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BioRxiv : the Preprint Server For... May 2023PTEN loss-of-function/PI3K pathway hyperactivation occurs in ∼50% of metastatic, castrate-resistant prostate cancer patients, resulting in poor therapeutic outcomes...
PURPOSE
PTEN loss-of-function/PI3K pathway hyperactivation occurs in ∼50% of metastatic, castrate-resistant prostate cancer patients, resulting in poor therapeutic outcomes and resistance to immune checkpoint inhibitors across multiple malignancies. Our prior studies in prostate-specific PTEN/p53-deleted genetically engineered mice (Pb-Cre;PTEN Trp53 GEM) with aggressive-variant prostate cancer (AVPC) demonstrated feedback Wnt/β-catenin signaling activation in 40% mice resistant to androgen deprivation therapy (ADT)/PI3K inhibitor (PI3Ki)/PD-1 antibody (aPD-1) combination, resulting in restoration of lactate cross-talk between tumor-cells and tumor-associated macrophages (TAM), histone lactylation (H3K18lac) and phagocytic suppression within TAM. Here, we targeted immunometabolic mechanism(s) of resistance to ADT/PI3Ki/aPD-1 combination, with the goal of durable tumor control in PTEN/p53-deficient PC.
EXPERIMENTAL DESIGN
Pb-Cre;PTEN Trp53 GEM were treated with either ADT (degarelix), PI3Ki (copanlisib), aPD-1, MEK inhibitor (trametinib) or Porcupine inhibitor (LGK 974) as single agents or their combinations. MRI was used to monitor tumor kinetics and immune/proteomic profiling/ co-culture mechanistic studies were performed on prostate tumors or established GEM-derived cell lines.
RESULTS
We tested whether Wnt/β-catenin pathway inhibition with LGK 974 addition to degarelix/copanlisib/aPD-1 therapy enhances tumor control in GEM, and observed resistance due to feedback activation of MEK signaling. Based on our observation that degarelix/aPD-1 treatment resulted in partial inhibition of MEK signaling, we substituted trametinib for degarelix/aPD-1 treatment, and observed a durable tumor growth control of PI3Ki/MEKi/PORCNi in 100% mice via H3K18lac suppression and complete TAM activation within TME.
CONCLUSIONS
Abrogation of lactate-mediated cross-talk between cancer cells and TAM results in durable ADT-independent tumor control in PTEN/p53-deficient AVPC, and warrants further investigation in clinical trials.
STATEMENT OF TRANSLATIONAL RELEVANCE
PTEN loss-of-function occurs in ∼50% of mCRPC patients, and associated with poor prognosis, and immune checkpoint inhibitor resistance across multiple malignancies. Our prior studies have demonstrated that ADT/PI3Ki/PD-1 triplet combination therapy controls PTEN/p53-deficient PC in 60% of mice via enhancement of TAM phagocytosis. Here, we discovered that resistance to ADT/PI3K/PD-1 therapy occurred via restoration of lactate production via feedback Wnt/MEK signaling following treatment with PI3Ki, resulting in inhibition of TAM phagocytosis. Critically, co-targeting of PI3K/MEK/Wnt signaling pathways using an intermittent dosing schedule of corresponding targeted agents resulted in complete tumor control and significantly prolonged survival without significant long-term toxicity. Collectively, our findings provide "proof-of-concept" that targeting lactate as a macrophage phagocytic checkpoint controls growth of murine PTEN/p53-deficient PC and warrant further investigation in AVPC clinical trials.
PubMed: 37292972
DOI: 10.1101/2023.05.23.540590 -
Medicine Jul 2016Our aim was to systematically evaluate the benefits of degarelix as antagonist versus agonists of gonadotropin-releasing hormones (GnRH) for the treatment of advanced... (Comparative Study)
Comparative Study Meta-Analysis Review
Our aim was to systematically evaluate the benefits of degarelix as antagonist versus agonists of gonadotropin-releasing hormones (GnRH) for the treatment of advanced prostate cancer (PC). This comparison was performed either in terms of biochemical or oncological or safety profiles. To this end we, carried out a systematic review and meta-analysis of the literature.We selected only studies directly and prospectively analyzing the two treatments in the same population (randomized phase III studies). We followed the Preferred Reporting Items for Systematic Reviews and meta-analyses process for reporting studies.After we eliminated studies according to the exclusion criteria, 9 publications were considered relevant to this review. These articles described 5 clinical trials that were eligible for inclusion. The follow-up duration in all trials did not exceed 364 days. This meta-analysis and review comprised a total of 1719 men, 1061 randomized to degarelix versus 658 to GnRH agonists treatment for advanced PC. Oncological results were evaluated only in 1 trial (CS21:408 cases) and they were not the primary endpoints of the study. Treatment emerging adverse events were reported in 61.4% and 58.8% of patients in the degarelix and GnRH agonists group, respectively (odds ratio, OR = 1.17; 95% confidence interval, 95% CI: 0.78-1.77, P > 0.1). Treatment related severe cardiovascular side effects were reported (trial CS21-30-35) in 1.6% and 3.6% of patients in the degarelix and GnRH agonists group, respectively (OR = 0.55, 95% CI: 0.26-1.14, P > 0.1).Our analysis evidences relevant limitations in particular for the comparative evaluation of the efficacy and the oncological results related to degarelix.
Topics: Gonadotropin-Releasing Hormone; Humans; Male; Neoplasm Staging; Oligopeptides; Prostatic Neoplasms; Randomized Controlled Trials as Topic
PubMed: 27399062
DOI: 10.1097/MD.0000000000003845 -
Journal of Oncology 2022To investigate the effects of docetaxel plus degarelix on quality of life and vascular endothelial growth factor in patients with prostate cancer.
OBJECTIVE
To investigate the effects of docetaxel plus degarelix on quality of life and vascular endothelial growth factor in patients with prostate cancer.
METHODS
Between 2018 and 2020, 38 patients with castration-resistant prostate cancer (CRPC) treated in our institution were assessed for eligibility and recruited. They were assigned at a ratio of 1 : 1 to receive either docetaxel plus degarelix (observation group) or degarelix (control group). Outcome measures included treatment efficacy, inflammatory factors level, vascular endothelial growth factor (VEGF) level, and quality of life of patients.
RESULTS
Docetaxel plus degarelix was associated with a significantly higher treatment efficacy (94.74%, including 9 (47.37%) cases of complete response (CR), 6 (31.58%) cases of partial response (PR), 4 (21.05%) cases of stable disease (SD), and 1 (5.36%) case of progressive disease (PD)) versus degarelix alone (63.16%, including 4 (21.05%) cases of CR, 5 (26.32%) cases of PR, 3 (15.79%) cases of SD, and 7 (36.84%) cases of PD) ( < 0.05). Before treatment, the two groups showed comparable levels of C-reaction protein (CRP), interleukin- (IL-) 6, and IL-10 ( > 0.05). Docetaxel plus degarelix resulted in significantly reduced levels of CRP and IL-6 and a significantly higher IL-10 level (28.84 ± 5.42, 25.31 ± 5.74, and 53.32 ± 11.02) versus degarelix alone (35.17 ± 6.31, 31.54 ± 8.17, and 42.76 ± 11.25) ( < 0.05). There were no significant differences in the urinary function, intestinal function, and hormone function scores between the two groups before treatment ( > 0.05). The patients receiving docetaxel plus degarelix had higher urinary function, intestinal function, and hormone function scores (38.87 ± 4.46, 86.51 ± 8.14, and 76.65 ± 7.15) versus monotherapy of degarelix (29.84 ± 3.58, 78.51 ± 7.31, and 66.78 ± 6.56) ( < 0.05). The two groups had similar pretreatment VEGF levels ( > 0.05). Docetaxel plus degarelix resulted in significantly lower VEGF levels (119.17 ± 21.38) versus degarelix (124.36 ± 23.14) at 6 months after treatment ( < 0.05).
CONCLUSION
Docetaxel plus degarelix can enhance the therapeutic efficacy of patients with prostate cancer, mitigate inflammatory response, inhibit the VEGF expression of cancer cells, and improve the patients' quality of life. Further clinical trials are, however, required prior to general use in clinical practice.
PubMed: 35874639
DOI: 10.1155/2022/9082501 -
Endocrinology Feb 2022The specific role of gonadotropin-releasing hormone (GnRH) on brain sexual differentiation remains unclear. To investigate whether gonadotropin and, in turn,...
The specific role of gonadotropin-releasing hormone (GnRH) on brain sexual differentiation remains unclear. To investigate whether gonadotropin and, in turn, testosterone (T) secretion is regulated by GnRH during the critical period for brain differentiation in sheep fetuses, we attempted to selectively suppress pituitary-testicular activation during midgestation with the long-acting GnRH antagonist degarelix. Fetuses received subcutaneous injections of the antagonist or vehicle on day 62 of gestation. After 2 to 3 weeks we examined consequences of the intervention on baseline and GnRH-stimulated plasma luteinizing hormone (LH) and T levels. In addition, we measured the effect of degarelix-treatment on messenger RNA (mRNA) expression for the pituitary gonadotropins and key gonadal steroidogenic enzymes. Baseline and GnRH-stimulated plasma LH levels were significantly suppressed in degarelix-treated male and female fetuses compared to control values. Similarly, T concentrations were suppressed in degarelix-treated males. The percentage of LHβ-immunoreactive cells colocalizing c-fos was significantly reduced by degarelix treatment indicating that pituitary sensitivity was inhibited. Degarelix treatment also led to the significant suppression of mRNA expression coding for the pituitary gonadotropin subunits and for the gonadal enzymes involved in androgen synthesis. These findings demonstrate that pharmacologic inhibition of GnRH early in gestation results in suppression of LH secretion and deficits in the plasma T levels of male lamb fetuses. We conclude that GnRH signaling plays a pivotal role for regulating T exposure during the critical period of sheep gestation when the brain is masculinized. Thus, disturbance to gonadotropin secretion during this phase of gestation could have long-term consequence on adult sexual behaviors and fertility.
Topics: Animals; Brain; Female; Fetal Blood; Gestational Age; Gonadotropin-Releasing Hormone; Gonadotropins, Pituitary; Injections, Subcutaneous; Luteinizing Hormone; Male; Oligopeptides; Ovary; Pituitary Gland, Anterior; Pregnancy; RNA, Messenger; Sex Differentiation; Sheep; Testis; Testosterone
PubMed: 34958103
DOI: 10.1210/endocr/bqab262 -
Expert Opinion on Pharmacotherapy Jun 2017Androgen deprivation therapy (ADT) is the mainstay for advanced, hormone-sensitive prostate cancer, and options include surgical castration, luteinizing... (Review)
Review
Androgen deprivation therapy (ADT) is the mainstay for advanced, hormone-sensitive prostate cancer, and options include surgical castration, luteinizing hormone-releasing hormone (LHRH) agonist, and more recently, gonadotropin releasing hormone (GnRH) antagonist therapy. Our understanding of the mechanisms and adverse effects of ADT has increased substantially, including the class-specific adverse effects of ADT. Areas covered: This review will summarize the pharmacodynamic and pharmacokinetic properties of the GnRH antagonist degarelix and its role in the management of advanced prostate cancer, the clinical evidence supporting its regulatory approval, as well as potential benefits and disadvantages over traditional LHRH agonist therapy. Expert opinion: Degarelix represents a newer class of ADT that results in a rapid and reliable decline in serum testosterone, a quality that makes it particularly advantageous in men presenting with symptomatic, hormone-sensitive prostate cancer. Due to differences in mechanism of action, there is observational data suggesting a potential cardiovascular and even oncologic benefit over traditional LHRH agonist therapy. Further research is ongoing to more clearly define this potential benefit.
Topics: Androgen Antagonists; Antineoplastic Agents, Hormonal; Drug-Related Side Effects and Adverse Reactions; Gonadotropin-Releasing Hormone; Humans; Male; Oligopeptides; Orchiectomy; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 28480768
DOI: 10.1080/14656566.2017.1328056 -
Asian Journal of Urology Jul 2020To establish non-inferiority of gonadotropin-releasing hormone degarelix compared with goserelin in suppressing and maintaining castrate testosterone levels from Day 28...
OBJECTIVE
To establish non-inferiority of gonadotropin-releasing hormone degarelix compared with goserelin in suppressing and maintaining castrate testosterone levels from Day 28 to Day 364 in Chinese patients with prostate cancer.
METHODS
This is an open-label, multi-centre study in which men aged ≥18 years were randomised in a 1:1 ratio to once-a-month subcutaneous injection of either degarelix (240/80 mg) or goserelin (3.6 mg) for 12 months. The primary endpoint was difference in 1-year cumulative probability of suppressing testosterone to ≤0.5 ng/mL. Non-inferiority was to be established if the lower 95% confidence interval (CI) limit for difference in cumulative probability between the treatment arms was greater than -10%. Secondary endpoints included cumulative probability of prostate-specific-antigen-progression-free-survival (PSA-PFS). Safety was also assessed.
RESULTS
Baseline demographics and disease characteristics were similar between degarelix (=142) and goserelin (=141) treatment arms. The difference in cumulative probability of maintaining castrate levels from Day 28-364 was 3.6% (95% CI:-1.5%, 8.7%), demonstrating non-inferiority of degarelix. The cumulative probability of PSA-PFS at Day 364 was higher for degarelix (82.3%, 95% CI: 74.7%, 87.7%) versus goserelin (71.7%, 95% CI: 63.2%, 78.5%, =0.038). Adverse events (AEs) were similar between treatment arms, except for more injection site reactions with degarelix versus goserelin. Four (2.8%) and nine (6.4%) patients discontinued due to AEs in degarelix and goserelin groups, respectively.
CONCLUSION
Degarelix was non-inferior to goserelin in achieving and maintaining testosterone suppression at castrate levels during 1-year treatment. PSA-PFS was significantly higher with degarelix, suggesting improved disease control. Both treatments were well tolerated.
PubMed: 32742930
DOI: 10.1016/j.ajur.2019.09.003 -
Asian Journal of Andrology 2021Androgen deprivation therapy (ADT) with gonadotropin-releasing hormone (GnRH) agonists and antagonists is the mainstay of advanced prostate cancer treatment. Both drug... (Review)
Review
Androgen deprivation therapy (ADT) with gonadotropin-releasing hormone (GnRH) agonists and antagonists is the mainstay of advanced prostate cancer treatment. Both drug classes decrease levels of luteinizing hormone and follicle-stimulating hormones (FSH), thereby lowering testosterone to castrate levels. This is associated with adverse events (AEs), including cardiovascular (CV) disorders, bone fractures, metabolic dysfunction, and impaired cognitive function. This literature review discusses these AEs, with a focus on CV and bone-related events. A hypothesis-generating meta-analysis of six clinical trials showed a potentially increased risk for CV disorders with GnRH agonists versus the GnRH antagonist degarelix. While no study has directly compared GnRH agonists versus antagonists with a primary CV outcome, one hypothesis for this observation is that GnRH agonists lead to initial surges in FSH that may negatively impact CV health, whereas antagonists do not. GnRH agonists are associated with metabolic and cognitive AEs and while data are lacking for GnRH antagonists, no differences in risk are predicted. Other common AEs with ADT include injection site reactions, which are much more common with degarelix than with GnRH agonists, which may reflect differing administration and injection techniques. Future studies are needed to further evaluate and compare the safety profiles of GnRH agonists and antagonists, especially in patients with pre-existing CV disease and other co-morbidities. Physicians should carefully evaluate benefits and risks when prescribing ADT and ensure that side effects are well managed.
Topics: Androgen Antagonists; Gonadotropin-Releasing Hormone; Humans; Male; Prostatic Neoplasms
PubMed: 32655041
DOI: 10.4103/aja.aja_22_20 -
Research and Reports in Urology 2017Therapeutically induced androgen deficiency (AD) is a standard treatment for patients with prostate cancer, but it is often associated with various adverse effects (AEs)...
INTRODUCTION
Therapeutically induced androgen deficiency (AD) is a standard treatment for patients with prostate cancer, but it is often associated with various adverse effects (AEs) that may lead to discontinuation. Some AEs may depend on the patient's health condition, while others may be due to complications of the drug delivery method. Degarelix is a gonadotropin-releasing hormone (GnRH) antagonist widely used for the treatment of androgen-dependent prostate cancer. This study aimed to ascertain the following: 1) the compatibility of degarelix treatment with diabetes and 2) any specific causal associations of degarelix injections with increased blood clotting and antithrombotic therapy requirements.
PATIENTS AND METHODS
The medical records of 162 patients with prostate cancer who had undergone degarelix treatment were retrospectively examined. The association of a medical history of diabetes and anticoagulant co-treatment with degarelix treatment discontinuation was analyzed statistically.
RESULTS
Rapid and significant decreases in prostate-specific antigen (PSA) levels during the course of degarelix treatment were detected for patients with prostate cancer regardless of clinical state. During the 27 months of treatment, 68 subjects (48%) ceased degarelix treatment, owing to several reasons, mainly financial issues. Among these subjects, 19 had diabetes, while 35 were treated with antithrombotics. Extensive statistical analysis indicated that there were no causal associations between degarelix treatment discontinuation and preexisting diabetes or antithrombotic therapy.
CONCLUSION
Our study suggests that preexisting diabetes and antithrombotic therapy were not significant factors for the discontinuation of degarelix treatment in patients with prostate cancer.
PubMed: 29264358
DOI: 10.2147/RRU.S146180 -
Frontiers in Public Health 2022To explore the cost-effectiveness of degarelix acetate for injection (degarelix) compared to leuprorelin in prostate cancer (Pca) castration treatment from Chinese...
OBJECTIVE
To explore the cost-effectiveness of degarelix acetate for injection (degarelix) compared to leuprorelin in prostate cancer (Pca) castration treatment from Chinese healthcare system perspective.
METHODS
A Markov model, adapted from the one established in Finland was conducted for the cost-effectiveness analysis of degarelix and leuprorelin for Pca treatment. The main data were derived from global phase III clinical trials of degarelix (CS21), published study and expert surveys. Outcomes, utility and costs of prostate cancer patients were calculated on a 30-year time horizon. The CS21 study based population of intention-to-treat (ITT) population and three scenarios were modeled. Taking three times of the Gross domestic product (GDP) per capita (242,928 yuan, 2021) as the acceptable threshold for cost-effectiveness. One-way and probabilistic sensitivity analyses were performed on key parameters, including transition probabilities, costs, utility, and discount rate to test the robustness of the model.
RESULTS
Base case analysis for ITT population revealed that total costs of degarelix and leuprorelin were 566,226 yuan and 489,693 yuan, while the total quality-adjusted life years (QALYs) were 5.19 and 4.51 during the 30-year time horizon, resulting an incremental cost effectiveness ratio (ICER) of 112,674 yuan/QALY which was 1.39 times the GDP per capita, lower than willingness-to-pay level of three times the GDP per capita. The results for scenario analyses revealed that compared to leuprorelin, degarelix for Pca treatment in China was cost-effective. One-way sensitivity analysis showed that the model was most sensitive to price of 80 mg degarelix, utility of 1st-line therapy, hazard ratio of PSA recurrence, price of 3.75 mg leuprorelin, response rate of docetaxel per cycle, and discount rate of cost. In probabilistic sensitivity analysis, compared to leuprorelin, the probability of degarelix to be cost-effective was 53 and 81% for willingness-to-pay threshold of one and three times the GDP per capita.
CONCLUSION
Compared to leuprorelin, degarelix for prostate cancer treatment is cost-effective. Moreover, scenario, one-way, and probabilistic sensitivity analyses revealed that the model was robust.
Topics: China; Clinical Trials, Phase III as Topic; Cost-Benefit Analysis; Humans; Leuprolide; Male; Oligopeptides; Prostatic Neoplasms
PubMed: 35923949
DOI: 10.3389/fpubh.2022.942800 -
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