The emergence of technological innovations has created the opportunity to envision new approaches to discover therapeutics at scale. We combined advances in high content microscopy with arrayed CRISPR genome editing techniques and machine learning (ML) to build a rigorously controlled dataset enabling exploration of biology and chemistry at scale. Phenotypes from millions of perturbations in multiple cell types were embedded in a unified representation space and leveraged to accelerate discovery and reverse translation, ultimately yielding novel biological insights, and optimizing the advancement of lead molecular series through structure-activity relationships (SAR). Here, we demonstrate the capability of our platform to discover potential cancer therapies with distinct mechanisms of action. First, we describe the identification of a novel compound series that potentiates the effects of immunotherapy in syngeneic mouse models, producing complete responses and immunological memory, while also limiting peripheral inflammation. Specific novel chemical entities (NCEs) caused robust CD45+ cell influx into the tumor microenvironment and significantly attenuated exhausted T cells and immunosuppressive macrophages, thereby enhancing anti-tumor immunity. Strikingly, the same NCEs suppressed peripheral inflammation while sustaining elevated levels of intra-tumoral proinflammatory cytokines. Second, we highlight a novel and differentiated strategy to potentiate PARP inhibitor response in homologous repair deficient (HRD) - negative or HR-proficient ovarian cancers. NCEs altered the expression of genes within the DNA damage repair (DDR) network and cell cycle checkpoints to synergize with PARP inhibition in vivo and re-sensitized a PARP-resistant patient-derived xenograft (PDX) model. Collectively, we believe future efforts on the industrialization and integration of various technological innovations across biology, chemistry, automation, data science, and engineering will ultimately modernize drug discovery and radically improve patient lives. Citation Format: Jenny Rudnick, Kiran Nadella, Chase Neumann, Shane Rowley, Ethan Gardner, Shadi Swaidani, Aimee Iberg, Lu Chen, Daria Beshnova, Aurora Blucher, Rebecca Sarto Basso, Malini Rajan, Kevin Fales, Ashraf Saeed, Christopher Bailey, Weston Judd, Chrissy Egbert, Joel Ellis, John Ansede, Pouya Hadipour, Kevin Jessing, Janet Paulsen, Paul Rearden, Vamshi Manda, Sashi Kasimsetty, Sashi Kasimsetty, Michael Hancock, Harish Shankaran, Bryan Ellis, Meenakshy Iyer, Carl Brooks, Ashish Bhandari, Chris Gibson, Irit Rappley, Laura Schaevitz, Imran Haque, Hayley Donnella, Michael Cuccarese, Marie Evangelista. A phenomics platform combining imaging and artificial intelligence for rapid validation and advancement of novel oncology targets [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB071.

binding globulin SHBG and concurrent disease states, an individual’s total circulating T may fall below the eugonadal range despite being asymptomatic. Decreased sex hormone binding globulin resulting from any number of separate pathologies may allow eugonadal levels of free T (unbound) despite hypogonadal levels of total T. Likewise, elevated levels of sex hormone binding globulin might result in hypogonadal symptoms, due to reduced levels of free T, despite eugonadal levels of total T. For these reasons it has been suggested that free T levels, along with associated symptoms of hypogonadism, be used in the positive diagnoses of LOH.3,8 Though it is accepted that eugonadal levels of total T are variable and patient specific, the range of approximately 300–1000 ng dl−1 (10.4–34.7 nmol l−1) has been adopted and is used to gauge the success of TRT. When T therapy is indicated, minimally therapeutic T levels are desired and the upper end of the eugonadal range for young men (1000 ng dl−1) is generally avoided as the risks associated with T therapy are thought to increase with the levels of exogenous T administered.9 Currently available T product labeling suggests monitoring serum T and dose adjustments to maintain appropriate T levels. T therapy has well‐established beneficial effects on body composition, including increases in lean body mass and decreases in fat mass.10,11 These effects are rapid (apparent after as little as 3 months of therapy) and durable (maintained after 3 years).12,13 Increases in muscle strength are less consistently reported due to training effects and technical challenges in measuring maximal muscle strength. 14 However, durable muscle strength benefits are reported in placebo controlled TRT trials performed in a hypogonadal population.15 Improvements in lumbar spine and hip BMD require extended treatment, but have been reported following T therapy in a placebo controlled setting.16 Rapid improvements in sexual function are a hallmark of T administration INTRODUCTION As the population ages, longitudinal and cross‐sectional studies have shown that a significant portion of men over the age of 60 have serum testosterone (T) levels below the lower limits of those seen in healthy younger men (20–30 years).1,2 Late onset hypogonadism (LOH) encompasses a broad list of signs and symptoms including sexual dysfunction, fatigue and reduced lean body mass and bone mineral density (BMD) that are associated with low T and are what typically drives the patient to seek medical attention.3 Due to the often varied intensity of these symptoms and their association with non‐pathological general ageing processes, a significant effort has been made to clearly define LOH and thus patients who might benefit from therapy.4 Despite such efforts, LOH prevalence remains controversial as does the treatment of men who do not display overt hypothalamic‐pituitary‐gonadal pathology where the risk benefit profile of androgen supplementation is more clearly established.5 Diagnostic tools like ANDROTEST have estimated a disease incidence of 10%–40% in men aged over 45 years and suggest that up to 60 million men in the United States, Europe and Japan suffer from LOH.3,6,7 Conversely, more stringent criteria have placed LOH rates at as little as 2.1% in similarly aged men.8 Regardless of the diagnostic criteria employed, the current gold standard for the treatment of hypogonadism in older men is T therapy.3

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.

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.

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).

Muscle wasting in cancer is a common and often occult condition that can occur prior to overt signs of weight loss and before a clinical diagnosis of cachexia can be made. Muscle wasting in cancer is an important and independent predictor of progressive functional impairment, decreased quality of life, and increased mortality. Although several therapeutic agents are currently in development for the treatment of muscle wasting or cachexia in cancer, the majority of these agents do not directly inhibit muscle loss. Selective androgen receptor modulators (SARMs) have the potential to increase lean body mass (LBM) and hence muscle mass, without the untoward side effects seen with traditional anabolic agents. Enobosarm, a nonsteroidal SARM, is an agent in clinical development for prevention and treatment of muscle wasting in patients with cancer (POWER 1 and 2 trials). The POWER trials are two identically designed randomized, double-blind, placebo-controlled, multicenter, and multinational phase 3 trials to assess the efficacy of enobosarm for the prevention and treatment of muscle wasting in subjects initiating first-line chemotherapy for non-small-cell lung cancer (NSCLC). To assess enobosarm's effect on both prevention and treatment of muscle wasting, no minimum weight loss is required. These pivotal trials have pioneered the methodological and regulatory fields exploring a therapeutic agent for cancer-associated muscle wasting, a process hereby described. In each POWER trial, subjects will receive placebo (n = 150) or enobosarm 3 mg (n = 150) orally once daily for 147 days. Physical function, assessed as stair climb power (SCP), and LBM, assessed by dual-energy X-ray absorptiometry (DXA), are the co-primary efficacy endpoints in both trials assessed at day 84. Based on extensive feedback from the US Food and Drug Administration (FDA), the co-primary endpoints will be analyzed as a responder analysis. To be considered a physical function responder, a subject must have ≥10 % improvement in physical function compared to baseline. To meet the definition of response on LBM, a subject must have demonstrated no loss of LBM compared with baseline. Secondary endpoints include durability of response assessed at day 147 in those responding at day 84. A combined overall survival analysis for both studies is considered a key secondary safety endpoint. The POWER trials design was established with extensive clinical input and collaboration with regulatory agencies. The efficacy endpoints are a result of this feedback and discussion of the threshold for clinical benefit in patients at risk for muscle wasting. Full results from these studies will soon be published and will further guide the development of future anabolic trials. Clinical Trial ID: NCT01355484. https://clinicaltrials.gov/ct2/show/NCT01355484 , NCT01355497. https://clinicaltrials.gov/ct2/show/NCT01355497?term=g300505&rank=1 .

You have accessJournal of UrologyProstate Cancer: Advanced (including Drug Therapy) III1 Apr 2016PD32-03 A PHASE 2 OPEN-LABEL TRIAL OF GTX-758 IN MEN WITH CASTRATION-RESISTANT PROSTATE CANCER, FINAL ANALYSIS OF THE PRIMARY ENDPOINT William Aronson, Evan Yu, Michael Hancock, Tamás Babicz, Ronald Tutrone, Christopher Ng, Laurence Belkoff, Zsuzsanna Pápai, Lajos Géczi, and Robert Getzenberg William AronsonWilliam Aronson More articles by this author , Evan YuEvan Yu More articles by this author , Michael HancockMichael Hancock More articles by this author , Tamás BabiczTamás Babicz More articles by this author , Ronald TutroneRonald Tutrone More articles by this author , Christopher NgChristopher Ng More articles by this author , Laurence BelkoffLaurence Belkoff More articles by this author , Zsuzsanna PápaiZsuzsanna Pápai More articles by this author , Lajos GécziLajos Géczi More articles by this author , and Robert GetzenbergRobert Getzenberg More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.679AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Recently approved agents that target the androgen receptor pathway emphasize the importance of the persistent activity of the androgen receptor pathway in castration-resistant prostate cancer (CRPC). This raises the possibility that agents with distinct mechanisms of action may add value. GTx-758 is a selective ERα agonist that can increase SHBG and therefore reduce biologically active testosterone (T) levels. Reported here are the results, including the final primary endpoint analysis, from the 250 mg daily GTx-758 cohort of a Phase 2 clinical trial in men on LHRH agonists that developed CRPC. METHODS This phase 2 open label trial (G200712, NCT01615120) treated men with high risk nmCRPC or mCRPC with T levels <50 ng/dL who continued to receive their current form of ADT along with either 125 mg or 250 mg of GTx-758 daily, for at least 90 days. The primary endpoint was the proportion of men with a PSA decline ≥50% by day 90, while secondary endpoints included serum total and free T, sex hormone binding globulin (SHBG), bone turnover markers and hot flashes. RESULTS The 250 mg cohort (n=39) has completed the time period for assessment of the primary endpoint. Ten of the 39 (26%) subjects exhibited a ≥50% decrease in PSA by Day 90, with 11/39 (28%) by Day 120, while 18/39 (46%) had PSA declines of ≥30%. Median SHBG levels increased 301% of baseline, confirming the principal mechanism of drug action. While on study, median free T decreases of 44% were observed across all subjects and 20/26 (77%) of the subjects with baseline serum free T levels >0.7 pg/ml fell below this level. Therefore, 250 mg GTx-758 decreased free testosterone levels in an additive fashion to their existing LHRH therapy. The bone turnover biomarker, C-telopeptide, decreased in 79% of the subjects. 250 mg of GTx-758 has been generally well tolerated with two reported possibly drug related SAEs (VTE and MI). CONCLUSIONS In this Phase 2 trial, 250 mg daily GTx-758 has activity, likely mediated by lowering free T levels in patients with CRPC on LHRH therapy, and may provide amelioration of estrogen deficiency side effects associated with ADT. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e761-e762 Advertisement Copyright & Permissions© 2016MetricsAuthor Information William Aronson More articles by this author Evan Yu More articles by this author Michael Hancock More articles by this author Tamás Babicz More articles by this author Ronald Tutrone More articles by this author Christopher Ng More articles by this author Laurence Belkoff More articles by this author Zsuzsanna Pápai More articles by this author Lajos Géczi More articles by this author Robert Getzenberg More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Background: The androgen receptor (AR) is the most highly expressed steroid receptor in breast cancer (BC) with expression seen in up to 95% of estrogen receptor positive (ER+) and up to 50% of ER negative disease. Historically, steroidal androgens exhibited virilizing side effects, thus limiting clinical use. In TNBC, the expression of AR and androgen synthesizing enzymes is associated with lower proliferation, lower tumor grade, better overall survival, and more favorable clinical outcomes as compared to those patients with TNBC not expressing AR. Data from two trials targeting AR in TNBC indicates low level but encouraging clinical activity. A non-steroidal, tissue-selective, AR modulator (SARM), such as GTx-024, offers a targeted approach of AR activation in AR+ TNBC without virilization or estrogenic effects. Trial Design: Open label, multicenter, multinational, Phase 2 study for the treatment of advanced or metastatic TNBC. Subjects will receive GTx-024, 18 mg orally (PO) daily, continued until evidence of disease progression or toxicity. Subjects whose tumors demonstrate Clinical Benefit (CB) will be treated on study drug until progression. Eligibility Criteria: Inclusion: Female, ≥18 years old, confirmed AR+ (≥10% staining) TNBC (confirmed by medical history), up to 1-2 prior chemotherapy regimens, available archived tumor tissue, measurable or bone-only disease, ECOG 0 or 1, with prior toxicities from chemotherapy resolved. Exclusion: Life expectancy Specific Aims: The primary aim is to measure the proportion of AR+ subjects with CB at 16 weeks; defined as subjects with a complete response (CR), partial response (PR), or stable disease (SD); per modified RECIST 1.1. Secondary endpoints include: objective response rate, progression free survival, and time to progression. Statistical Methods: Simon9s two-stage (optimal) design will be used to assess primary efficacy, requiring up to 41 evaluable subjects; i.e., subjects with centrally confirmed AR+ who receive at least one dose of study drug. The first stage will be assessed among the first 21 evaluable subjects. If at least 2/21 achieve CB per modified RECIST 1.1 at 16 weeks, then the trial will proceed to the second stage of recruitment of up to a total of 41 subjects in the evaluable subset of the Full Analysis Set. Otherwise, the trial will be discontinued for lack of efficacy. The trial will test for an unacceptably low CBR of ≤5% versus a CBR more consistent with ≥20%. Target Accrual: Up to 55 subjects will be enrolled. Trial Information: www.gtxinc.com Citation Format: Rugo H, Overmoyer B, Schwartzberg L, Palmieri C, Taylor R, Hancock M, Small S, Johnston MA. A phase 2 open label, multi-center, multinational study investigating the efficacy and safety of GTx-024 on advanced, androgen receptor-positive triple negative breast cancer (AR+ TNBC). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT2-01-07.

Muscle wasting in cancer is a common and often occult condition that can occur prior to overt signs of weight loss and before a clinical diagnosis of cachexia can be made. Muscle wasting in cancer is an important and independent predictor of progressive functional impairment, decreased quality of life, and increased mortality. Although several therapeutic agents are currently in development for the treatment of muscle wasting or cachexia in cancer, the majority of these agents do not directly inhibit muscle loss. Selective androgen receptor modulators (SARMs) have the potential to increase lean body mass (LBM) and hence muscle mass, without the untoward side effects seen with traditional anabolic agents. Enobosarm, a nonsteroidal SARM, is an agent in clinical development for prevention and treatment of muscle wasting in patients with cancer (POWER 1 and 2 trials). The POWER trials are two identically designed randomized, double-blind, placebo-controlled, multicenter, and multinational phase 3 trials to assess the efficacy of enobosarm for the prevention and treatment of muscle wasting in subjects initiating first-line chemotherapy for non-small-cell lung cancer (NSCLC). To assess enobosarm’s effect on both prevention and treatment of muscle wasting, no minimum weight loss is required. These pivotal trials have pioneered the methodological and regulatory fields exploring a therapeutic agent for cancer-associated muscle wasting, a process hereby described. In each POWER trial, subjects will receive placebo ( n = 150) or enobosarm 3 mg ( n = 150) orally once daily for 147 days. Physical function, assessed as stair climb power (SCP), and LBM, assessed by dual-energy X-ray absorptiometry (DXA), are the co-primary efficacy endpoints in both trials assessed at day 84. Based on extensive feedback from the US Food and Drug Administration (FDA), the co-primary endpoints will be analyzed as a responder analysis. To be considered a physical function responder, a subject must have ≥10 % improvement in physical function compared to baseline. To meet the definition of response on LBM, a subject must have demonstrated no loss of LBM compared with baseline. Secondary endpoints include durability of response assessed at day 147 in those responding at day 84. A combined overall survival analysis for both studies is considered a key secondary safety endpoint. The POWER trials design was established with extensive clinical input and collaboration with regulatory agencies. The efficacy endpoints are a result of this feedback and discussion of the threshold for clinical benefit in patients at risk for muscle wasting. Full results from these studies will soon be published and will further guide the development of future anabolic trials. Clinical Trial ID: NCT01355484. https://clinicaltrials.gov/ct2/show/NCT01355484 , NCT01355497. https://clinicaltrials.gov/ct2/show/NCT01355497?term=g300505&rank=1 .

185 Background: Recently approved agents that target the androgen receptor pathway emphasize the importance of the persistent activity of the androgen receptor pathway in castration-resistant prostate cancer (CRPC). This raises the possibility that agents with distinct mechanisms of action may add value. GTx-758 is a selective ERα agonist that can increase SHBG and therefore reduce biologically active testosterone (T) levels. Reported here are the results, including the final primary endpoint analysis, from the 250 mg daily GTx-758 cohort of a phase II clinical trial in men on LHRH agonists that developed CRPC. Methods: This phase II open label trial (G200712, NCT01615120) treated men with high risk nmCRPC or mCRPC with T levels < 50 ng/dL who continued to receive their current form of ADT along with either 125 mg or 250 mg of GTx-758 daily, for at least 90 days. The primary endpoint was the proportion of men with a PSA decline ≥ 50% by day 90, while secondary endpoints included serum total and free T, sex hormone binding globulin (SHBG), bone turnover markers and hot flashes. Results: The 250 mg cohort (n = 39) has completed the time period for assessment of the primary endpoint. Ten of the 39 (26%) subjects exhibited a ≥ 50% decrease in PSA by Day 90, with 11/39 (28%) by Day 120, while 18/39 (46%) had PSA declines of ≥ 30%. Median SHBG levels increased 301% of baseline, confirming the principal mechanism of drug action. While on study, median free T decreases of 44% were observed across all subjects and 20/26 (77%) of the subjects with baseline serum free T levels > 0.7 pg/ml fell below this level. Therefore, 250 mg GTx-758 decreased free testosterone levels in an additive fashion to their existing LHRH therapy. The bone turnover biomarker, C-telopeptide, decreased in 79% of the subjects. 250 mg of GTx-758 has been generally well tolerated with two reported possibly drug related SAEs (VTE and MI). Conclusions: In this phase II trial, 250 mg daily GTx-758 has activity, likely mediated by lowering free T levels in patients with CRPC on LHRH therapy, and may provide amelioration of estrogen deficiency side effects associated with ADT. Clinical trial information: NCT01615120.

Background: Historically, androgens have been utilized for the treatment of BC as the androgen receptor (AR) is the most highly expressed steroid receptor (∼95% in estrogen receptor positive (ER+), ∼50% in ER negative). However, steroidal androgens often exhibit virilizing side effects, thus limiting clinical use. A non-steroidal, tissue-selective, AR modulator (SARM), GTx-024, offers a targeted approach of AR activation in ER+/AR+ BC without virilization or estrogenic effects. A previous Phase 2 study of 9 mg GTx-024 in MET ER+ BC demonstrated proof-of-concept, with 6/17 ER+/AR+ patients (pts) exhibiting clinical benefit (CB) following 6 months (m) of treatment. Increasing the dose to 18 mg has the potential for greater efficacy without compromising safety. Trial Design: Open label, multinational, randomized, parallel design Phase 2 study to assess the efficacy and safety of GTx-024 in PM ER+/AR+ BC. Pts will be randomized to receive GTx-024, 9 mg or 18 mg orally (PO) daily. Therapy continues until disease progression. Pts achieving a CB can be treated for 12 m following the initiation of study treatment; those demonstrating continued CB are offered continuation in a safety extension study under a separate protocol. Eligibility Criteria: Inclusion: Informed consent, female, ≥18 years (yr), PM, MET or LA ER+ (≥1% staining) BC, HER2 negative, ≥1 prior hormonal treatment for BC (≥6 m response for MET; ≥3 yr response for adjuvant), provide archived tumor tissue for AR determination, measurable or bone-only disease, evidence of PD within 30 days (d), ECOG 0 or 1. Exclusion: u003e1 prior chemotherapy regimen for MET, uncontrolled CNS metastases, radiotherapy ≤14d prior to enrollment, major surgery ≤28d prior to enrollment, currently receiving hormone replacement, hepatitis B/C positive, HIV positive, another active cancer. Specific Aims: Primary endpoint: proportion of AR+ pts in each arm achieving a CB response (CBR) at 24 weeks (wks). CBR defined as pts with a complete response (CR), partial response (PR), or stable disease (SD); per modified RECIST 1.1. Secondary endpoints: objective response rate, progression free survival, time to progression, and duration of response. Statistical Methods: Simon9s two-stage (optimal) design will be used to assess primary efficacy, requiring up to 88 evaluable pts; i.e., pts with centrally confirmed AR+ who receive at least one dose of study drug. The trial will test for an unacceptably low CBR of ≤10% versus a CBR ≥30%. There is no intent to statistically compare the two dose arms, but to determine whether either or both doses result in an acceptable CBR. Target Accrual: Up to 118 pts will be enrolled. The first stage will be assessed in each arm among the first 18 evaluable pts. If at least 3/18 exhibit CB at 24 wks, then the arm will proceed to the second stage of recruitment up to a total of 44 pts. Otherwise, the arm will be discontinued for lack of efficacy. Trial Information: www.gtxinc.com Citation Format: Overmoyer B, Rugo H, Schwartzberg L, Palmieri C, Taylor R, Hancock M, Small S, Johnston MA. Phase 2 open label, multinational, randomized, parallel design study investigating the efficacy and safety of GTx-024 on metastatic (MET) or locally advanced (LA) ER+/AR+ breast cancer (BC) in postmenopausal (PM) women. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT2-01-06.

201 Background: LHRH agents used for androgen deprivation therapy (ADT) were intended to lower total testosterone (T) levels to those achieved by orchiectomy. Studies have now demonstrated that a significant percentage of men do not reach orchiectomy equivalent levels and that lower serum T levels correlate with improved outcomes. GTx-758 (Capesaris®) is an oral estrogen receptor α agonist that has the potential to increase sex hormone binding globulin (SHBG), lower T levels, and ameliorate estrogen deficiency side effects associated with ADT. Methods: In an ongoing Phase 2 open label study (G200712, NCT01615120), men with high risk nmCRPC and mCRPC were continued on their current form of ADT along with either 125 mg or 250 mg of GTx-758 daily, for at least 90 days. Men at increased risk for venous thromboembolic events (VTE) are being excluded. The primary endpoint of this trial is the proportion of men with a PSA decline ≥50%, while secondary endpoints include serum total and free T, SHBG, bone turnover and hot flashes. Results: As of October 2014, the 250 mg cohort of GTx-758 has completed enrollment of 28 patients, 20 of which (1 nmCRPC and 19 mCRPC) are evaluable, having been on study ≥90 days. The principal mechanism of drug action, induction of SHBG is confirmed in these patients with median SHBG levels increasing to 297% of baseline. 250 mg GTx-758 impacts T levels in an additive fashion to LHRH agents, as while on study, 4/4 subjects with total T levels >20 ng/dL have fallen below that level and 9/10 subjects with serum free T levels >0.7 pg/ml have fallen below that level. Six of the 20 (30%) subjects have exhibited a ≥50 decrease in PSA level while 17/20 (85%) had PSA declines of varying magnitude. The bone turnover biomarker C-telopeptide decreased in 81% of the subjects. 250 mg of GTx-758 has been generally well tolerated with one reported possibly drug related SAE (VTE). Conclusions: While the Phase 2 clinical trial is ongoing, these preliminary findings indicate that 250 mg of GTx-758 is generally well tolerated and has additive activity to LHRH agents to further decrease testosterone, increase SHBG, lower PSA and decrease bone turnover. Clinical trial information: NCT01615120.

e16020 Background: LHRH agents used for androgen deprivation therapy (ADT) were intended to lower total testosterone (T) levels to those achieved by orchiectomy. Studies have now demonstrated that a significant percentage of men do not reach orchiectomy equivalent levels and that lower serum T levels correlate with improved outcomes. GTx-758 (Capesaris) is an oral estrogen receptor α agonist that has the potential to increase sex hormone binding globulin (SHBG), lower T levels, and ameliorate estrogen deficiency side effects associated with ADT. Methods: In an ongoing Phase 2 open label study (G200712, NCT01615120), men with high risk nmCRPC and mCRPC were continued on their current form of ADT along with either 125 mg or 250 mg of GTx-758 daily, for at least 90 days. The primary endpoint of this trial is the proportion of men with a PSA decline ≥ 50%, while secondary endpoints include serum total and free T, SHBG, bone turnover and hot flashes. Results: As of February 2015, the 250 mg cohort of GTx-758 has completed enrollment of 33 patients, 25 of which (1 nmCRPC and 24 mCRPC) are evaluable, having been on study ≥ 90 days. 250 mg GTx-758 impacts T levels in an additive fashion to LHRH agents, as while on study, 3/3 subjects with total T levels > 20 ng/dL have fallen below that level and 11/13 subjects with serum free T levels > 0.7 pg/ml have fallen below that level. The median serum free T level on day 1 is 1.20 ± 1.71 pg/ml whereas at day 90, the level is 0.40 ± 0.49 pg/ml, a 58% decrease from baseline (p < .0001). A major mechanism of drug action, induction of SHBG is confirmed in these subjects, with median SHBG levels increasing to 268% of baseline. Seven of the 25 (28%) subjects have exhibited a ≥ 50% decrease in PSA levels while 11/25 (44%) had PSA declines of ≥ 30%. 250 mg of GTx-758 has been well tolerated with one reported possibly drug related SAE (VTE). Conclusions: While the Phase 2 clinical trial is ongoing, these preliminary findings indicate that 250 mg of GTx-758 is generally well tolerated and has activity in men with CRPC on LHRH agents to further decrease total and free T, increase SHBG, and lower PSA. Clinical trial information: NCT01615120.

Abstract Background: Historically, androgens have been utilized for the treatment of breast cancer (BC) as the androgen receptor (AR) is the most highly expressed steroid receptor in BC (75-95% of estrogen receptor positive (ER+) and 50% of ER negative). Reports of the use of androgens in metastatic BC (MBC) indicate that women progressing on tamoxifen have the ability to respond to synthetic androgens with overall response rates in the range of 20-60%; however, these steroidal androgens also exhibit virilizing side effects, thus limiting clinical use. A non-steroidal, tissue-selective, AR modulator (SARM), such as enobosarm, offers a targeted approach of AR activation without virilization or estrogenic effects. Methods: This is a phase II proof of concept study examining the efficacy and safety of once daily enobosarm 9 mg in post-menopausal women with ER+ MBC who had responded to adjuvant and/or salvage endocrine therapy. Therapy is continued until patients display evidence of disease progression. The proportion of AR+ patients with clinical benefit response (CBR) at 6 months is the primary endpoint; defined as patients with a complete response (CR), partial response (PR), or stable disease (SD) as detailed in modified RECIST 1.1. AR status of metastatic disease will be correlated with CBR. Serum prostate specific antigen (PSA) will be assessed as a biomarker of AR activation by drug. Secondary endpoint is progression free survival (PFS). Results: Patient demographics: mean age 63.7 years, mean time from diagnosis 11.0 years, 72.7% prior chemotherapy, 89% (17/19) AR+. After a median follow-up of 81 days (range 7-304 days), preliminary results of 22 patients: 9 SD as best response, median duration 212 days. Current disposition of patients: 15 PD after a median 80 days (range 15-304 days), 4 SD (1 on treatment for < 6 months), and 3 early discontinuations (days 7, 28, 255). Five patients have died due to PD off study. Among the 17 evaluable patients, 6 reached the primary endpoint (35.3%; 95% CI=16.6% to 59.4%) with increased PSA, thereby exceeding the pre-defined statistical threshold requiring that at least 3 of 14 patients with an AR+ metastatic lesion demonstrate clinical benefit. CR or PR has not been observed. Current six month Kaplan-Meier estimate of PFS is 43.8% (95% confidence interval=19.5% to 68.1%). Enobosarm is well-tolerated with common grade 1/2 toxicities of nausea (8%), menopausal symptoms (13%), pain (25%), fatigue (10%), weight change (4%); 5 (4%) grade 3 toxicities (3 unrelated to drug, 1 bone pain, 1 fatigue), and no grade 4 or higher toxicities reported. Final results of the study will be available in the fourth quarter of 2014. Conclusions: Enobosarm demonstrates promise as a novel endocrine agent for AR+ MBC. The primary endpoint has been achieved, with 6/17 AR+ patients meeting statistical threshold for success (35% CBR at 6 months). Serum PSA appears to be a surrogate marker for AR activity associated with enobosarm administration. Based upon these favorable preliminary findings, a larger phase II study is anticipated. Citation Format: Beth Overmoyer, Pedro Sanz-Altimira, Ann H Partridge, Martine Extermann, Jane Liu, Eric Winer, Nancy Lin, Michael Hassett, Leroy Parker, Ryan Taylor, Michael Hancock, Susan Small, Mary Ann Johnston. Enobosarm for the treatment of metastatic, estrogen and androgen receptor positive, breast cancer. Final results of the primary endpoint and current progression free survival [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-13-04.

568 Background: The androgen receptor (AR) is the most highly expressed steroid receptor in breast cancer (BC) with 75-95% of estrogen receptor positive (ER+) and 50% of ER negative BCs expressing AR. Prior studies have shown that women with metastatic BC (MBC) who are progressing on tamoxifen subsequently respond to non-tissue-selective, synthetic androgens with overall response rates of 20-60%. Unfortunately steroidal androgens have unwanted virilizing effects which limit clinical use. Enobosarm, a nonsteroidal, tissue-selective, AR modulator (SARM), provides a novel targeted approach to exploit the therapeutic benefits of AR activation without virilization or estrogenic effects. Methods: A proof of concept, phase II study is examining efficacy and safety of enobosarm 9mg daily in 22 postmenopausal women with ER+ MBC who previously responded to adjuvant and/or salvage endocrine therapy. Treatment continues until disease progression (PD). Primary endpoint is clinical benefit response (CBR) by 6 months (m) defined as patients (pts) having a complete response (CR), partial response (PR), or stable disease (SD). CBR will be correlated with AR status of metastatic tumor biopsy. Serum prostate specific antigen (PSA) will be evaluated as a biomarker of AR activity. Results: Pt demographics: mean age 63.7 years, mean time from diagnosis 11 years, 68% prior chemo, 94% (15/16) AR+. After a median f/u of 85 days (d) (range 84-209d), preliminary results of 16 pts: 8 SD as best response, median duration 4.5m; 9 PD after a median 84d. Among pts who reached 6m, 3 are AR+ with SD and increased PSA. 7 have yet to reach 6m and no CR or PR has been observed. Enobosarm is well-tolerated, with no drug related serious adverse events. Conclusions: Enobosarm is well tolerated and demonstrates promise as a novel targeted therapy for AR+ MBC. The primary endpoint has been achieved, with 3/15 AR+ pts meeting statistical threshold for success. Serum PSA appears to be a surrogate marker for AR activity and disease response. Final analysis is due in June 2014. Clinical trial information: NCT01616758.

60 Background: Luteinizing hormone-releasing hormone (LHRH) agents used for androgen deprivation therapy (ADT) were designed to lower total testosterone (T) levels to those achieved by orchiectomy for palliative care of advanced prostate cancer. This castration equivalent level was based upon the lower limits of quantitation (50ng/dL) of outdated assays. Contemporary assays reveal that actual total T levels in men after orchiectomy are significantly lower (<20ng/dL), with 30 to 40% of men on LHRH agonists not achieving that level. There is growing literature showing that lower T levels correlate with improved outcomes. Additionally, the biologically active form of T is unbound, free T. GTx-758 (Capesaris) is an oral estrogen receptor α agonist that increases sex hormone binding globulin (SHBG), lowers free T levels, and ameliorates estrogen deficiency side effects associated with ADT. Methods: In a phase II open label study (G200712), 38 men with metastatic castration resistant prostate cancer (mCRPC) were continued on their current form of ADT along with a low dose of GTx-758, 125 mg, for at least 90 days. Exclusion criteria included men at increased risk for venous thrombolic events (VTE). Results: The initial 14 patients in this trial completed 90 days on study and are evaluable for select trial endpoints. All treated men had a greater than or equal to a 150% increase in SHBG levels. Eleven of the 14 men began the study with suboptimal castration (free T >0.7 pg/ml) and 91% (10 out of 11) of these men became optimally castrated by day 90. Four out of 14 patients had a more than 45% decrease in prostate-specific antigen. Stable or improved hot flashes and bone turnover markers were observed in 71% and 73% of treated men, respectively. While some patients experienced adverse events, none were vascular related and there were no serious adverse events or VTEs. Conclusions: The majority of patients on an LHRH agonist enrolled in this phase II study had suboptimal levels of free T that were further lowered by GTx-758 administration. GTx-758 treatment resulted in stabilization and/or improvement in reported hot flashes and bone turnover, two major side effects of ADT. While the phase II clinical trial is ongoing, and full results are forthcoming, these preliminary findings show that 125 mg of GTx-758 has clinical effectiveness and is well tolerated. Exploration of 250 mg a day is planned. Clinical trial information: NCT01615120.

You have accessJournal of UrologyProstate Cancer: Advanced II1 Apr 2014MP70-17 OPTIMAL TESTOSTERONE SUPPRESSION ON MEDICAL ANDROGEN DEPRIVATION THERAPY SHOULD STRIVE TO SUPPRESS FREE TESTOSTERONE LEVELS, TO LEVELS SIMILAR TO ORCHIECTOMY--WHAT IS THAT VALUE? Evan Yu, Robert Getzenberg, Jordan Smith, Michael Hancock, Matthew Smith, S Bruce Malkowixz, Paul Sieber, James Dalton, and Mitchell Steiner Evan YuEvan Yu More articles by this author , Robert GetzenbergRobert Getzenberg More articles by this author , Jordan SmithJordan Smith More articles by this author , Michael HancockMichael Hancock More articles by this author , Matthew SmithMatthew Smith More articles by this author , S Bruce MalkowixzS Bruce Malkowixz More articles by this author , Paul SieberPaul Sieber More articles by this author , James DaltonJames Dalton More articles by this author , and Mitchell SteinerMitchell Steiner More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.2215AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES 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. Literature shows that based on more modern assays, medical ADT does not always provide optimal testosterone suppression equivalent to orchiectomy. With the understanding that free, or unbound, testosterone is the biologically and clinically relevant component, the therapeutic goal of ADT should be to decrease free testosterone to levels similar to orchiectomy. Free testosterone 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 testosterone 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 US and Mexico. Baseline characteristics, including whether men were on medical ADT or status post orchiectomy, were available. Serum free testosterone 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 years (range 51-90). Median serum free testosterone 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 serum free testosterone levels have been reported in men who underwent orchiectomy. In this cohort, median serum free testosterone is approximately 0.9 pg/ml. This value could be considered to be the optimal testosterone suppression of free testosterone 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 serum free testosterone levels by 20-60%. 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 testosterone in treating advanced prostate cancer. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e812 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Evan Yu More articles by this author Robert Getzenberg More articles by this author Jordan Smith More articles by this author Michael Hancock More articles by this author Matthew Smith More articles by this author S Bruce Malkowixz More articles by this author Paul Sieber More articles by this author James Dalton More articles by this author Mitchell Steiner More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Background: A need remains for new therapeutic approaches for men with advanced prostate cancer, particularly earlier in the disease course.Objective: To assess the ability of an oral selective estrogen receptor a agonist (GTx-758) to lower testosterone concentrations compared with leuprolide while minimizing estrogen deficiency-related side effects of androgen-deprivation therapy.Design, setting, and participants: Hormone-naive advanced prostate cancer patients were randomized to oral GTx-758 1000 mg/d, 2000 mg/d, or leuprolide depot. Intervention: GTx-758 and leuprolide. Outcome measurements and statistical analysis: The primary end point was the proportion of patients achieving total testosterone <= 50 ng/dl by day 60. Secondary end points included serum free testosterone, prostate-specific antigen (PSA), sex hormone-binding globulin, hot flashes, bone turnover markers, and insulin-like growth factor (IGF)-1 levels.Results and limitations: Of 159 randomized patients, leuprolide reduced total testosterone to <= 50 ng/dl in a greater proportion of patients than GTx-758 by day 60 (43.4%, 63.6%, and 88.2% of subjects receiving GTx-758 1000 mg [p < 0.001], GTx-758 2000 mg [p = 0.004], and leuprolide, respectively). GTx-758 reduced free testosterone and PSA earlier and to a greater degree than leuprolide. GTx-758 led to fewer hot flashes, decreases in bone turnover markers, and alterations in IGF-1 compared with leuprolide. A higher incidence of venous thromboembolic events (VTEs) was seen with GTx-758 (4.1%) compared with leuprolide (0.0%). Conclusions: Although leuprolide reduced total testosterone to <= 50 ng/dl in a greater proportion of patients compared with GTx-758, GTx-758 was superior in lowering free testosterone and PSA. GTx-758 reduced estrogen deficiency side effects of hot flashes, bone loss, and insulin resistance but with a higher incidence of VTEs.Patient summary: This paper reports findings that leuprolide lowered total testosterone more than GTx-758 but that GTx-758 lowered free testosterone and prostate-specific antigen more than leuprolide. GTx-758 also reduced estrogen deficiency side effects, albeit at a higher rate of vascular events.Trial registration: Clinicaltrials. gov identifier NCT01615120. (C) 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.