Determination of the ability of a novel, long-acting subcutaneous GnRH antagonist, VERU-100, to castrate without a testosterone surge in a rat model.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 128-128
Author(s):  
Robert H. Getzenberg ◽  
Jui-Chen Lin ◽  
Andrew Cerro ◽  
Christopher A. Rhodes ◽  
Mitchell S. Steiner
Keyword(s):  
Prostate Cancer ◽  
Advanced Prostate Cancer ◽  
Gnrh Antagonist ◽  
Animal Health ◽  
High Volume ◽  
Dose Finding ◽  
Loading Dose ◽  
Sprague Dawley ◽  
Gnrh Antagonists ◽  
Diagnostic Center

128 Background: Androgen deprivation therapy (ADT) is the mainstay for the treatment of advanced prostate cancer. LHRH agonists are frequently used for ADT but these agents often result in initial surges in testosterone (T) levels. Although they do not result in initial T surges, current injectable GnRH antagonists are short term (1 month) subcutaneous (sc) depots that require a high volume loading dose followed by monthly maintenance dosing. VERU-100 is a novel GnRH decapeptide antagonist for long term suppression of T to castrate levels and is administered as a low volume sc injection without the requirement of a loading dose. Eight distinct formulations were evaluated in rats in order to select the best formulation, VERU-100. Methods: Male Sprague Dawley rats (n=3 per group) were injected sc through a 21G needle, with approximately 200 μl of each formulation at a dose level of 20 mg/kg. Eight groups consisting of the distinct test formulations were evaluated. Blood samples were drawn at weekly intervals until week 4 and then bi-weekly for pharmacokinetic (PK) (Integrated Analytical Solutions) and testosterone (T) level determinations (Cornell University Animal Health Diagnostic Center). Results: Within approximately 24 hours after administration of the GHRH antagonist formulations, testosterone levels in the rats went from a mean of 7.36 ng/ml to undetectable. The T levels resulting from a single injection of the lead formulation in these studies, VH-030-002, remained undetectable for greater than 26 weeks (6 months) as did the other formulations tested. The corresponding PK analysis demonstrated that the GnRH antagonist levels were detectable for greater than 26 weeks and remained above 1 ng/ml for almost all of the study points. The T levels correlated to the exposure from the formulations, and PKPD was as consistent for GnRH antagonists. Conclusions: VERU-100 is a novel GnRH antagonist formulation that in this rodent study, with a low injection volume, resulted in undetectable T for at least six months. No surge of T is observed after administration. An IND submission is anticipated in early 2020 for the dose finding Phase 2 trial in men with advanced prostate cancer.

scholarly journals Relugolix: a novel androgen deprivation therapy for management of patients with advanced prostate cancer

2021 ◽  
Vol 13 ◽  
pp. 175883592199858
Author(s):  
Fred Saad ◽  
Neal D. Shore
Keyword(s):  
Prostate Cancer ◽  
Androgen Deprivation Therapy ◽  
Advanced Prostate Cancer ◽  
Gnrh Antagonist ◽  
Androgen Deprivation ◽  
Phase Iii ◽  
Intermittent Therapy ◽  
Gnrh Antagonists ◽  
Releasing Hormone ◽  
Lhrh Agonists

Androgen deprivation therapy (ADT) is the foundation of treatment for patients with locally advanced, recurrent and metastatic prostate cancer, most commonly using luteinizing releasing hormone (LHRH) agonists. More recently, a new approach to ADT has emerged with the development of gonadotropin-releasing hormone (GnRH) antagonists, which aim to overcome some of the potential adverse physiologic effects of LHRH agonists. This article focuses on the newest GnRH antagonist, relugolix – a once-daily treatment and the only oral GnRH antagonist that has now been approved for the treatment of advanced prostate cancer. In phase II and III studies, relugolix achieved rapid and sustained castration without the testosterone surge associated with LHRH agonists, thus avoiding the potential clinical consequences of tumor flare and the necessity for concomitant anti-androgen therapy. Relugolix also achieved rapid testosterone recovery, which may potentially reduce ADT-related adverse events and offer opportunities for combination and intermittent therapy strategies. Cardiovascular safety is a particular concern in men with prostate cancer and ADT further increases cardiovascular risk: indeed, LHRH agonists are required to have a drug label warning about an increased risk of cardiovascular disease. Data from the phase III HERO study demonstrate an improved cardiac safety profile for the GnRH antagonist relugolix compared with the LHRH agonist leuprolide, including a significantly reduced risk for a major adverse cardiovascular event. Taken together, the data indicate that relugolix may mitigate some of the cardiovascular concerns surrounding ADT and has the potential to become a new standard of care for men with prostate cancer. In summary, relugolix represents a novel and recently available prostate cancer management strategy, incorporating the mechanistic advantages of GnRH antagonists and the potential benefits of oral administration.

Abstract 17016: Cardiovascular Safety Profile of Gonadotropin Releasing Hormone (GnRH) Antagonist Compared to GnRH Agonist Among Patients With Prostate Cancer: A Meta-Analysis

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Courtney Campbell ◽  
Daniel Addison ◽  
Ragavendra Baliga ◽  
Ajay Vallakati
Keyword(s):  
Prostate Cancer ◽  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Gnrh Agonist ◽  
Cardiovascular Events ◽  
Gnrh Antagonist ◽  
Gnrh Agonists ◽  
Cardiovascular Safety ◽  
Gnrh Antagonists ◽  
Artery Disease

Introduction: Androgen deprivation therapy (ADT) is the cornerstone of advanced prostate cancer therapy. The degree that ADT contributes to cardiovascular disease remains uncertain with conflicting studies. ADT can be achieved through the use of gonadotrophin releasing (GnRH) hormone agonist or, more recently, GnRH antagonists. The objective of this study was to determine whether cardiovascular events differ after the initiation of GnRH agonist compared with GnRH antagonist in randomized control trials. Methods: From PubMed, Cochrane Central, and Embase we identified all randomized studies comparing GnRH antagonists with GnRH agonists in patients with prostate cancer from 2000-2020. Outcomes studied included major adverse cardiovascular events (MACE), coronary artery disease (CAD), cerebrovascular accidents (CVA), atrial fibrillation (AF), and heart failure (HF). A random effects model using the Mantel-Haenszel method was used to assess outcomes. Results: Overall, we identified 7 studies (n = 3298) which reported outcomes in prostate cancer patients receiving GnRH antagonists (n = 2127) compared with those receiving GnRH agonists (n = 1171). When compared to men receiving GnRH agonists, the incidence of MACE (RR 0.52, 95% CI 0.35-0.76, p<0.001) and CAD (RR 0.46, 95% CI 0.27 - 0.77, p=0.004) was lower in men receiving GnRH antagonists. There was no difference in the rates of CVA (RR 0.93, 95% CI 0.31-2.77, p=0.89), AF (RR 0.49, 95% CI 0.09-2.72, p=0.41), or HF (RR 0.55, 95% CI 0.19-1.59, p=0.52) between the two groups. Conclusion: For men with prostate cancer receiving ADT, GnRH antagonists decreased the incidence of MACE and coronary artery disease by half compared to men treated with GnRH agonists. GnRH antagonists have a more favorable cardiovascular safety profile than GnRH agonists.

scholarly journals Experience with degarelix in the treatment of prostate cancer

2012 ◽  
Vol 5 (1) ◽  
pp. 11-24 ◽  
Author(s):  
Neal D. Shore
Keyword(s):  
Prostate Cancer ◽  
Gnrh Agonist ◽  
Clinical Studies ◽  
Advanced Prostate Cancer ◽  
Gnrh Antagonist ◽  
Serum Alkaline Phosphatase ◽  
Specific Antigen ◽  
Progression Free Survival ◽  
Similar Efficacy ◽  
First Line

Degarelix is a gonadotrophin-releasing hormone (GnRH) antagonist for the first-line treatment of androgen-dependent advanced prostate cancer. It has a direct mechanism of action that blocks the action of GnRH on the pituitary with no initial surge in gonadotrophin or testosterone levels. Degarelix is the most extensively studied and widely available GnRH antagonist worldwide. Clinical studies have demonstrated similar efficacy to the GnRH agonist leuprolide in achieving testosterone suppression in patients with prostate cancer. However, degarelix produces a faster suppression of testosterone and prostate-specific antigen (PSA), with no testosterone surge or microsurges, thus preventing the risk of clinical flare in advanced disease. Clinical trials have demonstrated that degarelix can offer improved disease control when compared with a GnRH agonist in terms of superior PSA progression-free survival (suggesting that degarelix likely delays progression to castration-resistant disease), and a more significant impact on bone serum alkaline phosphatase and follicle-stimulating hormone. Degarelix is generally well tolerated, with no reports of systemic allergic reactions in any clinical studies. In conclusion, degarelix offers clinicians a rational first-line hormonal monotherapy option for the management of advanced prostate cancer.

Second interim analysis (IA2) results from a phase II trial of TAK-385, an oral GnRH antagonist, in prostate cancer patients (pts).

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 200-200 ◽  
Author(s):  
Fred Saad ◽  
James L. Bailen ◽  
Christopher Michael Pieczonka ◽  
Daniel R. Saltzstein ◽  
Paul R. Sieber ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Gnrh Antagonist ◽  
Phase 1 ◽  
Specific Antigen ◽  
Phase 2 ◽  
Open Label ◽  
Gnrh Antagonists ◽  
Parallel Group ◽  
Hot Flush ◽  
Secondary Endpoints

200 Background: Gonadotropin-releasing hormone (GnRH) antagonists achieve rapid decrease in testosterone (T) without transient T surge seen with GnRH agonists and thus may avoid clinical flare symptomatology. TAK-385 is an investigational, oral, non-peptide GnRH antagonist highly selective for the human GnRH receptor (IC50 0.12 nM). We report IA2 results from a phase 2, randomized, open label, parallel group study of TAK-385 in pts with advanced prostate cancer (NCT02083185). Methods: Pts aged ≥ 18 yrs with histologically confirmed prostate cancer, baseline T > 150 ng/dL and prostate-specific antigen (PSA) > 2 ng/mL, who were candidates for first-line androgen deprivation therapy, were randomized to receive oral TAK-385, 80 or 120 mg, once daily (QD) or leuprorelin (LEU) 22.5 mg subcutaneously every 12 wks, for 48 wks. The primary endpoint was effective castration rate of TAK-385 (T < 50 ng/dL) from wk 5–24. Secondary endpoints included: safety, pharmacokinetics (PK), and PSA. Results: At data cut-off, 75 pts had received TAK-385 (39 at 80 mg, 36 at 120 mg QD); 20 pts received LEU. Median age was 73 yrs with TAK-385 and 68.5 yrs with LEU; median treatment duration was 35.1 wks and 37.8 wks. After 3 days/4 wks/24 wks of treatment, median T was 36.9/10.6/8.9 ng/dL with TAK385 vs 648.1/13.0/11.5 ng/dL with LEU. T < 50 ng/dL was sustained over 5–24 wks in 92% vs 95% of pts (TAK-385 vs LEU). After 24 wks, PSA was reduced by 97.3% to a median of 0.1 ng/mL with TAK-385 vs 92.4% to 0.2 ng/mL with LEU. All-grade adverse events occurred in 91% vs 95% of pts (TAK-385 vs LEU); the most common were hot flush (59/60%), fatigue (21/15%), elevated alanine aminotransferase (9/10%), nasopharyngitis (8/5%), and elevated aspartate aminotransferase (5/10%). Initial analysis of pooled phase 1/2 data showed similar PK in the phase 2 pts and in previously studied healthy men, with dose-proportional plasma trough levels over > 6 mos. Conclusions: At IA2, the efficacy of TAK-385 was consistent with the GnRH antagonist mechanism of action and the safety profile was good. TAK-385 rapidly reduced T and sustained castration ( < 50 ng/dL) over 24 wks. Further investigation of TAK-385, as an option to injectable GnRH therapies, is warranted. Clinical trial information: NCT02083185.

scholarly journals Cardiovascular Safety of Degarelix versus Leuprolide in Patients with Prostate Cancer: The Primary Results of the PRONOUNCE Randomized Trial

Circulation ◽  
2021 ◽  
Author(s):  
Renato D. Lopes ◽  
Celestia S. Higano ◽  
Susan F. Slovin ◽  
Adam J. Nelson ◽  
Robert Bigelow ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
Gnrh Agonist ◽  
Primary Outcome ◽  
Gnrh Antagonist ◽  
Locally Advanced ◽  
Atherosclerotic Cardiovascular Disease ◽  
Cardiovascular Safety ◽  
Gnrh Antagonists ◽  
Clinical Trial Registration

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 (ASCVD) remains controversial. Methods: In this international, multicenter, prospective, randomized, open-label trial, men with prostate cancer and concomitant ASCVD were randomized 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 (MACE) (composite of death, myocardial infarction, or stroke) through 12 months. Results: Due to slower than projected enrollment and fewer than projected primary outcome events, enrollment was stopped before the 900 planned participants were accrued. From 3 May 2016 to 16 April 2020, a total of 545 patients from 113 sites across 12 countries were randomized. 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. MACE occurred in 15 (5.5%) patients assigned to degarelix and 11 (4.1%) assigned to leuprolide (hazard ratio [HR] 1.28, 95% confidence interval [CI] 0.59-2.79; p=0.53). Conclusions: PRONOUNCE 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 due to smaller than planned number of participants and events and no difference in MACE at 1 year between patients assigned to degarelix or leuprolide was observed. The relative cardiovascular safety of GnRH antagonists and agonists remains unresolved. Clinical Trial Registration: URL: https://clinicaltrials.gov Unique Identifier: NCT02663908

Cardiovascular morbidity in a randomized trial comparing GnRH-agonist and antagonist among patients with advanced prostate cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 5015-5015
Author(s):  
David Margel ◽  
Avivit Peer ◽  
Yaara Ber ◽  
Sivan Sela ◽  
Liat Shavit Grievink ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Patients ◽  
Gnrh Agonist ◽  
Gnrh Antagonist ◽  
Absolute Risk ◽  
Absolute Risk Reduction ◽  
Cerebrovascular Event ◽  
Gnrh Agonists ◽  
Open Label ◽  
Gnrh Antagonists

5015 Background: Androgen-deprivation therapy (ADT) used in prostate-cancer may increase risk of cardiovascular disease (CVD). Limited preclinical and retrospective clinical data suggest that use of gonadotrophin-releasing hormone (GnRH)-antagonist may be associated with lower risk of CVD compared to GnRH-agonist. Methods: We conducted a randomized open-label study comparing the one year incidence of major cardiovascular and cerebrovascular event (MACCE) in prostate-cancer patients with pre-existing CVD commencing on GnRH-agonists or antagonists. Patients were followed every 3 months for the development of MACCE defined as either death, myocardial infarction (MI), cerebrovascular event (CVA), or percutaneous-coronary intervention (PCI). Serum levels of N-terminal pro-B-type natriuretic peptide (NTproBNP) were analyzed at baseline, 3, 6 and 12-months. Results: Eighty patients were enrolled (41 randomized to GnRH-antagonist, 39 to GnRH-agonist). Patients in both arms had similar age, baseline cardiovascular and prostate-cancer characteristics. During follow-up 15 patients developed a new cardiovascular event. Of these, nine patients developed MACCE (two deaths, one MI, two CVAs, and four PCI). Twenty percent (n = 8) of patients randomized to GnRH-agonists had a MACCE compared to 3% (n = 1) randomized to antagonists (log-rank p = 0.013). The absolute risk reduction for MACCE at 12 months using GnRH-antagonist was 18% (95%CI 5-31). Baseline levels of NTproBNP predicted events (AUC = 0.73 95%CI 0.54-0.91 p = 0.03) and increased over time only among patients with CV events. Conclusions: This is the first prospective study to test cardiovascular outcome among prostate-cancer patients receiving ADT. We demonstrated that in patients with pre-existing CVD, GnRH-antagonists was associated with development of fewer cardiovascular events compared to GnRH-agonists. Clinical trial information: NCT02475057.

A phase II, dose finding, placebo-controlled, study of zuclomiphene citrate to amerliorate the frequency and severity of hot flashes caused by androgen deprivation in men with advanced prostate cancer.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. TPS338-TPS338
Author(s):  
Robert H. Getzenberg ◽  
Domingo Rodriguez ◽  
Michael L Hancock ◽  
Harry Fisch ◽  
Mitchell S. Steiner
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
Advanced Prostate Cancer ◽  
Bone Fractures ◽  
Hot Flashes ◽  
The United States ◽  
Androgen Deprivation ◽  
Dose Finding ◽  
Controlled Study ◽  
Study Results

TPS338 Background: Androgen deprivation therapy (ADT) is the mainstay of treatment for advanced prostate cancer. ADT not only lowers testosterone, but also decreases estrogen levels which can cause significant side effects including hot flashes, loss of bone and bone fractures, and decreases in libido. Up to 80% of the men on ADT report hot flashes and 30-40% of men have moderate to severe hot flashes. Concern over hot flashes make patients less likely to begin ADT and can lead to early discontinuation of ADT. While the off-label use of potent steroidal estrogens has demonstrated efficacy, the appropriate dose as well as dosing route or schedule of these potent estrogens, has not been established. Furthermore, the potential for safety issues with potent steroidal estrogens remains a significant limitation to their clinical utility. Zuclomiphene citrate, is novel weak nonsteroidal estrogenic agent that should ameliorate hot flashes caused by ADT, and as one of the isomers of clomiphene, has a 50 year safety history of being well tolerated in men. Methods: The Phase 2, placebo controlled, dose finding clinical trial (V72203) evaluating zuclomiphene citrate (VERU-944) capsules, oral daily dosing, for the treatment of moderate to severe hot flashes in men with prostate cancer on ADT is in progress. Men are randomized to daily doses of placebo or zuclomiphene 10mg, 50mg or 100mg. V72203 is enrolling approximately 36 men per arm in 10 sites in the United States. The primary efficacy endpoint is the mean change in frequency of moderate and/or severe hot flashes from baseline to week 4 and maintained until week 12. Secondary endpoints include changes from baseline in bone turnover markers, free and total testosterone, SHBG, PSA, and safety. Hot flashes are being measured in real time utilizing an electronic data capture device (ePRO) provided to each subject. We anticipate completion of enrollment by the end of 2018 with study results by second quarter of 2019. Clinical trial information: NCT03646162.

Relugolix, an oral gonadotropin-releasing hormone antagonist for the treatment of prostate cancer

2021 ◽  
Author(s):  
Daniel J George ◽  
David P Dearnaley
Keyword(s):  
Prostate Cancer ◽  
Advanced Prostate Cancer ◽  
Gnrh Antagonist ◽  
Gonadotropin Releasing Hormone ◽  
Leuprolide Acetate ◽  
Phase Iii ◽  
Major Adverse Cardiovascular Events ◽  
Gnrh Analogues ◽  
Releasing Hormone ◽  
Testosterone Levels

Androgen deprivation therapy using gonadotropin-releasing hormone (GnRH) analogues is standard treatment for intermediate and advanced prostate cancer. GnRH agonist therapy results in an initial testosterone flare, and increased metabolic and cardiovascular risks. The GnRH antagonist relugolix is able to reduce serum testosterone levels in men with prostate cancer without inducing testosterone flare. In the HERO Phase III trial, relugolix was superior to leuprolide acetate at rapidly reducing testosterone and continuously suppressing testosterone, with faster post-treatment recovery of testosterone levels. Relugolix was associated with a 54% lower incidence of major adverse cardiovascular events than leuprolide acetate. As the first oral GnRH antagonist approved for the treatment of advanced prostate cancer, relugolix offers a new treatment option.

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