapy is the treatment of choice. The addition of second-generation hormone therapy, plus the intensification of radiotherapy schedules, will likely change the treatment paradigm for these patients.
Topics: Male; Humans; Androgen Antagonists; Androgens; Prostatic Neoplasms; Consensus
PubMed: 38186065
DOI: 10.56434/j.arch.esp.urol.20237610.88