Castrate Levels Of Serum Testosterone Research Articles

Comparative Efficacy of Goserelin vs. Leuprolide in Advanced Prostate Cancer in Patients Undergoing Androgen Deprivation Therapy

Comparative Efficacy of Goserelin vs. Leuprolide in Advanced Prostate Cancer in Patients Undergoing Androgen Deprivation Therapy

6-month Formulations of Androgen Deprivation Therapy for Advanced Prostate Cancer: Effectiveness and Rationale for Extended Dosing

Background: Luteinizing hormone-releasing hormone (LHRH) agonists and GnRH antagonists are the most widely used androgen deprivation therapy to achieve castration levels of serum testosterone (T). Adherence to dosing schedules is important to avoid treatment failure. A recent analysis found a high non-adherence rate of 84% for LHRH agonist injections based on dosing schedules used in pivotal trials. Method: Narrative review of LHRH therapy and evaluation of which offers optimal efficacy, safety, and practicality. Results: 6-month LHRH agonist formulations require fewer appointments for injections than shorter-acting formulations. Therefore, the frequency of late/missed doses and overall non-adherence may be reduced compared to options requiring frequent dosing (e.g., oral therapies and shorter-acting injections). This flexibility may be preferable for patients who live in multiple locations throughout the year, live long distances from clinics, and/or lack access to reliable transportation. 6-month formulations may also have cost benefits compared to shorter-acting doses. Despite similar levels of T suppression during the labeled dosing period, individual 6-month LHRH agonist formulations appear to have unique profiles, e.g., 6-month subcutaneous leuprolide acetate (LA) results in lower T escape rates compared to 6-month intramuscular LA, if dosing is late. Conclusion: The efficacy and practicality offered by 6-month LHRH formulations suggest these could reduce opportunities for late injections by requiring fewer office visits and provide greater confidence that efficacy will be maintained should there be extenuating circumstances leading to delays in therapy administration, as experienced during the recent pandemic.

Triptorelin 3- and 6-month sustained-release formulations in locally advanced or metastatic prostate cancer: a profile of their use in the EU

Triptorelin [available in 1-, 3- and 6-month intramuscular sustained-release (SR) formulations] is a gonadotropin-releasing hormone (GnRH) agonist that effectively achieves and maintains castrate serum testosterone levels and is generally well tolerated in men with locally advanced or metastatic prostate cancer. The availability of the triptorelin 3- and 6-month SR formulations allows flexibility of treatment schedules for the patient and physician. The triptorelin 6-month SR formulation may improve convenience and patient’s potential adherence, health-related quality of life and resource use relative to GnRH agonists that require more frequent administration. This review provides a summary of the clinical evidence regarding the use of the 3- and 6-month SR formulations of triptorelin in the treatment of locally advanced and metastatic prostate cancer in the EU.

Prostate Cancer Stem-like Cells Contribute to the Development of Castration-Resistant Prostate Cancer.

Androgen deprivation therapy (ADT) has been the standard care for patients with advanced prostate cancer (PC) since the 1940s. Although ADT shows clear benefits for many patients, castration-resistant prostate cancer (CRPC) inevitably occurs. In fact, with the two recent FDA-approved second-generation anti-androgens abiraterone and enzalutamide, resistance develops rapidly in patients with CRPC, despite their initial effectiveness. The lack of effective therapeutic solutions towards CRPC largely reflects our limited understanding of the underlying mechanisms responsible for CRPC development. While persistent androgen receptor (AR) signaling under castration levels of serum testosterone (<50 ng/mL) contributes to resistance to ADT, it is also clear that CRPC evolves via complex mechanisms. Nevertheless, the physiological impact of individual mechanisms and whether these mechanisms function in a cohesive manner in promoting CRPC are elusive. In spite of these uncertainties, emerging evidence supports a critical role of prostate cancer stem-like cells (PCSLCs) in stimulating CRPC evolution and resistance to abiraterone and enzalutamide. In this review, we will discuss the recent evidence supporting the involvement of PCSLC in CRPC acquisition as well as the pathways and factors contributing to PCSLC expansion in response to ADT.

Androgen activity and markers of inflammation among men in NHANES III.

Inflammation contributes to chronic diseases. Lower serum testosterone among men is associated with less inflammation, yet immune defense is thought to trade-off against reproduction with androgens adversely affecting immune function. Anti-androgens are effective at castrate levels of serum testosterone, suggesting serum testosterone may not capture all androgen activity. The association of two androgen biomarkers with key markers of inflammation was examined. The adjusted association of serum testosterone and androstanediol glucuronide with C-reactive protein, white blood cell, granulocyte and lymphocyte count, fibrinogen, and hemoglobin, as a control outcome because testosterone administration raises hemoglobin, were examined in a nationally representative sample of 1,490 US men from the National Health and Nutrition Examination Survey III phase 1 (1988-1991) using multivariable linear regression. Serum testosterone and androstanediol glucuronide were weakly correlated (0.13). Serum testosterone was associated with lower white blood cell count [-0.26 × 10(-9) per standard deviation, 95% confidence interval (CI) -0.37 to -0.14] and granulocyte count (-0.21 × 10(-9) , 95% CI -0.29 to -0.13) but not with hemoglobin (0.02 g/l, 95% CI -0.89 to 0.92), adjusted for age, education, race/ethnicity, smoking, and alcohol. Similarly adjusted, androstanediol glucuronide was not associated with white blood cell count (0.10 × 10(-9) , 95% CI -0.05 to -0.25), granulocyte count (0.12 × 10(-9) , 95% CI -0.02 to 0.25), or fibrinogen (0.05 g/l, 95% CI -0.004 to 0.11), but was with hemoglobin (0.70 g/l, 95% CI 0.07 to 1.32). Different androgen biomarkers had different associations with inflammatory markers, highlighting the need to consider several androgen biomarkers. The possibility remains that androgens may generate inflammatory processes with implications for chronic diseases.

Triptorelin in the Management of Prostate Cancer

Among the therapies to achieve medical castration, gonadotropin-releasing hormone (GnRH) agonists have better safety profiles than estrogens and anti-androgens. In addition, slow-release formulations of GnRH agonists offer patients flexibility, improve quality of life and eventually reduce cost. To illustrate the role of medical castration in prostate cancer, this paper reviews data on the GnRH agonist triptorelin long-duration and shorter-duration formulations. A similar proportion of patients achieved and maintained castration levels of serum testosterone (≤50 ng/dl) with all triptorelin formulations. Moreover, using a stricter definition of medical castration (serum testosterone <20 ng/dl), castration was maintained in >90% of patients with the 6-month triptorelin formulation. The new formulation was also well-tolerated, whilst being more convenient for patients. This short review assesses the role of this GnRH agonist in the treatment of prostate cancer.

Targeting the androgen receptor signalling axis in castration‐resistant prostate cancer (CRPC)

What's known on the subject? and What does the study add? Castration resistance has been appreciated for decades, and several mechanisms theorising on this effect have been proposed. A rich pipeline of novel agents, including abiraterone and MDV3100, have provided proof of principle that novel agents targeting the AR signalling pathway with superior selectivity and activity than predecessors have yielded significant clinical benefit for patients with metastatic castration-resistant prostate cancer. Our review provides an update in the development of several novel agents targeting the AR signalling pathway now in clinical testing, as well as review novel therapies in development with distinct mechanisms of action showing promising preclinical activity. • Despite undergoing local therapy with curative intent, 20-30% of patients with prostate cancer will ultimately development metastatic disease, leading to morbidity and mortality. • Androgen-deprivation therapy (ADT) for men with metastatic prostate cancer results in transient clinical benefit, but ultimately, cancers progress despite castrate levels of serum testosterone, a clinical state classically referred to as 'hormone refractory' disease. • In this review, we examine mechanisms of resistance to ADT that have redefined our understanding of the more appropriately termed 'castration resistant' disease, and have paved the way for a new generation of therapeutics targeting the androgen signalling axis in advanced prostate cancer.

SOD Mimetics: A Novel Class of Androgen Receptor Inhibitors That Suppresses Castration-Resistant Growth of Prostate Cancer

Advanced prostate cancer is the second leading cause of cancer-related deaths among American men. The androgen receptor (AR) is vital for prostate cancer progression, even in the face of castrate levels of serum testosterone following androgen ablation therapy, a mainstay therapy for advanced prostate cancer. Downregulation of superoxide dismutase 2 (SOD2), a major intracellular antioxidant enzyme, occurs progressively during prostate cancer progression to advanced states and is known to promote AR activity in prostate cancer. Therefore, this study investigated the effects of SOD mimetics on AR expression and function in AR-dependent LNCaP, CWR22Rv1, and LAPC-4AD prostate cancer cells. Treatment with Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl), a SOD mimetic, not only lowered cellular superoxide levels but also concomitantly attenuated AR transcriptional activity and AR target gene expression in a dose- and time-dependent manner, in the presence and absence of dihydrotestosterone, the major endogenous AR agonist. Inhibition of AR by Tempol was mediated, in large part, by its ability to decrease AR protein via increased degradation, in the absence of any inhibitory effects on other nuclear receptors. Inhibitory effects of Tempol on AR were also reproducible with other SOD mimetics, MnTBAP and MnTMPyP. Importantly, effects of Tempol on AR function were accompanied by significant in vitro and in vivo reduction in castration-resistant prostate cancer (CRPC) survival and growth. Collectively, this study has shown for the first time that SOD mimetics, by virtue of their ability to suppress AR function, may be beneficial in treating the currently incurable CRPC, in which SOD2 expression is highly suppressed.

Abiraterone plus prednisone improves survival in metastatic castration-resistant prostate cancer.

Abiraterone plus prednisone improves survival in metastatic castration-resistant prostate cancer.

Abiraterone prolongs survival in metastatic prostate cancer

Abiraterone plus prednisone prolongs overall survival relative to prednisone alone in patients with metastatic castration-resistant prostate cancer who have disease progression after treatment with docetaxel. The survival gain observed in this pivotal trial is accomplished with few adverse events and conclusively demonstrates that patients with castration levels of serum testosterone remain sensitive to additional hormonal manipulation.

Clamp ablation of the testes compared to bilateral orchiectomy as androgen deprivation therapy for advanced prostate cancer

Burdizzo clamp ablation of the testes (CAT) may provide an incisionless, cost-effective form of androgen deprivation therapy (ADT) in men with adenocarcinoma of the prostate (ACP) who find bilateral orchiectomy (BO) unacceptable or can not afford medical ADT. The aim of this study was to compare CAT with BO as primary ADT in men with ACP. Written, informed consent was obtained from men with locally advanced or metastatic ACP. Patients were prospectively randomized to BO (n = 9) or CAT (n = 10) under local anaesthesia, and were evaluated 3 and 7 days, 6 weeks and 3 months post-procedure. The protocol was approved by the local institutional ethics committee. Statistical analysis was performed using Student's, Mann-Whitney's and Fisher's tests. Mean duration of the procedure was significantly longer for BO than CAT (16.9 vs. 10.9 minutes). Mean pain scores during and after the procedure did not differ significantly. Serum testosterone decreased significantly on days 3 and 7 after CAT, but increased at 6 weeks, and was significantly higher than after BO. Serum luteinizing hormone increased significantly from day 3 after BO and from day 7 after CAT. Serum prostate specific antigen decreased significantly after BO, but not after CAT. Minor complications were more common after BO (89%) than CAT (40%). In the 9 men who did not achieve castrate levels of testosterone after CAT, BO was performed. CAT was quicker to perform and had a lower complication rate, but was not as effective as BO in achieving castrate serum testosterone levels.

Novel Targeted Agents on the Horizon for Castration-Resistant Prostate Cancer

Androgen deprivation treatment in prostate cancer patients is well established; however, resistance to such treatment manifests itself by progression to castration-resistant prostate cancer (CRPC). Despite significant advances in treatment options for patients with CRPC, their prognosis remains poor. Resistance results from multiple processes that facilitate cancer cell growth and survival. Mechanisms underlying the shift to castrate resistance have been attributed to a complex interplay of clonal selection, reactivation of the androgen receptor axis despite castrate levels of serum testosterone, stress-induced prosurvival genes and cytoprotective chaperone networks and alternative mitogenic growth factor pathways. This article discusses several pathways involved in the development of CRPC, with a particular focus on those mechanisms that have led to the development of new targeted therapies.

Triptorelin Embonate (6-Month Formulation)

A 6-month formulation of the gonadotropin-releasing hormone agonist triptorelin embonate (designed to deliver 22.5 mg of triptorelin over a 6-month period) has been developed for use in the treatment of advanced prostate cancer. Following intramuscular administration of the 6-month formulation of triptorelin embonate 22.5 mg to men with advanced prostate cancer (subset of 15 patients from the pivotal clinical trial), serum testosterone levels initially increased, followed by a rapid, sustained decrease. Castrate serum testosterone levels (i.e. < or =1.735 nmol/L) were achieved in a geometric mean time of 18.8 days. The 6-month formulation of triptorelin embonate achieved and maintained castrate serum testosterone levels in patients with advanced prostate cancer (n = 120), according to the results of the pivotal, noncomparative, multicentre trial (patients received intramuscular triptorelin embonate 22.5 mg on day 1 and at month 6 [week 24]). By day 29, 97.5% of patients had castrate serum testosterone levels. Castrate serum testosterone levels were maintained from months 2 to 12 in 93.0% of patients. Prior to the second injection at month 6, 98.3% of patients had castrate serum testosterone levels, and 98.3% of patients had castrate serum testosterone levels at study completion. The 6-month formulation of triptorelin embonate 22.5 mg was generally well tolerated in patients with advanced prostate cancer; adverse events were of mild severity in the majority of patients. Drug-related adverse events (e.g. hot flushes) were consistent with the pharmacological action of triptorelin. Injection-site reactions occurred in 6.7% of triptorelin embonate recipients.

Triptorelin 6-Month Formulation in the Management of Patients with Locally Advanced and Metastatic Prostate Cancer

Triptorelin 6-month formulation was developed to offer greater convenience to both patients and physicians by reducing the injection frequency. The efficacy, pharmacokinetics and safety of a new 6-month formulation of triptorelin were investigated over 12 months (48 weeks). The primary objective was to evaluate the formulation in achieving castrate serum testosterone levels (< or = 1.735 nmol/L or < or = 50 ng/dL) on day 29 and in maintaining castration at months 2-12. Absence of luteinizing hormone (LH) stimulation and change in prostate-specific antigen (PSA) level were also assessed. An open-label, non-comparative, phase III study in 120 patients with advanced prostate cancer was conducted from July 2006 to August 2007 in private and public institutions in South Africa. Each patient received two consecutive intramuscular injections of triptorelin embonate (pamoate) 22.5 mg at an interval of 24 weeks. In all patients, testosterone (primary outcome measurement) was measured at baseline and then every 4 weeks; LH was measured before and 2 hours after the two injections. PSA was measured on day 1 and at weeks 12, 24, 36 and 48. Adverse events were recorded at each visit. In the intent-to-treat population, 97.5% (95% CI 92.9, 99.5) of patients achieved castrate serum testosterone levels by day 29, and 93.0% (95% CI 86.8, 97.0) maintained castration at months 2-12. After the second injection, 98.3% of patients showed absence of LH stimulation. The most frequent drug-related adverse events were hot flushes (71.7% of patients). No patient withdrew from the study as a result of an adverse event. The triptorelin 6-month formulation was well tolerated and was able to achieve and maintain castration for the treatment of locally advanced and metastatic prostate cancer. By reducing the frequency of required injections, this new formulation offers a more convenient treatment regimen. (Clinical Trial Registration,NCT00751790 at www.clinicaltrials.gov).

The relationship of body mass index and serum testosterone with disease outcomes in men with castration-resistant metastatic prostate cancer

5074 Background: We sought to evaluate the relationship of baseline body mass index (BMI), NIH-defined presence of obesity, and serum testosterone levels with disease-specific outcomes and prognosis in men with castration resistant metastatic prostate cancer (CRPC). Methods: BMI and testosterone level were evaluated for their ability to predict overall survival (OS) and progression-free survival (PFS) in multivariable analysis using data from the TAX327 clinical trial. This was an international phase III randomized controlled trial of one of two schedules of docetaxel and prednisone compared with mitoxantrone and prednisone. BMI and testosterone were additionally examined for prognostic significance in determining PSA declines with chemotherapy as well as the relationship to other prognostic factors. Results: In this study of 1006 men with CRPC, the median serum testosterone level was 14.5 ng/dl (range 0–270), the median BMI was 27 kg/m2 (range 15.7–46.5), and 26% of men were obese or morbidly obese (BMI > 30). Obese men were significantly more likely to be younger, have fewer visceral metastases, lower PSA and alkaline phosphatase, and have higher performance status, primary Gleason sum, testosterone, and hemoglobin levels as compared to non-obese men. In multivariable analysis, neither BMI nor the presence of obesity was significantly associated with PSA declines with therapy, progression-free survival, or overall survival. Baseline testosterone in the castrate range was also not associated with disease outcome, including PSA declines, PFS, or OS. Conclusions: In this multicenter international trial of men with CRPC, neither BMI nor serum testosterone in the castrate range were associated with prostate cancer outcomes. The cut-off threshold for castrate levels of serum testosterone should remain ≤50 ng/dl. Higher levels of serum testosterone among obese men suggest incomplete gonadal suppression with current therapies, but these differences may not be clinically relevant in men with CRPC. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration sanofi-aventis sanofi-aventis sanofi-aventis

Failure to Maintain a Suppressed Level of Serum Testosterone during Long-Acting Depot Luteinizing Hormone-Releasing Hormone Agonist Therapy in Patients with Advanced Prostate Cancer

Objectives: It was the aim of this study to analyze the failure rates in achieving or maintaining castrate levels of serum testosterone in patients with advanced prostate cancer treated with the 3-month luteinizing hormone-releasing hormone agonist (LH-RH) therapy. Methods:Total serum testosterone was determined in 234 patients with prostate cancer in a cross-sectional study. A subset of 90 patients submitted to radical prostatectomy was used as the control group (group 1), and 144 patients with advanced prostate cancer under androgen suppression therapy were included in the study group (groups 2 and 3). The study group was divided into 93 patients (group 2) treated with 50 mg daily bicalutamide and LH-RH agonist (maximal androgen blockade, MAB) and 51 patients treated with the LH-RH agonist alone (group 3). Median follow-up after androgen suppression was 42 months. The castrate testosterone level was defined below 50 ng/dl. Results: The mean serum testosterone level was 29.1 ng/dl in patients undergoing MAB (group 2) and 29.5 ng/dl in patients treated with the LH-RH agonist (group 3; p > 0.05). In group 1, the mean serum testosterone was 445.2 ng/dl (p < 0.0001). The rate of patients with a serum testosterone level higher than 50 ng/dl was 10.9% in patients undergoing androgen suppression, 10% in patients with MAB treatment and 12.5% in those with LH-RH agonist therapy (p > 0.05). In group 1, 98.9% of the patients had a serum testosterone level higher than 50 ng/dl. Conclusions: A small but clinically significant rate of patients under 3-month LH-RH agonist therapy fail to achieve or maintain castrate testosterone serum levels. This finding supports the need of monitoring testicular response during LH-RH agonist therapy.

Phase II study of xyotax (PPX) for androgen independent prostate cancer (AIPC)

14624 Background: PPX is a polymer conjugate of paclitaxel. In preclinical studies, PPX has an improved therapeutic profile relative to paclitaxel, in addition demonstrated activity in paclitaxel-resistant tumor models. This study investigates whether single agent PPX can induce PSA responses and increase time to progression in AIPC. Methods: Eligibility included: progressive disease based on at least one of the following: a) 3 consecutive rising PSA levels or b) new or progressive measurable disease, or c) new or progressive metastatic lesions on bone scan. Castrate levels of serum testosterone (≤ 50 ug/l), anti-androgen withdrawal, no more than 1 prior chemotherapy regimen, Zubrod performance status of ≤ 2, neuropathy ≤ grade 1, and adequate organ/marrow function. PPX is administered intravenously over 10–20 minutes without routine premedications, at a dose of 150 mg/m2 every 28 days. Dose modifications are based on nature and grade of toxicity observed. Patients (pts) are restaged every 8 weeks until progression or a maximum of 12 months of therapy. Results: 12 patients (pts) (11 previously treated/1 untreated) have been enrolled to date. 7 of the previously treated pts received prior taxanes. 3 pts continue on treatment. 9 pts have completed a range of 6–28 weeks of therapy. Based on a reduction in PSA of at least 50% and maintained for at least 8 weeks, 2 previously treated pts (1 prior taxotere) responded to treatment. 3 pts demonstrated a delay in their PSA velocity. Adverse events were assessed and included: 1 pt who developed a hypersensitivity reaction, 5 pts with grade 2/3 neuropathy, 5 pts with grade 2/3 leukopenia, 2 pts with grade 3/4 neutropenia and 1 pt with grade 4 thrombocytopenia. Other common reversible grade 1/2 toxic effects have been: nausea, fatigue, elevated LFTs and anemia. 6 pts have required dose reduction. Conclusion: PPX is well tolerated and demonstrates promising activity in patients with AIPC. Efficacy assessments are measured by: absolute PSA response, PSA velocity changes, and toxicity data will be presented. [Table: see text]

Rapamycin for androgen-independent prostrate cancer (AIPC)

14584 Background: Genetic alterations targeting the PTEN tumor-suppressive gene are among the most frequently noted mutations in human cancers. Prostate cancer has been reported as a PTEN-null cancer. Absence of functional PTEN in cancer cells leads to activation of downstream components of the P13K pathway, including the Akt and mTOR kinases. Drug targeting of these kinases might have significant therapeutic activity in PTEN-null cancers. Rapamycin has been reported to inhibit metastatic prostate tumor growth and angiogenesis in in vivo mouse models. This clinical trial is designed to assess the anti-tumor activity, toxicity and the clinical relationship between tissue and plasma levels of vascular endothelial growth factor and tissue microarray for PTEN tumor-suppressive gene. Methods: Eligibility included: a minimum of 2 consecutive rises in prostate-specific antigen (PSA), with or without radiographic evidence of disease, castrate levels of serum testosterone (≤ 50 ug/l), anti-androgen withdrawal, no more than 2 prior therapeutic regimens, Zubrod performance status of ≤ 2 and adequate organ/marrow function. The initial dose of Rapamycin is 0.15 mg/kg followed by 0.04 mg/kg daily without interruption. Rapamycin levels are obtained every 28 days with a dose adjustment of 0.04 to 0.06 mg/kg in order to maintain a level between 6–10 ng/ml. Results: To date, 12 patients (pts) have been enrolled. 2 pts have demonstrated a definitive change in their PSA velocity, 1 pt &gt; 40% regression in their absolute PSA. 2 pts with measurable disease have demonstrated regression of &lt; 20%. Toxicity consisted of grade 1/2: fatigue, mucositis, elevated transaminases, diarrhea and rash. 1 pt continues to receive Rapamycin. Median duration of Rapamycin is 32.5 weeks (4–40+). Conclusion: Rapamycin has been well tolerated with signs of anti-tumor activity observed. Information regarding PSA response and time to progression in association with Rapamycin level will be presented. [Table: see text]

Failure to Achieve Castration Levels in Patients Using Leuprolide Acetate in Locally Advanced Prostate Cancer

ObjectiveIn a cross-sectional, retrospective, non-randomised study to investigate the possibility that some patients treated with luteinizing hormone releasing hormone analogues (LHRH analogues) fail to reach castration levels of serum testosterone. Methods40 patients treated with a 3-monthly formulation of leuprolide acetate and continuous use of an oral antiandrogen (“Leu group”) and 25 patients treated with a 3-monthly formulation of goserelin acetate and an oral antiandrogen for one month (“Gos group”) were identified from our hospital's registry. Serum testosterone was measured during treatment with the respective LHRH-analogue and compared between the two groups. In the Leu group, serum testosterone was measured during week 11 or 12 of treatment. In the Gos group, serum testosterone was assessed during week 23 or 24. ResultsFour patients (10%) treated with leuprolide acetate failed to reach the castration level of serum testosterone after treatment with one injection of a three-monthly formulation of leuprolide acetate. All patients treated with goserelin acetate achieved the castration level. ConclusionAlthough the overwhelming majority of prostate cancer patients during treatment of LHRH analogue achieve serum testosterone values within the castration range, individual patients may fail to reach this therapeutic goal, probably more often during treatment with leuprolide acetate than with goserelin acetate.

Phase II study of CC-4047 in patients (pts) with metastatic hormone-refractory prostate cancer (HRPC)

4629 Background: CC-4047 is a new analog of thalidomide with potent immunomodulatory and anti-angiogenesis properties. similar to thalidomide. This study investigates whether single agent CC-4047 can induce PSA responses and increase time to progression in HRPC. Eligibility included: histologically confirmed HRPC, 2 consecutive rises in prostate-specific antigen (PSA) with an absolute change of at least 1ng/ml separated by 28 days, with or without radiographic evidence of disease, castrate levels of serum testosterone (≤50 ng/dL), failure to androgen withdrawal, ≤1 prior chemotherapy regimen, ECOG performance status of ≤1, life expectancy ≥3 months, and normal organ/marrow function. Methods: CC-4047 was administered orally in doses of 1 or 2mg/day without interruption. Pts. are followed every 4 weeks with re-evaluation at week 12. Forty-four pts have been enrolled. Pt characteristics: 1mg dose level: 22 pts enrolled, median age 69 years (range 58–82). Fourteen pts with bone involvement only. Four pts with bone and nodal involvement. Four pts with nodal or visceral tumor involvement only. Median PSA 157 (0.8–313). 2mg dose level: 22 pts enrolled, median age 68 years (range 44–84). Seven pts with bone involvement only. Two pts with bone and nodal involvement. Five pts with bone and visceral involvement. Three pts with nodal or visceral tumor involvement. Four pts with prostate intact. Median PSA: 70 (0.6–139). Results: Of the 22 pts at 1mg, 20 pts have completed 12 weeks of therapy. One pt remains on study for 60+ weeks. PSA decreased in 6 pts, 3 pts with >50% decrease. Of the 22 pts at 2mg, 19 completed 12 weeks of therapy. Nine pts remain on study. PSA decreased in 9 pts, with 2 pts having a >50% reduction. Grade 1–2 toxicity included: constipation, nausea, vomiting, and fatigue. One Grade 3 toxicity consisting of nausea. One pt expired secondary to a CNS bleed while on therapeutic doses of coumadin. Of the 22 pts at 2mg, 16 completed 12 weeks of therapy. Nine pts remain on study. PSA decreased in 9 pts, with 2 pts having a >50% reduction. Conclusion: CC-4047 shows promising activity in pts with HRPCa, with an acceptable tolerability. Response, progression-free survival and toxicity data will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Celgene Celgene Celgene, Chiron Celgene, Chiron, Endocyte