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.

Optimal testosterone suppression on medical ADT should strive to suppress free testosterone levels to levels similar to orchiectomy: What is that value?

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 144-144
Author(s):  
Evan Y. Yu ◽  
Robert H. Getzenberg ◽  
Jordan Smith ◽  
Michael L. Hancock ◽  
Matthew Raymond Smith ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
Advanced Prostate Cancer ◽  
Bone Fractures ◽  
Controlled Trial ◽  
Equilibrium Dialysis ◽  
Serum Testosterone ◽  
Double Blind ◽  
Serum Free ◽  
Median Serum

144 Background: The goal of medical androgen deprivation therapy (ADT) for advanced prostate cancer is to provide an equivalency to orchiectomy based upon older assays for serum testosterone (T). Literature shows that based on more modern assays, medical ADT does not always provide optimal total T suppression equivalent to orchiectomy. With the understanding that free, or unbound, T is the biologically and clinically relevant component, the therapeutic goal of ADT should be to decrease free T to levels similar to orchiectomy. Free T has not been well studied in a substantial number of orchiectomized men. The purpose of this study was to examine a subpopulation of orchiectomized men in a clinical trial to determine the level of serum-free T in advanced prostate cancer. Methods: Baseline data was utilized from a double blind, randomized, placebo controlled trial (G300203) to determine the capacity of toremifene 80 mg to prevent bone fractures in men on ADT. This study included 1,389 men from 150 sites in the U.S. and Mexico. Baseline characteristics, including whether men were on medical ADT or status post orchiectomy, were available. Free T levels were assayed at baseline by radioimmunoassay (RIA) (Diagnostic Products Corporation) and are reported for men who underwent orchiectomy. Results: A subpopulation of 114 men underwent orchiectomy. Median age was 76 (range 51 to 90). Median serum free T level was 0.92 pg/ml (min. 0.35 pg/ml and max. 33.95 pg/ml) with a mean level of 1.71 pg/ml ± 2.77. Conclusions: This study is believed to be the largest cohort in which free T levels have been reported in men who underwent orchiectomy. In this cohort, median serum free T is approximately 0.9 pg/ml. This value could be considered to be the optimal testosterone suppression of free T with orchiectomy and represents the goal of medical ADT. At the time this study was performed, RIA was considered to be the standard but has since been shown to underestimate free T levels by 20 to 60%. Currently, equilibrium dialysis coupled with LC-MS/MS is the gold standard, but the results from this analysis provide us with increased understanding of the optimal level of free T in treating advanced prostate cancer. Clinical trial information: NCT00129142.

Rate of hot flashes in patients with advanced prostate cancer treated with GTx-758.

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 129-129
Author(s):  
Evan Y. Yu ◽  
Marc Gittelman ◽  
Thomas E. Keane ◽  
Ronald Tutrone ◽  
Laurence Belkoff ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
Phase Ii ◽  
Advanced Prostate Cancer ◽  
Hot Flashes ◽  
Lower Percentage ◽  
Total Testosterone ◽  
Treatment Groups ◽  
Increased Risk ◽  
Venous Thromboembolic Events

129 Background: When androgen deprivation therapy (ADT) for prostate cancer was first developed, life expectancy for men with advanced disease was short and the systemic effects were of limited relevance. GTx-758 is a selective ERα agonist that effects serum total testosterone (T), free T, SHBG and PSA. Herein we compare the effects of GTx-758 and leuprolide on hot flashes, one of the common side effects in men on ADT. Methods: In a Phase II study (G200705), men with advanced prostate cancer (n=159) received 1000 mg or 2000 mg of GTx-758 daily or leuprolide. Utilizing a standardized instrument to measure the frequency and severity of hot flashes, data was compiled at baseline, day 28 and day 90. The number of men experiencing hot flashes were those reporting any in the period between the respective time point and the prior patient visit. All p values describe the comparison of both GTx-758 treatment groups to the leuprolide treated men. Results: At the baseline, there were no significant differences in the number of men reporting hot flashes in any of the treatment groups (p=0.065). The percentage of men who experienced a hot flash while receiving leuprolide increased significantly to 60.4% (p<0.0001) by Day 28 and increased further to 80.9% (p<0.0001) by Day 90. Although some subjects experienced hot flashes while receiving GTx-758, these men were a significantly lower percentage, 18.8 and 5.6% at the 1000 mg and 2000 mg doses of GTx-758 respectively at day 90. As a result of an increased risk of venous thromboembolic events (VTEs) at these higher doses of GTx-758, the trial was stopped prior to its completion and not all of the men on the study reached the 90 day treatment date (99 evaluable). Conclusions: Men with advanced prostate cancer, receiving GTx-758 experienced a greater than 4-fold reduction in their reported hot flashes at day 90. Since hot flashes are a major side effect that impacts the quality of life in men on ADT, the ability to significantly decrease their likelihood would seem to be of great benefit. A Phase II clinical trial utilizing lower doses of GTx-758 (G200712) is currently being performed that will determine if similar effects on serum free testosterone, PSA and hot flashes can be shown with a lower rate of VTEs. Clinical trial information: NCT01326312.

scholarly journals Preclinical Characterization of a Novel Diphenyl Benzamide Selective ERα Agonist for Hormone Therapy in Prostate Cancer

Endocrinology ◽  
2012 ◽  
Vol 153 (3) ◽  
pp. 1070-1081 ◽  
Author(s):  
Christopher C. Coss ◽  
Amanda Jones ◽  
Deanna N. Parke ◽  
Ramesh Narayanan ◽  
Christina M. Barrett ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Side Effects ◽  
Androgen Deprivation Therapy ◽  
Advanced Prostate Cancer ◽  
Hot Flashes ◽  
Specific Antigen ◽  
Disease Free Survival ◽  
Estrogen Deficiency ◽  
Androgen Deprivation ◽  
Term Therapy

Androgen deprivation therapy (ADT) is the mainstay of treatment for advanced prostate cancer. ADT improves overall and disease-free survival rates, but long-term therapy is associated with severe side effects of androgen and estrogen depletion including hot flashes, weight gain, depression, and osteoporosis. Effective hormone reduction can be achieved without estrogen deficiency-related side effects by using therapy with estrogenic compounds. However, cardiovascular complications induced by estrogens coupled with the availability of LHRH agonists led to discontinuation of estrogen use for primary androgen deprivation therapy in the 1980s. New treatments for prostate cancer that improve patient outcomes without the serious estrogen deficiency-related toxicities associated with ADT using LHRH analogs are needed. Herein we describe a novel nonsteroidal selective estrogen receptor-α agonist designed for first-line therapy of advanced prostate cancer that in animal models induces medical castration and minimizes many of the estrogen deficiency-related side effects of ADT. The present studies show that orally administered GTx-758 reversibly suppressed testosterone to castrate levels and subsequently reduced prostate volume and circulating prostate-specific antigen in relevant preclinical models without inducing hot flashes, bone loss, thrombophilia, hypercoagulation, or increasing fat mass.

scholarly journals Recent Advances in Nanomedicine for the Diagnosis and Treatment of Prostate Cancer Bone Metastasis

Molecules ◽  
2021 ◽  
Vol 26 (2) ◽  
pp. 384
Author(s):  
Daniel E. Hagaman ◽  
Jossana A. Damasco ◽  
Joy Vanessa D. Perez ◽  
Raniv D. Rojo ◽  
Marites P. Melancon
Keyword(s):  
Prostate Cancer ◽  
Bone Metastases ◽  
Advanced Prostate Cancer ◽  
Bone Fractures ◽  
Diagnosis And Treatment ◽  
Survival Times ◽  
Preclinical Research ◽  
Relieve Pain ◽  
Translational Models

Patients with advanced prostate cancer can develop painful and debilitating bone metastases. Currently available interventions for prostate cancer bone metastases, including chemotherapy, bisphosphonates, and radiopharmaceuticals, are only palliative. They can relieve pain, reduce complications (e.g., bone fractures), and improve quality of life, but they do not significantly improve survival times. Therefore, additional strategies to enhance the diagnosis and treatment of prostate cancer bone metastases are needed. Nanotechnology is a versatile platform that has been used to increase the specificity and therapeutic efficacy of various treatments for prostate cancer bone metastases. In this review, we summarize preclinical research that utilizes nanotechnology to develop novel diagnostic imaging tools, translational models, and therapies to combat prostate cancer bone metastases.

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