Castrate Levels Research Articles

Testosterone and Voluntary Exercise, Alone or Together Increase Cardiac Activation of AKT and ERK1/2 in Diabetic Rats

BackgroundImpaired angiogenesis in cardiac tissue is a major complication of diabetes. Protein kinase B (AKT) and extracellular signal regulated kinase (ERK) signaling pathways play important role during capillary-like network formation in angiogenesis process.ObjectivesTo determine the effects of testosterone and voluntary exercise on levels of vascularity, phosphorylated Akt (P- AKT) and phosphorylated ERK (P-ERK) in heart tissue of diabetic and castrated diabetic rats.MethodsType I diabetes was induced by i.p injection of 50 mg/kg of streptozotocin in animals. After 42 days of treatment with testosterone (2mg/kg/day) or voluntary exercise alone or in combination, heart tissue samples were collected and used for histological evaluation and determination of P-AKT and P-ERK levels by ELISA method.ResultsOur results showed that either testosterone or exercise increased capillarity, P-AKT, and P-ERK levels in the heart of diabetic rats. Treatment of diabetic rats with testosterone and exercise had a synergistic effect on capillarity, P-AKT, and P-ERK levels in heart. Furthermore, in the castrated diabetes group, capillarity, P-AKT, and P-ERK levels significantly decreased in the heart, whereas either testosterone treatment or exercise training reversed these effects. Also, simultaneous treatment of castrated diabetic rats with testosterone and exercise had an additive effect on P-AKT and P-ERK levels.ConclusionOur findings suggest that testosterone and exercise alone or together can increase angiogenesis in the heart of diabetic and castrated diabetic rats. The proangiogenesis effects of testosterone and exercise are associated with the enhanced activation of AKT and ERK1/2 in heart tissue.

Abstract B18: Intratumor lysophosphatidylinositol metabolites in a treatment naïve patient-derived bone metastatic prostate cancer xenograft

Abstract A patient-derived bone metastatic prostate cancer (PCa) xenograft (MDA-PCa-183) was used to investigate early resistance mechanisms after androgen deprivation therapy (ADT). The patient-derived xenograft (PDX) expresses wild-type androgen receptor (AR), TMPRSS2-ERG and was found to have homozygous loss of PTEN [1]. MDA-PCa-183 PDX was established as described by Li et al. [2] using a bone biopsy procured from a patient with metastatic PCa prior to ADT. Tumors were grown in intact male immunodeficient mice (n=23) with a subset of mice (n=16) castrated when they reached a size of approximately 900 mm3. At day 11 after castration tumors from 6 mice were harvested and these were considered at maximal androgen ablation (MAA). Of the remaining ten castrated mice, seven responded to androgen ablation by tumor shrinkage or detention of tumor growth (responsive tumors). Tumors of three mice demonstrated sustained growth after castration (relapsed tumors), were harvested between 30 to 40 days after castration and prostate specific antigen (PSA) blood levels were measured. The androgen signaling biomarkers, AR, cytochrome P450 17-alpha-hydroxylase/17,20-lyase (CYP17) and TMPSSR2-ERG protein expression were determined using immunohistochemistry. A biochemical profile consisting of lipid, amino acid, bioenergy, nucleotide (Metabolon, Inc.) and steroid were measured. The levels of testosterone, androstenedione, dihydrotestosterone, progesterone and 17-alpha-hydroxy-progestone were <0.1 pg/mg tissue in MAA and relapsed tumors. Immunostaining showed that tumors from castrate mice expressed AR and CYP17, but were negative for TMPSSR2-ERG. AR and CYP17 were localized in cytoplasm of epithelial cells. PSA levels were low for all castrate tumors (<35 ng/dL). Notably, the lipid profile showed that the lysolipids (LL); 1-palmitoylglycerophosphoinositol, 1-stearoylglycerophosphoinositol, 2-stearoylglycerophosphoinositol, were increased in MAA and relapsed tumors (P<0.05) and 2-oleoylglycerophosphoinositol, 1-oleoylglycerophosphoinositol, 2-arachidonoylglycerophosphoinositol levels were higher in MAA tumors versus intact control tumors (P<0.05). Arachidonic acid levels were also increased in MAA and relapsed tumors (P<0.05). In contrast, the eicosanoids (prostaglandin D2, prostaglandin E2 and 5-HETE) levels were similar in the MAA, relapse and control tumors. The long chain fatty acids, palmitate and oleate, levels were similar in MAA, relapsed and control tumors, however stearate levels decreased in MAA and relapsed tumors (P<0.05). Inositol 1-phosphate (I1P), a metabolite of glycerophosphoinositols (GPIs), levels are similar in MAA and control tumors but are increased in relapsed tumors versus control (P<0.05). Our data supports a possible mechanism of AR independent cell proliferation in relapsed MDA-PCa-183 PDX by LL activation of G protein-coupled receptor-55 (GPR55) signaling. The intracellular LL together with ABCC1 and GPR55 generate an autocrine loop that promotes epithelial cell growth [3] after ADT. LL signaling may also support endothelial cell proliferation within the PDX during ADT. I1P levels, a metabolite of LL, indicate that GPIs may act as a paracrine regulator of osteoblast differentiation. Overall, LL biosynthesis and metabolic metabolites may support early resistance to ADT.

Prospects of 2nd line chemotherapy personalization in patients with metastatic castration-resistant prostate cancer

Prostate cancer (PC) is one of the most challenging and pressing problems of modern oncourology because of high morbidity associated with the disease worldwide. About 1 100 000 new cases are diagnosed each year. The main approach to treatment of locally advanced and/or metastatic PC is hormonal therapy. Androgen deprivation therapy allows to achieve stabilization in more than 90 % of patients, but average time until progression after hormonal therapy in patients with metastatic PC is about 2 years. Then patients with tumor progression accompanied by castration level of testosterone enter the stage of so-called castration-resistant PC (CRPC). Prognosis for regional CRPC is unfavorable, and it substantially lowers patients’ quality of life. Taxane-based chemotherapy remains a standard method of treatment in this patient cohort. The article reviews studies of efficacy of different doses and regimes of 2nd line chemotherapy using cabazitaxel in patients with metastatic CRPC.

A Randomised Comparison Evaluating Changes in Bone Mineral Density in Advanced Prostate Cancer: Luteinising Hormone-releasing Hormone Agonists Versus Transdermal Oestradiol

BackgroundLuteinising hormone-releasing hormone agonists (LHRHa), used as androgen deprivation therapy (ADT) in prostate cancer (PCa) management, reduce serum oestradiol as well as testosterone, causing bone mineral density (BMD) loss. Transdermal oestradiol is a potential alternative to LHRHa. ObjectiveTo compare BMD change in men receiving either LHRHa or oestradiol patches (OP). Design, setting, and participantsMen with locally advanced or metastatic PCa participating in the randomised UK Prostate Adenocarcinoma TransCutaneous Hormones (PATCH) trial (allocation ratio of 1:2 for LHRHa:OP, 2006–2011; 1:1, thereafter) were recruited into a BMD study (2006–2012). Dual-energy x-ray absorptiometry scans were performed at baseline, 1 yr, and 2 yr. InterventionsLHRHa as per local practice, OP (FemSeven 100μg/24h patches). Outcome measurements and statistical analysisThe primary outcome was 1-yr change in lumbar spine (LS) BMD from baseline compared between randomised arms using analysis of covariance. Results and limitationsA total of 74 eligible men (LHRHa 28, OP 46) participated from seven centres. Baseline clinical characteristics and 3-mo castration rates (testosterone ≤1.7 nmol/l, LHRHa 96% [26 of 27], OP 96% [43 of 45]) were similar between arms. Mean 1-yr change in LS BMD was −0.021g/cm3 for patients randomised to the LHRHa arm (mean percentage change −1.4%) and +0.069g/cm3 for the OP arm (+6.0%; p<0.001). Similar patterns were seen in hip and total body measurements. The largest difference between arms was at 2 yr for those remaining on allocated treatment only: LS BMD mean percentage change LHRHa −3.0% and OP +7.9% (p<0.001). ConclusionsTransdermal oestradiol as a single agent produces castration levels of testosterone while mitigating BMD loss. These early data provide further supporting evidence for the ongoing phase 3 trial. Patient summaryThis study found that prostate cancer patients treated with transdermal oestradiol for hormonal therapy did not experience the loss in bone mineral density seen with luteinising hormone-releasing hormone agonists. Other clinical outcomes for this treatment approach are being evaluated in the ongoing PATCH trial. Trial registrationISRCTN70406718, PATCH trial (ClinicalTrials.gov NCT00303784).

Abstract B29: A multicenter, open-label phase 1/2 study of oral CFG920, in combination with prednisone in adult patients with metastatic castration-resistant prostate cancer

Abstract Introduction CYP17 is a crucial enzyme in androgen synthesis. CYP17 inhibition results in virtually undetectable serum and intratumoral androgens and antitumor activity in metastatic castration-resistant prostate cancer (mCRPC). Abiraterone (ABI) acetate, a CYP17 inhibitor, is approved for mCRPC treatment. CFG920, a dual CYP17 and CYP11B2 inhibitor showed favorable efficacy and safety profile in repeat-dose toxicity studies in vivo. Here, we report data from the phase 1 part of the first-in-human study (CFG920×2101) of CFG920 and prednisone combination in patients with mCRPC. Methods Patients received escalating doses of CFG920 (50-200 mg twice daily [bid]) and prednisone (5 mg bid) in 28-day cycles. The primary objective was to determine maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). Dose escalation decisions were made based on the synthesis of all relevant data, guided by an adaptive Bayesian logistic regression model (BLRM) with overdose control (EWOC) principle, based on the dose limiting toxicities (DLTs) data in cycle 1. Results Overall, 31 patients (median age 69 years) were enrolled and treated (median duration 18.6 weeks [range 1-96]). As of the data cut-off date, treatment was ongoing in 1 patient. DLTs (grade 3 hyponatremia, hyperkalemia, and hyperglycemia) occurred in 3 patients (at 100 mg bid, 150 mg bid and 200 mg bid) within the first 28 days of treatment; 2 patients permanently discontinued treatment, 1 in cycle 1 and 1 at the start of cycle 8. Serious adverse events (AEs), regardless of causality, occurred in 12 patients (38.7%); asthenia, confusional state, dehydration, and urosepsis occurred in 2 patients each. The common drug-related AEs (any grade) included fatigue (19.4%), nausea (19.1%), and thrombocytopenia (19.1%). Overall, 2 patients died during treatment; 1 due to cardiac arrest (100 mg bid; study drug unrelated), and 1 due to mCRPC (50 mg bid). Due to AEs, 7 patients discontinued treatment, and 6 patients had dose reductions. At ≥12 weeks after the first CFG920 dose, 8 patients (25.8%) had ≥50% decrease in prostate specific antigen (PSA). Serum testosterone and dehydroepiandrosterone-sulfate (DHEAS) levels were reduced markedly beyond castration levels at all doses, including in patients pretreated with abiraterone and ketoconazole. Reduction in serum aldosterone was also marked but transient. No clear dose-dependency was seen in PSA response or testosterone reduction. CFG920 was rapidly absorbed with Tmax of 0.5 to 2 hours after single or multiple doses. AUC increased dose-proportionally after a single dose and slightly more than dose-proportionally after repeat dose. Steady state was reached at cycle 1 day 15. The estimated half-life was 3 to 6 hours. As per the BLRM with EWOC principle, CFG920 300 mg bid dose had the highest probability to be in the target toxicity interval and satisfied the EWOC principle. Based on the available clinical safety, efficacy, pharmacokinetic, and pharmacodynamic data, 100 mg bid dose was declared as the RP2D of CFG920, without MTD declaration. Conclusion The safety profile was acceptable, and with the exception of unexplained thrombocytopenia, was in line with preclinical studies. The study was voluntarily terminated due to an already competitive prostate cancer landscape, and the phase 2 did not start. Citation Format: Sebastien J. Hotte, Joan Carles, John Sarantopoulos, Charles J. Ryan, Joshua M. Lang, Bruce Montgomery, Koichi Fukino, Gwendolyn Gobbo, Xiaoming Cui, Prakash Mistry, Chun Pan, Jean-Pascal Machiels. A multicenter, open-label phase 1/2 study of oral CFG920, in combination with prednisone in adult patients with metastatic castration-resistant prostate cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B29.

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.

The first experience in using abiraterone acetate in patients with castration-refractory prostate cancer

Even in the mid-twentieth century, Huggins and Hodges proved the susceptibility of prostate cancer cells to hormonal manipulations, by using surgical castration as an example. An average of 18–36 months after initiation of first-line hormonal therapy, patients develop the castration resistance in prostate cancer, one of the causes of which was hyperproduction of the tumor receptors of prostate cancer cells and their hypersusceptibility to the castration levels of testosterone. Long-term treatment in patients with castration-refractory prostate cancer was extremely symptomatic and quality of life and overall survival were low. In the 2000s, investigations aimed at designing drugs to treat this category of patients were underway, which have culminated in the advent of three drugs (two of which belong to chemotherapy) that are now used in the Russian Federation. The second-line hormonal agent abiraterone acetate (Zytiga) is one of these drugs, which was officially registered in 2011. Its mechanism of action is due to inhibition of the enzyme CYP17, leading to the blocked synthesis of testosterone at all levels, including at the intracrine level, and achieving testosterone levels below the postcastration ones. The paper reviews the literature regarding abiraterone acetate and the first experience in using second-line hormonal therapy in three patients.

Medical Castration Using the Investigational Oral GnRH Antagonist TAK-385 (Relugolix): Phase 1 Study in Healthy Males

TAK-385 is a highly selective, oral, nonpeptide GnRH antagonist being investigated as a possible prostate cancer treatment. The objectives were to evaluate safety, tolerability, pharmacokinetics, and pharmacodynamics of TAK-385 on LH and testosterone. This was a three-part, randomized, double-blind, placebo-controlled, phase 1 dose-escalation study in 176 healthy male UK volunteers. Part 1, single doses of TAK-385 (0 [placebo], 80, 120, 180, or 360 mg). Part 2, 14-day TAK-385 (0, 20, 40, 80, or 180 mg) daily. Part 3, 28-day TAK-385 (40 [with loading dose], 60, 80, or 160 mg) or placebo daily. Parts 2 and 3 included men aged 40-75 years. Main outcome measures included plasma concentrations of TAK-385, LH, and testosterone. Oral TAK-385 was readily absorbed, and steady state was reached in ≤ 14 days. Food reduced TAK-385 systemic exposure by 47-52%. Mean serum testosterone levels declined ≤ 6 hours after TAK-385 administration. Loading doses up to 360 mg on day 1 or 360 mg on day 1 followed by 240 mg on day 2 reduced the time to achieve castrate testosterone levels from ≥ 7 to <3 days. TAK-385 doses ≥ 80 mg/d achieved sustained medical castration and trough TAK-385 concentrations >4 ng/mL. After discontinuation of TAK-385 on day 28, testosterone levels normalized in most subjects in ≤ 28 days. Common adverse events included bradycardia, headache, and hot flush (all grade ≤ 2). Oral TAK-385 (40-180 mg/d) was well tolerated and effectively lowered testosterone in healthy men. Planned phase 2 doses in men with hormone-sensitive prostate cancer are 80 and 120 mg/d.

Development of enzalutamide for metastatic castration-resistant prostate cancer.

Prostate cancer is the most prevalent cancer among men in the Western world and a leading cause of cancer-related death among men. Within 5 years of initial diagnosis, approximately 10-20% of men will progress to metastatic castration-resistant prostate cancer (mCRPC). Often characterized by increased prostate-specific antigen and androgen receptor (AR) activity despite castrate levels of testosterone, mCRPC has a poor prognosis and causes significant deterioration in quality of life. Enzalutamide is an AR inhibitor approved to treat mCRPC in both post- and pre-chemotherapy settings on the basis of results from two phase III randomized, placebo-controlled trials, AFFIRM and PREVAIL, respectively. Enzalutamide significantly prolonged overall survival (hazard ratio (HR), AFFIRM 0.63, 95% confidence interval (CI) 0.53-0.75, P < 0.001; PREVAIL 0.71, 95% CI 0.60-0.84, P < 0.001) and radiographic progression (HR, AFFIRM 0.40, 95% CI 0.35-0.47, P < 0.001; PREVAIL 0.19, 95% CI 0.15-0.23, P < 0.001), and significantly improved quality of life. With an acceptable safety profile, enzalutamide is one of several emerging alternative options for men with mCRPC. Studies are ongoing to explore potential benefits of enzalutamide in earlier stages of prostate cancer and in breast cancer.

Abstract 3450: Resistance to P450c17 inhibitors in castration-resistant prostate cancer may result from the DHEA-S depot that remains and can be used by AKR1C3 for intratumoral androgen biosynthesis

Abstract Localized intermediate and high-risk prostate cancer can be treated with androgen deprivation therapy (ADT). Initially, patients undergo remission but inevitably relapse due to the emergence of castration resistant prostate cancer (CRPC). Newer agents such as the P450c17 inhibitor, abiraterone acetate (AA), have gained approval for the treatment of CRPC and increased median survival by 4 months. We have developed a novel and validated stable isotope dilution liquid chromatography selected reaction monitoring mass spectrometry (SID-LC/ESI/SRM/MS) method for the quantification of conjugated and unconjugated keto-androgens in human serum (J Steroid Biochem Mol Biol (2013) 138:281). This method was applied to human serum from patients enrolled in a neoadjuvant AA clinical trial (J Clin Oncol (2014) 32:3705). We found that testosterone (T) and 5α-dihydrotestosterone (DHT) did not always decrease in tandem, which suggests that pathways that bypass T may lead to DHT. These may include the alternative pathway (Δ4-androstene-3,17-dione -&amp;gt; 5α-androstane-3,17-dione -&amp;gt; DHT) or the backdoor pathway (androsterone -&amp;gt; 5α-androstane-3α,17β-diol -&amp;gt; DHT). Second, despite achieving &amp;gt;90% inhibition of P450c17, the level of dehydroepiandrosterone sulfate (DHEA-S) that remains (20,000 ng/dL) is 4,000-fold higher than castrate levels of T achieved in the trial. We hypothesize that the DHEA-S depot that remains is sufficient to feed intratumoral androgen biosynthesis and that this could account for the clinical failure of P450c17 inhibitors in CRPC. Adaptive intratumoral androgen biosynthesis may be facilitated by the up-regulation of AKR1C3 (type 5 17β-hydroxysteroid dehydrogenase). In order to test our hypothesis, we have developed a panel of isogenic prostate cancer cell lines that either express AKR1C3 or are AKR1C3 null. These cell lines are then challenged with post-AA levels of circulating androgens (DHEA-S, DHEA and Δ4-androstene-3,17-dione) to determine whether they can still make sufficient androgens to activate the androgen receptor (AR), where androgen metabolism is measured using SID-LC/ESI/SRM/MS. Using LNCaP and LNCaP-AKR1C3 cells, we find that the level of T detected as T-17β-glucuronide in the AKR1C3 expressing cells could be sufficient to activate the AR. These results would suggest that AKR1C3 inhibitors in combination with AA could benefit patients who might otherwise fail AA treatment. [Supported by grants: R25-CA101871 to DT; P30-ES-13508 to TMP; P01-CA-163337 to SPB, EM, TMP and PSN)] Citation Format: Daniel Tamae, Elahe Mostaghel, Bruce Montgomery, Peter S. Nelson, Steven P. Balk, Philip W. Kantoff, Mary-Ellen Taplin, Trevor M. Penning. Resistance to P450c17 inhibitors in castration-resistant prostate cancer may result from the DHEA-S depot that remains and can be used by AKR1C3 for intratumoral androgen biosynthesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3450. doi:10.1158/1538-7445.AM2015-3450

Abstract 2567: Cabazitaxel chemotherapy targets mitotic kinesins resulting in multi-nucleation of prostate cancer cells: A novel mechanism of cross-resistance with antiandrogens in advanced CRPC

Abstract Progression to castration-resistant prostate cancer (CRPC) is characterized by increased androgen receptor (AR) and activated AR signaling despite castrate levels of androgens. The FDA-approved next generation microtubule stabilizing taxane, Cabazitaxel (CBZ) and novel anti-androgen Enzalutamide (MDV) have demonstrated additional survival benefits for patients with advanced CRPC. The present study pursued the mechanism of therapeutic resistance to CBZ and antiandrogen treatment in models of CRPC. The effect CBZ and/or MDV was examined in human prostate cancer cells: androgen independent (DU145 and PC3), androgen responsive (LNCaP and VCaP) and CRPC (22Rv1 and PC3-ARv567, harboring AR variants). Cell viability assessment revealed that CRPC PC3-ARv567es and the androgen-sensitive VCaP cells exhibited resistance to CBZ; however the 22Rv1 cells responded to CBZ and MDV combination with a significant increase in growth (P&amp;lt;0.05). Confocal microscopy and Western blot analysis were used to establish the subcellular localization and protein expression in prostate cancer cells. Antiandrogen (MDV) treatment (24hrs;1uM) led to a cytoplasmic accumulation of AR, while treatment with CBZ (72hrs, 35 -100nM) decreased AR expression, but it did not inhibit its nuclear localization. Furthermore CBZ induced mono-astral spindle formation, centrosomal clustering and multi-nucleation, potentially via targeting the “pro-mitotic kinesins”, MCAK and HSET, regardless of androgen status. To determine the in vivo efficacy of CBZ and androgen axis targeting, we used a transgenic mouse model of prostate cancer (Dominant negative TGFβRII/TRAMP) that is driven to metastasis by epithelial-mesenchymal transition (EMT). Immunohistochemical profiling of prostate tumors from untreated control and CBZ treated mice demonstrated that combination of CBZ and castration-induced androgen depletion reduced kinesin and AR expression and reversed EMT, impairing prostate cancer progression. Furthermore, CBZ treatment restored normal glandular differentiation (by H&amp;E), without significant effect on apoptosis in tumor epithelial cells. Cell proliferation was significantly decreased in response to castration-induced androgen depletion in combination with CBZ (2wks) (P&amp;lt;0.05). These findings support the ability of CBZ to target pro-mitotic kinesins, providing an insight into a new mechanism of action of this taxane that can be exploited for targeting CRPC patients with kinesin overexpression. Moreover, the in vivo evidence identified that CBZ chemotherapy has novel effects beyond suppressing tumor growth, by inducing prostate glandular differentiation. This study is of translational significance in introducing a novel mechanism to overcome cross-resistance to CBZ chemotherapy and anti-androgens in advanced CRPC. Citation Format: Sarah K. Martin, Hong Pu, Craig Horbinski, Zheng Cao, Natasha Kyprianou. Cabazitaxel chemotherapy targets mitotic kinesins resulting in multi-nucleation of prostate cancer cells: A novel mechanism of cross-resistance with antiandrogens in advanced CRPC. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2567. doi:10.1158/1538-7445.AM2015-2567

Identification of Androgen Receptor Splice Variants in the Pten Deficient Murine Prostate Cancer Model.

Androgen receptor (AR) variants are associated with resistance to anti androgen therapy both in human prostate cancer cell lines and clinical samples. These observations support the hypothesis that AR isoform accumulation is a consequence of selective therapeutic pressure on the full length AR. The Pten deficient prostate cancer model proceeds with well-defined kinetics including progression to castration resistant prostate cancer (CRPC). While surgical castration and enzalutamide treatments yield an initial therapeutic response, Pten-/-epithelia continue to proliferate yielding locally invasive primary tumor pathology. That most epithelium remains AR positive, but ligand independent, suggests the presence of oncogenic AR variants. To address this hypothesis, we have used a panel of recently described Pten-/- tumor cell lines derived from both from hormone intact (E4, E8) and castrated Pten mutants (cE1, cE2) followed by RACE PCR to identify and characterize three novel truncated, amino terminus containing AR variants (mAR-Va, b, c). Variants appear not only conserved throughout progression but are correlated with nearly complete loss of full length AR (AR-FL) at castrate androgen levels. The overexpression of variants leads to enhanced transcriptional activity of AR while knock down studies show reduced transcriptional output. Collectively, the identification of truncated AR variants in the conditional PTEN deletion model supports a role for maintaining the CRPC phenotype and provides further therapeutic applications of this preclinical model.

Androgen receptor aberrations in the era of abiraterone and enzalutamide.

Prostate cancer is the most prevalent non-skin cancer and the second leading cause of cancer death in men of the western world. As growth and differentiation of prostate cancer largely depend on androgens, inhibition of the androgen/androgen receptor signaling axis is the main treatment for locally advanced and/or metastatic tumors. Although first-line androgen deprivation therapies like chemical/surgical castration and/or administration of anti-androgens are able to control the disease for several years, prostate cancer almost invariably recurs as castration-resistant prostate cancer. This stage of the disease is characterized by a sustained AR-signaling despite castrate levels of circulating androgens. Various molecular mechanisms were shown to induce castration resistance. This review will discuss the most recent and relevant experimental findings on AR-signaling in castration-resistant prostate cancer in order to provide a comprehensive interpretation of the clinical behavior of this tumor entity following treatments with abiraterone, enzalutamide, ARN-509 or taxanes.

Stable castration level of testosterone in androgendeprivation therapy for clear cell renal cell carcinoma

One of the most important strategies for treating prostate cancer is to achieve and maintain effective suppression of testosterone levels in men receiving androgen deprivation. Historically, testosterone levels below 50 ng/dl was regarded as castration level. Current data indicate that in an attempt to maximize the therapeutic result of a new target for any surgical or chemical castration is a testosterone level below 20 ng/dl. The phenomenon of flash testosterone and exacerbation of chronic conditions by introducing an analog of luteinizing hormone releasing hormone can cause testosterone levels to rise periodically, sometimes up to a non-castration levels. The study of androgen ablation is to identify those agents with which achieved and maintained lowest levels of testosterone.

Continuous release, solid depot, subcutaneous leuprolide acetate formulations to achieve and maintain castrate level serum testosterone levels below 20ng/dL in 4 open label, fixed dose studies.

e16062 Background: Growing evidence (eg, Klotz et al, EAU Congress 2014) suggest that prostate cancer patients undergoing androgen deprivation therapy who attained castrate levels of testosterone (...

The prognostic value of nadir testosterone levels in prostate cancer patients treated with combined androgen blockade in Japanese men.

e16049 Background: The most clinically significant castration level during androgen deprivation therapy (ADT) remains controversial. Moreover, no past studies demonstrated the prognostic impact of ...

Serum follicle-stimulating hormone levels predict time to development of castration-resistant prostate cancer.

Treatment of advancing prostate cancer focuses on blocking the activation of the androgen receptor with resultant prolonged perturbation of the hypothalamic-pituitary-gonadal axis. Androgen deprivation therapy (ADT) is marked, however, by eventual progression to castration- resistant prostate cancer (CRPC). Emerging evidence has postulated that follicle-stimulating hormone (FSH) may lead to proliferative and mutagenic responses of prostate cancer. We investigated the association of serum FSH and time to castration resistance. This was a single-centre retrospective study assessing serum FSH levels of patients undergoing ADT for advancing prostate cancer. The primary outcome was time of ADT initiation to the development of CRPC. For each patient on treatment and with castrate levels of testosterone, the maximum FSH value between ADT commencement and CRPC was identified and recorded. FSH was analyzed as a continuous and categorical variable. Cox multivariate regression in a step-wise fashion was used to explore the association between FSH levels and time to CRPC. From a database of 323 prostate cancer patients actively managed with ADT, 103 men had a documented FSH value while castrate, with 45 men progressing to CRPC. The mean ± standard deviation maximum FSH value of these patients was 6.66 ± 4.22 mIU/mL (range: 1.5-28.1). The mean duration from ADT commencement to CRPC was 3.03 ± 0.34 years (range: 0.36-9.71). Univariate analysis suggested a trend of a negative correlation between FSH values and time to castrate resistance. A FSH value of less than or equal to the lowest tertile (4.8 mIU/mL) was associated with a longer time to CRPC (hazard ratio 0.46; p = 0.006). In the Cox regression analysis, elevated FSH was associated with a shorter duration time to CRPC (p = 0.03). This retrospective, single-centre study would suggest there may be an association between serum FSH levels and time to CRPC for men treated palliatively with ADT for advancing prostate cancer. Further clinical investigation in a larger cohort of men is required to determine any clinical utility of FSH as a biomarker of progression or target for therapy.

MP73-16 SOLID DEPOT, CONTINUOUS RELEASE, SUBCUTANEOUS LEUPROLIDE ACETATE FORMULATIONS LASTING 1-6 MONTHS ACHIEVE AND MAINTAIN SERUM TESTOSTERONE LEVELS BELOW 20NG/DL IN 4 OPEN LABEL, FIXED DOSE STUDIES

INTRODUCTION AND OBJECTIVES: Increasing evidence suggests that lower serum testosterone (T) levels during androgen deprivation therapy (ADT) impact clinical outcomes in prostate cancer. Recent studies demonstrated increased overall survival and time to PSA progression free survival among patients who consistently attained castrate levels of T 20 ng/dL. While the US definition for effective castration has historically been T 50 ng/dL, the European Association of Urology guidelines have updated the target level to T 20 ng/dL. Hence, the objective of this analysis was to evaluate subcutaneous (SQ) Atrigel technology leuprolide acetate (LA) pivotal trial data in 1, 3, 4, and 6 month dose formulations to determine whether a SQ depot LHRH agonist suppressed T to achieve a more rigorous androgen suppression level of 20 ng/dL. METHODS: In 4 open label, fixed dose studies, male patients aged 40-86 years with prostate cancer, whom had not undergone ADT, were treated with a single SQ depot formulation of LA: 7.5 mg over 28 days, 22.5 mg over 3 months, 30 mg over 4 months, or 45 mg of drug over 6 months. Serum T was sampled at screening, baseline, 2, 4, 8 hours post-dosing, days 1, 2, 3, 7, and every week until the next dose, at which time, the sampling schedule repeated until the end of study (6 months for 1 and 3 month doses, 8 months for 4 month dose, and 12 months for 6 month dose). Descriptive statistics were used to summarize the concentrations at each time point as well as to determine time to T suppression. RESULTS: Mean serum T levels at end of study were consistently below 20 ng/dL for each trial (6.1 0.4, 10.1 0.7, 12.4 0.8, 12.6 2.1 for the 1 [N1⁄4117], 3 [N1⁄4111], 4 [N1⁄482], 6-month doses [N1⁄4103], respectively). During the 12-month trial of the 6 month formulation, a high proportion (94%) of study patients achieved serum T 20 ng/dL within 6 weeks after dosing. 92-96% of patients maintained serum T 20 ng/dL from week 6-24. CONCLUSIONS: All doses of SQ-LA rapidly achieved and maintained consistent mean serum T below the more rigorous 20 definition of castration. These data suggest that SQ-LA via Atrigel technology achieves a favorable lower level of T suppression, which may represent an important metric for improving survival and delaying progression in prostate cancer.

PII-LBA10 A MULTICENTER PHASE 2 STUDY OF ENZALUTAMIDE (ENZA) VERSUS BICALUTAMIDE (BIC) IN MEN WITH NONMETASTATIC (M0) OR METASTATIC (M1) CASTRATION-RESISTANT PROSTATE CANCER (CRPC): THE STRIVE TRIAL

You have accessJournal of UrologyPlenary Session II – Late Breaking Abstracts1 Apr 2015PII-LBA10 A MULTICENTER PHASE 2 STUDY OF ENZALUTAMIDE (ENZA) VERSUS BICALUTAMIDE (BIC) IN MEN WITH NONMETASTATIC (M0) OR METASTATIC (M1) CASTRATION-RESISTANT PROSTATE CANCER (CRPC): THE STRIVE TRIAL David Penson, Andrew Armstrong, Raoul Concepcion, Neeraj Agarwal, Fong Wang, Kenneth Wu, Andree Amelsberg, De Phung, and Celestia Higano David PensonDavid Penson More articles by this author , Andrew ArmstrongAndrew Armstrong More articles by this author , Raoul ConcepcionRaoul Concepcion More articles by this author , Neeraj AgarwalNeeraj Agarwal More articles by this author , Fong WangFong Wang More articles by this author , Kenneth WuKenneth Wu More articles by this author , Andree AmelsbergAndree Amelsberg More articles by this author , De PhungDe Phung More articles by this author , and Celestia HiganoCelestia Higano More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.03.124AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail BACKGROUND ENZA, an androgen receptor inhibitor, improves overall survival vs placebo in metastatic CRPC (Scher et al 2012; Beer et al 2014). BIC 50 mg/day is a commonly used therapy in men who progress despite castrate levels of testosterone. The Phase 2 STRIVE trial (NCT01664923) compared ENZA vs BIC in men with progressive M0 or M1 CRPC to evaluate the comparative effectiveness of these agents in both populations. METHODS STRIVE was a randomized, double-blind trial that enrolled men in the US to either ENZA 160 mg/day or BIC 50 mg/day. The primary endpoint was progression free survival (PFS), defined as time from randomization to radiographic progression, PSA progression, or death from any cause, whichever occurred first. RESULTS A total of 396 men were enrolled; 198 men were randomized to each of the ENZA and BIC arms. Baseline characteristics were comparable between groups. For all patients (pts), median age was 73 years; 35% were M0 and 65% were M1; median baseline PSA was 12. Median time on treatment with ENZA was 14.7 months (mos) vs 8.4 mos with BIC. For ENZA vs BIC, respectively: median PFS was 19.4 vs 5.7 mos (HR 0.24; CI 0.18-0.32; p<0.0001); median rPFS was not reached (NR) vs 11.2 mos (HR 0.3; CI 0.21-0.44); median time to PSA progression was NR vs 8.3 mos (HR 0.19; CI 0.14-0.26; p<0.0001); PSA response ≥50% was 81.3% vs 31.3% (p<0.0001). Efficacy data by status M0 vs M1 is shown in table. Serious adverse events (AEs) and ≥3 grade cardiac AEs were similar: 29.4% and 5.1% ENZA vs 28.3% and 4.0% in BIC, respectively. One seizure was reported with ENZA. Common (≥10%) AEs reported more frequently with ENZA vs BIC were (in %): fatigue (37.6 vs 28.3), back pain (17.8 vs 15.7), hot flush (15.7 vs 9.6), fall (13.7 vs 8.1), hypertension (12.2 vs 5.1), dizziness (12.2 vs 7.1), decreased appetite (11.7 vs 8.6). CONCLUSIONS In men with either M0 or M1 CRPC, treatment with ENZA demonstrated significantly superior PFS, rPFS, time to PSA progression, and PSA response rates compared with BIC. The safety profile of ENZA was consistent with that seen in previous studies of men with mCRPC. The STRIVE study was the first head-to-head trial of antiandrogen therapy that included men with M0 CRPC. Endpoints: M0 M1 ENZA (N=70) BIC (N=69) ENZA (N=128) BIC (N=129) Median PFS (months) NR 8.6 16.5 5.5 HR (95% CI) 0.24 (0.14-0.42) 0.24 (0.17-0.34) Median radiographic PFS (months) NR NR NR 8.3 HR (95% CI) 0.24 (0.10-0.56) 0.32 (0.21-0.50) Median Time to PSA Progression (months) NR 11.1 24.9 5.7 HR (95% CI) 0.18 (0.10-0.34) 0.19 (0.13-0.28) PSA Response (≥50%) 90.9% 42.0% 76.2% 25.4% CI=confidence interval; HR=hazard ratio; NR=not reached; PSA=prostate-specific antigen © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e499 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information David Penson More articles by this author Andrew Armstrong More articles by this author Raoul Concepcion More articles by this author Neeraj Agarwal More articles by this author Fong Wang More articles by this author Kenneth Wu More articles by this author Andree Amelsberg More articles by this author De Phung More articles by this author Celestia Higano More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Efficacy of triptorelin pamoate 11.25 mg administered subcutaneously for achieving medical castration levels of testosterone in patients with locally advanced or metastatic prostate cancer

Gonadotropin-releasing hormone agonists are widely used as androgen deprivation therapy in many men with locally advanced or metastatic prostate cancer. Gonadotropin-releasing hormone agonists are delivered by intramuscular injection every 1, 3 or 6 months, but in some patients subcutaneous injection may be more appropriate. This study assessed the efficacy and safety profile of the gonadotropin-releasing hormone agonist, triptorelin pamoate, when administered by the subcutaneous route. In this multicentre, open-label, single-arm study, androgen deprivation therapy-naïve men with locally advanced or metastatic prostate cancer received the gonadotropin-releasing hormone agonist triptorelin pamoate 11.25 mg (3-month formulation) by the subcutaneous route twice (at baseline and 13 weeks later). The co-primary efficacy endpoints were the proportion of patients with a castration level of serum testosterone (<50 ng/dl) after 4 weeks, and of these, those still castrated after 26 weeks. Of the 126 treated patients, 123 [97.6%; 95% confidence interval (CI): 93.2-99.5)] were castrated 4 weeks after the first subcutaneous injection, and 115/119 patients (96.6%; 95% CI: 91.6-99.1) castrated at 4 weeks maintained castration at 26 weeks. Median prostate-specific antigen levels were reduced by 64.2 and 96.0% at 4 and 26 weeks, respectively. The probability of maintaining a testosterone level <20 ng/dl up to 26 weeks was 90.0% (95% CI: 85.0-95.0). The most frequently occurring treatment-related adverse events were typical of gonadotropin-releasing hormone agonist treatment (hot flushes, increased weight, erectile dysfunction and hyperhidrosis). This study demonstrates that triptorelin pamoate 11.25 mg administered by the subcutaneous route every 3 months is as efficacious and well tolerated as administration via the intramuscular route in men with locally advanced or metastatic prostate cancer.