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Emerging Drugs for Prostate Cancer

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Review Emerging drugs for prostate cancer † Paul H Chung, Bishoy A Gayed, Gregory R Thoreson & Ganesh V Raj † 1. Background UT Southwestern Medical Center, Department of Urology, Dallas, TX, USA 2. Medical need Introduction: Androgen deprivation therapy is the mainstay treatment for 3. Existing treatment patients with prostate cancer who are not candidates for definitive 4. Market review treatment, are diagnosed with advanced disease on initial presentation or 5. Current research goals progress after primary treatment. Patients who stop responding to androgen deprivation therapy develop castration resistant prostate cancer (CRPC). 6. Scientific rationale Emerging drugs undergoing clinical evaluation and drugs that have recently 7. Competitive environment received FDA approval for the treatment of CRPC are reviewed. 8. Potential development issues Areas covered: As the natural history and signaling pathways of prostate 9. Conclusion cancer are better understood, new treatments and targeted therapies will 10. Expert opinion be developed. The FDA recently approved 5 medications that increase survival in patients with CRPC. Additional medications and drug classes are being explored that may eventually lead to new treatment options. Articles were identified using a PubMed database search. Expert opinion: Recent FDA medication approvals and the development of emerging treatments are promising for the future of patients with prostate cancer. The addition of new medications challenges physicians to identify the optimal sequence and/or combination in which newer and older medications should be administered. Physicians treating patients with prostate cancer have a growing responsibility to keep pace with these new medications so that they may counsel and treat patients appropriately. For personal use only. Keywords: abiraterone, androgen deprivation therapy, androgen receptor, antiandrogens, cabazitaxel, castration resistance, denosumab, docetaxel, emerging drugs, enzalutamide, prostate cancer, PSA-TRICOM, radium-223, sipuleucel-T, zoledronic acid Expert Opin. Emerging Drugs (2013) 18(4):533-550 1. Background In the USA, 238,000 new cases of prostate cancer will be diagnosed in 2013 and more than 29,000 deaths will occur predominantly due to metastatic disease [1]. Intent to cure is the primary approach for non-locally advanced prostate cancer. Patients and their multi-disciplinary physicians discuss the risks and benefits of Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by Nyu Medical Center on 12/02/13 each treatment modality (surgery, radiation or active surveillance) to determine how best to proceed. Androgen deprivation therapy (ADT) is the first-line therapy for patients with metastatic disease or recurrence after primary treatment. ADT tar- gets the androgen axis and is the mainstay treatment for disease progression since Huggins identified in 1941 that prostate cancer is hormone-driven [2]. ADT reduces 90-- 95% of circulating testosterone and results in a median progression-free survival (PFS) of 12 -- 33 months when measured from the time of clinically symptomatic disease [3]. Docetaxel chemotherapy, approved in 2004, is the mainstay therapy for castration-resistant prostate cancer (CRPC) [4,5]. Since 2010, the FDA has approved five new agents from distinct drug classes for the treatment of CRPC (Table 1 and Figure 1) [6-11]. With the advent of new drugs, physicians are challenged with keeping pace with these new mediations so that they may counsel and treat patients appropriately. 10.1517/14728214.2013.864635 © 2013 Informa UK, Ltd. ISSN 1472-8214, e-ISSN 1744-7623 533 All rights reserved: reproduction in whole or in part not permitted 534 P. H. Chung Table 1. Emerging drugs and selected associated trials. Drug Mechanism Phase of study Primary endpoint Description of study Outcome Clinical Trial Identifier et al Abiraterone Inhibits 17-a hydroxylase III/FDA approved OS Randomized, double-blind, Improved OS with abiraterone NCT00638690 . and 17-20 lyase abiraterone plus prednisone versus placebo plus prednisone in patients with mCRPC and prior docetaxel Abiraterone Inhibits 17-a hydroxylase III/FDA approved rPFS, OS Randomized, double-blind, Improved rPFS and trended NCT00887198 and 17-20 lyase abiraterone plus prednisone toward improved OS with versus placebo plus prednisone abiraterone in patients with chemotherapy- naı¨ve mCRPC Orteronel Inhibits 17-20 lyase III OS Randomized, double-blind, No improvement in OS with NCT01193257 (TAK-700) orteronel plus prednisone versus orteronel Expert Opin. Emerging Drugs placebo plus prednisone in patients with mCRPC and prior For personal use only. docetaxel Orteronel Inhibits 17-20 lyase III OS Randomized, double-blind, Active, not recruiting NCT01193244 (TAK-700) orteronel plus prednisone versus placebo plus prednisone in patients with chemotherapy- naı¨ve mCRPC Galeterone Inhibits 17-20 lyase II Safety, PSA Single arm, open-label, Recruiting NCT01709734 (2013) (TOK-001) response galeterone in patients with chemotherapy-naı¨ve mCRPC 18 Enzalutamide Binds androgen receptor III/FDA approved OS Randomized, double-blind, Increased OS with enzalutamide NCT00974311 (4) (MDV3100) enzalutamide versus placebo in patients with mCRPC with prior docetaxel Enzalutamide Binds androgen receptor III OS Randomized, double-blind, Active, not recruiting NCT01212991 Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by Nyu Medical Center on 12/02/13 (MDV3100) enzalutamide versus placebo in patients with chemotherapy- naı¨ve mCRPC ARN-509 Binds androgen receptor II QOL Randomized, open-label, Recruiting NCT01790126 ARN-509 with or without LHRH agonist versus LHRH agonist alone in patients with hormone sensitive patients with BCR Cabazitaxel Stabilizes microtubules III/FDA approved OS Randomized, open-label, Increased OS with cabazitaxel NCT00417079 cabazitaxel plus prednisone versus mitoxantrone plus CTC: Circulating tumor cell; CTLA: Cytotoxic T-Lymphocyte Antigen; FDA: Food and Drug Administration; HDAC: Histone deacetylase; HGF: Hepatocyte growth factor; HSP-27: Heat shock protein-27; LHRH: Luteinizing- hormone-releasing hormone; mCRPC: Metastatic castration-resistant prostate cancer; OS: Overall survival; PSA: Prostate-specific antigen; PFS: Progression-free survival; Rpfs: Radiographic PFS; TRICOM: Triad of costimulatory molecules; TKI: Tyrosine kinase inhibitor; VEGF: Vascular endothelial growth factor; VEGFR: VEGF receptor. Table 1. Emerging drugs and selected associated trials (continued). Drug Mechanism Phase of study Primary endpoint Description of study Outcome Clinical Trial Identifier prednisone in patients with mCRPC and prior docetaxel Ixabepilone Stabilizes microtubules II Safety, PSA Single-arm, open-label, Acceptable toxicity, but NCT00087139 response ixabepilone in patients with acceptable PSA response only in mCRPC and no prior chemo, patients with prior taxane prior taxane or two prior treatment chemotherapy regimens Eribulin mesylate Stabilizes microtubules II Safety, PSA Single-arm, open-label, eribulin Acceptable toxicity and NCT00278993 response mesylate in patients with moderate antitumor activity mCRPC with or without prior taxane chemotherapy Denosumab Monoclonal antibody III/FDA approved Bone-metastasis- Randomized, double-blind, Increased bone-metastasis-free NCT00321620 For personal use only. against RANK-L free survival denosumab versus placebo in survival with denosumab Expert Opin. Emerging Drugs patients with non-metastatic CRPC Radium-223 Emits alpha particle in III/FDA approved OS Randomized, double-blind, Increased OS with radium-223 NCT00699751 areas of increased bone radium-223 versus placebo in turnover patients with mCRPC and bone metastases Dasatinib Inhibits Src tyrosine kinase III OS Randomized, double-blind, Greater toxicity and no NCT00744497 docetaxel plus dasatinib versus improvement in OS with docetaxel plus placebo in dasatinib (2013) patients with mCRPC Becacizumab Monoclonal antibody to III OS Randomized, double-blind, Greater toxicity and no NCT00110214 18 (4) VEGF docetaxel plus prednisone with improvement in OS with or without becacizumab in becacizumab Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by Nyu Medical Center on 12/02/13 patients with mCRPC Aflibercept Recombinant fusion III OS Randomized, double-blind, Greater toxicity and no NCT00519285 protein to VEGF docetaxel plus prednisone with improvement in OS with or without aflibercept in aflibercept Emerging drugs for prostate cancer patients with mCRPC Cabozantinib TKI targeting VEGFR and III OS Randomized, double-blind, Recruiting NCT01605227 MET cabozantinib versus placebo in patients with mCRPC and prior docetaxel and abiraterone or enzalutamide Rilotumumab Monoclonal antibody II OS Randomized, double-blind, Manageable toxicities and no NCT00770848 against HGF mitoxantrone and prednisone improvement in OS with with and without rilotumumab rilotumumab CTC: Circulating tumor cell; CTLA: Cytotoxic T-Lymphocyte Antigen; FDA: Food and Drug Administration; HDAC: Histone deacetylase; HGF: Hepatocyte growth factor; HSP-27: Heat shock protein-27; LHRH: Luteinizing- hormone-releasing hormone; mCRPC: Metastatic castration-resistant prostate cancer; OS: Overall survival; PSA: Prostate-specific antigen; PFS: Progression-free survival; Rpfs: Radiographic PFS; TRICOM: Triad of 535 costimulatory molecules; TKI: Tyrosine kinase inhibitor; VEGF: Vascular endothelial growth factor; VEGFR: VEGF receptor. 536 P. H. Chung Table 1. Emerging drugs and
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    LEUKEMIA CHEMOTHERAPY REGIMENS (Part 1 of 2) The selection, dosing, and administration of anti-cancer agents and the management of associated toxicities are complex. Drug dose modifications and schedule and initiation of supportive care interventions are often necessary because of expected toxicities and because of individual patient variability, prior treatment, and comorbidities. Thus, the optimal delivery of anti-cancer agents requires a healthcare delivery team experienced in the use of such agents and the management of associated toxicities in patients with cancer. The chemotherapy regimens below may include both FDA-approved and unapproved uses/regimens and are provided as references only to the latest treatment strategies. Clinicians must choose and verify treatment options based on the individual patient. REGIMEN DOSING Acute Myeloid Leukemia (AML) Induction Therapy Cytarabine (Cytosar-U; ARA-C) + Days 1–3: An anthracycline (eg, daunorubicin at least 60mg/m2/day IV, an anthracycline idarubicin 10–12mg/m2/day IV, or mitoxantrone 10–12mg/m2/day IV), plus (daunorubicin [Cerubidine], Days 1–7: Cytarabine 100–200mg/m2/day continuous IV infusion. idarubicin [Idamycin], OR mitoxantrone [Novantrone])1, 2 Days 1–3: An anthracycline (eg, daunorubicin 45mg/m2/day IV, idarubicin 12mg/m2/day IV, or mitoxantrone 12mg/m2/day IV), plus Days 1–7: Cytarabine 100mg/m2/day continuous IV infusion. Intermediate-dose cytarabine3 Cycle 1 Days 1–7: Cytarabine 200mg/m2/day continuous IV infusion, plus Days 5–6: Idarubicin 12mg/m2/day IV. Cycle 2 Days 1–6: Cytarabine 1,000mg/m2 continuous IV infusion for 3 hrs twice daily, plus Days 3, 5 and 7: Amsacrine 120mg/m2/day.