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Clinical Cancer Research : An Official... May 2023Phosphatase and tensin homolog (PTEN) loss of function occurs in approximately 50% of patients with metastatic castrate-resistant prostate cancer (mCRPC), and is...
PURPOSE
Phosphatase and tensin homolog (PTEN) loss of function occurs in approximately 50% of patients with metastatic castrate-resistant prostate cancer (mCRPC), and is associated with poor prognosis and responsiveness to standard-of-care therapies and immune checkpoint inhibitors. While PTEN loss of function hyperactivates PI3K signaling, combinatorial PI3K/AKT pathway and androgen deprivation therapy (ADT) has demonstrated limited anticancer efficacy in clinical trials. Here, we aimed to elucidate mechanism(s) of resistance to ADT/PI3K-AKT axis blockade, and to develop rational combinatorial strategies to effectively treat this molecular subset of mCRPC.
EXPERIMENTAL DESIGN
Prostate-specific PTEN/p53-deficient genetically engineered mice (GEM) with established 150-200 mm3 tumors, as assessed by ultrasound, were treated with either ADT (degarelix), PI3K inhibitor (copanlisib), or anti-PD-1 antibody (aPD-1), as single agents or their combinations, and tumors were monitored by MRI and harvested for immune, transcriptomic, and proteomic profiling, or ex vivo co-culture studies. Single-cell RNA sequencing on human mCRPC samples was performed using 10X Genomics platform.
RESULTS
Coclinical trials in PTEN/p53-deficient GEM revealed that recruitment of PD-1-expressing tumor-associated macrophages (TAM) thwarts ADT/PI3Ki combination-induced tumor control. The addition of aPD-1 to ADT/PI3Ki combination led to TAM-dependent approximately 3-fold increase in anticancer responses. Mechanistically, decreased lactate production from PI3Ki-treated tumor cells suppressed histone lactylation within TAM, resulting in their anticancer phagocytic activation, which was augmented by ADT/aPD-1 treatment and abrogated by feedback activation of Wnt/β-catenin pathway. Single-cell RNA-sequencing analysis in mCRPC patient biopsy samples revealed a direct correlation between high glycolytic activity and TAM phagocytosis suppression.
CONCLUSIONS
Immunometabolic strategies that reverse lactate and PD-1-mediated TAM immunosuppression, in combination with ADT, warrant further investigation in patients with PTEN-deficient mCRPC.
Topics: Male; Animals; Mice; Humans; Prostatic Neoplasms, Castration-Resistant; Tumor Suppressor Protein p53; Proto-Oncogene Proteins c-akt; Androgen Antagonists; Lactic Acid; Phosphatidylinositol 3-Kinases; Proteomics; Wnt Signaling Pathway; Immunosuppression Therapy; Macrophages; PTEN Phosphohydrolase
PubMed: 36862086
DOI: 10.1158/1078-0432.CCR-22-3350 -
Circulation Oct 2021The relative cardiovascular safety of gonadotropin-releasing hormone (GnRH) antagonists compared with GnRH agonists in men with prostate cancer and known atherosclerotic... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The relative cardiovascular safety of gonadotropin-releasing hormone (GnRH) antagonists compared with GnRH agonists in men with prostate cancer and known atherosclerotic cardiovascular disease remains controversial.
METHODS
In this international, multicenter, prospective, randomized, open-label trial, men with prostate cancer and concomitant atherosclerotic cardiovascular disease were randomly assigned 1:1 to receive the GnRH antagonist degarelix or the GnRH agonist leuprolide for 12 months. The primary outcome was the time to first adjudicated major adverse cardiovascular event (composite of death, myocardial infarction, or stroke) through 12 months.
RESULTS
Because of slower-than-projected enrollment and fewer-than-projected primary outcome events, enrollment was stopped before the 900 planned participants were accrued. From May 3, 2016, to April 16, 2020, a total of 545 patients from 113 sites across 12 countries were randomly selected. Baseline characteristics were balanced between study groups. The median age was 73 years, 49.8% had localized prostate cancer; 26.3% had locally advanced disease, and 20.4% had metastatic disease. A major adverse cardiovascular event occurred in 15 (5.5%) patients assigned to degarelix and 11 (4.1%) patients assigned to leuprolide (hazard ratio, 1.28 [95% CI, 0.59-2.79]; =0.53).
CONCLUSIONS
PRONOUNCE (A Trial Comparing Cardiovascular Safety of Degarelix Versus Leuprolide in Patients With Advanced Prostate Cancer and Cardiovascular Disease) is the first, international, randomized clinical trial to prospectively compare the cardiovascular safety of a GnRH antagonist and a GnRH agonist in patients with prostate cancer. The study was terminated prematurely because of the smaller than planned number of participants and events, and no difference in major adverse cardiovascular events at 1 year between patients assigned to degarelix or leuprolide was observed. The relative cardiovascular safety of GnRH antagonists and agonists remains unresolved. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02663908.
Topics: Aged; Humans; Leuprolide; Male; Oligopeptides; Prospective Studies; Prostatic Neoplasms
PubMed: 34459214
DOI: 10.1161/CIRCULATIONAHA.121.056810 -
Clinical Interventions in Aging 2009Degarelix is a gonadotropin-releasing hormone (GnRH) antagonist for the treatment of patients with prostate cancer in whom hormonal therapy is indicated. Two phase II... (Review)
Review
Degarelix is a gonadotropin-releasing hormone (GnRH) antagonist for the treatment of patients with prostate cancer in whom hormonal therapy is indicated. Two phase II trials and one phase III have been published as full papers in the literature. In the dose-finding phase II studies an initial dose of 240 mg degarelix sc followed by a monthly injection of 80 mg or 160 mg degarelix sc was sufficient to keep testosterone levels < or = 0.5 ng/ml. In a phase III trial it was demonstrated that degarelix was not inferior (in terms of testosterone suppression and prostate-specific antigen [PSA] decline) compared to standard hormonal therapy, ie, a GnRH agonist such as leuprolide. In fact, degarelix was associated with a faster testosterone suppression and PSA decline than leuprolide. Adverse events such as injection site reactions (40% vs <1%) and chills (4% vs 0%) were more commonly associated with degarelix. Also, degarelix is currently only available as one-month depot whereas in daily practice three-month depots (of GnRH agonists) are the preferred regimen. However, degarelix was recently approved by the US Food and Drug Administration for the treatment of advanced prostate cancer.
Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Drug-Related Side Effects and Adverse Reactions; Humans; Male; Middle Aged; Oligopeptides; Prostatic Neoplasms; Randomized Controlled Trials as Topic
PubMed: 19503784
DOI: 10.2147/cia.s3503 -
Oncology (Williston Park, N.Y.) Dec 2018Androgen deprivation therapy (ADT) comes in several forms, such as surgical castration or medical castration using gonadotropin-releasing hormone (GnRH) agonist or GnRH... (Review)
Review
Androgen deprivation therapy (ADT) comes in several forms, such as surgical castration or medical castration using gonadotropin-releasing hormone (GnRH) agonist or GnRH antagonist therapy. ADT is a critical treatment for high-risk and metastatic prostate cancer. There are important differences between GnRH agonists and antagonists. Here we review the mechanism of action between GnRH agonists and antagonists and the studies that led to the approval of degarelix. We also comment on the potential risks and benefits of degarelix, particularly when it comes to cardiovascular health. Finally, we describe an oral GnRH antagonist, which is not currently used in prostate cancer, but is included for completeness.
Topics: Androgen Antagonists; Antineoplastic Agents, Hormonal; Gonadotropin-Releasing Hormone; Humans; Male; Oligopeptides; Phenylurea Compounds; Prostatic Neoplasms; Pyrimidinones
PubMed: 30632129
DOI: No ID Found -
Indian Journal of Cancer Mar 2022Luteinizing hormone-releasing hormone agonist (LHRH-A), goserelin, and antagonist, degarelix, are both indicated for the treatment of advanced prostate cancer (PCa);... (Review)
Review
A review of clinical evidence to assess differences in efficacy and safety of luteinizing hormone-releasing hormone (LHRH) agonist (goserelin) and LHRH antagonist (degarelix).
Luteinizing hormone-releasing hormone agonist (LHRH-A), goserelin, and antagonist, degarelix, are both indicated for the treatment of advanced prostate cancer (PCa); however, large comparative trials evaluating their efficacy and safety are lacking. In this review, we assessed the available evidence for both the drugs. Although degarelix achieves an early rapid decline in testosterone (T) and prostate-specific antigen (PSA) levels, median T and PSA levels, in addition to prostate volume and International Prostate Symptom Scores, become comparable with goserelin over the remaining treatment period. Degarelix causes no initial flare, therefore it is recommended in patients with spinal metastases or ureteric obstruction. Goserelin achieves lower PSA, improved time to progression, and better survival outcomes when administered adjunctively to radiotherapy compared with radiotherapy alone, with significant results even over long-term follow-up. The evidence supporting adjuvant degarelix use is limited. Goserelin has better injection site safety, single-step delivery, and an efficient administration schedule compared with degarelix, which has significantly higher injection site reactions and less efficient administration mechanism. There is conflicting evidence about the risk of cardiovascular disease (CVD), and caution is required when using LHRH-A in patients with preexisting CVD. There is considerable long-term evidence for goserelin in patients with advanced PCa, with degarelix being a more recent option. The available comparative evidence of goserelin versus degarelix has several inherent limitations related to study design, sample size, conduct, and statistical analyses, and hence warrants robust prospective trials and long-term follow-up.
Topics: Gonadotropin-Releasing Hormone; Goserelin; Humans; Male; Oligopeptides; Prospective Studies
PubMed: 35343199
DOI: 10.4103/ijc.IJC_1415_20 -
European Urology Oncology Apr 2022Degarelix is associated with high rates of injection site reaction. The US Food and Drug Administration approved relugolix, an oral gonadotropin-releasing hormone (GnRH)... (Meta-Analysis)
Meta-Analysis Review
CONTEXT
Degarelix is associated with high rates of injection site reaction. The US Food and Drug Administration approved relugolix, an oral gonadotropin-releasing hormone (GnRH) antagonist, for the treatment of advanced prostate cancer patients.
OBJECTIVE
This systematic review and network meta-analysis aimed to compare the efficacy and safety of relugolix versus degarelix.
EVIDENCE ACQUISITION
A systematic search was performed using major web databases for studies published before January 30, 2021, according to the Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA) extension statement for a network meta-analysis. Studies that compared the efficacy (12-mo castration rate with testosterone ≤50 ng/dl) and safety (adverse events [AEs]) of relugolix or degarelix and of the control group (GnRH agonists) were included. We used the Bayesian approach in the network meta-analysis.
EVIDENCE SYNTHESIS
Four studies (n = 2059) met our eligibility criteria. The main efficacy analysis was conducted for two different treatments (relugolix and all doses of degarelix vs GnRH agonists); relugolix (risk ratio [RR] 1.09, 95% credible interval [CrI]: 0.95-1.23) and degarelix (RR 0.98, 95% CrI: 0.91-1.06) were not associated with different 12-mo castration rates. In the subgroup analysis, degarelix 480 mg was significantly associated with a lower castration rate (RR 0.46, 95% CrI: 0.07-0.92). In all efficacy ranking analyses, relugolix achieved the best rank. The safety analyses showed that relugolix (RR 0.99, 95% CrI: 0.6-1.6 and RR 0.72, 95% CrI: 0.4-1.3, respectively) and degarelix (RR 1.1, 95% CrI: 0.75-1.35 and RR 1.05, 95% CrI: 0.42-2.6, respectively) were not associated with either all AE or serious AE rates. In the ranking analyses, degarelix achieved the worst rank of all AEs and the best rank of serious AEs. Relugolix (RR 0.44, 95% CrI: 0.16-1.2) and degarelix (RR 0.74, 95% CrI: 0.37-1.52) were not associated with different cardiovascular event (CVE) rates; both were associated with lower CVE rates than GnRH agonists in the ranking analyses.
CONCLUSIONS
We found that the efficacy and safety of relugolix are comparable with those of degarelix, albeit with no injection site reaction. Such data should be interpreted with caution until large-scale direct comparison studies with a longer follow-up are available.
PATIENT SUMMARY
We found that relugolix, an oral gonadotropin-releasing hormone (GnRH) antagonist, has comparable efficacy and safety with degarelix, a parenteral GnRH antagonist, for the treatment of advanced prostate cancer patients.
Topics: Bayes Theorem; Gonadotropin-Releasing Hormone; Humans; Male; Network Meta-Analysis; Oligopeptides; Phenylurea Compounds; Prostatic Neoplasms; Pyrimidinones; Randomized Controlled Trials as Topic; United States
PubMed: 34301529
DOI: 10.1016/j.euo.2021.07.002 -
Circulation Oct 2020The optimal duration of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention with drug-eluting stents remains uncertain. We compared short-term... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The optimal duration of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention with drug-eluting stents remains uncertain. We compared short-term (<6-month) DAPT followed by aspirin or P2Y12 inhibitor monotherapy; midterm (6-month) DAPT; 12-month DAPT; and extended-term (>12-month) DAPT after percutaneous coronary intervention with drug-eluting stents.
METHODS
Twenty-four randomized, controlled trials were selected using Medline, Embase, Cochrane library, and online databases through September 2019. The coprimary end points were myocardial infarction and major bleeding, which constituted the net clinical benefit. A frequentist network meta-analysis was conducted with a random-effects model.
RESULTS
In 79 073 patients, at a median follow-up of 18 months, extended-term DAPT was associated with a reduced risk of myocardial infarction in comparison with 12-month DAPT (absolute risk difference, -3.8 incident cases per 1000 person-years; relative risk, 0.68 [95% CI, 0.54-0.87]), midterm DAPT (absolute risk difference, -4.6 incident cases per 1000 person-years; relative risk, 0.61 [0.45-0.83]), and short-term DAPT followed by aspirin monotherapy (absolute risk difference, -6.1 incident cases per 1000 person-years; relative risk, 0.55 [0.37-0.83]), or P2Y12 inhibitor monotherapy (absolute risk difference, -3.7 incident cases per 1000 person-years; relative risk, 0.69 [0.51-0.95]). Conversely, extended-term DAPT was associated with a higher risk of major bleeding than all other DAPT groups. In comparison with 12-month DAPT, no significant differences in the risks of ischemic end points or major bleeding were observed with midterm or short-term DAPT followed by aspirin monotherapy, with the exception that short-term DAPT followed by P2Y12 inhibitor monotherapy was associated with a reduced risk of major bleeding. There were no significant differences with respect to mortality between the different DAPT strategies. In acute coronary syndrome, extended-term in comparison with 12-month DAPT was associated with a reduced risk of myocardial infarction without a significant increase in the risk of major bleeding.
CONCLUSIONS
The present network meta-analysis suggests that, in comparison with 12-month DAPT, short-term DAPT followed by P2Y12 inhibitor monotherapy reduces major bleeding after percutaneous coronary intervention with drug-eluting stents, whereas extended-term DAPT reduces myocardial infarction at the expense of more bleeding events.
Topics: Acute Coronary Syndrome; Aspirin; Drug-Eluting Stents; Humans; Incidence; Myocardial Infarction; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Randomized Controlled Trials as Topic
PubMed: 32795096
DOI: 10.1161/CIRCULATIONAHA.120.046308 -
The Cochrane Database of Systematic... Aug 2021Degarelix is a gonadotropin-releasing hormone antagonist that leads to medical castration used to treat men with advanced or metastatic prostate cancer, or both. It is... (Review)
Review
BACKGROUND
Degarelix is a gonadotropin-releasing hormone antagonist that leads to medical castration used to treat men with advanced or metastatic prostate cancer, or both. It is unclear how its effects compare to standard androgen suppression therapy.
OBJECTIVES
To assess the effects of degree compared with standard androgen suppression therapy for men with advanced hormone-sensitive prostate cancer.
SEARCH METHODS
We searched multiple databases (CENTRAL, MEDLINE, Embase, Scopus, Web of Science, LILACS until September 2020), trial registries (until October 2020), and conference proceedings (until December 2020). We identified other potentially eligible trials by reference checking, citation searching, and contacting study authors.
SELECTION CRITERIA
We included randomized controlled trials comparing degarelix with standard androgen suppression therapy for men with advanced prostate cancer.
DATA COLLECTION AND ANALYSIS
Three review authors independently classified studies and abstracted data from the included studies. The primary outcomes were overall survival and serious adverse events. Secondary outcomes were quality of life, cancer-specific survival, clinical progression, other adverse events, and biochemical progression. We used a random-effects model for meta-analyses and assessed the certainty of evidence for the main outcomes according to GRADE.
MAIN RESULTS
We included 11 studies with a follow-up of between three and 14 months. We also identified five ongoing trials. Primary outcomes Data to evaluate overall survival were not available. Degarelix may result in little to no difference in serious adverse events compared to standard androgen suppression therapy (risk ratio (RR) 0.80, 95% confidence interval (CI) 0.62 to 1.05; low-certainty evidence; 2750 participants). Based on 114 serious adverse events in the standard androgen suppression group, this corresponds to 23 fewer serious adverse events per 1000 participants (43 fewer to 6 more). We downgraded the certainty of evidence for study limitations and imprecision. Secondary outcomes Degarelix likely results in little to no difference in quality of life assessed with a variety of validated questionnaires (standardized mean difference 0.06 higher, 95% CI 0.05 lower to 0.18 higher; moderate-certainty evidence; 2887 participants), with higher scores reflecting better quality of life. We downgraded the certainty of evidence for study limitations. Data to evaluate cancer-specific survival were not available. The effects of degarelix on cardiovascular events are very uncertain (RR 0.15, 95% CI 0.04 to 0.61; very low-certainty evidence; 80 participants). We downgraded the certainty of evidence for study limitations, imprecision, and indirectness as this trial was conducted in a unique group of high-risk participants with pre-existing cardiovascular morbidities. Degarelix likely results in an increase in injection site pain (RR 15.68, 95% CI 7.41 to 33.17; moderate-certainty evidence; 2670 participants). Based on 30 participants per 1000 with injection site pain with standard androgen suppression therapy, this corresponds to 440 more injection site pains per 1000 participants (192 more to 965 more). We downgraded the certainty of evidence for study limitations. We did not identify any relevant subgroup differences for different degarelix maintenance doses.
AUTHORS' CONCLUSIONS
We did not find trial evidence for overall survival or cancer-specific survival comparing degarelix to standard androgen suppression, but serious adverse events and quality of life may be similar between groups. The effects of degarelix on cardiovascular events are very uncertain as the only eligible study had limitations, was small with few events, and was conducted in a high-risk population. Degarelix likely results in an increase in injection site pain compared to standard androgen suppression therapy. Maximum follow-up of included studies was 14 months, which is short. There is a need for methodologically better designed and executed studies with long-term follow-up evaluating men with metastatic prostate cancer.
Topics: Disease Progression; Hormones; Humans; Male; Oligopeptides; Prostatic Neoplasms; Quality of Life
PubMed: 34350976
DOI: 10.1002/14651858.CD012548.pub2