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Managing Metastatic Castration-Resistant Prostate Cancer in the Pre-chemotherapy Setting: A Changing Approach in the Era of New Targeted Agents

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Abstract

In recent years, the therapeutic options for treating men with metastatic castration-resistant prostate cancer have increased substantially. The hormonal treatments abiraterone acetate and enzalutamide, the chemotherapeutics docetaxel and cabazitaxel, the radiopharmaceutical alpharadin and the immunotherapeutic Sipuleucel-T have entered the field. Additionally, corticosteroids, which are used extensively, have documented activity but no documented survival benefit. Physicians treating patients with metastatic prostate cancer immediately after castration resistance develops currently have at least four different options to choose from for the first treatment. These therapeutic choices and their several possible ways of sequential use have not yet been compared to each other head-to-head and may never be. Therefore, there is an unmet need to inform their use with prospective clinical data. Additionally, the new indications of docetaxel for hormone naïve prostate cancer is changing the landscape of prostate cancer treatment and questions the traditional classifications ‘pre-chemotherapy’ and ‘post-chemotherapy’. In this work we attempt to address these challenges in the treatment of metastatic castration-resistant prostate cancer with the focus mainly on the non-cytotoxic agents. We try to integrate available clinical and preclinical information to suggest optimal ways of treatment.

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Acknowledgements

Professor de Bono’s team acknowledges support from Cancer Research UK, Prostate Cancer UK, Movember, Department of Defense, a Stand Up To Cancer—Prostate Cancer Foundation ‘Prostate Cancer Dream Team’ Translational Cancer Research Grant, an Experimental Cancer Medicine Center grant and the National Institute for Health Research Biomedical Research Center.

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Correspondence to Johann S. de Bono.

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Conflict of interest

JdB is an employee of the ICR which has a commercial interest in abiraterone acetate, PARP inhibitors in BRCA cancers, Pi3K and AKT inhibitors. JbB has served as a consultant for AstraZeneca, Astellas, Genentech, GSK, Janssen, Sanofi Aventis. ZZ, AJ and AS declare that they have no conflicts of interest.

Appendix

Appendix

See Table.

Clinical trials

NCT Number

Official Title

Trial Name

NCT00638690

A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Abiraterone Acetate (CB7630) Plus Prednisone in Patients With Metastatic Castration Resistant Prostate Cancer Who Have Failed Docetaxel-Based Chemotherapy

COU-AA-301

NCT00887198

A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Abiraterone Acetate (CB7630) Plus Prednisone in Asymptomatic or Mildly Symptomatic Patients With Metastatic Castration Resistant Prostate Cancer

COU-AA-302

NCT00974311

A Multinational, Phase 3, Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study of Oral MDV3100 in Patients With Progressive Castration Resistant Prostate Cancer Previously Treated With Docetaxel-Based Chemotherapy

AFFIRM

NCT01212991

A Multinational Phase 3, Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study of Oral MDV3100 in Chemotherapy- Naïve Patients With Progressive Metastatic Prostate Cancer Who Have Failed Androgen Deprivation Therapy

PREVAIL

NCT00309985

Chemo-Hormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer

CHAARTED

NCT00268476

Systemic Therapy in Advanced or Metastatic Prostate Cancer: Evaluation of Drug Efficacy - Androgen Suppression-Based Therapy Alone or Combined With Zoledronic Acid, Docetaxel, Prednisolone, Celecoxib, Abiraterone, Enzalutamide and/or Radiotherapy in Treating Patients With Locally Advanced or Metastatic Prostate Cancer

STAMPEDE

NCT00104715

Randomized Phase III Trial Comparing an Association of Hormonal Treatment and Docetaxel Versus Hormonal Treatment Alone in Metastatic Prostate Cancers

GETUG-AFU 15

 

Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for Advanced Prostate Cancer

TAX-327

NCT00699751

A Double-Blind, Randomised, Multiple Dose, Phase III, Multicentre Study of Alpharadin in the Treatment of Patients With Symptomatic Hormone Refractory Prostate Cancer With Skeletal Metastases

ALSYMPCA

NCT00065442

A Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial of Immunotherapy With Autologous Antigen Presenting Cells Loading With PA2024 (Provenge(R), APC8015) in Men With Metastatic Androgen Independent Prostatic Adenocarcinoma

IMPACT

NCT01682772

A Phase II Trial of Olaparib in Patients With Advanced Castration Resistant Prostate Cancer

TOPARP

NCT02125357

A Randomized Phase II Study of Sequencing Abiraterone Acetate and Enzalutamide in Metastatic Castration Resistant Prostate Cancer

 

NCT02116582

A Multicenter, Single Arm Study of Enzalutamide in Patients With Progressive Metastatic Castration Resistant Prostate Cancer Previously Treated With Abiraterone Acetate

 

NCT02268175

A Phase II Randomized Study of Enzalutamide + Leuprolide Versus Enzalutamide + Leuprolide + Abiraterone Acetate + Prednisone as Neoadjuvant Therapy for High-Risk Prostate Cancer Undergoing Prostatectomy

 

NCT02043678

A Phase III Randomized, Double-Blind, Placebo-Controlled Trial of Radium-223 Dichloride in Combination With Abiraterone Acetate and Prednisone/Prednisolone in the Treatment of Asymptomatic or Mildly Symptomatic Chemotherapy-Naïve Subjects With Bone Predominant Metastatic Castration Resistant Prostate Cancer

 

NCT01867333

A Randomized Phase II Trial Combining Vaccine Therapy With PROSTVAC /TRICOM and Enzalutamide vs. Enzalutamide Alone in Men With Metastatic Castration Resistant Prostate Cancer

 

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Zafeiriou, Z., Jayaram, A., Sharp, A. et al. Managing Metastatic Castration-Resistant Prostate Cancer in the Pre-chemotherapy Setting: A Changing Approach in the Era of New Targeted Agents. Drugs 76, 421–430 (2016). https://doi.org/10.1007/s40265-015-0530-7

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