18 oe VOL. 13, NO. 3, AUGUST 2014 FEATURE Two decades in review Progress in the treatment of mCRPC by Brandon Bernard, MD, FRCPC, Arun A. Azad, MBBS, PhD, FRACP, Kim N. Chi, MD, FRCPC Kim N. Chi, MD, FRCPC is Professor of Medicine at the University of British Columbia, Medical Oncologist at the BC Cancer Agency, Vancouver Cancer Centre, and Chair of the Genitourinary Tumour Group Brandon Bernard, MD, FRCPC is Co-Chief Resident, Medical Oncology at the British Columbia Cancer Agency and University of British Columbia Arun A. Azad, MBBS, PhD, FRACP, is a Genitourinary Medical Oncology Fellow at the BC Cancer Agency Corresponding author: Dr. Kim N. Chi, BC Cancer Agency, 600 West 10 th Avenue, Vancouver, British Columbia, Canada, V5Z 4E6. Phone: (604) 877-6000, FAX: (604) 877-0585, e-mail: kchi@bccancer.bc.ca ABSTRACT B etween the mid-1990s and now, median overall survival for men with metastatic castrate resistant prostate cancer (CRPC) starting on chemotherapy has risen from 1 year to almost 3 years. This review summarizes progress made over the last 2 decades in the systemic management of patients with CRPC and evolving treatment directions. Keywords: Metastatic castration-resistant prostate cancer, androgen deprivation therapy, chemotherapy, androgen receptor antagonist, radiopharmaceutical, immunotherapy, bone-targeted therapy, predictive biomarker INTRODUCTION In Canada, it is estimated that 4000 men will die of prostate cancer in 2014, making it the third leading cause of cancer- related death among men. 1 When metastatic, the backbone of treatment is androgen deprivation therapy (ADT), typically in the form of either surgical castration or medical castration with a gonadotropin-releasing hormone agonist or antagonist (GnRHa). Initially, most patients achieve durable response with ADT; however, the development of castration-resistant prostate cancer (CRPC) inevitably occurs. Patients with CRPC are a heterogeneous group defined as having castrate levels of testosterone plus 1 or more of: radiographic pro- gression of metastases, clinical progression, and rising serum prostate-specific antigen (PSA) levels. 2 Numerous negative prognostic factors have been identified, including: poor patient performance status, presence of pain, presence of visceral metastases, elevated alkaline phosphatase, elevated lactate dehydrogenase, anemia and rapid PSA doubling time. 3 In the late 1990s, the median overall survival (OS) for patients with metastatic CRPC starting on first-line chemo- therapy was approximately 1 year. 4,5 By 2012, trials demon- strated median OS approaching 3 years from time of first chemotherapy. 6 Such progress reflects a dramatically altered landscape of clinical care for men with CRPC with the introduction of new systemic therapies with proven ability to improve outcomes (see Figure 1). This review summarizes the progress made over the last 2 decades in the systemic management of patients with CRPC. CHEMOTHERAPY The first advance in chemotherapy for CRPC focused on symptom control. Recognizing the advanced age and co- morbidities of many patients with CRPC, together with the limited antitumour activity of available agents in the 1990s, Tannock et al initiated a randomized trial to assess the impact of mitoxantrone, a well tolerated anthracycline ana- logue, looking at pain improvement as the primary endpoint. 4 One hundred and sixty-one patients with pain/symptomatic disease were randomized to mitoxantrone plus prednisone vs prednisone alone (of note: the study was not blinded). Twenty-nine percent of patients on the mitoxantrone arm achieved a palliative response (reduction in patient-reported pain scores and/or reduction in analgesic consumption) compared with 12% of those who received prednisone alone (p=0.01). Moreover, the pain response was prolonged, with a median duration of 43 weeks in the experimental arm vs 18 weeks in the control group (p<0.0001). No dif- ference in OS was seen between the 2 groups. This lack of survival improvement with mitoxantrone was confirmed in a subsequent study by Kantoff et al, which assessed OS as the primary endpoint. 5 It was not until 2004 that a treatment for CRPC was associated with an OS advantage. (Table 1 lists this and other trials showing OS improvements). The TAX 327 multinational trial randomized 1006 patients with mCRPC to mitoxantrone every 3 weeks, the taxane docetaxel every 3 weeks, or docetaxel weekly for 5 weeks out of 6; all patients received prednisone 10 mg daily and OS was the primary endpoint. 7 Patients who received docetaxel every 3 weeks experienced a median OS of 18.9 months, compared to 16.5 months for those who received mitoxantrone, which translates into a 24% reduction in risk of death (HR 0.76 [95% CI 0.62–0.94], p=0.009). In addition, a signifi- cantly higher number of patients experienced a reduction in pain in the docetaxel arm compared to the mitoxantrone arm (35% vs 22%, respectively; p=0.01). Significant differ- ences in favour of docetaxel were also seen in reduction of PSA ≥50% from baseline and in quality of life (QOL) improvement. 7 The survival advantage with docetaxel-based chemotherapy was confirmed with the simultaneous publi- cation of results from the SWOG 99-16 trial. 8 This study