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Prostate Cancer Cabazitaxel in the Management of Metastatic Castration-resistant Prostate Cancer Progressing After Docetaxel-based Chemotherapy Axel Heidenreich, MD, PhD 1 and David Pfister, MD 2 1. Chairman and Director; 2. Head Urologist, Conservative Uro-oncology, Department of Urology, RWTH Aachen University Abstract Docetaxel is the guideline-recommended first-line chemotherapy in men with castration-resistant prostate cancer (CRPC). Despite its proven survival benefit, however, all patients will experience disease progression after a mean interval of six to eight months. Recently, the US Food and Drug Administration approved cabazitaxel and abiraterone acetate as effective second-line treatment options in this clinical scenario. Compared with mitoxantrone, cabazitaxel improves progression-free survival, overall survival, time to prostate surface antigen (PSA) progression, and time to metastatic progression. On the other hand, cabazitaxel is associated with a significantly higher frequency of grade 3/4 hematotoxic and gastrointestinal side effects than mitoxantrone. In experienced hands, and with the use of proactive therapeutic measures (weekly monitoring, adequate patient counselling, appropriate application of the guidelines on management and prophylaxis of neutropenia and diarrhea), all side effects can be handled easily without harming the patient, as has been shown recently by the analysis of the results of the German and European compassionate use programs. Cabazitaxel is one of the key components in the management of disease progression after docetaxel, and might be of benefit in men with high metastatic burden, rapid PSA doubling time, and minimal side effects during first-line docetaxel therapy. Keywords Castration-resistant prostate cancer, docetaxel, cabazitaxel, abiraterone acetate Disclosure: Axel Heidenreich, MD, PhD, has received honoraria from AMGEN, Astellas, Bayer, GlaxoSmithKline, IPSEN, Janssen Cilag, Pfizer, Sanofi, and Takeda and has served on advisory boards for Astellas, IPSEN, Takeda, and Sanofi. David Pfister, MD, has no conflicts of interest to declare. Received: December 6, 2011 Accepted: January 9, 2012 Citation: Oncology & Hematology Review, 2012;8(1):61–4 Correspondence: Axel Heidenreich, MD, PhD, Chairman and Director, Department of Urology, RWTH Aachen University, Pauwelsstr. 30, 52074 Aachen, Germany. E: Prostate cancer is the second most common cause of cancer death in men in the US and the third most common cause of death in other developed countries. 1 For patients with metastatic prostate cancer, androgen deprivation therapy via medical or surgical castration is the standard treatment to improve symptoms and prolong progression-free survival (PFS). 2 After a mean duration of three to four years, all patients invariably develop progressive disease despite the presence of castrate testosterone serum levels. On the basis of an improvement in survival compared with mitoxantrone (Onkotrone ® , Baxter) plus prednisone in patients with metastatic castration-resistant prostate cancer (CRPC), docetaxel (Taxotere ® , Sanofi) in combination with prednisone is the standard, guideline-recommended first-line chemotherapy. 3,4 Docetaxel has been proven to prolong survival time by three months when compared with mitoxantrone. However, despite the high therapeutic efficacy of docetaxel, all patients will ultimately experience disease relapse within six to eight months of the last treatment cycle. Until recently, no second-line treatment had been approved by the US Food and Drug Administration (FDA) for the management of recurrent castration- and docetaxel-resistant prostate cancer. A variety of therapeutic © TOUCH BRIEFINGS 2012 approaches has been used in daily clinical routine, including docetaxel rechallenge, low-dose metronomic docetaxel, siltiximab, paclitaxel, and carboplatin, among others. 5–7 However, at best, only an improvement of PFS time was achieved; none of the various approaches resulted in a prolongation of survival. In 2011, two drugs – the CYP17 inhibitor abiraterone acetate (Zytiga ® ; Janssen) and the tubuline-binding taxane cabazitaxel (Jevtana ® ; Sanofi) – were approved by the FDA on the basis of their significant survival benefit when compared with placebo and with mitoxantrone. 8,9 Characteristics of Cabazitaxel Cabazitaxel is a tubulin-binding taxane drug as potent as docetaxel in cell lines. 10–13 In addition, the drug has antitumor activity in models resistant to paclitaxel and docetaxel. 10–13 Cabazitaxel has been shown to have a lower affinity for the drug resistance mediator P-glycoprotein compared with the other taxanes (docetaxel and paclitaxel), so that it is still active in docetaxel-resistant cancer cells. 14 Preclinical studies in rats and mice have also demonstrated that cabazitaxel is able to cross the blood–brain-barrier, so it may also have clinical benefit in patients with intracerebral metastases or leptomeningiosis carcinomatosa. 15 61