Current and Emerging Treatments in the Management of Castration-Resistant Prostate Cancer

David Shapiro; Basir Tareen

Disclosures

Expert Rev Anticancer Ther. 2012;12(7):951-964. 

In This Article

Approved Palliative Options

Given that metastatic prostate cancer is often found in the bones and can cause significant pain, effective palliative therapies are crucial to treating this disease. This section examines the efficacy of the current palliative medications in terms of self-reported pain relief, bone metastasis-free survival, and the main adverse events faced by patients on these medications (Table 2).

Chemotherapy

Mitoxantrone Plus Prednisone Prostate cancer was considered unresponsive to chemotherapy until 1996, when a Canadian study demonstrated that the combination of mitoxantrone plus prednisone was an effective palliative treatment for patients with CRPC.[28] This combination has been shown to alleviate pain and constipation, and improve mood, physical functioning and quality of life more frequently and for a longer duration than prednisone alone. Despite its success in the palliative care realm, this regimen did not improve survival.[24,28,41] Side effects were minimal and included neutropenia, nausea, vomiting, cardiac toxicity and alopecia.

Bone-targeted Therapy

Prostate cancer has a strong predilection to metastasize to the bone and subsequently lead to significant complications known as skeletal-related events (SREs). SREs include spinal cord compression and pathological fractures. These complications are a primary cause of morbidity, chronic pain and poor quality of life in patients with prostate cancer.[42] Preventing and or delaying the onset of complications secondary to bony metastases is the ultimate goal of these bone-targeted palliative therapies.

Zoledronic Acid The potent bisphosphonate zoledronic acid (Zometa®, Novartis Pharmaceuticals Corporation, NJ, USA) is currently the standard of care for prevention of SREs in patients with metastatic CRPC. In the Zometa 039 Phase III trial, men with CRPC and bony metastases who were given zoledronic acid had fewer SREs than the placebo group at 15 months follow-up (33.2 vs 44.2%; p = 0.021) and had increased median time to first SRE (488 vs 321 days; p = 0.009) after 24 months of follow-up.[43,44] Despite its success, the drug is known for its detrimental effect on kidney function. Patients on the drug must have serum creatinine monitored.

Denosumab Denosumab (Xgeva®, Amgen, CA, USA) is a fully-human monoclonal antibody, administered subcutaneously, that blocks the RANK ligand, thereby preventing bone resorption through the activation of osteoclasts.[45] Two Phase III clinical trials have shown favorable results for patients with prostate cancer treated with denosumab. The initial trial found that when prostate cancer patients currently on ADT were given denosumab, they experienced significant increases in bone mineral density at the hip, femoral neck and distal third of the radius at all time points throughout the study and experienced 2.4% less vertebral fractures.[46]

The more recent Phase III double-blinded randomized controlled trial of 1904 men with CRPC and bony metastases assigned to either denosumab or zoledronic acid showed that denosumab was more effective in delaying onset of first on-study SREs (21.7 vs 17.1 months; p = 0.008) and reducing the rates of multiple SREs (p = 0.008). A second Phase III trial including over 1400 men with nonmetastatic CRPC found that denosumab significantly increased bone metastasis-free survival by 4.2 months and delayed time to first bone metastasis by 3.7 months compared with placebo, but overall survival did not significantly differ between the groups.[47]

In both studies, patients in experimental and control groups experienced comparable rates of adverse events. These side effects included anemia, bone/back pain, nausea, urinary tract infection, fatigue and constipation.[48] Advantages to using denosumab include ease of administration (as compared with intravenous zoledronic acid) and reduced need for monitoring serum creatinine for signs of nephrotoxicity.[8] However, it must be noted that a small but not insignificant subset of patients given denosumab experienced the devastating side effects of jaw osteonecrosis and grade 3 or 4 hypocalcemia. Therefore, clinicians must perform routine oral examination and monitor serum calcium levels for patients taking denosumab.

Although studies have shown that denosumab can delay progression of bony metastases and their sequelae and the FDA has approved denosumab for use in the prevention of SREs in prostate cancer patients with bony metastases, many clinicians feel that the clinical benefits of this agent are minimal at best and would not routinely use it in this setting, especially given its potential adverse effects.

Radionuclide Therapy (Samarium-153 & Strontium-89) Samarium-153 (Quadramet®, EUSA Pharma, PA, USA) and strontium-89 (Metastron™, GE Healthcare, IL, USA) are currently the only two targeted radioisotopes approved by the FDA for palliation of bone pain resulting from CRPC. These agents rely on selective uptake and prolonged retention at sites of increased osteoblastic activity. Subsequently, they utilize ionizing radiation to damage DNA, thereby killing cancer cells and decreasing tumor burden.[49] Studies of patients with metastatic CRPC have shown that administering a radionuclide in addition to chemotherapy improves pain control, slows progression of bony metastases, and may increase survival compared with chemotherapy alone.[50–52] A recent Phase I study found that 50% of patients with taxane-resistant CRPC receiving combination chemoradiotherapy experienced significant PSA declines and had reduced bone remodeling.[53] Side effects of this therapy are typically mild and include transient myelosuppression and a temporary increase in pain, known as the flare phenomenon, which is typically short-lived.

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