Castrate Levels Research Articles

Detection of metastatic disease as a leading cause of screening failure in a phase III trial of zibotentan versus placebo in patients with nonmetastatic castration-resistant prostate cancer (CRPC).

4655 Background: Many patients with biochemical relapse after definitive therapy for prostate cancer receive androgen deprivation therapy. PSA levels eventually will rise despite castrate levels of testosterone. Many of these patients have nonmetastatic disease and do not develop metastases for a median of 30 mos (Smith MR JCO, 2005). However, there is no standard therapy for patients with nonmetastatic CRPC. ENTHUSE M0 (Study 15) is a global phase III study, now closed to enrollment, comparing zibotentan 10 mg vs placebo in nonmetastatic CRPC patients. Coprimary endpoints are overall survival and radiographic progression or death. Patients are screened for metastases by bone and CT/MRI scans. An unexpectedly high number of patients failed screening, prompting this analysis. Methods: All screened patients were included. For each investigator, the number of patients who enrolled and who failed screening were recorded. Screen fail reasons were recorded. Screen failure rates were computed by clinical specialty (oncology or urology) and geographic region by dividing the number of screen failures by the number of enrolled patients in each category. Results: As of January 14, 2011, 2583 patients completed screening, and 1169 (45%) failed screening. Screen failure rates were not different by clinical specialty or by geographic region. The leading causes of screen failures by clinical specialty are listed in the table. Conclusions: These data suggest that detectable asymptomatic metastatic disease may exist in about 30% of presumed nonmetastatic CRPC. These findings stress the value of periodic staging studies in men with CRPC, as those with detectable metastatic CRPC may benefit from emerging therapies. Screen failure criteria, n (%) Oncology (631 patients enrolled) Urology (1,885 patients enrolled) Detection of metastatic disease 184 (29) 566 (30) Creatinine clearance of <50 mL/min 45 (7) 156 (8) Long QTc interval 24 (4) 82 (4) Absence of biochemical progression 27 (4) 76 (4) Testosterone level >70 ng/dL (noncastrate) 15 (2) 71 (4) Total screen failures, n 283* 873* * Some patients had >1 reason for screening failure.

Continuous vs. intermittent androgen deprivation therapy for metastatic prostate cancer

ObjectivesTo analyze the predictive value of PSA for progression and the role of testosterone for quality of life (QOL) in patients with androgen deprivation therapy (ADT) for metastatic prostate cancer. Materials and methodsPSA and testosterone data were used from a phase III trial randomizing patients without progression and PSA < 4 ng/ml (n = 193), after 6 months induction course, between continuous (CAD) (n = 96) and intermittent (IAD) (n = 97) ADT. The 2-year risk of progression was calculated for baseline PSA, ‘fast’ and ‘slow’ PSA decline to < 4 ng/ml (60 days cut-off), PSA nadir, performance status and pain. Testosterone kinetics and QOL were also evaluated. Univariate Kaplan Meier survival analysis and log rank tests were used to compare the risk of progression. ResultsFor progression analysis, 173 patients' data were available. The 2-year risk of progression for baseline PSA < 50 ng/ml, 50 to <500 ng/ml, and ≥500 ng/ml was 25%, 55%, and 76% (P = 0.03) in CAD, and 38%, 64%, and 85% (P = 0.006) in IAD, respectively. The 2-year risk of progression for PSA nadir ≤ 0.2 ng/ml, and > 0.2 to 4 ng/ml in CAD was 31% and 70% (P < 0.001), respectively. In the IAD group, a similar trend was seen. Patients with PSA nadir ≤ 0.2 ng/ml, though had significantly higher 2-year risk of progression compared to CAD (53% vs. 31% (P = 0.03), respectively. PSA decline showed no predictive value. Patients without pain had a significantly lower 2-year risk of progression in both groups. Without ADT testosterone remained at castrate level for 4 months. After the first and second IAD cycle 92% and 46%, respectively, had a normalized testosterone. No QOL difference was found, although more side effects occurred in CAD. ConclusionsMetastatic prostate cancer patients with high baseline PSA, pain, and high PSA nadir have a poor prognosis with ADT. Patients with low PSA nadir do significantly worse with IAD compared with CAD. Low testosterone after ADT and incomplete testosterone recovery may explain similar QOL. Therefore, IAD is not a good treatment option for many metastatic prostate cancer patients.

Progression of metastatic castrate-resistant prostate cancer: impact of therapeutic intervention in the post-docetaxel space.

Despite the proven success of hormonal therapy for prostate cancer using chemical or surgical castration, most patients eventually will progress to a phase of the disease that is metastatic and shows resistance to further hormonal manipulation. This has been termed metastatic castrate-resistant prostate cancer (mCRPC). Despite this designation, however, there is evidence that androgen receptor (AR)-mediated signaling and gene expression can persist in mCRPC, even in the face of castrate levels of androgen. This may be due in part to the upregulation of enzymes involved in androgen synthesis, the overexpression of AR, or the emergence of mutant ARs with promiscuous recognition of various steroidal ligands. The therapeutic options were limited and palliative in nature until trials in 2004 demonstrated that docetaxel chemotherapy could significantly improve survival. These results established first-line docetaxel as the standard of care for mCRPC. After resistance to further docetaxel therapy develops, treatment options were once again limited. Recently reported results from phase 3 trials have shown that additional therapy with the novel taxane cabazitaxel (with prednisone), or treatment with the antiandrogen abiraterone (with prednisone) could improve survival for patients with mCRPC following docetaxel therapy. Compared with mitoxantrone/prednisone, cabazitaxel/prednisone significantly improved overall survival, with a 30% reduction in rate of death, in patients with progression of mCRPC after docetaxel therapy in the TROPIC trial. Similarly, abiraterone acetate (an inhibitor of androgen biosynthesis) plus prednisone significantly decreased the rate of death by 35% compared with placebo plus prednisone in mCRPC patients progressing after prior docetaxel therapy in the COU-AA-301 trial. Results of these trials have thus established two additional treatment options for mCRPC patients in the "post-docetaxel space." In view of the continued AR-mediated signaling on mCRPC, results from additional phase 3 studies with novel antiandrogens which are directed at inhibition of the AR (e.g., MDV3100), as well as other agents, are awaited with interest and may further expand the treatment choices for this difficult-to-manage population of patients.

Effect of testosterone administration to men with prostate cancer is unpredictable: a word of caution and suggestions for a registry

To assess the evidence for the concept that the androgen receptor of prostate cancer (PCa) cells becomes saturated when testosterone values exceed castrate levels, so that testosterone administration in hypogonadal men with untreated PCa does not stimulate tumour growth. To propose basic criteria for administration of testosterone to untreated patients with PCa and, as this is a rare clinical situation, to encourage the establishment of an international registry for these patients. Men with a diagnosis of PCa and symptomatic testosterone deficiency received testosterone therapy (TTh). Patients were assessed quarterly. Prostate-specific antigen (PSA) velocity was used as the criterion to discontinue therapy and a return to nadir PSA levels allowed re-initiation of testosterone supplementation. The responses to testosterone supplementation were varied according to each individual and were unpredictable. While some men showed little change after years of treatment, others exhibited a rapid and significant increase in PSA levels. In others, the use of intermittent therapy resulted in synchronous changes in PSA levels. Interruption of TTh invariably translated into a decrease in PSA to pre-therapy levels. Available evidence regarding the effect of testosterone administration to hypogonadal men with untreated PCa is too limited to be considered reliable. In addition, the response to this treatment appears to be varied and unpredictable. Hypogonadism associated with untreated PCa is not common, therefore, we propose the establishment of an international registry as the quickest way to establish the basic parameters for consideration of TTh in this situation and recommendations for follow-up. Until credible evidence becomes available, the current restrictions regarding the administration of testosterone to men with PCa should remain in place.

Abstract 4541: Binding and transcriptional activity of the androgen receptor isoforms in 22Rv1 prostate cancer cells

Abstract Prostate carcinoma (CaP) is a heterogeneous multifocal disease where gene expression and regulation is altered as the disease progresses but the androgen receptor (AR) continues to be a pivotal regulatory molecule. The 22Rv1 castrate resistant cell line, derived from the androgen dependent CWR22 xenograft model, continues to express the AR and remains androgen responsive. However, in additional to the full length AR, these cells also express several low molecular weight isoforms. These isoforms are the predominant (95%) forms present in the nucleus in castrate androgen levels. siRNA knockdown of all AR isoforms in castrate levels of androgen decreases cell growth indicating that AR is required for proliferation. Analysis of ChIP-promoter array data identified 128 binding sites (FDR&amp;lt;=0.05) in Rv1 cells proliferating in androgen-depleted media. A closer examination of these 128 binding sites revealed that 20% of the sites showed exactly the same start and end position in the absence or presence of DHT. The remainder (80%) were within ∼35-1000bp upstream of the start position or downstream of the end position. Only 6% of the binding sites contained the palendromic consensus AR-response element and 48% contained the AR half-site motif. The 128 binding sites were associated with 118 genes. To define the role of AR binding in regulating transcription, the expression of 20 of the 118 genes was analyzed following knockdown of AR in castrate levels of androgen. One third of these genes are transactivated, while 1/3 are repressed, arguing that AR activating and repressing complexes co-exist in these cells. Notably the expression of CDKN1B (p27) RNA and protein is highly activated following AR knockdown, suggesting that AR-dependent repression of this cell cycle inhibitor may be important for proliferation of 22Rv1 cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4541. doi:10.1158/1538-7445.AM2011-4541

2012 CYCLOOXYGENASE-2 PROTECTS GERM CELLS AGAINST SPERMATOGENESIS DISTURBANCE IN EXPERIMENTAL CRYPTORCHIDISM MODEL MICE

INTRODUCTION AND OBJECTIVES: The roles of Cyclooxygenases (COXs) in the male reproductive tract remain unclear. However, there are some reports that suggest the COX-2 might effect on the spermatogenesis or steroidogenesis. In this study, we examined whether COX-2 induced in the testes being impaired and also investigated possible role of COXs in the testes using experimental cryptorchidism model mice. METHODS: Five-week-old male mice underwent an operation to induce unilateral cryptorchidism by an abdominal incision and suturing the left testes to the lateral abdominal wall. For each animal, the left testis was treated as the experimental organ while the right testis remained completely untouched throughout the procedure. Then the mice were divided into three groups: (1) experimental cryptorchidism plus SC560 (selective COX-1 inhibitor) administration; (2) experimental cryptorchidism plus NS398 (selective COX-2 inhibitor) administration; (3) experimental cryptorchidism alone. The expressions of COX-1 and COX-2 were determined by immunohistological staining and quantitative reverse transcriptional polymerase chain reaction (RT-PCR). The influence of COX inhibitors on testis was assessed by measuring the concentration of serum testosterone and evaluating the seminiferous tubules according to the Johnsen score (JS). TdT-mediated dUTPbiotin nick end-labeling (TUNEL) staining was also performed for the detection of apoptosis in the testes. RESULTS: Immunohistological staining and RT-PCR revealed that the expression of COX-2 was increased in the experimental cryptorchidism testes (group 1–3). The concentration of serum testosterone was significantly lower in group 2 at 5 weeks after surgery than that in other groups, however not in the level of castration. Johnsen score of cryptorchidism testes in group 2 was significantly lower than that in other groups at 5 weeks after surgery. The TUNEL staining revealed that the apoptotic cells were significantly increased in group 2 compared with that in other groups. Meanwhile, COX-1 inhibitor does not appear to affect spermatogenesis in the experimental cryptorchid testes. CONCLUSIONS: These results suggest that COX-2 inhibitor could reinforce testicular damage in the experimental cryptorchidism by inducing germ cell apoptosis. The expressions of COX-2 might be induced to protect germ cells from heat-stress caused by experimental cryptorchidism.

Cabazitaxel for the treatment of prostate cancer

Introduction: Prostate cancer is a frequently diagnosed male cancer. In men presenting locally advanced or metastatic disease, the mainstay of treatment is hormonal suppression. Despite the castrate levels of testosterone, with time, prostate cancer gradually evolves into a castration-refractory state. Chemotherapeutic agents are able to influence the natural history of metastatic castration-resistant prostate cancer. Docetaxel is a clinically relevant, FDA-approved taxane. Today, it is the first-line chemotherapeutic agent in castration-refractory prostate cancer (CRPC). There is no standard second-line chemotherapeutic regimen.Areas covered: This review provides information on the efficacy of cabazitaxel as a second-line treatment for CRPC. The medline database was searched for clinical trials on chemotherapeutical treatment options of castration-resistant prostate cancer. All available data on the efficacy of cabazitaxel are summarized.Expert opinion: New treatment strategies for castration-resistant prostate cancer should primarily focus on quality of life. In this view, vaccination therapy seems promising because of the acceptable level of toxicity. However, more research is needed to prove their efficacy in the treatment of castration-resistant prostate cancer. Cabazitaxel seems to be a promising second-line therapy in CRPC.

Maintenance of the suppressed level of serum testosterone by administration of three-monthly formulations of luteinizing hormone-releasing hormone agonists at six-month intervals in Japanese patients with prostate cancer: A prospective study.

159 Background: Treatment with an LH-RH agonist is a standard alternative to surgical castration for prostate cancer patients. The serum testosterone level is kept at castrate levels continuously during LH-RH agonist therapy in almost all patients (Fujii Y, BJU Int 2008). LH- RH agonists, however, are more expensive than surgical castration, with drugs costing between US $300 and $500 per month in Japan. Recent studies suggest that 3-monthly formulations of LH-RH agonists suppress the serum testosterone levels far longer than the 3-month dosing interval. Methods: A total of 43 Japanese patients with prostate cancer who were treated with 3-monthly LH-RH agonists (23 with 11.25mg leuprolide, and 20 with 10.8 mg goserelin) for one year or longer and whose testosterone levels were kept at castrate level (defined as &lt; 50 ng/dL) were entered into this prospective, longitudinal study. After entry, the 43 men received the same 3-monthly LH-RH agonists at 6-month intervals, and had serum LH and testosterone tests performed at 3-month intervals. Bicalutamide was combined with the LH-RH agonists in 12 of the patients. Results: At entry, median patient age was 74 years (range 59 to 89), median duration of LH-RH agonists treatment was 26 months (12 to 125), and median LH and testosterone levels were &lt;10 ng/dL (&lt;10 to 60) and 5 ng/dL (&lt;5 to 18), respectively. The 43 patients received a total of 162 administrations (median 5, range 1 to 6) of the LH-RH agonists at 6-month intervals, and had a total 335 hormonal tests (median 10, range 2 to12) performed during the median followup period of 30 months. Serum LH and testosterone levels were kept suppressed during the treatment. Of the 43 patients, two had serum testosterone just above the castrate level (54 and 56 ng/dL) once each among their 12 and 8 hormonal assays, respectively. Conclusions: Administration of 3-monthly LH-RH agonists, either leuprolide or goserelin, at 6-month intervals could maintain the castrate level of serum testosterone at least in Japanese prostate cancer patients who have received LH-RH agonists treatment for one year or longer. No significant financial relationships to disclose.

The efficacy and safety of degarelix, a GnRH receptor antagonist: A multicenter, randomized, maintenance dose-finding phase II study with Japanese prostate cancer patients.

154 Background: Degarelix, a GnRH receptor antagonist inducing rapid, profound and sustained suppression of serum testosterone levels, without testosterone surge, was evaluated in a phase II dose finding study in Japan. Methods: A total of 278 patients with adenocarcinoma of the prostate were randomized and 273 patients (any stage; median age, approx. 76 years; median testosterone, 4.46 ng/mL; median prostate-specific antigen (PSA) level, 22.8 ng/mL) received study treatment. Degarelix was administered subcutaneously at an initial dose of 240 mg followed by monthly maintenance doses of either 80 mg or 160 mg. The treatment continued for 12 months in the study. Results: The primary endpoint was the proportion of patients with testosterone suppression to castrate level of ≤0.5 ng/mL during 12 months treatment. Both dose regimens of 80 mg and 160 mg kept 94.5% and 95.2% of patients on castrate level respectively throughout the treatment period. At 3 days of treatment, approximately 99% of the patients reached the castrate level without testosterone surge. The percentage change in serum PSA reduction exceeded 76% at 4 weeks. The overall tumor response rates (proportion of patients with complete and partial responses) were from 77.4% to 90.8% across the groups. Eighteen patients (6.6%) withdrew from the study due to adverse events. The most common adverse events were injection site reactions; other adverse events included pyrexia, weight increased, hypertension and hot flush. Degarelix appeared well tolerated. Conclusions: With an initial dose of 240 mg followed by monthly maintenance doses of 80 mg or 160 mg, Degarelix resulted in a rapid profound and sustained testosterone suppression to castrate level and PSA reduction without testosterone surge for 12 months. Degarelix was well tolerated. The maintenance doses of 80 mg and 160 mg had similar efficacy and safety profiles. The study shows results similar to those from the degarelix pivotal phase III study (CS21). Assessment of risk-benefit would support the recommendation of the maintenance dose of 80 mg as a safe and effective monthly dose for the treatment of prostate cancer. [Table: see text]

Cardiovascular events and clinical responses in prostate cancer patients treated with transcutaneous estrogen patches compared with LHRH analogues: Results from a randomized phase II trial (MRC PR09 PATCH).

201 Background: Androgen-deprivation therapy (ADT) with a luteinising hormone-releasing hormone analogue (LHRHa) is widely used in the management of prostate cancer. LHRHa suppresses testosterone to castrate levels but can lead to long term toxicities including osteoporosis, adverse metabolic effects and cardiovascular (CV) complications. Transcutaneous oestrogen is an attractive potential alternative to ADT. This approach circumvents first-pass hepatic metabolism and so should avoid the CV effects previously reported with oral oestrogen in men with prostate cancer. Castrate levels of testosterone, and hence prostate cancer outcomes, are expected to be equivalent but the side-effects associated with ADT will potentially be avoided. Methods: PATCH is a multi-centre phase II randomized study of 254 men with locally advanced or metastatic prostate cancer assigned (2:1) to either oestrogen patches (Merck FemSeven 100mcg/24hr; 4 patches changed twice-weekly, reducing to 3 after 4 weeks) or LHRHa. The primary outcome is CV morbidity and mortality, including arterial and venous thromboembolic events, acute coronary syndrome and heart failure. These have been assessed by an independent committee, blind to the treatment arm. Secondary outcome measures include PSA response, serum testosterone and also toxicities. Results: Baseline data on the 254 men will be presented including age, cardiovascular risk factors (smoking history, lipid levels and family history), and stage/grade of tumour at presentation and randomisation. CV events will be presented by randomisation arm and by treatment at the time of the event. Data relating to rates of castrate levels of hormones, PSA responses, sexual dysfunction, other toxicities (including gynaecomastia, hot flushes, anaemia and bone fractures) and compliance will also be available. Conclusions: Providing the data demonstrate that the patches are a safe and potentially efficacious therapy we propose to recruit a further 410 patients with progression-free survival as the primary outcome. CV events will continue to be closely monitored, alongside other outcomes. [Table: see text]

Intermittent androgen-deprivation therapy in the management of castrate-resistant prostate cancer (CRPCa): Results of a multi-institutional randomized prospective clinical trial.

131 Background: Patients who develop CRPCa typically continue on androgen deprivation therapy (ADT). Whether these patients need to remain on ADT has not been well studied. We conducted a multicenter randomized trial to compare intermittent versus continuous approach to ADT in CRPCa patients. Overall survival, health related quality of life (QOL) and cost were the main endpoints. We hypothesized that the intermittent approach would be cost-saving while maintaining similar oncologic and QOL outcomes. Methods: CRPCa patients were randomized 1:2 to continuous or intermittent luteinizing hormone releasing hormone agonists (LHRHa). Patients were followed with clinical assessments, laboratory investigations, and QOL questionnaires (EORTC QLQ-C30 or PROSQOLI) every 2 months. If the serum testosterone rose above castrate levels (1.75nmol/L), LHRHa were re-initiated. The study was designed to close if &gt;50% of patients needed to restart ADT in the intermittent arm. Results: 31 patients were followed with a median follow-up of 26.8 months; 18 in the intermittent arm and 13 in the continuous. 12/18 patients on the intermittent arm were re-initiated on LHRHa at a median time of 17.9 months. There was no difference in overall or cancer-specific survival between the two arms. There was no statistically significant difference in QOL between the two arms at 0 and 12 months. The total mean costs at 24 months were significantly lower in the intermittent arm (3135 $CAD vs 8253 $CAD, p=0.0167) compared to the continuous arm largely due to the reduced costs of the LHRHa. Conclusions: We have observed that intermittent ADT in patients with CRPCa, using a testosterone of &gt;1.75 ngmol/L as a trigger to re-initiate LHRHa, results in a substantial cost savings with no negative impact on oncologic and QOL outcomes. These findings need to be corroborated in a study with a larger sample size. [Table: see text]

Response to degarelix after resistance to luteinizing hormone–releasing hormone agonist therapy for metastatic prostate cancer

Androgen deprivation with a luteinizing hormone-releasing hormone (LH-RH) agonist is the standard treatment for patients with metastatic prostate cancer who prefer nonsurgical options. Therapy with these agents is usually successful in achieving and maintaining castrate levels (< 50 ng/dl) of serum testosterone, but failures have been reported in up to 10% of patients. Traditionally, these patients are offered surgical castration with bilateral orchiectomy. However, the novel LH-RH antagonists may offer a nonsurgical alternative. We describe two patients with advanced prostate cancer who failed to achieve castrate levels of testosterone while on an LH-RH agonist, but subsequently responded to the LH-RH antagonist, degarelix. The first patient is a 63-year-old man who was treated with leuprolide for metastatic prostate cancer. He initially responded with prostate-specific antigen (PSA) that fell to 0.6 ng/ml. However, after 15 months of therapy, his PSA rose to 18.3 ng/ml and his testosterone was noted to be 208 ng/dl. He was switched to degarelix, and 4 weeks later his testosterone was adequately suppressed at 16 ng/dl. The second patient is a 41-year-old man with metastatic prostate cancer who was started on leuprolide, but after 3 months of therapy, was found to have a rising PSA and a testosterone of 96 ng/dl. Four weeks after switching to degarelix, his testosterone was 18 ng/dl and his PSA decreased concordantly. With continued monthly injections of degarelix, his testosterone has consistently remained to be at less than 20 ng/dl over 7 months of follow-up.

A phase II, open-label, single-arm, efficacy, and safety study of MDV3100 in patients with hormone-naïve prostate cancer.

177 Background: MDV3100 is a novel androgen receptor (AR) antagonist in clinical development for the treatment of prostate cancer (PCa). Compared to bicalutamide, MDV3100 has higher in vitro AR binding affinity and no evidence of partial agonism. Preliminary phase I-II data show antitumor activity with MDV3100 in men with advanced PCa who were concurrently using androgen deprivation therapy (ADT; Scher HI, et al. Lancet. 2010;375:1437-46). Phase II and III studies in men with progressive and earlier-stage PCa are ongoing. This abstract describes the design of a phase II study of MDV3100 in men with hormone-naïve PCa (HNPCa) who are candidates for ADT. Methods: This 25-week, open-label, single-arm, efficacy and safety study of MDV3100 (160 mg/d orally) will be initiated at ∼20 investigational sites in late 2010 (planned countries: Austria, Belgium, Czech Republic, Denmark, Germany). Inclusion criteria include histologically confirmed, locally advanced PCa (all stages), noncastrate testosterone (T; ≥230 ng/dL), prostate-specific antigen (PSA) ≥2 ng/mL (screening), Eastern Cooperative Oncology Group score of 0, and life expectancy ≥1 year. Exclusion criteria include, among others, previous/current hormonal therapy or chemotherapy for PCa. The primary endpoint is PSA response, defined as an ≥80% decrease from baseline to wk 25. A binary PSA response per patient (wk 25) will be determined, allowing for generation of a PSA response rate (95% CI) from all patients for the study. Secondary endpoints include: PSA dynamics; pharmacokinetics; change in gonadotropin, T, dihydrotestosterone, estradiol, sex-hormone binding globulin, and prolactin levels; and safety/tolerability. Exploratory endpoints include changes in bone mineral density, bone turnover markers, metabolic parameters, and quality of life. Results: The planned enrollment is 60 patients. With a 20% dropout rate, the study will have 80% power to reject the unwanted PSA response rate of ≤50% (5% significance). Efficacy and safety data will be published later. Conclusions: Previous data were in men with castrate levels of T (≤50 ng/dL). This trial will be the first to investigate the use of MDV3100 monotherapy in HNPCa. [Table: see text]

Efficacy of triptorelin in lowering serum testosterone (sT) in patients with advanced prostate cancer.

162 Background: Medical castration using gonadotropin-releasing hormone (GnRH) agonists is the mainstay of treatment for advanced prostate cancer. Achievement and maintenance of castrate serum testosterone (sT) levels &lt;50 ng/dL (1.735 nmol/mL) has been the goal of therapy. However, patients are able to achieve and maintain sT levels &lt;15 ng/dL after surgical castration (Oefelein M et al. J Urology 2000; 56: 1021-4). Some authors have suggested that 20 ng/dL should be the target threshold for medical castration(Perachino M et al. BJU Int 2010; 105: 648-51) but the clinical relevance of achieving such low sT levels (&lt;20 ng/dL) remains unknown. Methods: The efficacy and safety of sustained-release triptorelin pamoate 22.5 mg 6-month formulation was recently evaluated in a 12-month (48-week), multicentre, open-label, phase III study in 120 patients with locally advanced or metastatic prostate cancer and/or increased prostate specific antigen (PSA) after failed local therapy. Initial results based on the standard castration level of 50 ng/dL were previously presented in comparison to triptorelin 1- and 3-month formulations (Lundström E et al. Clin Drug Investig 2009; 29: 757-65). We report the proportions of patients achieving sT levels of &lt;20 ng/dL with the triptorelin pamoate 1-, 3- and 6-month formulations. Results: With the 6-month formulation, sT levels of &lt;20 ng/dL were achieved in &gt;90% of patients on Day 169 (6 months after first triptorelin injection) and on Day 337 (6 months after second injection; Table). Similar sT levels were achieved with triptorelin 1- and 3-month formulations in a phase III study over 9 months (Table). Conclusions: A high proportion of patients receiving the 6-month triptorelin formulation achieve sT levels &lt;20 ng/dL. This compares favorably to the triptorelin 1- and 3-month formulations. [Table: see text] [Table: see text]

Role of detection of metastatic disease as a leading cause of screening failure in an ongoing phase III trial of zibotentan versus placebo in patients with nonmetastatic castration-resistant prostate cancer (CRPC).

135 Background: Many patients with biochemical relapse after definitive therapy for prostate cancer receive androgen deprivation therapy. Although most patients experience a decline in PSA, PSA eventually rises despite a castrate level of testosterone. Many of these patients have non-metastatic disease and do not develop metastases for a median of 30 mos (Smith MR. JCO, 2005). However, there is no standard therapy for asymptomatic patients with non-metastatic CRPC. ENTHUSE M0 (Study 15) is an ongoing global phase III study comparing zibotentan 10 mg (an oral specific endothelin A receptor antagonist) vs placebo in non-metastatic CRPC patients. Co-primary endpoints are overall survival and progression-free survival; secondary endpoints are safety, PSA, quality of life, and time to symptomatic progression. Eligible patients are screened for metastases by bone and CT/MRI scan and other parameters. An unexpectedly high number of patients failed screening, prompting this analysis. Methods: All patients who were screened were included in the analysis. Reasons for exclusion were recorded. Results: As of June 3, 2010, 1,756 patients completed screening. Of these patients, 960 (55%) were randomized and 796 (45%) failed screening. The leading causes of screen failures are listed in the table. Exclusion rates by investigator specialty and country will be reported. Conclusions: As 30% of patients had metastatic disease on screening and were excluded, these data suggest that the frequency of asymptomatic metastases is high in men thought to have non-metastatic CRPC. These findings stress the value of periodic staging studies in men progressing from hormone sensitive to non-metastatic CRPC as metastatic CRPC patients may benefit from standard treatments or research treatments on other protocols. [Table: see text] [Table: see text]

Prospective Randomised Controlled Trial Comparing Sub-Epididymal Orchiectomy Versus Conventional Orchiectomy in Metastatic Carcinoma of Prostate

Androgen blockade (surgical or medical castration) is a standard procedure for patients with metastatic carcinoma prostate. Sub-epididymal orchiectomy involves removal of testis leaving behind epididymis. This epididymal stump over a period gives a pseudo testicular feel within the scrotum. We present a prospective randomized study to assess the functional utility of this procedure and compare it with total orchiectomy in terms of achieving castrate levels. From July 2005-Jan 2008, 60 patients with metastatic carcinoma prostate were alternately randomised and allotted to two groups, 30 underwent sub-epididymal orchiectomy (group A) and remaining 30 (group B) underwent total orchiectomy. Age: 56-80years. Serum PSA: 55-268ng/ml. Preoperative serum testosterone: Group A-300-650ng/ml and group B-320-640ng/ml. Postoperative serum testosterone: group A-2-18ng\ml and group B-7-15ng\ml on day 7 after surgery. Operating time-26-40mins for group A and 20-34mins for group B. Follow up-6weeks and 3months. At 3months patients were asked to grade appearance of scrotum for asthetic value on a scale of 1-100 using visual analogue score. Postoperative serum testosterone reached castrate levels in seven days (both groups). Duration of surgery in both groups was comparable. Complications-wound infection in 1 patient (group A) & 1 scrotal hematoma (group B). Satisfaction score for group A (83.5 ± 9.7) was significantly (p < 0.05) better (95%CI-18.58-28.42), compared to that of group B (60 ± 9.4) by using't' test. Sub epididymal orchiectomy is comparable to total orchiectomy in terms of achieving castrate levels with similar operating time. It has significant advantage in terms of mental satisfaction to patients. It is a simple and safe procedure that can be conveniently performed in an outpatient clinic setting using pure local anaesthesia.

ADT and the metabolic syndrome: no good deed goes unpunished

Although androgen deprivation therapy (ADT) has been used for more than half a century to treat prostate cancer, its mechanism and associated side effects are continuously updated. Androgens are key players in glucose homeostasis and lipid metabolism. In fact, lower total testosterone predicts a higher incidence of the metabolic syndrome, a cluster of risk factors predisposing patients to late onset diabetes mellitus, atherosclerosis and cardiovascular (CVS) morbidity and mortality.1 Since CVS disease is the most common competing cause for mortality, we should make all efforts to minimize our iatrogenic contribution to the metabolic syndrome and familiarize ourselves with the growing body of evidence linking ADT to the metabolic syndrome.2,3 Mohamedali and colleagues present their experience with the impact of long-term ADT on blood glucose levels in non-diabetic prostate cancer patients. The authors demonstrated that 1 year of ADT use is associated with elevated fasting glucose levels.4 This data is in line with a recent review of the ADT/metabolic syndrome which showed a clear casual association between ADT and diabetes mellitus, but the causal association is not as strong with CVS morbidity.5 The link needs to be better explored as novel ADT strategies are about to change our practice. In recent years it has become clear that current modes of castration are far from optimal in achieving complete androgen deprivation in prostate cancer cells. Multiple pre-clinical evidences suggest that prostate cancer cells can produce androgens which activate the androgen receptor already in concentrations lower than those traditionally defined as castrated serum testosterone levels (<20 ng/dL). Accordingly, although not completely validated, clinical observations suggest the lower the testosterone level under ADT, the longer the survival;6 it is possible that even lower levels of testosterone within and it is possible that even transient events of testosterone break through within the framework of ADT can accelerate disease progression.7 Hence, the current trend in ADT is a more strict deprivation of androgens in castrate resistant prostate cancer, and what we used to define as maximal androgen blocked (MAB) will certainly be expanded with the introduction of novel products, such as arbiraterone and MDV3100. It is reasonable to expect that novel therapeutic strategies that induce more effective testosterone suppression will reciprocally accentuate the metabolic side effect profile of ADT. Data comparing the long-term metabolic side effect of different modes of castration is currently limited,8 but once available, should better guide us in treating patients with known risk factors for CVS disease. We should incorporate routine baseline and follow-up assessments of metabolic measurements (fasting glucose levels, lipids, BMI) and advocate lifestyle modification for our ADT patients. We should also stay tuned for potentially more detrimental metabolic side effects with more strict MAB regimens.

A role for dihydrotestosterone treatment in older men?

A role for dihydrotestosterone treatment in older men?

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.

LHRH antagonist Cetrorelix reduces prostate size and gene expression of proinflammatory cytokines and growth factors in a rat model of benign prostatic hyperplasia

Recent findings suggest that BPH has an inflammatory component. Clinical trials have documented that therapy with LHRH antagonist Cetrorelix causes a marked and prolonged improvement in LUTS in men with symptomatic BPH. We investigated the mechanism of action and effect of Cetrorelix in a rat model of BPH. Adult male Wistar rats were used. BPH was induced in rats by subcutaneous injections of TE 2 mg/day for 4 weeks. Control animals received injections of corn oil. After induction of BPH, rats received depot Cetrorelix pamoate at the doses of 0.625, 1.25, and 12.5 mg/kg on days 1 and 22 and TE-control rats received vehicle injections. Whole prostates were weighed and processed for RNA and protein. Real-time RT-PCR assays for numerous inflammatory cytokines and growth factors were performed. Quantitative analyses of prostatic LHRH receptor, LHRH, androgen receptor (AR) and 5α-reductase 2 were done by real-time RT-PCR and immunoblotting; serum DHT, LH, PSA, and IGF-1 by immunoassays. mRNA levels for inflammatory cytokines IFN-γ, IL-3, IL-4, IL-5, IL-6, IL-8, IL-13, IL-15, and IL-17 and for growth factors EGF, FGF-2, FGF-7, FGF-8, FGF-14, TGF-β1, and VEGF-A were significantly reduced by Cetrorelix 0.625 mg/kg (P < 0.05). Prostate weights were also significantly lowered by any dose of Cetrorelix. This study suggests that Cetrorelix reduces various inflammatory cytokines and growth factors in rat prostate and, at doses which do not induce castration levels of testosterone, can lower prostate weights. Our findings shed light on the mechanism of action of LHRH antagonists in BPH.