GTx Incorporated

Most breast cancers express androgen receptors (ARs). This prospective imaging substudy explored imaging of ARs with 18F-fluoroapy (GTx-024). Metkods: Eleven postmenopausal women with estroand at 6 and 12 wk after starting SARM therapy. Abnormal tumor 18F-FDHT uptake was quantified using SUVmax. AR status was determined from tumor biopsy specimens. 18F-FDHT SUVmax percentage change between scans was calculated. Best overall response was categorized as clinical benefit (nonprogressive disease) or progressive disease using RECIST 1.1. Results: The median baseline 18F-FDHT SUVmaxwas 4.1 (range, 1.4-5.9) for AR-positive tumors versus 2.3 (range, 1.5-3.2) for AR-negative tumors (P = 0.22). Quantitative AR expression and baseline 18F-FDHT uptake were weakly correlated (Pearson p = 0.39, P= 0.30). Seven participants with clinical benefit at 12 wk tended to have larger declines in 18F-FDHT uptake than did those with progressive disease both at 6 wk after starting GTx-024 (median, -26.8% [range, -42.9% to -14.1%], vs. -3.7% [range,-31% to +29%], respectively; P = 0.11) and at 12 wk after starting GTx-024 (median, -35.7% [range, -69.5% to -7.7%], vs. -20.1% [range, -26.6% to +56.5%], respectively; P = 0.17). Conclusion: These hypothesis-generating data suggest that 18F-FDHT PET/ CT is worth further study as an imaging biomarker for evaluating the response of MBC to SARM therapy and reiterate the feasibility of including molecular imaging in multidisciplinary therapeutic trials.

An open-label phase 2 trial was performed to assess the ability of GTx-758, an oral selective estrogen receptor alpha agonist, to induce a >= 50% decrease in prostate-specific antigen (PSA) decline by day 90, modulate free testosterone and sex hormone -binding globulin (SHBG) levels, and affect estrogen deficiency -related adverse events in men with castratation-resistant prostate cancer. The 250 mg/d cohort met statistical significance for the PSA decline rate. SHBG levels were increased, there were beneficial effects on hot flashes, and there was a minimal rate of venous thromboembolic events. Introduction: Novel estrogen therapy has the potential to be efficacious, with a favorable adverse event profile, in castration-resistant prostate cancer (CRPC). We performed a phase 2 trial to assess the ability of GTx-758, an oral selective estrogen receptor alpha agonist, to result in a >= 50% PSA decline by day 90, modulate free testosterone and sex hormone-binding globulin (SHBG) levels, and affect estrogen deficiency adverse events. Patients and Methods: CRPC patients received GTx-758 in two dose cohorts, 125 and 250 mg/d. The primary endpoint was the proportion of subjects who experienced a >= 50% PSA decline by day 90. Secondary endpoints included changes in testosterone, SHBG, bone turnover markers, and hot flashes, as well as safety. Results: Four (10.5%) of 38 (95% CI, 2.9, 24.8; P = .120) and 10 (25.6%) of 39 patients (95% CI, 13.0, 42.1; P .001) in the GTx-758 125 and 250 mg/d cohorts, respectively, experienced >= 50% PSA decline. SHBG was increased, providing a mechanism for notable decreases in free testosterone. In the 250 mg/d cohort, 9 men presented with moderate to severe hot flashes, and after 12 weeks, 4 (44%) of 9 reported either mild or no hot flashes (P = .001). The rate of venous thromboembolic events was 0% and 5.1% in the 125 and 250 mg/d arms, respectively. Conclusion: GTx-758 has clinical activity for CRPC in a dose-dependent fashion. GTx-758 resulted in a reduction in hot flashes. On the basis of these findings, further clinical investigation of novel estrogen therapies is warranted. (C) 2020 Elsevier Inc. All rights reserved.

Abstract Purpose: Androgen receptor (AR)-targeting prostate cancer drugs, which are predominantly competitive ligand-binding domain (LBD)-binding antagonists, are inactivated by common resistance mechanisms. It is important to develop next-generation mechanistically distinct drugs to treat castration- and drug-resistant prostate cancers. Experimental Design: Second-generation AR pan antagonist UT-34 was selected from a library of compounds and tested in competitive AR binding and transactivation assays. UT-34 was tested using biophysical methods for binding to the AR activation function-1 (AF-1) domain. Western blot, gene expression, and proliferation assays were performed in various AR-positive enzalutamide-sensitive and -resistant prostate cancer cell lines. Pharmacokinetic and xenograft studies were performed in immunocompromised rats and mice. Results: UT-34 inhibits the wild-type and LBD-mutant ARs comparably and inhibits the in vitro proliferation and in vivo growth of enzalutamide-sensitive and -resistant prostate cancer xenografts. In preclinical models, UT-34 induced the regression of enzalutamide-resistant tumors at doses when the AR is degraded; but, at lower doses, when the AR is just antagonized, it inhibits, without shrinking, the tumors. This indicates that degradation might be a prerequisite for tumor regression. Mechanistically, UT-34 promotes a conformation that is distinct from the LBD-binding competitive antagonist enzalutamide and degrades the AR through the ubiquitin proteasome mechanism. UT-34 has a broad safety margin and exhibits no cross-reactivity with G-protein–coupled receptor kinase and nuclear receptor family members. Conclusions: Collectively, UT-34 exhibits the properties necessary for a next-generation prostate cancer drug.

Visual Abstract In a prospective clinical trial, [18F]fluoro-5α-dihydrotestosterone ([18F]FDHT), the radiolabeled analog of the androgen dihydrotestosterone, was used as a PET/CT imaging agent for in vivo assessment of metastatic androgen receptor–positive breast cancer in postmenopausal women. To our knowledge, this article presents the first report of PET/CT image–based radiation dosimetry of [18F]FDHT in women. Methods: [18F]FDHT PET/CT imaging was performed on a cohort of 11 women at baseline before the start of therapy and at 2 additional time points during selective androgen receptor modulator (SARM) therapy for androgen receptor–positive breast cancer. Volumes of interest (VOIs) were placed over the whole body and within source organs seen on the PET/CT images, and the time-integrated activity coefficients of [18F]FDHT were derived. The time-integrated activity coefficients for the urinary bladder were calculated using the dynamic urinary bladder model in OLINDA/EXM software, with biologic half-life for urinary excretion derived from VOI measurements of the whole body in postvoid PET/CT images. The time-integrated activity coefficients for all other organs were calculated from VOI measurements in the organs and the physical half-life of 18F. Organ dose and effective dose calculations were then performed using MIRDcalc, version 1.1. Results: At baseline before SARM therapy, the effective dose for [18F]FDHT in women was calculated as 0.020 ± 0.0005 mSv/MBq, and the urinary bladder was the organ at risk, with an average absorbed dose of 0.074 ± 0.011 mGy/MBq. Statistically significant decreases in liver SUV or uptake of [18F]FDHT were found at the 2 additional time points on SARM therapy (linear mixed model, P < 0.05). Likewise, absorbed dose to the liver also decreased by a small but statistically significant amount at the 2 additional time points (linear mixed model, P < 0.05). Neighboring abdominal organs of the gallbladder wall, stomach, pancreas, and adrenals also showed statistically significant decreases in absorbed dose (linear mixed model, P < 0.05). The urinary bladder wall remained the organ at risk at all time points. Absorbed dose to the urinary bladder wall did not show statistically significant changes from baseline at any of the time points (linear mixed model, P ≥ 0.05). Effective dose also did not show statistically significant changes from baseline (linear mixed model, P ≥ 0.05). Conclusion: Effective dose for [18F]FDHT in women before SARM therapy was calculated as 0.020 ± 0.0005 mSv/MBq. The urinary bladder wall was the organ at risk, with an absorbed dose of 0.074 ± 0.011 mGy/MBq.

Dear Editor, In the 1940s, Charles Huggins discovered that surgical castration produced remarkable palliative benefits for men with advanced prostate cancer, an effect we now understand to be mediated through depriving the androgen receptor (AR) from its ligands (i.e., testicular-derived androgens). In the years since, medical forms of androgen deprivation therapy (ADT) have largely replaced orchiectomy as the predominate means of achieving castrate testosterone (T) levels, and currently, luteinizing hormone-releasing hormone (LHRH) agonists (e.g., leuprolide) are the most common form of ADT. Importantly, studies have shown that LHRH agonists are clinically efficacious and, similar to surgical castration, drive T below 50 ng dl−1 for most patients.1 While T <50 ng dl−1 is the most frequently cited definition for what constitutes a castrate level T, it should be recognized that multiple studies have demonstrated better outcomes with lower T levels. For instance, Klotz et al.2 reported that, in patients enrolled to the Phase III PR-7 study testing intermittent versus continuous ADT in nonmetastatic biochemically recurrent prostate cancer patients, a total T level <20 ng dl−1 was associated with improved disease-specific survival and time-to-castration resistance compared those with a total T level >20 ng dl−1. This observation has led to the European Association of Urology to recommend that a level of <20 ng dl−1 should be used to define a castrate level of T. It is important to note that the total serum T levels include both free and protein-bound (e.g., sex hormone-binding globulin, albumin) fractions, while older studies have shown that LHRH agonists suppress total T levels below castrate levels; it is widely understood that free, or unbound, T is the biologically and clinically relevant component.3 That being the case, the therapeutic goal of medical ADT should be to decrease free T levels to those achieved with orchiectomy. However, to date, free T has not been well studied in large cohorts of orchiectomized men. The purpose of this study was to examine total T and free T levels in men who have undergone orchiectomy or received medical ADT in the context of a prospective clinical trial. These determinations will help set expectations for future development of novel agents that effect androgen levels. Baseline data were utilized from a double-blind, randomized, placebo-controlled trial (G300203) that was designed to determine the capacity of toremifene (a second-generation selective estrogen receptor modulator) to prevent bone fractures in men on ADT. This study included 1389 men from 150 sites in the US and Mexico. Patients were randomized in the ratio of 1:1 to receive toremifene 80 mg by mouth daily or matched placebo. Results from the primary analysis have already been published.4 Baseline characteristics, including whether men were on medical ADT or status postorchiectomy, were available. The primary objective of this study is to describe baseline hormone levels in men receiving medical ADT or who underwent orchiectomy before initiating toremifene. Hormone levels were determined in a centralized clinical testing facility utilizing an Food and Drug Administration-approved radioimmunoassay (RIA) (Diagnostic Products Corporation, Los Angeles, CA, USA). Free testosterone levels were estimated using RIA and equilibrium dialysis as previously described.5 We also evaluated for differences in hormone levels between groups using the Wilcoxon rank-sum test. This study was conducted in accordance with the Declaration of Helsinki and was approved by the local ethics committees of the participating institutions. Informed written consent was obtained from all patients before their enrollment in this study. Between November 2003 and October 2005, 1284 men with prostate cancer receiving ADT were randomized between placebo and toremifene. Of this cohort, castrating therapy was administered as follows: 1191 received an LHRH agonist, 56 underwent bilateral orchiectomy, 27 underwent bilateral orchiectomy with androgen receptor blockade, and 10 underwent bilateral orchiectomy and also received an LHRH agonist. Details for why ten patients received LHRH agonist therapy and orchiectomy are not available as these data were gleaned from case report forms which are no longer available for review. LH levels were significantly lower and estradiol levels were significantly higher in men receiving LHRH agonist therapy. There was no significant difference in total or free T levels between groups (Table 1). However, there was less variability in total and free T levels in orchiectomized patients compared to those receiving LHRH agonists. For instance, the total T ranged from 0.69 ng dl−1 to 29.5 ng dl−1 in men receiving LHRH agonist therapy alone compared to 0.69 ng dl−1 to 13.01 ng dl−1 in patients who underwent orchiectomy.Table 1: Baseline demographics and hormone levelsTo our knowledge, this study is the largest to report free T levels in men who underwent orchiectomy. In this cohort, the mean serum-free T was approximately 1.9 pg ml−1. This value could be considered to be the optimal suppression of free T with orchiectomy and represents the goal of medical ADT. Reassuringly, there was no difference in free T levels between the orchiectomy cohort and those receiving an LHRH agonist. An interesting observation from this study was that, while there was no difference in total or free T levels between treatment groups, LH levels were significantly lower and estradiol levels were significantly higher in patients receiving LHRH agonist therapy. Given that LHRH agonists inhibit testicular androgen biosynthesis by impairing LH release from the pituitary gland, it is not surprising that LH levels were lower in men receiving these drugs. Somewhat less clear is why estradiol levels are elevated in men receiving an LHRH agonist compared to other groups. LH receptors are present in the adrenal gland, and it is possible that LH may exert some influence on adrenal estradiol biosynthesis that has yet to be explained.67 Given that mass spectrometry has been demonstrated to be more accurate means to quantitate low hormone levels, a limitation of this analysis was the use of RIA to measure circulating androgen levels.8 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%–60%.910 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. This study provides greater clarity on the effects that LHRH agonists and orchiectomy have on circulating hormone levels. Importantly, as determined by RIA, there is no significant difference in total or free T levels irrespective of whether a man received surgical or medical ADT. These circulating hormone levels should serve as a benchmark for future studies investigating novel forms of medical ADT, with the goal being to meet or exceed this level of free and total T suppression. AUTHOR CONTRIBUTIONS This study was designed by MTS, EYY, and RHG. Statistical analysis was performed by MLH and all authors helped to analyze the data. The manuscript was prepared by MTS. All authors read and approved the final manuscript. COMPETING INTERESTS MLH and RHG are former employees of GTx, Inc, the sponsor of the clinical trial from which these data were derived. MTS and EYY have no competing interests to declare. ACKNOWLEDGMENTS We thank all the men who generously participated in this research. We acknowledge funding support from PNW Prostate SPORE CA097186 (MTS and EYY), DOD award W81XWH-16-1-0484 (MTS), and a Prostate Cancer Foundation Young Investigator Award (MTS).