**4. Sipuleucel-T**

Aside from cytotoxic therapies and androgen deprivation approaches, immunotherapy has emerged in prostate cancer drug development. Sipuleucel-T (Provenge, Dendreon) is an immunotherapy that can enhance response to the prostate cell tumor antigen, prostatic acid phosphatase. Generation of the immunotherapy involves collection of peripheral blood cells by leukophoresis and subsequent exposure to prostatic acid phosphatase and granulocyte macrophase colony stimulating growth factor. The cells are then reintroduced into the patient. Sipuleucel-T is an autologous dendritic cell vaccine which enhances prostatic acid phosphatase related T cell response.

Encouraging phase I/II trial results led to the pivotal randomized, double-blind, placebocontrolled, multicenter trial (Study 9902B) known as the IMPACT trial (Immunotherapy for Prostate Adenocarcinoma Treatment), with a primary endpoint of overall survival (Kantoff *et al.*, 2010). All patients underwent three leukapheresis procedures (Weeks 0, 2, and 4), followed 3 days later by either sipuleucel-T or the non-activated control. Eligible CRPC patients had metastatic disease in soft tissue and/or bone with evidence of radiologic or biochemical disease progression. Patients with moderate to severe prostate cancer-related pain and/or use of narcotics were excluded. Tumor expression of prostatic acid phosphatase of 25% or more was required. Five hundred twelve patients were randomized (2:1) to sipuleucel-T (n=341) or control (n=171). The sipuleucel-T arm had a 4.l months improvement in median overall survival (25.8 mos versus 21.7 mo, p= 0.032, HR 0.775, 95% CI 0.61, 0.98). There was no difference in time-to-progression. Common adverse events (AE) for sipuleucel-T were mild or moderate and included chills, fatigue, fever, back pain, nausea, joint ache and headache. Serious adverse reactions (SAE) more common with sipuleucel-T were acute infusion reactions and stroke. Similar survival and tolerability results were seen in two additional trials, which ultimately led to approval by the US Food and Drug Administration in 2010 (Small *et al.*, 2006; Higano *et al.*, 2009). Priced at \$31,000 per treatment, Sipuleucel-T is one of the most expensive treatments ever, and as such may not be as widely available as either abiraterone or cabazitaxel.
