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European Urology Feb 2024Despite the lack of level 1 evidence, metastasis-directed therapy (MDT) is used widely in the management of metastatic prostate cancer (mPCa) patients. Data are... (Meta-Analysis)
Meta-Analysis Review
CONTEXT
Despite the lack of level 1 evidence, metastasis-directed therapy (MDT) is used widely in the management of metastatic prostate cancer (mPCa) patients. Data are continuously emerging from well-designed prospective studies.
OBJECTIVE
To summarise and report the evidence on oncological and safety outcomes of MDT in the management of mPCa patients.
EVIDENCE ACQUISITION
We searched the PubMed, Scopus, and Web of Science databases for prospective studies assessing progression-free survival (PFS), local control (LC), androgen deprivation therapy (ADT)-free survival (ADT-FS), overall survival (OS), and/or adverse events (AEs) in mPCa patients treated with MDT. A meta-analysis was performed for 1- and 2-yr PFS, LC, ADT-FS, OS, and rate of AEs. Meta-regression and sensitivity analysis were performed to account for heterogeneity and identify moderators.
EVIDENCE SYNTHESIS
We identified 22 prospective studies (n = 1137), including two randomised controlled trials (n = 116). Two studies were excluded from the meta-analysis (n = 120). The estimated 2-yr PFS was 46% (95% confidence interval [CI]: 36-56%) or 42% (95% CI: 33-52%) after excluding studies using biochemical or ADT-related endpoints. The estimated 2-yr LC, ADT-FS, and OS were 97% (95% CI: 94-98%), 55% (95% CI: 44-65%), and 97% (95% CI: 95-98%), respectively. Rates of treatment-related grade 2 and ≥3 AEs were 2.4% (95% CI: 0.2-7%) and 0.3% (95% CI: 0-1%), respectively.
CONCLUSIONS
MDT is a promising treatment strategy associated with favourable PFS, excellent LC, and a low toxicity profile that allows oligorecurrent hormone-sensitive patients to avoid or defer ADT-related toxicity. Integration of MDT with other therapies offers a promising research direction, in particular, in conjunction with systemic treatments and as a component of definitive care for oligometastatic PCa. However, in the absence of randomised trials, using MDT for treatment intensification remains an experimental approach, and the impact on OS is uncertain.
PATIENT SUMMARY
Direct treatment of metastases is a promising option for selected prostate cancer patients. It can delay hormone therapy and is being investigated as a way of intensifying treatment at the expense of manageable toxicity.
Topics: Male; Humans; Prostatic Neoplasms; Prospective Studies; Androgen Antagonists; Progression-Free Survival; Hormones
PubMed: 37945451
DOI: 10.1016/j.eururo.2023.10.012 -
JAMA Jan 2024Adverse outcomes associated with treatments for localized prostate cancer remain unclear. (Comparative Study)
Comparative Study Observational Study
IMPORTANCE
Adverse outcomes associated with treatments for localized prostate cancer remain unclear.
OBJECTIVE
To compare rates of adverse functional outcomes between specific treatments for localized prostate cancer.
DESIGN, SETTING, AND PARTICIPANTS
An observational cohort study using data from 5 US Surveillance, Epidemiology, and End Results Program registries. Participants were treated for localized prostate cancer between 2011 and 2012. At baseline, 1877 had favorable-prognosis prostate cancer (defined as cT1-cT2bN0M0, prostate-specific antigen level <20 ng/mL, and grade group 1-2) and 568 had unfavorable-prognosis prostate cancer (defined as cT2cN0M0, prostate-specific antigen level of 20-50 ng/mL, or grade group 3-5). Follow-up data were collected by questionnaire through February 1, 2022.
EXPOSURES
Radical prostatectomy (n = 1043), external beam radiotherapy (n = 359), brachytherapy (n = 96), or active surveillance (n = 379) for favorable-prognosis disease and radical prostatectomy (n = 362) or external beam radiotherapy with androgen deprivation therapy (n = 206) for unfavorable-prognosis disease.
MAIN OUTCOMES AND MEASURES
Outcomes were patient-reported sexual, urinary, bowel, and hormone function measured using the 26-item Expanded Prostate Cancer Index Composite (range, 0-100; 100 = best). Associations of specific therapies with each outcome were estimated and compared at 10 years after treatment, adjusting for corresponding baseline scores, and patient and tumor characteristics. Minimum clinically important differences were 10 to 12 for sexual function, 6 to 9 for urinary incontinence, 5 to 7 for urinary irritation, and 4 to 6 for bowel and hormone function.
RESULTS
A total of 2445 patients with localized prostate cancer (median age, 64 years; 14% Black, 8% Hispanic) were included and followed up for a median of 9.5 years. Among 1877 patients with favorable prognosis, radical prostatectomy was associated with worse urinary incontinence (adjusted mean difference, -12.1 [95% CI, -16.2 to -8.0]), but not worse sexual function (adjusted mean difference, -7.2 [95% CI, -12.3 to -2.0]), compared with active surveillance. Among 568 patients with unfavorable prognosis, radical prostatectomy was associated with worse urinary incontinence (adjusted mean difference, -26.6 [95% CI, -35.0 to -18.2]), but not worse sexual function (adjusted mean difference, -1.4 [95% CI, -11.1 to 8.3), compared with external beam radiotherapy with androgen deprivation therapy. Among patients with unfavorable prognosis, external beam radiotherapy with androgen deprivation therapy was associated with worse bowel (adjusted mean difference, -4.9 [95% CI, -9.2 to -0.7]) and hormone (adjusted mean difference, -4.9 [95% CI, -9.5 to -0.3]) function compared with radical prostatectomy.
CONCLUSIONS AND RELEVANCE
Among patients treated for localized prostate cancer, radical prostatectomy was associated with worse urinary incontinence but not worse sexual function at 10-year follow-up compared with radiotherapy or surveillance among people with more favorable prognosis and compared with radiotherapy for those with unfavorable prognosis. Among men with unfavorable-prognosis disease, external beam radiotherapy with androgen deprivation therapy was associated with worse bowel and hormone function at 10-year follow-up compared with radical prostatectomy.
Topics: Humans; Male; Middle Aged; Androgen Antagonists; Prostate-Specific Antigen; Prostatic Neoplasms; Urinary Incontinence; United States; SEER Program; Aged; Prostatectomy; Patient Reported Outcome Measures; Prognosis; Watchful Waiting; Radiotherapy
PubMed: 38261043
DOI: 10.1001/jama.2023.26491 -
Cancer Research Oct 2023Androgen receptor (AR) inhibition by androgen deprivation and/or antiandrogen administration is the mainstay therapy for advanced prostate cancer. However, most prostate... (Meta-Analysis)
Meta-Analysis
UNLABELLED
Androgen receptor (AR) inhibition by androgen deprivation and/or antiandrogen administration is the mainstay therapy for advanced prostate cancer. However, most prostate cancers ultimately become resistant to these therapies, indicating the importance of identifying mechanisms driving resistance to improve patient outcomes. Here we demonstrated that acute treatment with the antiandrogen enzalutamide (ENZ) decreased glutathione (GSH) production, increased lipid peroxidation, and induced ferroptosis in prostate cancer cells. Consistently, meta-analysis of transcriptomic data linked the androgen-AR axis to metabolism-related biological processes, including lipid metabolism. The cystine transporter gene SLC7A11 was a key AR target, and full-length AR (AR-FL) transactivated SLC7A11 transcription by directly occupying the SLC7A11 promoter and putative enhancer regions. AR variants (AR-V) preferentially bound the SLC7A11 enhancer and upregulated SLC7A11 expression, thereby conferring resistance to ferroptosis induced by ENZ treatment. However, this effect was abolished following downregulation of AR-Vs using the dual CBP/p300 and BET inhibitor NEO2734. These findings reveal ferroptosis induction as an anticancer mechanism of antiandrogens and SLC7A11 as a direct target gene of AR-FL and AR-Vs. AR-V-mediated SLC7A11 expression represents a mechanism coupling ferroptosis resistance to prostate cancer progression.
SIGNIFICANCE
Upregulation of SLC7A11 can be induced by androgen receptor variants to inhibit antiandrogen-induced prostate cancer cell ferroptosis and to drive castration resistance in prostate cancer.
Topics: Male; Humans; Receptors, Androgen; Androgen Antagonists; Androgens; Prostatic Neoplasms, Castration-Resistant; Ferroptosis; Nitriles; Castration; Cell Line, Tumor; Drug Resistance, Neoplasm
PubMed: 37527336
DOI: 10.1158/0008-5472.CAN-23-0285 -
BMJ Case Reports Oct 2023A man in his 50s presented to our clinic with obvious progressive hair thinning in the occipital area below the creeping alopecia crown vertex accompanied by the typical...
A man in his 50s presented to our clinic with obvious progressive hair thinning in the occipital area below the creeping alopecia crown vertex accompanied by the typical Hamilton-Norwood pattern of male androgenetic alopecia (MAGA) hair loss. Based on his clinical features, trichoscopy findings and histological features, as well as his good response to conventional anti-MAGA therapeutic drugs, such as finasteride and minoxidil, a novel isotype of MAGA, named inverse-MAGA, was first identified, and this isotype should be widely evaluated in future studies.
Topics: Male; Humans; Alopecia; Minoxidil; Finasteride; Androgen Antagonists; Treatment Outcome
PubMed: 37907317
DOI: 10.1136/bcr-2022-254361 -
Cancer Discovery Dec 2023Signaling rewiring allows tumors to survive therapy. Here we show that the decrease of the master regulator microphthalmia transcription factor (MITF) in lethal prostate...
UNLABELLED
Signaling rewiring allows tumors to survive therapy. Here we show that the decrease of the master regulator microphthalmia transcription factor (MITF) in lethal prostate cancer unleashes eukaryotic initiation factor 3B (eIF3B)-dependent translation reprogramming of key mRNAs conferring resistance to androgen deprivation therapy (ADT) and promoting immune evasion. Mechanistically, MITF represses through direct promoter binding eIF3B, which in turn regulates the translation of specific mRNAs. Genome-wide eIF3B enhanced cross-linking immunoprecipitation sequencing (eCLIP-seq) showed specialized binding to a UC-rich motif present in subsets of 5' untranslated regions. Indeed, translation of the androgen receptor and major histocompatibility complex I (MHC-I) through this motif is sensitive to eIF3B amount. Notably, pharmacologic targeting of eIF3B-dependent translation in preclinical models sensitizes prostate cancer to ADT and anti-PD-1 therapy. These findings uncover a hidden connection between transcriptional and translational rewiring promoting therapy-refractory lethal prostate cancer and provide a druggable mechanism that may transcend into effective combined therapeutic strategies.
SIGNIFICANCE
Our study shows that specialized eIF3B-dependent translation of specific mRNAs released upon downregulation of the master transcription factor MITF confers castration resistance and immune evasion in lethal prostate cancer. Pharmacologic targeting of this mechanism delays castration resistance and increases immune-checkpoint efficacy. This article is featured in Selected Articles from This Issue, p. 2489.
Topics: Male; Humans; Prostatic Neoplasms; Transcription Factors; Androgen Antagonists; Immune Evasion; Receptors, Androgen; Castration; Prostatic Neoplasms, Castration-Resistant
PubMed: 37676710
DOI: 10.1158/2159-8290.CD-23-0306 -
Current Opinion in Urology Nov 2023Over the last years, there have been striking changes in the management of metastatic hormone-sensitive prostate cancer (mHSPC) based on survival advantage of combining... (Review)
Review
PURPOSE OF REVIEW
Over the last years, there have been striking changes in the management of metastatic hormone-sensitive prostate cancer (mHSPC) based on survival advantage of combining either a new hormonal agent (NHA) or docetaxel (D) with androgen deprivation therapy (ADT). Some of these studies primarily assessing doublet treatment included men who underwent concomitant or sequential treatment with D. Most recently, prospective randomized evidence emerged on this triplet strategy too. We aimed to outline the current data and ongoing trials evaluating the usage of the triplet therapy in male individuals with mHSPC.
RECENT FINDINGS
Phase III trials PEACE-1 and ARASENS showed that the upfront triplet treatment with ADT+D and either abiraterone acetate or darolutamide outperformed ADT+D in terms of survival, while severe toxicity was mainly driven by D. Importantly, prospective evidence comparing triplet vs. ADT+NHA is still lacking.
SUMMARY
Men with de novo high-volume disease benefit most from the triplet, while in cases with metachronous and/or low-volume disease, survival advantage is still disputable. As efficacy of ADT+NHA does not appear to be substantially amplified by combination with D, those men with a more favorable underlying tumor biology might mostly benefit from this doublet, also taking quality-adjusted survival into account.
Topics: Humans; Male; Prostatic Neoplasms; Androgen Antagonists; Prospective Studies; Antineoplastic Combined Chemotherapy Protocols; Hormones; Treatment Outcome
PubMed: 37655968
DOI: 10.1097/MOU.0000000000001125 -
International Journal of Molecular... Jul 2023Androgen deprivation therapy (ADT) has been the mainstay of prostate cancer (PCa) treatment, with success in developing more effective inhibitors of androgen synthesis... (Review)
Review
Androgen deprivation therapy (ADT) has been the mainstay of prostate cancer (PCa) treatment, with success in developing more effective inhibitors of androgen synthesis and antiandrogens in clinical practice. However, hormone deprivation and AR ablation have caused an increase in ADT-insensitive PCas associated with a poor prognosis. Resistance to ADT arises through various mechanisms, and most castration-resistant PCas still rely on the androgen axis, while others become truly androgen receptor (AR)-independent. Our research identified the human tousled-like kinase 1 (TLK1) as a crucial early mediator of PCa cell adaptation to ADT, promoting androgen-independent growth, inhibiting apoptosis, and facilitating cell motility and metastasis. Although explicit, the growing role of TLK1 biology in PCa has remained underrepresented and elusive. In this review, we aim to highlight the diverse functions of TLK1 in PCa, shed light on the molecular mechanisms underlying the transition from androgen-sensitive (AS) to an androgen-insensitive (AI) disease mediated by TLK1, and explore potential strategies to counteract this process. Targeting TLK1 and its associated signaling could prevent PCa progression to the incurable metastatic castration-resistant PCa (mCRPC) stage and provide a promising approach to treating PCa.
Topics: Male; Humans; Prostatic Neoplasms; Androgens; Prostatic Neoplasms, Castration-Resistant; Androgen Antagonists; Receptors, Androgen; Signal Transduction; Orchiectomy; Protein Serine-Threonine Kinases
PubMed: 37446279
DOI: 10.3390/ijms241311100 -
Urology Practice Nov 2023Hormonal therapy is the standard of care in prostate cancer treatment. The approval of the first oral androgen deprivation therapy, relugolix, to treat prostate cancer... (Review)
Review
INTRODUCTION
Hormonal therapy is the standard of care in prostate cancer treatment. The approval of the first oral androgen deprivation therapy, relugolix, to treat prostate cancer patients provides an opportunity to review adherence to oral and injectable/implantable hormonal therapies to aid patients and physicians in making informed decisions.
METHODS
A PubMed search for available literature on adherence to hormonal therapy in prostate cancer was conducted, including published data on relugolix.
RESULTS
Adherence to oral antiandrogen therapy was above 90% by medication possession ratio in several studies worldwide and from 75% to 91% by proportion of days covered. For injectable/implantable androgen deprivation therapy, adherence to treatment ranged from 71% to 95%. In general, 60% and 29% of injections were reported to be delayed by more than 1 week and 2 weeks, respectively, with some patients experiencing testosterone increases (tests above 50 ng/dL). Although real-world data on adherence to relugolix are currently unavailable, pharmacokinetic/pharmacodynamics models demonstrated that, if necessary, treatment interruption up to 7 days would still maintain testosterone suppression levels.
CONCLUSIONS
In general, adherence to hormonal therapy is high in prostate cancer. Studies revealed that adherence to injectable androgen deprivation therapy dosing schedules is important to maintain castrate levels. Pharmacokinetic/pharmacodynamics models showed that relugolix treatment interruption up to 7 days had minimal impact on testosterone suppression levels.
Topics: Male; Humans; Prostatic Neoplasms; Androgen Antagonists; Androgens; Prostate-Specific Antigen; Antineoplastic Agents, Hormonal; Testosterone
PubMed: 37647139
DOI: 10.1097/UPJ.0000000000000445 -
European Urology Aug 2023Few phase 3 studies have evaluated optimal systemic treatment strategies for patients with oligometastatic hormone-sensitive prostate cancer (HSPC), who may be at risk... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Few phase 3 studies have evaluated optimal systemic treatment strategies for patients with oligometastatic hormone-sensitive prostate cancer (HSPC), who may be at risk of undertreatment.
OBJECTIVE
To evaluate outcomes for patients with oligometastatic and polymetastatic HSPC treated with enzalutamide plus androgen deprivation therapy (ADT) versus placebo plus ADT.
DESIGN, SETTING, AND PARTICIPANTS
This was a post hoc analysis of data for 927 patients with nonvisceral metastatic HSPC in the ARCHES trial (NCT02677896).
INTERVENTION
Patients were randomized 1:1 to enzalutamide (160 mg/d orally) plus ADT or placebo plus ADT with HSPC categorized as oligometastatic (1-5 metastases) or polymetastatic (≥6 metastases).
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS
The treatment effect on radiographic progression-free survival (rPFS), overall survival (OS), and secondary efficacy endpoints was evaluated in terms of the number of metastases. Safety was assessed. Cox proportional hazards models were used to generate hazard ratios (HRs). The Brookmeyer and Crowley method was used to generate 95% confidence intervals (CIs) for Kaplan-Meier median values.
RESULTS AND LIMITATIONS
Enzalutamide plus ADT improved rPFS (HR 0.27, 95% CI 0.16-0.46; p < 0.001), OS (HR 0.59, 95% CI 0.40-0.87; p < 0.005), and secondary endpoints in patients with oligometastatic or polymetastatic disease (rPFS: HR 0.33, 95% CI 0.23-0.46; p < 0.001; OS: HR 0.55, 95% CI 0.41-0.74; p < 0.001). Safety profiles were generally similar across subgroups. Limitations include the small numbers of patients with fewer than three metastases.
CONCLUSIONS
This post hoc analysis demonstrated the utility of enzalutamide, irrespective of metastatic burden or type of oligometastatic disease, and suggests that earlier treatment intensification with systemic potent androgen receptor inhibition is advantageous.
PATIENT SUMMARY
This study considered two treatment options for metastatic hormone-sensitive prostate cancer in patients with one to five metastases or six or more metastases. Treatment with enzalutamide plus ADT improved survival and other outcomes over ADT alone, whether patients had few or many metastases.
Topics: Male; Humans; Prostatic Neoplasms; Androgen Antagonists; Androgens; Disease-Free Survival; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome
PubMed: 37179240
DOI: 10.1016/j.eururo.2023.04.002 -
Current Opinion in Urology May 2024To summarize the recent findings on the subject of metastasis-directed therapy (MDT) in the treatment of oligometastatic prostate cancer (omPCa). (Review)
Review Meta-Analysis
PURPOSE OF REVIEW
To summarize the recent findings on the subject of metastasis-directed therapy (MDT) in the treatment of oligometastatic prostate cancer (omPCa).
RECENT FINDINGS
Evidence from two randomized clinical trials (RCTs) and a meta-analysis show favorable toxicity profiles, and the potential to delay androgen-deprivation therapy (ADT) for up to two years in nearly half of patients with metachronous hormone-sensitive omPCa. Another RCT showed promising results of MDT as treatment-escalation method combined with androgen receptor signaling inhibitors (ARSI) in first-line treatment for castration-resistant omPCa.Surveys by radiation oncologists and consensus guidelines advocate for MDT across various omPCa scenarios. Multiple single-arm trials present encouraging results; however, the evidence for the benefit of MDT is still weak requiring further investigation to assess its impact on pivotal endpoints, such as survival and quality of life.
SUMMARY
MDT is a promising approach in omPCa, and can be used to defer ADT in newly diagnosed metachronous omPCa patients, or to add to ARSI treatment at first diagnosis of castration-resistance. Ongoing prospective trials are needed to guide its optimal utilization in other settings, and patients should be informed about the evolving landscape of systemic therapies with proven survival benefits alongside MDT options.
Topics: Male; Humans; Prostatic Neoplasms; Antineoplastic Agents, Hormonal; Androgen Antagonists
PubMed: 38426229
DOI: 10.1097/MOU.0000000000001169