**6. Denosumab**

266 Prostate Cancer – Diagnostic and Therapeutic Advances

will likely be done on a case by case basis after careful consideration of the rate of disease progression, overall burden of disease, performance status and toxicity profile of

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

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

Over the last 10 years, there has also been growing interest in the issue of bone health in prostate cancer as it is known that both androgen deprivation therapy, and bony metastases can promote bone destruction. Zoledronic acid, is a nitrogen-containing bisphosphonate that inhibits osteoclast-mediated bone resorption. In a randomized placebo controlled clinical trial in men with CRPC and bone metastases, zoledronic acid reduced skeletal related events and decreased bone pain leading to its approval by the FDA in 2002 (Saad *et al.*, 2002). Bone resorption is a process that is dependent on RANK Ligand, a protein that acts as the primary mediator of osteoclast formation, function and survival. Preclinical models have demonstrated that inhibiting RANK Ligand significantly improves cortical and trabecular bone density, volume and strength. Studies with a novel bone targeting agent

either drug.

**4. Sipuleucel-T** 

**5. Zoledronic acid** 

phosphatase related T cell response.

be as widely available as either abiraterone or cabazitaxel.

Denosumab is a fully humanized monoclonal antibody against the RANK ligand. RANK plays a major role in osteoclast activation. In the phase III trial of 1901 CRPC patients with one or more metastases, compared to zoledronic acid, denosumab delayed time to skeletal related events by approximately 3 months with a 2.3% incidence of osteonecrosis of the jaw compared to 1.3% in the zoledronic acid arm. Notably, there was no difference in overall survival (Fizazi *et al.*, 2011). This phase III study garnered FDA approval for Denosumab for the prevention of skeletal related events (SRE) in CRPC patients with bone metastases. Denosumab is also being evaluated for its ability to delay the development of bone metastases in CRPC patients. A third role for denosumab may be in protecting against ADT related osteoporosis. In this study, 912 patients on ADT received denosumab 60 mg subcutaneously every 6 months. At 24 months followup, denosumab was associated with increased bone mineral density at all sites and a reduction in the incidence of new vertebral fractures (Smith *et al.*, 2009). Denosumab also offers the benefit of being subcutaneously administered, and this might be an advantage for patients who are not otherwise requiring intravenous treatments.
