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5049 Background: Sabizabulin is a novel oral cytoskeleton disruptor being developed for use in metastatic castration resistant prostate cancer (mCRPC). A Phase 1b/2 clinical study was conducted to establish the maximum tolerated dose (MTD) and evaluate the preliminary efficacy in men with mCRPC resistant to androgen receptor targeting agents. Methods: The Phase 1b portion of the study in 39 men utilized escalating and expanding dose and duration. The Phase 2 portion studied 41 men with mCRPC at the recommended Phase 2 dose of 63 mg daily. Efficacy was assessed by bone/CT scans. A final analysis of the safety and efficacy data including the primary endpoint, the median progression-free survival was conducted. Results: Although the MTD was not reached in the Phase 1b, the recommended Phase 2 dose was set at 63 mg/day to maximize GI tolerability. The most common adverse events (> 10% frequency) at the 63 mg oral daily dosing (combined Phase 1b/2 data) were predominantly Grade 1-2. Grade ³3 events included diarrhea (7.4%), fatigue (5.6%) and ALT/AST elevations (5.6% and 3.7%, respectively). Neurotoxicity and neutropenia were not observed. Preliminary efficacy data in patients treated with ≥1 continuous cycle (21 days) of 63 mg or higher (n = 55) included an objective response rate of 6/29 (20.7%) in patients with measurable disease (1 complete, 5 partial). 14/48 (29.2%) of the patients had PSA declines. The Kaplan-Meier median radiographic progression-free survival was estimated to be 11.4 months (95% C.I. 29.63-65.79) (n = 55). Durable responses lasting > 2.75 years were observed with 14.5% (8/55) demonstrating a response greater than 12 months. Conclusions: This clinical trial demonstrated that chronic oral daily dosing of sabizabulin has a favorable safety profile with significant preliminary cytotoxic and cytostatic antitumor activity. These data support the ongoing Phase 3 VERACITY trial of sabizabulin in men with mCRPC who have progressed on an androgen receptor targeting agent. Clinical trial information: NCT03752099.

TPS1121 Background: Targeting the androgen receptor (AR) may be the next important endocrine therapy for advanced breast cancer. The AR has been demonstrated to be a tumor suppressor when activated. Enobosarm is an oral selective AR targeting agonist that activates the AR in breast cancer. Preclinical studies in CDK4/6 inhibitor resistant PDX models demonstrated combinatorial synergistic activity of enobosarm plus CDK 4/6 inhibitors. An open-label, Phase 2 study, was conducted in 136 women with heavily pretreated ER+ HER2- metastatic breast cancer that were randomized to oral daily enobosarm at a dose of 9 or 18 mg. The efficacy evaluable (EE) group were patients that were AR positive (> 10% AR nuclear staining). In the EE population with measurable disease at baseline, 10 patients had received prior endocrine therapy + a CDK 4/6 inhibitor. Subsequent treatment with enobosarm resulted in a clinical benefit rate of 50% and the best overall response rate (ORR) was 30% (2CRs and 1 PR). Of the 10 patients, 7 had AR nuclear staining ≥40%. None of the patients with AR nuclear staining < 40% responded to enobosarm. Although a small subset of the study, it appears that enobosarm has activity in patients who had ≥40% AR staining and who had progressed on standard endocrine therapy with a CDK 4/6 inhibitor. Overall, treatment with enobosarm was well tolerated with significant positive effects on quality-of-life measurements. Methods: The ENABLAR-2 trial is an ongoing Phase 3, randomized, open-label, efficacy and safety study in patients with AR+ ER+ HER2- MBC with AR nuclear staining of ≥40%, who have progressed after one line of systemic therapy comprising estrogen blocking agent and palbociclib. The planned sample size is 186 patients randomized 1:1 to enobosarm + abemaciclib OR fulvestrant if the first line of therapy for MBC was a non-steroidal AI plus palbociclib, until disease progression, toxicity, or loss of clinical benefit. If first line therapy for metastatic breast cancer was fulvestrant plus palbociclib, then the patient will be randomized 1:1 to either enobosarm + abemaciclib OR an AI. Randomization will be stratified by AR% nuclear staining, ≥60% versus < 60%, as well as by estrogen blocking agent such that each cohort will have the same number of subjects previously receiving fulvestrant + palbociclib in first line therapy. The key objectives are to determine the safety and efficacy of enobosarm and abemaciclib combination versus an alternative estrogen blocking agent with the primary endpoint of PFS. Secondary endpoints include ORR, duration of response, overall survival, change from baseline in Short Physical Performance Battery (SPPB), change in EORTC Quality of Life Questionnaire (EORTC-QLQ) and change in body composition as measured by DEXA. Clinical trial information: NCT05065411.

TPS5102 Background: Sabizabulin is a first-in-class, oral agent that inhibits microtubule polymerization disrupting the cytoskeleton and arresting cellular proliferation. A Phase 1b/2 clinical study was conducted to establish the MTD and evaluate the preliminary efficacy in men with metastatic castrate resistant prostate cancer (mCRPC) who progressed on at least one androgen receptor targeting agent (ARTA). The most common AEs reported were mild to moderate diarrhea, fatigue, nausea, and vomiting with no clinically relevant neurotoxicity or neutropenia. In the Phase 1b/2, the median radiographic progression free survival for the 63mg dose (n = 55) was 11.4 months (range 6-36+ months) in the Phase 1b portion including responses > 2.75 years. The Phase 3 reformulation which had improved bioavailability is 32mg PO qd. Methods: VERACITY is an ongoing Phase 3 multicenter, randomized, active-control study designed to evaluate sabizabulin in the treatment of mCRPC who have progressed on at least one ARTA. Patients on the study will be chemotherapy naive. Subjects (n = 245) are being randomized in a 2:1 ratio to receive sabizabulin (32 mg/d oral) or active control (alternative ARTA) and will remain on study until radiographic progression-free survival (rPFS). Randomization will be stratified by: measurable disease vs bone-only disease and by prior exposure to ARTA (progressed on one vs more than one prior ARTA). The primary efficacy endpoint of the study is median rPFS. Secondary endpoints include: objective response rate (ORR), duration of objective response, overall survival and time to intravenous (IV) chemotherapy. The Phase 3, VERACITY registration clinical trial is current ongoing in approximately 45 clinical sites with enrollment anticipated to be completed in 2022 and with unblinded results presented in 2023 Based upon the Phase 1b/2 clinical trial, sabizabulin daily chronic oral dosing has a favorable safety profile, is feasible to administer chronically, and has significant and durable antitumor activity. mCRPC that has progressed following ARTAs and prior to taxane chemotherapy, remains an urgent unmet medical need for patients with advanced disease. Sabizabulin is an exciting first-in-class agent that may add to the armamentarium for the treatment of mCRPC following progression on ARTA’s. Clinical trial information: NCT04844749.

TPS217 Background: Sabizabulin is a first-in-class, oral agent that inhibits microtubule polymerization disrupting the cytoskeleton and arresting cellular proliferation. In prostate cancer, targeted inhibition of microtubule polymerization further blocks the transport of the androgen receptor into the nucleus. A phase 1b/2 clinical study was conducted to establish the MTD and evaluate the preliminary efficacy in men with metastatic castrate resistant prostate cancer (mCRPC) who progressed on at least one androgen receptor targeting agent (ARTA). The most common AEs reported were mild to moderate diarrhea, fatigue, nausea, and vomiting with no clinically relevant neurotoxicity or neutropenia. In the phase 1b/2, in all evaluable patients that would qualify for the VERACITY study (n=26), the ORR was 23.1%. Median radiographic progression free survival was >12 months (range 6-28+ months) in the phase 1b portion including responses >two years. The revised formulation for use in the Phase 3 study, with improved bioavailability, is 32mg PO qd. Methods: VERACITY is an ongoing phase 3 multicenter, randomized, active-control study designed to evaluate sabizabulin in the treatment of mCRPC who have progressed on at least one ARTA. Patients on the study will be chemotherapy naive. Subjects (n=245) are being randomized in a 2:1 ratio to receive sabizabulin (32 mg/d oral) or active control (alternative ARTA) and will remain on study until radiographic progression-free survival (rPFS). Randomization will be stratified by: measurable disease vs. bone-only disease and by prior exposure to ARTA (progressed on one vs more than one prior ARTA). The primary efficacy endpoint of the study is median rPFS. Secondary endpoints include: objective response rate (ORR), duration of objective response, overall survival and time to intravenous (IV) chemotherapy. The phase 3, VERACITY registration clinical trial is current ongoing in approximately 45 clinical sites with enrollment anticipated to be completed in 2022 and with unblinded results presented in 2023. Based upon the phase 1b/2 clinical trial, sabizabulin daily chronic oral dosing has a favorable safety profile, is feasible to administer chronically, and has significant and durable antitumor activity. Metastatic prostate cancer that has become refractory to newer generation ARTAs and prior to IV chemotherapy, remains an urgent unmet medical need for patients with advanced disease. Sabizabulin is an exciting first-in-class agent that will add to the armamentarium for the treatment of metastatic castration and ARTA resistant prostate cancer. Clinical trial information: NCT04844749.

110 Background: Sabizabulin is a novel oral cytoskeleton disruptor being developed for use in metastatic castration resistant prostate cancer (mCRPC). A phase 1b/2 clinical study was conducted to establish the maximum tolerated dose (MTD) and evaluate the preliminary efficacy in men with mCRPC resistant to androgen receptor targeting agents (ARTAs). Methods: The phase 1b portion of the study in 39 men utilized escalating and expanding dose and duration. The phase 2 portion studied 41 men with mCRPC at the recommended phase 2 dose (RP2D) of 63 mg daily. Based upon the phase 1b/2 data, sabizabulin appears to have both cytotoxic and cytostatic activity. A analysis was conducted evaluating the best clinical response (BCR) defined as either an objective response assessed by PCWG3 criteria and/or stable disease defined as ≥5 cycles (≥15 weeks) of continuous treatment. Results: Of the combined 80 patients in the phase 1b/2 portions of the study, the BCR was 37.5% (30/80) and 5 of the responders remain on study with the longest being treated for more than 30 months. Of the patients with measurable disease at study entry, the BCR was 59% (17/29). Prior to study entry, 11/30 (37%) of those with a BCR had previously been treated with and subsequently progressed on a minimum of 2 ARTAs. The remaining 19/30 (63%) had progressed on a single ARTA agent. 11 (37%) were previously treated with enzalutamide or apalutamide and 8 (27%) with abiraterone as single agents. 8 (27%) received enzalutamide and abiraterone and 3 (10%) patients received more than two ARTAs. As described previously, the safety profile continues to be favorable with no clinically relevant neutropenia or neurotoxicity. Conclusions: In this analysis, sabizabulin has demonstrated not only cytotoxic, but also significant cytostatic activity with similar responses in men that have progressed on a single or multiple ARTA agents. Sabizabulin is a novel agent with the potential provide men with mCRPC a well-tolerated chronic treatment cytostatic option after progressing on an ARTA and is being tested in the open phase 3 VERACITY trial. Clinical trial information: NCT03752099.

5056 Background: VERU-111 is an oral cytoskeletal disruptor that disrupts microtubules supporting the cytoskeleton and has no affinity for multidrug resistance proteins. A phase 1b/2 clinical study has been conducted to establish the maximum tolerated dose (MTD) and evaluate the preliminary efficacy in men with mCRPC also resistant to androgen receptor targeting agents. Methods: In the phase 1b component of the study, a 3+3 design with escalating oral dosing of 4.5 mg to 81 mg (7 days on drug/14 days off per 21-day cycle) was utilized. The schedule was also expanded to continuous dosing/cycle. The phase 2 portion utilized 63 mg daily dosing to evaluate efficacy in approximately 40 taxane-naïve men with mCRPC that have failed at least one androgen receptor targeting agent. Results: In the phase 1b portion of the study, 30 taxane-naïve men with mCRPC and a median age of 76 (61-92) were enrolled. 8 had received prior enzalutamide, 12 abiraterone and 10 both. 8 men had bone mets, 5 lymph node, 5 mixed and 1 had soft tissue metastases at study entry. The MTD of VERU-111 is 72mg (3/11 men had grade 3 diarrhea) and the recommended phase 2 dose is 63mg. Grade 3 diarrhea was not observed at doses ≤ 63mg per day and the most common non-dose limiting AEs were mild to moderate nausea, vomiting, diarrhea, and fatigue, with no observed neurotoxicity or neutropenia. Efficacy was assessed by PSA and bone/CT scans. In men treated for ≥ 4 continuous 21-day cycles, 6/10 (60%) had PSA declines, 4(40%) men had ≥ 30% declines and 2(20%) ≥ 50% declines compared to their 21-day cycle baseline PSA. Median PFS is currently 12 months (6-23+ months) with 3 patients continuing on study, 2 of which have been on study for approximately 2 years. In patients receiving at least a single dose of ≥ 63 mg daily (n=19), objective tumor responses were seen in 3 men (16%). The median rPFS in these patients is currently 12.4 months. In the phase 2 portion of the study, 55% of the patients had bone only metastases, 11% had nodal only, 32% had mixed bone and nodal disease and 3% had visceral disease at study entry. 6/32 (19%) were previously treated with abiraterone alone, 12/32 (38%) with enzalutamide alone, and 14/32 (44%) had abiraterone in combination with enzalutamide, proxalutamide or apalutamide. The phase 2 portion of the study is ongoing and objective tumor responses have been observed including a CR and PRs and PSA decreases >50%. Patients have been on study as long as 9 months. Conclusions: This phase 1b/2 clinical trial, demonstrates that oral daily dosing of VERU-111 has a favorable safety profile and that chronic dosing is feasible. The recommended phase 2 dose of 63mg daily has significant durable antitumor activity. These data support a potential prominent role of VERU 111 for the treatment of men with mCRPC who previously failed an androgen receptor targeting agent and prior to the administration of intravenous chemotherapy. Clinical trial information: NCT03752099.

1020 Background: The AR is expressed in up to 90% of ER+ breast cancer where it acts as a tumor suppressor. Historically, therapy with synthetic androgens had efficacy, but virilizing side effects and toxicity limited their use. Enobosarm is a selective AR activating agent that does not cause masculinization and has positive attributes such as promotion of bone and improvement of physical function. In a phase 2 study, correlation between the degree of AR staining and antitumor activity in AR+/ER+ patients with metastatic breast cancer (MBC) was examined. Methods: A phase 2, open label, parallel design randomized study was conducted in 136 patients to evaluate the efficacy and safety of enobosarm in heavily pretreated women with AR+/ER+ MBC. Patients were randomized to 9 mg (n=72) or 18 mg (n=64) of oral daily enobosarm. AR expression (%AR nuclei staining) in breast cancer samples was determined centrally by immunohistochemistry. The correlation between %AR staining and clinical outcomes was examined with a focus on the 9mg dose, selected for the phase 3 study and the optimal %AR staining established. Results: Tumor objective outcomes correlated with percent AR staining (Table). Further, using a 40% AR staining cutoff in patients with measurable disease, the clinical benefit rate (CBR) for ≥40% AR is 80% and

131 Background: VERU-111 is an oral, cytoskeletal disruptor that crosslinks α & ß tubulin and inhibits microtubule polymerization with no affinity for multidrug resistance proteins. A Phase 1b/2 clinical study has been conducted to establish the maximum tolerated dose (MTD) and evaluate the preliminary efficacy in men with progressive mCRPC resistant to androgen receptor targeting agent (ARTA). Methods: In the Phase 1b portion of the study, a 3+3 design with escalating oral dosing of 4.5 - 81 mg (7 days on drug/14 days off per 21 day cycle) was utilized. After no dose limiting toxicity was observed, the dose was increased in the next cohort. The schedule was also expanded in those completing the 7 days on/14 days off cycle to continuous dosing/cycle. The recommended Phase 2 study dose is 63 mg daily and the trial is fully enrolled with 40 taxane-naiive men with mCRPC that have failed at least one ARTA. Results: In the Phase 1 portion of the study, 30 taxane-naïve mCRPC men with a median age of 76 (61-92) were enrolled. 8 received prior enzalutamide, 12 abiraterone and 10 both. 8 men had bone mets, 5 lymph node, 5 mixed and 1 had soft tissue metastases. The MTD of VERU-111 is 72mg (3 /11 men had Grade 3 diarrhea). No Grade 3 diarrhea was observed at doses < 72 mg per day. At doses < 72mg/d, the most common AEs were mild to moderate nausea, vomiting, diarrhea, and fatigue, with no observed neurotoxicity or neutropenia. In the Phase 1b, antitumor activity was assessed by PSA and bone/CT scans in men that were treated for ≥ 4 continuous 21-day cycles. 6/10 (60%) had PSA declines: 4 (40%) men had ≥ 30% and 2(20%) ≥ 50% declines compared to their 21 day cycle baseline. Based on PCWG3/RECIST 1.1 criteria, objective tumor responses were seen in 2 men (soft tissue and bone). Median duration of response is 11 months (6-18+ months). In the Phase 2 portion of the study, 49% had bone only metastases, 54% have bone only metastases, 11% have nodal disease, 32% had mixed bone and nodal disease and 3% had visceral disease. This portion of the study is ongoing and results will be reported. 9/29 (31%) had previously abiraterone, 10/29 (34%)( enzalutmide, 7/29 (24%) both enzalutmide and abiraterone and 4/29 (14%) apalutamide. Conclusions: Based upon this Phase 1b/2 clinical trial, oral VERU-111 has a favorable safety profile allowing for chronic administration and significant and durable antitumor activity. The daily dose of 63mg is being tested in the fully enrolled Phase 2 portion. Oral administration, safe long-term treatment and evidence of antitumor activity highlight a potential prominent role of VERU 111 for the treatment of men with mCRPC who failed an androgen receptor targeting agent. Clinical trial information: NCT03752099.

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.

235 Background: Androgen Deprivation Therapy (ADT) is a mainstay in the treatment of advanced prostate cancer. ADT-induced estrogen deficiency related side effects may cause men to delay, pause, or discontinue ADT, increases morbidity and mortality, and can significantly impact quality of life. ADT-induced effects include hot flashes, bone loss and fractures, fatigue, decreased libido, and metabolic and lipid changes. Currently there are no FDA approved treatments for ADT-induced hot flashes in men with advanced prostate cancer. In this study, a survey was conducted on the impact of hot flashes, one of the hallmark ADT-induced estrogen deficiency effects, in a contemporary cohort. Methods: During the period of August/September 2019, 212 men with advanced prostate cancer on ADT participated in a digital survey conducted by the Prostate Cancer Research Institute (PCRI) focused on the frequency, severity and impact of their hot flashes. The men were at least 50 years of age with 61% being 70 or older. ADT types included LUPRONÒ(64%), ELIGARDÒ(12%), ZOLADEXÒ(7%) and other forms of hormonal therapy (17%). Results: Of the 212 men surveyed, 99% reported hot flashes with 80% indicating that they experience clinically significant, moderate to severe hot flashes. 77% of men reported that the number of hot flashes stayed the same or increased during their hormonal therapy. 37% of the men experienced more than 5 hot flashes per day and 23% indicated that they felt embarrassed about their hot flashes. Only 51% had either researched how to address their hot flashes or discussed them with their physician. Importantly, 16% considered halting ADT as a result of their hot flashes. Conclusions: This contemporary survey underscores the significant unmet medical need to treat moderate to severe hot flashes which occurred in 80% of the men studied. As about half of the men have not discussed their symptoms with a physician either because of embarrassment or lack of treatment options, the number of men with moderate to severe hot flashes appears to be greatly under-reported. As men on ADT are living longer with prostate cancer, finding an effective and safe treatment for debilitating hot flashes must be a priority.

299 Background: A dose limiting toxicity of taxane chemotherapy, including docetaxel and cabazitaxel, is neutropenia. VERU-111 is a novel, oral aand btubulin inhibitor that blocks tubulin polymerization and is not a substrate for multi-drug resistance mechanisms. Nonclinical toxicity studies were recently performed in order to assess the effects of daily, high-dose administration of orally dosed daily VERU-111. Methods: Toxicity of VERU-111 was evaluated in a 28-day oral dosing toxicity study which was conducted in both rats and dogs. These studies were performed at an independent facility under GLP conditions. Results: In both species evaluated, at oral doses of ≤3 mg/kg/day (rat) and ≤8 mg/kg/day (dog) there were no significant observed findings of neutropenia, myelosuppression, or abnormal liver function. Conclusions: In contrast to cabazitaxel and docetaxel, which are given once every 3 weeks IV, VERU-111 given oral, daily for 28 days in toxicity studies in dog and rat did not result in neutropenia, and myelosuppression. Furthermore, VERU-111 orally each day did not affect liver function tests. These nonclinical toxicity studies provide the basis for progressing VERU-111 into a Phase 1b/2 study which targets men with metastatic castration and androgen blocking agent (abiraterone and enzalutamide) resistant prostate cancer.

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.

TPS330 Background: VERU-111 is a novel oral small molecule (NCE) that targets α and β-tubulin subunits of microtubules resulting in the inhibition of tubulin polymerization. Agents that target microtubules are among the most effective for the treatment of metastatic cancers. However, these currently available agents target only the β-tubulin subunit and are administered IV. VERU-111 has high oral bioavailability and does not interact with MDR proteins. In nonclinical models, VERU-111 has high activity against many tumor types as well as against prostate cancers that have become resistant to taxanes and novel androgen blocking agents (abiraterone and enzalutamide). In 28-day dog and rat toxicity studies, no neutropenia, myelosuppression, or liver function test changes were observed at oral daily doses in blood concentrations that resulted in antitumor activity in preclinical models. Based on these unique properties, VERU-111 has advanced into a Phase1b/2 clinical trial. Methods: V1011101 is a Phase 1b/2 study, being conducted in at least three sites in the US, evaluating the safety and preliminary efficacy of VERU-111 in men with metastatic castration and androgen blocking agent resistant prostate cancer (mCARPC). The Phase 1b portion of the study consists of 21-day cycles where VERU-111 is taken daily, orally for 7-days followed by a 14-day hiatus (dose cycle). Safety/tolerability of VERU-111 and MTD of VERU-111 will be determined. The Phase 2 will use the selected dose cycle from the Phase 1b and the primary endpoint will be the PSA50 response rate, defined as a decline in PSA to > 50% of baseline level, confirmed with a second measurement at least 3 weeks apart (PCWG3) and determine the pharmacokinetic profile of VERU-111. The secondary endpoints include determining the safety/tolerability of VERU-111 as defined as incidence of CTCAE v5.0 grade ≥3 toxicities; estimating the median PSA progression-free survival (PCWG3); estimating the median progression-free survival (PCWG3); and estimating the objective response rate. It is anticipated that based upon the Phase 1b/2 clinical findings VERU-111 will also be expanded into other cancer types.

167 Background: VERU-111 is a novel, oral α and β tubulin inhibitor that blocks tubulin polymerization and is not a substrate for multi-drug resistance. In xenograft mouse models of taxane responsive and resistant cancers, VERU-111 results in tumor inhibition at ≤20 mg/kg orally dosed infrequently as 1/week. VERU-111 and docetaxel were tested in the human PCa model, 22Rv1, which expresses androgen receptor splice variants, including AR-V7, and is resistant to abiraterone and enzalutamide. Methods: Human 22Rv1 cells were implanted into SCID mice. When tumors reached 150-200 mm , the animals were randomized into 4 groups (n = 10 per group): PO vehicle; PO VERU-111 5 or 20 mg/kg; or IP docetaxel 10 mg/kg 3X per week. Animal weights and tumor volumes were measured 2X week and at study end. Animals were removed from study when the tumor volume exceeded 2000 mm or upon treatment for 28 days. Results: VERU-111 (PO 5 and 20 mg/kg) 3X/week significantly reduced tumors by 31% (p = 0.049) and 49% (p = 0.010), respectively, compared to vehicle. Administration of 10 mg/kg docetaxel IP had a nonsignificant reduction in tumor size. With respect to toxicity, mice treated with oral VERU-111 either significantly gained (5 mg/kg) or maintained their weight (20 mg/kg), whereas the docetaxel treated mice lost weight (p = 0.013). There was a significantly greater weight in mice treated with VERU-111 versus docetaxel (p = 0.014). Conclusions: VERU-111, a next generation, orally α and β tubulin inhibitor, has significant anti-tumor activity against PCa and other tumors. In the human PCa model 22Rv1, VERU-111 had a statistically significant reduction in tumor growth and was well tolerated. In contrast, IP docetaxel did not significantly reduce tumor growth and had greater toxicity. A phase 1/2 trial evaluating VERU-111 in men with metastatic castration and novel androgen blocking agent (abiraterone or enzalutamide) resistant prostate cancer is in progress. [Table: see text]

e17003Background: VERU-111 is a novel, oral α and β tubulin inhibitor that blocks tubulin polymerization and is not a substrate for multi-drug resistance mechanisms. In xenograft models of taxane r...

302 Background: Following proven efficiacy of docetaxel against hormone sensitive advanced prostate cancer (CHAARTED and STAMPEDE studies), the use of docetaxel for the treatment of hormone sensitive and castrate resistant metastatic prostate cancer has increased. Unfortunately, the utility of taxanes in prostate cancer has been limited because of the development of resistance, the need for IV infusion, and the associated treatment toxicity. VERU-111 is a highly orally available, novel α and β tubulin inhibitor, developed using a rationale design strategy to bind through hydrogen bonds to the α and β subunits of tubulin. VERU-111 inhibits tubulin polymerization and is not a substrate for multi-drug resistance proteins, a common mechanism for taxane resistance. Methods: In this study, dosing regimens of VERU-111 (oral) were tested in comparison with docetaxel (IV) and a vehicle (oral) in PC3 as well as in paclitaxel resistant PC3 (PC3-TXR). xenograft models. VERU-111 was evaluated at 3.3 mg/kg (5 days/week), 10 mg/kg (3 days/week), 15 mg/kg (2 days per week), 15 mg/kg (3 days per week) and 20 mg/kg (1 day/week). The animals were treated for 28 days and tumor volume and percentage size were calculated. Results: In the parental PC-3 model, animals treated with oral VERU-111, in all of the dose schemes tested, performed statistically indistinguishably from the IV docetaxel administration. In the PC3-TXR model, IV docetaxel had no impact on tumor growth whereas oral VERU-111 resulted in almost complete inhibition of tumor growth at 3.3 mg/kg (5 days/week) and 10 mg/kg (3 days/ week) as well as 20 mg/kg (1 day/week). In early toxicity studies, the animals treated with VERU-111 did not suffer any significant safety signals and gained weight during treatment. Conclusions: VERU-111 is a novel, oral α and β tubulin inhibitor that has drug characteristics making it an ideal candidate to be a therapeutic option for hormone sensitive and castrate resistant advanced prostate cancer. VERU-111 can be administered, with efficacy, as infrequent as once per week and will not require daily dosing. Additional toxicity studies are currently being performed with a Phase 1/2 study being planned to begin later this year.

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.

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 ...

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.

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 (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.

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.

e16015 Background: Androgen deprivation therapy (ADT) improves disease-free survival but disease progression is related, in part, to ineffective castration. The free hormone hypothesis states that the biological activity of steroid hormones is affected by its unbound (free) rather than its protein-bound concentration. Serum total testosterone (T) concentrations predominantly reflect the T bound to plasma proteins and do not accurately predict prostatic levels of T. Methods: In a Phase II study (G200705), men with advanced prostate cancer (n=159) were randomized to receive 1000 mg or 2000 mg GTx-758 daily or leuprolide as their initial ADT. Serum total T (mass spectrometry), free T (equilibrium dialysis), SHBG and PSA concentrations were measured. A second Phase II study (G20007) was performed in men (n=9) with CRPC who then received GTx-758 2000 mg daily. Results: Although both treatments reduced serum total T levels to < 50 ng/dL, leuprolide decreased them to a greater extent. However, GTx-758 caused greater reductions in serum PSA, suggesting that total T concentrations did not accurately reflect the suppression of androgen activity. Both dosages of GTx-758 reduced free T levels to a greater extent (mean of 0.7 and 0.4 pg/ml at day 60, and 0.4 and 0.4 pg/ml on day 90, respectively) than leuprolide (mean of 1.4 pg/ml on day 60 and 1.4 pg/ml on day 90; p values

171 Background: The insulin pathway and, in particular, insulin-like growth factor-1 (IGF-1), has been implicated in the development of prostate cancer, and serum IGF-1 levels have been associated with advanced disease. GTx-758, an ERα agonist that is being evaluated for the treatment of advanced prostate cancer, reduces serum total testosterone (T) and free T and increases SHBG. Herein, we compare the effects of GTx-758 and leuprolide on serum IGF-1 levels in men with advanced prostate cancer treated with 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. Serum samples were collected from all of the men in the study and serum IGF-1 levels (ng/ml) were analyzed by a reference laboratory. All p values describe the comparison of GTx-758 treatment groups to the leuprolide treated men. Results: Through day 90, in men receiving the 1000 mg and 2000 mg doses of GTx-758 , serum IGF-1 levels were decreased by more than 70 ng/ml (greater than 50%), while levels stayed constant or increased slightly in men on leuprolide (p

222 Background: Men with advanced prostate cancer are being treated with androgen deprivation therapy (ADT) for longer periods of time. The use of ADT can be limited by estrogen deficiency side effects, including a loss of bone and a higher incidence of fractures. GTx-758 is an ERα agonist that lowers serum free testosterone greater than an LHRH agonist. Herein we compare the effects of GTx-758 and leuprolide on markers of bone turnover, C-terminal telopeptides and bone specific alkaline phosphatase, in men with advanced prostate cancer treated with 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. Serum samples were collected and analyzed by a reference laboratory. C-terminal telopeptides (pg/ml) and bone specific alkaline phosphatase (U/L) were measured as indicators of bone turnover. All p values describe the comparison of the GTx-758 treatment groups to the leuprolide treated men at day 120. Results: Men receiving the 1000 mg and 2000 mg doses of GTx-758 had lower C-terminal telopeptide levels with a mean percentage change of -56.9 ± 12.5 and -54.8 ± 23.1, respectively, as compared with an increase of 46.0 ± 48.9 percentage in the men receiving the leuprolide (p

104 Background: Androgen deprivation therapy (ADT) improves disease-free survival in men with advanced prostate cancer, but patients develop castrate resistant prostate cancer (CRPC); one of the causes of which is ineffective castration. Total serum testosterone (T) does not accurately predict prostatic levels of T. Further reduction of androgens in men with CRPC can result in improvement of survival. Herein we compare the effects GTx-758 an oral, selective estrogen receptor alpha (ERα) agonist versus leuprolide on total and free (unbound) serum T levels in men with advanced prostate cancer. Methods: In Phase II studies, men with advanced prostate cancer (n=164) received 1000 mg or 2000 mg GTx-758 daily or Lupron Depot (4 month), while men with CRPC (n=9) received 2000 mg GTx-758 daily. Serum concentrations of total T, free T, SHBG and PSA were determined at baseline and during treatment. Results: In ADT naïve advanced prostate cancer patients, 28 days of 1000 mg or 2000 mg daily GTx-758 or Lupron therapy castrated (T

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

257 Background: To determine whether urinary soluble Met (sMet) can differentiate between benign conditions and bladder cancer (CaB), and in cases of bladder cancer, between different stages of transitional cell carcinoma (TCC). Methods: Urinary samples from patients with (Total: 63, pTa: 12, pTis: 22, pT1: 13, ≥ pT2: 16) and without (Total: 27) CaB from three different institutions were prospectively collected prior to cystosopy, TURBT or cystectomy. sMet levels were determined by electrochemiluminescence immunoassay and normalized to urinary creatinine values. Normalized sMet values were compared to final pathologic stage. AUC values were obtained comparing patients with and without TCC. Results: Urinary sMet levels accurately differentiated between patients with and without CaB (AUC: 78%, sensitivity, specificity and negative predictive value were: 68%, 78% and 95%, respectively), patients with no CaB and those with lamina propria invasion (AUC: 79%, sensitivity, specificity and negative predictive value were: 65%, 81% and 95%, respectively) and patients with no CaB and those with muscle invasive CaB (AUC: 85%, sensitivity, specificity and negative predictive value were: 75%, 83% and 97%, respectively). Conclusions: Urinary sMet levels accurately distinguish patients with CaB from those without, and between patients with different CaB stages. These results suggest that urinary sMet may have utility as a bladder cancer marker for screening, treatment follow-up and clinical trial design. No significant financial relationships to disclose.

e15110 Background: Bladder cancer has the highest cost per patient in the US compared to all other cancers, reflecting the complexity and prevalence of this disease. Current methods of bladder canc...