orteronel and Prostatic-Neoplasms

Orteronel (TAK-700) is an oral, non-steroidal 17,20-lyase inhibitor with higher specificity for 17,20 lyase over 17 hydroxylase. The first phase III studies showed an advantage with orteronel compared with placebo in terms of progression free survival and response of PSA. Unfortunately orteronel did not significantly prolong the overall survival. In order to assess the efficacy of orteronel in prostate cancer, we evaluated all available data on orteronel in the management of prostate cancer. A total of 2716 patients were evaluated from 3 randomized trials. We showed orteronel improved the progression free survival, time to PSA progression and PSA response compared with the placebo. In conclusion, given the limitations a literature rather than on individual patients' data meta-analysis, our data show a clinical efficacy of orteronel in prostate cancer, therefore we deem that orteronel may be investigated in combination with the other approved agents for CRPC or be tested in prior setting of disease such as the hormone sensitive prostate cancer.

Topics: Antineoplastic Agents; Disease-Free Survival; Humans; Imidazoles; Male; Naphthalenes; Prostate-Specific Antigen; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Steroid 17-alpha-Hydroxylase

Given prostate cancer is driven, in part, by its responsiveness to androgens, treatments historically employ methods for their removal from circulation. Approaches as crude as castration, and more recently blockade of androgen synthesis or receptor binding, are still of limited use long term, since other steroids of adrenal origin or tumor origin can supersede that role as the 'castration resistant' tumor re-emerges. Broader inhibition of steroidogenesis using relatively nonselective P450 inhibitors such as ketoconazole is not an alternative since a general disruption of steroid biosynthesis is neither safe nor effective. The recent emergence of drugs more selectively targeting CYP17 have been more effective, and yet extension of life has been on the scale of months rather than years. It is now becoming clear this shortcoming arises from the adaptive capabilities of many tumors to initiate local steroid synthesis and/or become responsive to novel early pathway adrenal steroids that are synthesized when lyase activity is not selectively blocked, and ACTH rises in the face of declining cortisol feedback. Abiraterone has been described as a lyase selective inhibitor, yet its use still requires co-administration of prednisone to suppress such a rise of ACTH and fall in cortisol. So is creation of a selective lyase inhibitor even possible? Can C19 steroid production be achieved without a prominent decline in cortisol and corresponding rise in ACTH? Decades of scientific study of CYP17 in humans and nonhuman primates, as well as nature's own experiments of gene mutations in humans, reveal 'true' or 'isolated' 17,20 lyase deficiency does quite selectively prevent C19 steroid biosynthesis whereas simple 17 hydroxylase deficiency also suppresses cortisol. We propose these known outcomes of natural mutations should be used to guide analysis of clinical trials and long term outcomes of CYP17 targeted drugs. In this review, we use that framework to re-evaluate the basic and clinical outcomes of many compounds being used or in development for treatment of castration resistant prostate cancer. Specifically, we include the nonselective drug ketoconazole, and then the CYP17 targeted drugs abiraterone, orteronel (TAK-700), galaterone (TOK-001), and seviteronel (VT-464). Using this framework, we can fully discriminate the clinical outcomes for ketoconazole, a drug with broad specificity, yet clinically ineffective, from that of abiraterone, the first CYP17 targeted therapy

Topics: Adrenal Hyperplasia, Congenital; Androstadienes; Androstenes; Antineoplastic Agents; Benzimidazoles; Cytochrome P-450 CYP3A Inhibitors; Drug Therapy, Combination; Humans; Hydrocortisone; Imidazoles; Ketoconazole; Male; Naphthalenes; Prednisone; Prostate; Prostatic Neoplasms; Protective Factors; Steroid 17-alpha-Hydroxylase; Triazoles

New drugs have recently been developed, through a better understanding of the mechanisms involved in the progression of prostate cancer, including castration-resistant ones (CRPC). This article aims to describe the mechanisms of action of these new hormonal treatments and their major clinical outcomes and development programs.. A bibliographic research in French and English using Medline(®) and Embase(®) using the keywords "castration-resistant prostate cancer", "abiraterone acetate", "orteronel", "enzalutamide", and "clinical trials" was performed.. the androgen signaling pathway remains the cornerstone of advanced cancers management. Hence, some molecules target the androgen biosynthesis, as abiraterone acetate and orteronel, which are selective inhibitors of the enzyme CYP17. Others act as antagonists of the androgen receptor: the enzalutamide, RNA-509 and ODM201. Finally, galeterone combines the two effects.. Progress conferred by these molecules in terms of overall survival and quality of life in patients with metastatic CRPC, suggest that their use at earlier stages of the disease could reduce morbidity and mortality from prostate cancer. Determining the best strategy for sequence or combination therapy to optimize the use of these new molecules should be investigated.

Topics: Abiraterone Acetate; Androgen Antagonists; Androgen Receptor Antagonists; Androstadienes; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Benzamides; Clinical Trials as Topic; Drug Resistance, Neoplasm; Humans; Imidazoles; Male; Naphthalenes; Neoplasm Staging; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Quality of Life; Steroid 17-alpha-Hydroxylase; Treatment Outcome

Advanced prostate cancer that progresses under androgen deprivation therapy has long been thought to be refractory to further hormonal treatment. The identification of the mechanism of cancer cells has revolutionized this understanding. Today it is known that castration-resistant prostate cancer (CRPC) still receives signals through the androgen receptor transduction pathways and furthermore is sensitive to hormone therapy. New substances, such as abiraterone, enzalutamide (MDV3100) and TAK 700 target these mechanisms of resistance of cancer cells, stop testosterone production and show not only better tolerance but also effective antitumor activity. Due to the heterogeneity of tumors with cells in varying states of differentiation, the treatment of CRPC with androgen deprivation therapy remains a cornerstone of disease management. To what extent the experimental findings and the recommendations in the guidelines are put into practice was the subject of a survey among urologists analyzing their treatment strategies with CRPC patients.

Topics: Androgen Antagonists; Androstenes; Androstenols; Antineoplastic Agents, Hormonal; Benzamides; Biomarkers, Tumor; Disease Progression; Drug Resistance, Neoplasm; Humans; Imidazoles; Male; Naphthalenes; Nitriles; Orchiectomy; Phenylthiohydantoin; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms

Androgen and the androgen receptor (AR) pathway remain the key targets for emerging new therapies against castration-resistant prostate cancer (CRPC). Adrenal androgens and intratumoral testosterone production appear to be sufficient to activate AR in the castration-resistant setting. This process re-engages AR and allows it to continue to be the primary target responsible for prostate cancer progression. Adrenal androgen production can be blocked by inhibiting cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17), a key enzyme for androgen synthesis in adrenal glands and peripheral tissues. Therapeutic CYP17 inhibition by ketoconazole or by the recently approved adrenal inhibitor abiraterone acetate is the only available choice to target this pathway in CRPC. A new CYP17 inhibitor, with more selective inhibition of 17,20-lyase over 17α-hydroxylase, orteronel (TAK-700), is currently undergoing phase III clinical trials in pre- and postchemotherapy CRPC. In a completed phase II trial in CRPC patients, orteronel demonstrated its efficacy by lowering the levels of circulating androgens, reducing prostate-specific antigen (PSA) levels, and decreasing the levels of circulating tumor cells. Ongoing studies evaluating orteronel in CRPC will further define its safety and role in the management of this disease.

Topics: Androgen Antagonists; Antineoplastic Agents; Clinical Trials as Topic; Humans; Imidazoles; Male; Naphthalenes; Orchiectomy; Prostatic Neoplasms; Steroid 17-alpha-Hydroxylase

• It is >70 years since the responsiveness of symptomatic metastatic prostate cancer to androgen deprivation was first demonstrated. • Since those pivotal studies, progress in hormonal therapy of prostate cancer has been marked by several important developments and the availability of various androgen-suppressing agents. • Treatment guidelines have continued to evolve with clinical and therapeutic progress, but androgen-deprivation therapy (ADT) remains the standard of care for non-localised prostate cancer. • Because of the long-term experience (>20 years) and wealth of evidence from the large number of clinical trials, the luteinizing hormone-releasing hormone (LHRH) agonists are currently the main forms of ADT. • Treatment strategies should be adapted to the individual patient in terms of timing, duration and choice of agent. • Prostate cancer remains the most common type of cancer in men and the development of castration-resistant disease seems inevitable, which together drive the clear and continuing need for new, effective agents for ADT to be used alongside the LHRH agonists.

Topics: Abiraterone Acetate; Androgen Antagonists; Androstadienes; Antineoplastic Agents, Hormonal; Benzamides; Combined Modality Therapy; Humans; Imidazoles; Male; Naphthalenes; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Treatment Outcome

Androgen receptor (AR)-mediated signaling is critical to the growth and survival of prostate cancer. Although medical castration and antiandrogen therapy can decrease AR activity and lower PSA, castration resistance eventually develops. Recent work exploring the molecular structure and evolution of AR in response to hormonal therapies has revealed novel mechanisms of progression of castration-resistant prostate cancer and yielded new targets for drug development. This review focuses on understanding the mechanisms of persistent AR signaling in the castrate environment, and highlights new therapies either currently available or in clinical trials, including androgen synthesis inhibitors and novel direct AR inhibitors.

Topics: Androgen Antagonists; Androstadienes; Antineoplastic Agents; Benzamides; Benzimidazoles; Humans; Imidazoles; Male; Naphthalenes; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Receptors, Androgen; Steroid 17-alpha-Hydroxylase; Testosterone; Thiohydantoins

Cytochrome P450 (P450) 17A1 catalyzes the 17α-hydroxylation of progesterone and pregnenolone as well as the subsequent lyase cleavage of both products to generate androgens. However, the selective inhibition of the lyase reactions, particularly with 17α-hydroxy pregnenolone, remains a challenge for the treatment of prostate cancer. Here, we considered the mechanisms of inhibition of drugs that have been developed to inhibit P450 17A1, including ketoconazole, seviteronel, orteronel, and abiraterone, the only approved inhibitor used for prostate cancer therapy, as well as clotrimazole, known to inhibit P450 17A1. All five compounds bound to P450 17A1 in a multistep process, as observed spectrally, over a period of 10 to 30 s. However, no lags were observed for the onset of inhibition in rapid-quench experiments with any of these five compounds. Furthermore, the addition of substrate to inhibitor-P450 17A1 complexes led to an immediate formation of product, without a lag that could be attributed to conformational changes. Although abiraterone has been previously described as showing slow-onset inhibition (t

Topics: Androgens; Androstenes; Antineoplastic Agents, Hormonal; Catalytic Domain; Cytochrome P-450 CYP3A; Enzyme Inhibitors; Humans; Imidazoles; Ketoconazole; Kinetics; Male; Naphthalenes; Pregnenolone; Progesterone; Prostatic Neoplasms; Steroid 17-alpha-Hydroxylase

The orteronel, abiraterone and galeterone, which were developed to treat castration resistant prostate cancer, inhibit 17,20 lyase activity but little is known about their effects on adrenal androgen biosynthesis. We studied the effect of several inhibitors and found that orteronel was selective towards 17,20 lyase activity than abiraterone and galeterone. Gene expression analysis showed that galeterone altered the expression of HSD3B2 but orteronel did not change the expression of HSD3B2, CYP17A1 and AKR1C3. The CYP19A1 activity was not inhibited except by compound IV which lowered activity by 23%. Surprisingly abiraterone caused complete blockade of CYP21A2 activity. Analysis of steroid metabolome by gas chromatography - mass spectrometry revealed changes in steroid levels caused by different inhibitors. We can conclude that orteronel is a highly specific inhibitor of 17,20 lyase activity. The discovery of these specific drug actions on steroidogenic enzyme activities would be valuable for understanding the regulation of androgens.

Topics: Adrenal Glands; Androgens; Androstadienes; Androstenes; Antineoplastic Agents; Benzimidazoles; Cell Line; Dose-Response Relationship, Drug; Humans; Imidazoles; Male; Naphthalenes; Prostatic Neoplasms; Steroid 17-alpha-Hydroxylase

Orteronel (also known as TAK-700) is a novel hormonal therapy that is currently in testing for the treatment of prostate cancer. Orteronel inhibits the 17,20 lyase activity of the enzyme CYP17A1, which is important for androgen synthesis in the testes, adrenal glands and prostate cancer cells. Preclinical studies demonstrate that orteronel treatment suppresses androgen levels and causes shrinkage of androgen-dependent organs, such as the prostate gland. Early reports of clinical studies demonstrate that orteronel treatment leads to reduced prostate-specific antigen levels, a marker of prostate cancer tumor burden, and more complete suppression of androgen synthesis than conventional androgen deprivation therapies that act in the testes alone. Treatment with single-agent orteronel has been well tolerated with fatigue as the most common adverse event, while febrile neutropenia was the dose-limiting toxicity in a combination study of orteronel with docetaxel. Recently, the ELM-PC5 Phase III clinical trial in patients with advanced-stage prostate cancer who had received prior docetaxel was unblinded as the overall survival primary end point was not achieved. However, additional Phase III orteronel trials are ongoing in men with earlier stages of prostate cancer.

Topics: Androgen Antagonists; Androgens; Clinical Trials as Topic; Drug Evaluation; Drug-Related Side Effects and Adverse Reactions; Humans; Imidazoles; Male; Naphthalenes; Prostate-Specific Antigen; Prostatic Neoplasms; Steroid 17-alpha-Hydroxylase

Endogenous androgens play a role in the development and progression of prostate cancer (PC), thus androgen suppression may offer an effective therapeutic strategy for this disease. Orteronel (TAK-700), 6-[(7S)-7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl]-N-methyl-2-naphthamide, is a novel, non-steroidal, selective inhibitor of the 17,20-lyase activity of CYP17A--a key enzyme in the production of steroidal hormones--and is being developed as a therapy for PC. The purpose of this study was to elucidate the inhibitory activity of orteronel, in particular its specificity for androgen synthesis enzymes, in male rats--an androgen-synthesis model that largely reflects this pathway in humans. Orteronel inhibited 17,20-lyase activity in rats with an IC(50) of 1200 nM but did not inhibit 17α-hydroxylase or 11β-hydroxylase (CYP11B1) activity in rats at concentrations up to 10 μM. In cellular steroidogenesis assays using rat testicular cells, orteronel suppressed testosterone and androstenedione production with an IC(50) of 640 nM and 210 nM, respectively, but did not suppress either corticosterone or aldosterone production in rat adrenal cells at concentrations up to 30 μM. In addition, serum testosterone and androstenedione levels in human chorionic gonadotropin-injected hypophysectomized rats were significantly reduced by single oral administration of orteronel at a dose of 30 mg/kg (both p ≤ 0.01); serum corticosterone and aldosterone levels in ACTH-injected hypophysectomized rats did not result in significant differences compared with controls, following orteronel administration at doses up to 300 mg/kg. Serum testosterone levels in intact male rats were significantly reduced by orteronel 4h after dosing at 100mg/kg (p ≤ 0.01); testosterone levels showed a tendency to recover afterward. In intact male rats, the weight of the prostate glands and seminal vesicles was decreased in a dose-dependent manner following multiple doses of orteronel at 37.5, 150, and 600 mg/kg, TID for 4 days. The reversibility of orteronel was further confirmed using a human adrenocortical tumor cell line. In summary, orteronel is a selective and reversible 17,20-lyase inhibitor, and decreases the weight of androgen-dependent organs in male rats. Our data suggests that orteronel would therefore be effective for androgen-dependent disorders such as PC.

Topics: Adrenal Glands; Androgens; Animals; Imidazoles; Male; Naphthalenes; Organ Size; Prostatic Neoplasms; Rats; Steroid 11-beta-Hydroxylase; Steroid 17-alpha-Hydroxylase; Steroids; Testis

A highly sensitive, specific and high-throughput LC-ESI-MS/MS method in the positive mode has been developed and validated for the quantitation of Orteronel® (TAK-700) in rat plasma using YM-55208 as an internal standard.. The assay procedure involves extraction of Orteronel and internal standard from rat plasma with liquid-liquid extraction method. Chromatographic separation was achieved using an isocratic mobile phase at a flow rate of 0.6 ml/min on an Atlantis dC18 column with a total run time of 2.5 min. The MS/MS ion transitions monitored were m/z 308.4→95.0 for Orteronel and m/z 262.3→194.2 for IS. Method validation was performed as per US FDA guidelines. The LLOQ achieved was 0.42 ng/ml and the linearity range extended from 0.42 to 814 ng/ml.. The results met the acceptance criteria. The validated method was successfully applied to characterize the pharmacokinetic parameters of Orteronel in rat plasma.

Topics: Animals; Chromatography, Reverse-Phase; Drug Stability; Guidelines as Topic; Humans; Imidazoles; Limit of Detection; Linear Models; Liquid-Liquid Extraction; Male; Naphthalenes; Prostatic Neoplasms; Rats; Reference Standards; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry; United States; United States Food and Drug Administration

A novel naphthylmethylimidazole derivative 1 and its related compounds were identified as 17,20-lyase inhibitors. Based on the structure-activity relationship around the naphthalene scaffold and the results of a docking study of 1a in the homology model of 17,20-lyase, the 6,7-dihydro-5H-pyrrolo[1,2-c]imidazole derivative (+)-3c was synthesized and identified as a potent and highly selective 17,20-lyase inhibitor. Biological evaluation of (+)-3c at a dose of 1mg/kg in a male monkey model revealed marked reductions in both serum testosterone and dehydroepiandrosterone concentrations. Therefore, (+)-3c (termed orteronel [TAK-700]) was selected as a candidate for clinical evaluation and is currently in phase III clinical trials for the treatment of castration-resistant prostate cancer.

Topics: Animals; Antineoplastic Agents; Crystallography, X-Ray; Dehydroepiandrosterone; Enzyme Inhibitors; Haplorhini; Humans; Imidazoles; Inhibitory Concentration 50; Magnetic Resonance Spectroscopy; Male; Models, Molecular; Molecular Dynamics Simulation; Naphthalenes; Prostatic Neoplasms; Stereoisomerism; Steroid 17-alpha-Hydroxylase; Structure-Activity Relationship; Testosterone