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Prostate Cancer Modern Management of Castration-resistant Prostate Cancer Axel Heidenreich, 1 David Pfister, 1 Axel Merseburger 2 and Georg Bartsch 3 for the German Working Group on Castration-resistant Prostate Cancer (GWG-CRPC) 1. Department of Urology, RWTH University Aachen; 2. Department of Urology and Urologic Oncology, Hannover Medical School, Hannover; 3. Department of Urology, Johann-Wolfgang-Goethe University, Frankfurt, Germany Abstract The approval or clinical evaluation of several new agents – cabazitaxel, enzalutamide, sipuleucel-T, radium-223 and abiraterone acetate – has significantly changed the management of patients with metastatic castration-resistant prostate cancer (mCRPC) prior to or after docetaxel- based chemotherapy. All of these agents have resulted in a significant survival benefit compared with their control group. However, treatment responses might differ depending on the associated comorbidities and the extent and the biological aggressiveness of the disease. Furthermore, treatment-associated side effects differ between the various drugs. As new drugs are approved, new treatment strategies and markers to best select which patients will best respond to which drug are needed. It is the aim of this article to (1) summarise the data of established treatment options in mCRPC, (2) highlight new developments of medical treatment, (3) provide clinically useful algorithms for the daily routine and to (4) point out future developments of medical treatment. Keywords Metastatic castration-resistant, prostate cancer, treatment, docetaxel, cabazitaxel, abiraterone acetate, enzalutamide, radium-223, orteronel, cabozantinib Disclosure: Axel Heidenreich has received honoraria from Astellas, Amgen, Dendreon, Ferring, IPSEN, Jansen Cilag, Sanofi-Aventis and Takeda. He has received research grants from Astellas and Sanofi-Aventis. David Pfister has received honoraria from Astellas, IPSEN, Jansen Cilag and Sanofi-Aventis. Axel Merseburger has received honoraria from Astellas, IPSEN, Jansen Cilag and Sanofi-Aventis. Georg Bartsch has no conflicts of interest to declare. Received: 4 April 2013 Accepted: 25 April 2013 Citation: European Oncology & Haematology, 2013;9(1):34–41 Correspondence: Axel Heidenreich, Department of Urology, RWTH University Aachen, Pauwelsstr. 30, 52074 Aachen, Germany. E: Apart from skin cancers, prostate cancer is the most common cancer in men living in the US and Europe. 1–3 About one in nine men will develop prostate cancer during their lifetime, and, in 2008, 899,000 new cases were diagnosed worldwide. 4 Ten to 20  % of all patients will develop castration-resistant prostate cancer (CRPC) within 5  years of follow up. 5–7 Approximately 84 % of men with CRPC will present with metastatic disease at time of diagnosis and another 5 % will develop the disease within 2 years after diagnosis of CRPC. 8 According to recent analyses, median survival from CRPC diagnosis is 14 months. 9 However, new therapeutic options, e.g. abiraterone acetate (AA), enzalutamide (ENZ), cabazitaxel (CBZ) and radium-223, which prolong survival significantly, were not considered in any of these analyses. 10–13 Metastatic CRPC (mCRPC) is a characterised by disease progression following surgical or medical castration. The European Association of Urology defines mCRPC as castrate levels of serum testosterone, three consecutive increases in prostate-specific antigen (PSA) resulting in two 50  % increases above the nadir, anti-androgen withdrawal for at least 4  weeks, PSA progression despite secondary hormonal manipulations and/or progression of osseous or soft-tissue lesions. 15 Molecular Basis of Castration Resistance Various molecular mechanisms are involved in the development of CRPC. Amplification of the androgen receptor (AR) was identified as one of the first mechanisms in up to 30 % of the patients after initiation of androgen- deprivation therapy (ADT). 15 Since then, many other molecular events have 34 been identified as the result of cellular acquisition of mechanisms that might overcome the proliferation-inhibiting effect of serum castrate levels of testosterone. Ligand-independent AR activation, intratumoral androgen synthesis, increased expression of AR messenger RNA (mRNA) and enhanced intracellular conversion of adrenal androgens to testosterone and dihydrotestosterone (DHT) are some mechanisms retaining hormonal sensitivity of prostate cancer cells despite serum castrate levels of testosterone. 16–20 Two of the main mechanisms underlying the onset of castration resistance are intratumoral biosynthesis of androgens via 17-hydroxylase-17,20-lyase (CYP17) and androgen-independent activation of the AR, which can be a result of AR overexpression, structural changes of the AR caused by genetic mutations and overexpression of co- activators. 21 CRPC has a heterogeneous morphology, immunophenotype and genotype, demonstrating that ‘metastatic disease’ is a group of diseases between patients and even within the same patient. 20–22 Patients with mCRPC have a poor prognosis and those patients with metastases are expected to survive up to 18 to 19 months. 14 As patients progress, quality of life deteriorates and, until recently, few treatment options were available. Several new therapies have shown an improvement in overall survival (OS) for patients with mCRPC who have already received chemotherapy with docetaxel. 10–13 The impact of these new data on daily clinical practice, treatment sequencing and best care for individual patients is not yet fully understood. It is the aim of the current article to (1) summarise the data of established treatment options in mCRPC, (2) highlight new developments of medical © Touch ME dica l ME dia 2013