DOCSLIB.ORG

Phase 1/2 Trial of Orteronel (TAK-700) – an Investigational 17,20-Lyase

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Phase 1/2 Trial of Orteronel (TAK-700) – an Investigational 17,20-Lyase Author Manuscript Published OnlineFirst on January 13, 2014; DOI: 10.1158/1078-0432.CCR-13-2436 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Phase 1/2 trial of 17,20-lyase inhibitor orteronel in mCRPC Phase 1/2 Trial of Orteronel (TAK-700) – an Investigational 17,20-Lyase Inhibitor – in Patients with Metastatic Castration-Resistant Prostate Cancer Authors: Robert Dreicer1, David MacLean2, Ajit Suri2, Walter M. Stadler3, Daniel Shevrin4, Lowell Hart5, Gary R. MacVicar6, Omid Hamid7, John Hainsworth8, Mitchell E. Gross10, Yuanjun Shi2, Iain J. Webb9, and David B. Agus10 Author affiliations: 1Cleveland Clinic, Cleveland, OH, USA 2Takeda Pharmaceuticals International Company, Cambridge, MA, USA 3University of Chicago, Chicago, IL, USA 4NorthShore University Health System, Evanston, IL, USA 5Florida Cancer Specialists, Fort Myers, FL, USA 6Northwestern University Feinberg School of Medicine, Chicago, IL, USA 7The Angeles Clinic & Research Institute, Los Angeles, CA, USA 8Sarah Cannon Cancer Research Institute, Nashville, TN, USA 9Millennium: The Takeda Oncology Company, Cambridge, MA 10University of Southern California Westside Cancer Center, Beverly Hills, CA, USA Corresponding author: Robert Dreicer, M.D., M.S., FACP, FASCO 9500 Euclid Ave R35, Cleveland, OH 44195, USA Phone: 216-445-4623 Fax: 216-445-2360 Email: [email protected] 1 Dreicer_201 manuscript_28Oct2013 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2014 American Association for Cancer Research. Author Manuscript Published OnlineFirst on January 13, 2014; DOI: 10.1158/1078-0432.CCR-13-2436 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Phase 1/2 trial of 17,20-lyase inhibitor orteronel in mCRPC Running title: Phase 1/2 trial of 17,20-lyase inhibitor orteronel in mCRPC (limit 60 characters) Keywords: TAK-700, orteronel, castration-resistant prostate cancer Funding: Takeda Pharmaceuticals International Company Statement of originality: The authors confirm that this manuscript contains original material. Conflicts of Interest Employment: DBM, AS, and YS (Takeda Pharmaceuticals International Company); IW (Millennium: The Takeda Oncology Company); Consultant or advisory role: RD, WMS, DBA (Millennium: The Takeda Oncology Company); Honoraria: RD (Millennium: The Takeda Oncology Company); Research support/travel grant: OH, MEG (Millennium: The Takeda Oncology Company); No conflicts to disclose: DS, LH, GRM, JH Journal: Clinical Cancer Research Article type: Cancer Therapy: Clinical Statement of translational relevance: 121 (limit 120–150 words) Summary word count: 239 (limit 250 words) Word count: 3071 (limit 5000 words for main body text only) Figures/tables: 3/3 (limit 6 Figures/Tables in total) References: 24 (limit 50) Supplemental materials: 1 Table 2 Dreicer_201 manuscript_28Oct2013 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2014 American Association for Cancer Research. Author Manuscript Published OnlineFirst on January 13, 2014; DOI: 10.1158/1078-0432.CCR-13-2436 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Phase 1/2 trial of 17,20-lyase inhibitor orteronel in mCRPC Prior presentations of this study: Agus DB, Stadler WM, Shevrin DH et al. Safety, efficacy, and pharmacodynamics of the investigational agent TAK-700 in metastatic castration-resistant prostate cancer (mCRPC): Updated data from a phase I/II study. ASCO Meeting Abstracts 2011;29 (15_suppl):4531. Agus DB, Stadler WM, Shevrin D et al. Safety, efficacy, and pharmacodynamics of the investigational agent TAK-700 in metastatic castration-resistant prostate cancer (MCRPC): Updated data from a phase 1/2 study. Presented at the 34th Congresso Brasileiro de Urologia, Florianópolis, Santa Catarina, Brazil, November 22-26, 2011. Agus DB, Stadler WM, Shevrin D et al. Safety, efficacy, and pharmacodynamics of the investigational agent orteronel (TAK-700) in metastatic castration-resistant prostate cancer (mCRPC): Updated data from a phase 1/2 study. Presented at the 20th Malaysian Urological Conference-Asia Pacific Society of Uro-Oncology Conference, Kuala Lumpur, Malaysia, November 25-27, 2011. Gross M, Shevrin D, Dreicer R et al. Phase 1/2 Study of TAK-700, an Investigational 17,20- Lyase Inhibitor, in Chemotherapy-naïve Patients with Metastatic Castration-Resistant Prostate Cancer (mCRPC): Safety, Efficacy, and Evaluation of Circulating Tumor Cells (CTCs). Presented at the 3rd European Multidisciplinary Meeting on Urological Cancers (EMUC), Barcelona, Spain, November 4-6, 2011. Agus DB, Stadler WM, Shevrin D et al. Safety, efficacy, and pharmacodynamics of the investigational agent orteronel (TAK-700) in metastatic castration-resistant prostate cancer (mCRPC): Updated data from a phase 1/2 study. ASCO-GU Meeting Abstracts 2012; J Clin Oncol 2012;30 (suppl 5):(Abstr 98). 3 Dreicer_201 manuscript_28Oct2013 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2014 American Association for Cancer Research. Author Manuscript Published OnlineFirst on January 13, 2014; DOI: 10.1158/1078-0432.CCR-13-2436 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Phase 1/2 trial of 17,20-lyase inhibitor orteronel in mCRPC MacLean DB, Stadler WM, Shevrin D et al. Selective inhibition of androgen synthesis by orteronel (TAK-700), an investigational 17,20-lyase inhibitor, in men with metastatic castrate resistant prostate cancer (mCRPC). Poster presented at the Endocrine Society’s 94th Annual Meeting & Expo, June 23–26, 2012, Houston, Texas, USA. Role of the funding source Employees of Takeda Pharmaceuticals International Company participated in trial design, data collection, data analysis, data interpretation, and writing of the report. The sponsor of the study was involved in the design of the trial and provided grants to trial sites and had no other involvement in conduct of trial. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. 4 Dreicer_201 manuscript_28Oct2013 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2014 American Association for Cancer Research. Author Manuscript Published OnlineFirst on January 13, 2014; DOI: 10.1158/1078-0432.CCR-13-2436 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Phase 1/2 trial of 17,20-lyase inhibitor orteronel in mCRPC Statement of Translational Relevance This phase 1/2 trial of orteronel tests the concept of selective inhibition of the androgen synthesis pathway combined with continued adrenal cortisol synthesis by targeting the 17,20-lyase activity over the 17α-hydroxylase activity of CYP17A1 in the treatment of men with metastatic castration-resistant prostate cancer (mCRPC) and increased sensitivity to low remaining androgens. Alleviating the effects of early castration resistance can contribute to the development of more effective orteronel-based treatment for mCRPC. In this trial, we conducted dose escalation studies to evaluate the clinical benefits and pharmacokinetics of orteronel. This is the first clinical manuscript to report the safety and efficacy of orteronel. Our findings are currently being validated in ongoing phase III trials in patients with mCRPC. 5 Dreicer_201 manuscript_28Oct2013 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2014 American Association for Cancer Research. Author Manuscript Published OnlineFirst on January 13, 2014; DOI: 10.1158/1078-0432.CCR-13-2436 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Phase 1/2 trial of 17,20-lyase inhibitor orteronel in mCRPC Abstract Purpose: The androgen receptor pathway remains active in men with prostate cancer whose disease has progressed following surgical or medical castration. Orteronel (TAK-700) is an investigational, oral, non-steroidal, selective, reversible inhibitor of 17,20-lyase, a key enzyme in the production of androgenic hormones. Experimental Design: We conducted a phase 1/2 study in men with progressive, chemotherapy-naïve, metastatic castration-resistant prostate cancer (mCRPC) and serum testosterone <50 ng/dL. In the phase 1 part, patients received orteronel 100–600 mg twice- daily (BID) or 400 mg BID plus prednisone 5 mg BID. In phase 2, patients received orteronel 300 mg BID, 400 mg BID plus prednisone, 600 mg BID plus prednisone or 600 mg once- daily without prednisone. Results: In phase 1 (n = 26), no dose-limiting toxicities were observed and 13/20 evaluable patients (65%) achieved ≥50% prostate-specific antigen (PSA) decline from baseline at 12 weeks. In phase 2 (n = 97), 45/84 evaluable patients (54%) achieved a ≥50% decline in PSA and at 12 weeks, substantial mean reductions from baseline in testosterone (–7.5 ng/dL) and dehydroepiandrosterone-sulfate (DHEA-S; –45.3 μg/dL) were observed. Unconfirmed partial responses were reported in 10/51 evaluable phase 2 patients (20%). Decreases in circulating tumor cells were documented. Fifty-three percent of phase 2 patients experienced grade ≥3 adverse events irrespective of causality; most common were fatigue, hypokalemia, hyperglycemia, and diarrhea. Conclusions: 17,20-lyase inhibition by orteronel was tolerable and results in declines in PSA and testosterone, with evidence of radiographic responses. Category: Clinical
Load more

Recommended publications
  • A Phase 1 Multiple-Dose Study of Orteronel in Japanese Patients with Castration-Resistant Prostate Cancer
    Cancer Chemother Pharmacol (2015) 75:373–380 DOI 10.1007/s00280-014-2654-y ORIGINAL ARTICLE A phase 1 multiple-dose study of orteronel in Japanese patients with castration-resistant prostate cancer Kazuhiro Suzuki · Seiichiro Ozono · Akito Yamaguchi · Hidekazu Koike · Hiroshi Matsui · Masao Nagata · Takatoshi Takubo · Kana Miyashita · Takafumi Matsushima · Hideyuki Akaza Received: 6 November 2014 / Accepted: 14 December 2014 / Published online: 24 December 2014 © The Author(s) 2014. This article is published with open access at Springerlink.com Abstract Cycle 1 in this study. Adverse events (AEs) were reported Purpose Orteronel (TAK-700) is a non-steroidal, selec- in all 15 patients. Most common AEs (>30 %) were hyper- tive, reversible inhibitor of 17,20-lyase. We evaluated the lipasemia (47 %), hyperamylasemia (40 %), and consti- safety, tolerability, pharmacokinetics, pharmacodynamics, pation (33 %). Acute pancreatitis (Grades 2 and 3) and and antitumor effect of orteronel with or without predniso- pancreatitis (Grade 1) were complicated in three patients lone in Japanese patients with castration-resistant prostate during the study. Dose-dependent increase in plasma orte- cancer (CRPC). ronel concentrations was indicated over the 200–400 mg Methods We conducted a phase 1 study in men with pro- BID dose range. Prednisolone coadministered did not alter gressive and chemotherapy-naïve CRPC. Patients received PK of orteronel. Serum testosterone was rapidly suppressed orteronel orally at doses of 200–400 mg twice daily (BID) below the lower limit of quantification across all doses. Of with or without oral prednisolone (5 mg BID). Dose-limit- 15 subjects, 13 achieved at least a 50 % reduction from ing toxicity (DLT) was assessed during Cycle 1 (28 days).
    [Show full text]
  • (19) United States (12) Patent Application Publication (Io) Pub
    llIIlIlllIlIlIllIlIllIllIllIIlIlllIlIIllllIIlllIIlIlllIIlIlllllIIIlllIlIllIIIIIIIIIIIIIIII US 20160015712AI (19) United States (12) Patent Application Publication (Io) Pub. No. : US 2016/0015712 A1 DORSCH et al. (43) Pub. Date: Jan. 21, 2016 (54) TRIAZOLO [4,5-D]PYRIMIDINE Publication Classification DERIVATIVES (51) Int. Cl. (71) Applicant: MERCK PATENT GMBH, Darmstadt 261K31/519 (2006.01) (DE) 261K31/53 77 (2006.01) C07D 519/00 (2006.01) (72) Inventors: Dieter DORSCH, Ober-Ramstadt (DE); C07D 487/04 (2006.01) Guenter HOELZEMANN, (52) U.S. Cl. Seeheim- Jugenheim (DE); Michel CPC ............ 261K31/519 (2013.01); C07D 487/04 CALDERINI, Darmstadt (DE); Ansgar (2013.01);261K31/5377 (2013.01); C07D WEGENER, Heusenstamm (DE); 519/00 (2013.01) Oliver POESCHKE, Wiesbaden (DE) (57) ABSTRACT (73) Assignee: MERCK PATENT GMBH, Darmstadt (DE) Compounds of the formula I (21) Appl. No. : 14/772, 865 (22) PCT Filed: Feb. 10, 2014 H (86) PCT No. : PCT/EP2014/000361 II ) 371 (c)(I), NX N (2) Date: Sep. 4, 2015 (30) Foreign Application Priority Data in which R' and R have the meanings indicated in Claim 1, are inhibitors of GCN2, and can be employed, inter alia, for Mar. 5, 2013 (EP) ... 13001110.9 the treatment of cancer. US 2016/0015712 A1 Jan. 21, 2016 TRIAZOLO [4,5-D]PYRIMIDINE [0006] Several mechanistic studies discovered that DERIVATIVES immune escape has an important interface with metabolic alterations within the tumor microenvironment. Here impor- BACKGROUND OF THE INVENTION tant roles in mediating immune tolerance to antigens have been associated to the catabolism ofthe essential amino acids [0001] The invention had the object of finding novel com- tryptophan and arginine, carried out by the enzymes pounds having valuable properties, in particular those which indoleamine 2,3-dioxygenase (IDO) and arginase I (ARG), can be used for the medicaments.
    [Show full text]
  • Galeterone for the Treatment of Castration- Resistant Prostate Cancer Bruce Montgomery1, Mario A
    Published OnlineFirst November 2, 2015; DOI: 10.1158/1078-0432.CCR-15-1432 Cancer Therapy: Clinical Clinical Cancer Research Androgen Receptor Modulation Optimized for Response (ARMOR) Phase I and II Studies: Galeterone for the Treatment of Castration- Resistant Prostate Cancer Bruce Montgomery1, Mario A. Eisenberger2, Matthew B. Rettig3, Franklin Chu4, Roberto Pili5, Joseph J. Stephenson6, Nicholas J. Vogelzang7, Alan J. Koletsky8, Luke T. Nordquist9, William J. Edenfield10, Khalid Mamlouk11, Karen J. Ferrante11, and Mary-Ellen Taplin12 Abstract Purpose: Galeterone is a selective, multitargeted agent that Results: In ARMOR1, across all doses, 49.0% (24/49) achieved a inhibits CYP17, antagonizes the androgen receptor (AR), and 30% decline in prostate-specific antigen (PSA; PSA30) and reduces AR expression in prostate cancer cells by causing an 22.4% (11/49) demonstrated a 50% PSA decline (PSA50). In increase in AR protein degradation. These open-label phase I ARMOR2 part 1, across all doses, PSA30 was 64.0% (16/25) and and II studies [Androgen Receptor Modulation Optimized PSA50 was 48.0% (12/25). In the 2,550-mg dose cohort, PSA30 for Response-1 (ARMOR1) and ARMOR2 part 1] evaluated was 72.7% (8/11) and PSA50 was 54.5% (6/11). Galeterone was the efficacy and safety of galeterone in patients with treat- well tolerated; the most common adverse events were fatigue, ment-naive nonmetastatic or metastatic castration-resistant increased liver enzymes, gastrointestinal events, and pruritus. Most prostate cancer (CRPC) and established a dose for further were mild or moderate in severity and required no action and there study. were no apparent mineralocorticoid excess (AME) events.
    [Show full text]
  • WO 2018/111890 Al 21 June 2018 (21.06.2018) W !P O PCT
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2018/111890 Al 21 June 2018 (21.06.2018) W !P O PCT (51) International Patent Classification: EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, C07K 16/28 (2006.01) A61K 31/4166 (2006.01) MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, 59/595 (2006.01) TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). (21) International Application Number: PCT/US20 17/065841 Declarations under Rule 4.17: (22) International Filing Date: — as to applicant's entitlement to apply for and be granted a 12 December 2017 (12.12.2017) patent (Rule 4.1 7(H)) — as to the applicant's entitlement to claim the priority of the (25) Filing Language: English earlier application (Rule 4.17(Hi)) (26) Publication Langi English — of inventorship (Rule 4.1 7(iv)) (30) Priority Data: Published: 62/433,158 12 December 2016 (12.12.2016) US — with international search report (Art. 21(3)) — with sequence listing part of description (Rule 5.2(a)) (71) Applicant (for all designated States except AL, AT, BE, BG, CH, CN, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IN, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, P T RO, RS, SE, SI, SK, SM, TR): GENENTECH, INC. [US/US]; 1 DNA Way, South San Francisco, CA 94080-4990 (US).
    [Show full text]
  • Tanibirumab (CUI C3490677) Add to Cart
    5/17/2018 NCI Metathesaurus Contains Exact Match Begins With Name Code Property Relationship Source ALL Advanced Search NCIm Version: 201706 Version 2.8 (using LexEVS 6.5) Home | NCIt Hierarchy | Sources | Help Suggest changes to this concept Tanibirumab (CUI C3490677) Add to Cart Table of Contents Terms & Properties Synonym Details Relationships By Source Terms & Properties Concept Unique Identifier (CUI): C3490677 NCI Thesaurus Code: C102877 (see NCI Thesaurus info) Semantic Type: Immunologic Factor Semantic Type: Amino Acid, Peptide, or Protein Semantic Type: Pharmacologic Substance NCIt Definition: A fully human monoclonal antibody targeting the vascular endothelial growth factor receptor 2 (VEGFR2), with potential antiangiogenic activity. Upon administration, tanibirumab specifically binds to VEGFR2, thereby preventing the binding of its ligand VEGF. This may result in the inhibition of tumor angiogenesis and a decrease in tumor nutrient supply. VEGFR2 is a pro-angiogenic growth factor receptor tyrosine kinase expressed by endothelial cells, while VEGF is overexpressed in many tumors and is correlated to tumor progression. PDQ Definition: A fully human monoclonal antibody targeting the vascular endothelial growth factor receptor 2 (VEGFR2), with potential antiangiogenic activity. Upon administration, tanibirumab specifically binds to VEGFR2, thereby preventing the binding of its ligand VEGF. This may result in the inhibition of tumor angiogenesis and a decrease in tumor nutrient supply. VEGFR2 is a pro-angiogenic growth factor receptor
    [Show full text]
  • Therapies Targeted to Androgen Receptor Signaling Axis in Prostate Cancer: Progress, Challenges, and Hope
    cancers Review Therapies Targeted to Androgen Receptor Signaling Axis in Prostate Cancer: Progress, Challenges, and Hope Sirin Saranyutanon 1,2, Sanjeev Kumar Srivastava 1,2,*, Sachin Pai 3, Seema Singh 1,2,4 and Ajay Pratap Singh 1,2,4,* 1 Department of Pathology, College of Medicine, University of South Alabama, Mobile, AL 36617, USA; [email protected] (S.S.); [email protected] (S.S.) 2 Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA 3 Department of Medical Oncology, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA; [email protected] 4 Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL 36688, USA * Correspondence: [email protected] (S.K.S.); [email protected] (A.P.S.); Tel.: +1-251-445-9874 (S.K.S.); +1-251-445-9843 (A.P.S.) Received: 4 November 2019; Accepted: 18 December 2019; Published: 23 December 2019 Abstract: Prostate cancer is the mostly commonly diagnosed non-cutaneous malignancy and the second leading cause of cancer-related death affecting men in the United States. Moreover, it disproportionately affects the men of African origin, who exhibit significantly greater incidence and mortality as compared to the men of European origin. Since androgens play an important role in the growth of normal prostate and prostate tumors, targeting of androgen signaling has remained a mainstay for the treatment of aggressive prostate cancer. Over the years, multiple approaches have been evaluated to effectively target the androgen signaling pathway that include direct targeting of the androgens, androgen receptor (AR), AR co-regulators or other alternate mechanisms that impact the outcome of androgen signaling.
    [Show full text]
  • Orteronel for Metastatic Hormone-Relapsed Prostate Cancer
    Horizon Scanning Centre March 2013 Orteronel for metastatic hormone- relapsed prostate cancer following chemotherapy SUMMARY NIHR HSC ID: 4870 Orteronel is intended to be used as therapy for the treatment of hormone- relapsed prostate cancer following progression despite docetaxel-containing chemotherapy. If licensed, it will provide an additional treatment option for this patient group. Orteronel is a reversible, non-steroidal androgen biosynthesis inhibitor that selectively inhibits the 17,20 lyase enzyme, This briefing is suppressing the production of testosterone. based on information Prostate cancer is the most common cancer in men in the UK, accounting for available at the time 25% of all male cancers. The main risk factor is increasing age, with an of research and a average of 75% of cases diagnosed in men aged 65 years and over. In 2010, limited literature there were 37,354 new diagnoses registered in England and Wales and in search. It is not 2011, there were 9,671 deaths. intended to be a definitive statement Current treatment options include hormonal therapies, (glucocorticoids, low- on the safety, dose oestrogens, selective 17,20 lyase inhibitors, or novel androgen receptor efficacy or antagonists), chemotherapies (docetaxel, mitoxantrone) and effectiveness of the immunotherapies (sipuleucel-T). Orteronel is currently in phase III clinical health technology trials comparing its effect on overall survival and event-free survival against covered and should treatment with placebo. These trials are expected to complete in 2013 and not be used for 2015. commercial purposes or commissioning without additional information. This briefing presents independent research funded by the National Institute for Health Research (NIHR).
    [Show full text]
  • Download Product Insert (PDF)
    PRODUCT INFORMATION Orteronel Item No. 24191 CAS Registry No.: 566939-85-3 Formal Name: 6-[(7S)-6,7-dihydro-7-hydroxy- 5H-pyrrolo[1,2-c]imidazol-7-yl]-N- O methyl-2-naphthalenecarboxamide Synonym: TAK-700 N MF: C H N O 18 17 3 2 H OH N FW: 307.3 Purity: ≥98% N UV/Vis.: λmax: 237, 280 nm Supplied as: A crystalline solid Storage: -20°C Stability: ≥2 years Information represents the product specifications. Batch specific analytical results are provided on each certificate of analysis. Laboratory Procedures Orteronel is supplied as a crystalline solid. A stock solution may be made by dissolving the orteronel in the solvent of choice. Orteronel is soluble in organic solvents such as ethanol, DMSO, and dimethyl formamide (DMF), which should be purged with an inert gas. The solubility of orteronel in ethanol is approximately 0.2 mg/ml and approximately 10 mg/ml in DMSO and DMF. Description Orteronel is a non-steroidal inhibitor of the 17,20-lyase activity of the cytochrome P450 (CYP) isoform CYP17A1 (IC50s = 48 and 19 nM for the rat and human enzyme, respectively), which is the CYP17A1 activity that converts progestogens into androgens.1 Orteronel is selective for the 17,20-lyase activity of CYP17A1 over its 11-hydroxylase activity and CYP3A4 (IC50s = >1,000 and >10,000 nM, respectively). It decreases adrenocorticotropic hormone-induced production of DHEA, androstenedione, cortisol, and aldosterone in monkey adrenal cells (IC50s = 110, 130, 310, and 4,400 nmol/L, respectively) and inhibits DHEA production in NCI-H295R human adrenocortical tumor cells.2 A single oral dose of orteronel (0.3-10 mg/kg) dose-dependently decreases DHEA, cortisol, and testosterone levels in the plasma of intact cynomolgus monkeys for at least 10 hours, and chronic dosing of 15 mg/kg twice daily suppresses levels for up to seven days of treatment.
    [Show full text]
  • Prostate Cancer
    Antonarakis_RL_EU Uro 13/12/2011 12:46 Page 251 Prostate Cancer Management of Metastatic Castration-resistant Prostate Cancer Emmanuel S Antonarakis Assistant Professor of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Abstract The management of men with metastatic castration-resistant prostate cancer (CRPC) has taken several leaps forwards in the last two years, with the demonstration of improved overall survival with three novel agents (sipuleucel-T, cabazitaxel and abiraterone acetate) and a significant delay in skeletal-related events observed with denosumab. The pipeline of systemic therapies in prostate cancer remains strong, as multiple agents with a diverse array of mechanisms of action are demonstrating preliminary signs of clinical benefit, leading to more definitive Phase III confirmatory trials. In this review, we will discuss the evolving landscape of treatment options for men with CRPC, with a particular focus on currently approved and emerging treatment options for these patients. Knowledge of these evolving standards will help to optimise delivery of care and long-term outcomes in men with advanced CRPC. Keywords Castration-resistant prostate cancer, novel therapies, drug development, sipuleucel-T, cabazitaxel, abiraterone, denosumab, orteronel, MDV3100, ipilimumab Disclosure: Emmanuel S Antonarakis has served as an advisor/consultant for Sanofi-Aventis. Received: 12 August 2011 Accepted: 19 October 2011 Citation: European Oncology & Haematology, 2011;7(4):251–6 DOI: 10.17925/EOH.2011.07.04.251 Correspondence: Emmanuel S Antonarakis, Prostate Cancer Research Program, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 1650 Orleans Street, CRB1-1M45, Baltimore, MD 21231-1000, US. E: [email protected] While much of the recent focus on prostate cancer relates to the for the second-line treatment of metastatic CRPC.
    [Show full text]
  • HSD3B1 and Response to a Nonsteroidal CYP17A1 Inhibitor in Castration-Resistant Prostate Cancer
    Research JAMA Oncology | Brief Report HSD3B1 and Response to a Nonsteroidal CYP17A1 Inhibitor in Castration-Resistant Prostate Cancer Nima Almassi, MD; Chad Reichard, MD; Jianbo Li, PhD; Carly Russell, MS; Jaselle Perry, MS; Charles J. Ryan, MD; Terence Friedlander, MD; Nima Sharifi, MD Invited Commentary page 562 IMPORTANCE The HSD3B1 (1245C) germline variant encodes for a gain-of-function missense Related article page 558 in 3β-hydroxysteroid dehydrogenase isoenzyme 1 (3βHSD1) that results in increased dihydrotestosterone synthesis from extragonadal precursors and is predictive of more rapid progression to castration-resistant prostate cancer (CRPC). OBJECTIVE To determine whether the HSD3B1 (1245C) genotype is predictive of clinical response to extragonadal androgen ablation with nonsteroidal 17α-hydroxylase/17,20-lyase (CYP17A1) inhibition in men with metastatic CRPC. DESIGN, SETTING, AND PARTICIPANTS An observational study of men with metastatic CRPC treated with ketoconazole between June 1998 and December 2012 was conducted at the University of California, San Francisco. EXPOSURES Extragonadal androgen ablation with the nonsteroidal CYP17A1 inhibitor ketoconazole among men with metastatic CRPC. MAIN OUTCOMES AND MEASURES The primary end points of analysis were duration of ketoconazole therapy and time to disease progression stratified by HSD3B1 genotype. Disease progression was defined as either biochemical or radiographic progression, using the Prostate Cancer Working Group 3 and Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 definitions, respectively. Kaplan-Meier analysis was used to estimate time on therapy and time to disease progression. A log-rank test for trend was used to compare outcomes by HSD3B1 genotype. RESULTS A total of 90 men (median [interquartile range] age, 61.5 [55.3-67.0] years) with metastatic CRPC were included in the analysis, with sufficient data to determine duration of ketoconazole therapy and time to disease progression in 88 and 81 patients, respectively.
    [Show full text]
  • Slow Tight Binding Inhibition of CYP17A1 by Abiraterone Redefines Its Kinetic Selectivity and Dosing Regimen
    JPET Fast Forward. Published on June 17, 2020 as DOI: 10.1124/jpet.120.265868 This article has not been copyedited and formatted. The final version may differ from this version. JPET # 265868 Slow tight binding inhibition of CYP17A1 by abiraterone redefines its kinetic selectivity and dosing regimen Eleanor Jing Yi Cheong1, Pramod C Nair2, Rebecca Wan Yi Neo1, Ho Thanh Tu1, Fu Lin3, Edmund Chiong4,5, Kesavan Esuvaranathan4,5, Hao Fan6, Russell Z. Szmulewitz7, Cody J. Peer8, William D. Figg8, Christina Li Lin Chai1, John O Miners2, Eric Chun Yong Chan1,9 1Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore; 2Department of Clinical Pharmacology and Flinders Centre for Downloaded from Innovation in Cancer, College of Medicine and Public Health, Flinders University, Adelaide, Australia; 3Bioinformatics Institute, Biotransformation Innovation Platform (BioTrans), Agency for Science, Technology and Research (A*STAR), 30 Biopolis Street, Singapore 138671; 4Department of Surgery, jpet.aspetjournals.org National University Health System, 5 Lower Kent Ridge Road, Singapore 119074, Singapore; 5Department of Urology, National University Hospital, 5 Lower Kent Ridge Road, Singapore 119074; 6Bioinformatics Institute, Agency for Science, Technology and Research (A*STAR), 30 Biopolis Street, at ASPET Journals on September 27, 2021 Singapore 138671; Department of Biological Sciences, National University of Singapore, 14 Science 23 Drive 4, Singapore 117543; Centre for Computational Biology, DUKE-NUS Medical School, 8 College Road, Singapore 169857; 7The University of Chicago, Chicago, 8National Cancer Institute, Rockville, MD, 9National University Cancer Institute, Singapore (NCIS), NUH Medical Centre (NUHMC), 5 Lower Kent Ridge Road, Singapore 119074 1 | Page JPET Fast Forward.
    [Show full text]
  • Role of Heat Shock Protein 27 and Lyn Tyrosine Kinase in Regulation of Androgen Receptor Expression and Activity in Prostate Cancer
    ROLE OF HEAT SHOCK PROTEIN 27 AND LYN TYROSINE KINASE IN REGULATION OF ANDROGEN RECEPTOR EXPRESSION AND ACTIVITY IN PROSTATE CANCER by Anousheh Zardan A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in The Faculty of Graduate Studies (Experimental Medicine) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) April 2012 © Anousheh Zardan, 2012 Abstract Prostate Cancer (PCa) is the most common male cancer and the second leading cause of cancer‐related deaths in North America. While many gains have been made in early detection and treatment of localized PCa, many men still die of the metastatic disease. Androgen ablation therapy remains the most effective therapy for patients with advanced disease. While ~80% of patients respond initially to this treatment, most patients progress to Castrate Resistant Prostate Cancer (CRPC) stage. Current literature indicates that CRPC tumours are not uniformly hormone refractory and may remain sensitive to therapies directed against the AR axis. Therefore, several new classes of AR‐targeting agents are now in clinical development, including more potent AR antagonists (MDV3100) and inhibitors of steroidogenesis (abiraterone). Although enthusiasm for this approach remains high, prostate tumour heterogeneity and the inevitable development of resistance dictates a critical need to better understand the mechanisms of resistance in which AR remain active. In the current doctoral thesis role of heat shock protein (Hsp) 27 and Lyn tyrosine kinase in regulation of AR protein expression was investigated. The central hypothesis is that increased expression and activity of Hsp27 and Lyn kinase stabilizes and activates AR protein and leads to prostate cancer progression through promoting prostate cancer cell survival.
    [Show full text]