Metastatic Castration-resistant Prostate Cancer
Metastatic cancer cells in the bone microenvironment release a number of cytokines and growth factors that induce an alteration of bone resorption/formation processes, resulting in lytic bone lesions, blastic bone lesions or both. Although metastatic bone lesions from prostate cancer are typically osteoblastic, osteolysis is also a common feature. Increased osteoclastic activity is not confined to metastatic sites only; rather, it may also be found in the whole bone tissue. This is commonly caused by secondary hyperparathyroidism due to the so-called 'hungry bone syndrome' and by androgen deprivation-induced osteoporosis. Due to increased osteolysis, bone metastatic prostate cancer patients commonly experience SREs. If the disease is androgen sensitive, SREs are rare. However, they become frequent when the tumor is castration resistant. SREs are associated with reduced survival and quality of life and also impose a significant healthcare burden.
Zoledronic acid, a powerful third-generation nitrogen-containing bisphosphonate, was the first agent to be approved for the management of bone metastases in patients with CRPC. In 2002, a Phase III placebo-controlled trial of zoledronic acid versus placebo was conducted in 643 patients with mCRPC. Zoledronic acid 4 mg was administered every 21 days and significantly reduced the incidence of SREs; 44% of patients in the placebo group experienced a SRE compared with 33% in the experimental group (p = 0.021; Table 3). Zoledronic acid also significantly increased the time to first SRE (488 vs 321 days; p = 0.009). Pain scores and the use of analgesic drugs favored zoledronic acid, but there were no differences in either disease progression or OS.
The RANK/RANKL pathway plays a central role in bone resorption regulation. RANKL is part of the TNF family and is produced by osteoblasts. RANKL is able to bind RANK on the surface of both osteoclast precursors and osteoclasts, inducing osteoclast maturation, survival and activity.
Denosumab is a fully human monoclonal antibody against RANKL and prevents RANKL from activating its receptor, RANK, thus inhibiting osteoclast formation, function and survival, decreasing bone resorption and increasing bone mass and strength in both cortical and trabecular bone. When compared with zoledronic acid in a Phase III trial that enrolled 1904 patients with mCRPC to the bone, denosumab at 120 mg every 28 days improved the median time to first SRE by 3.6 months (HR: 0.82; p = 0.008); results from this pivotal study are reported in Table 3. The two groups had similar OS and time to disease progression. Adverse event rates were also similar, with the exception of an increased incidence of hypocalcemia (13% in the denosumab group vs 6% in the zoledronic acid group; p < 0.0001). Based on these data, the FDA and EMA have approved denosumab for the treatment of mCRPC patients with bone metastases.
Radium-223 is a targeted α-emitter that acts as a calcium mimetic and selectively binds areas of new bone growth in and around bone metastases. Unlike β-emitting agents that are myelotoxic, radium-233 emits ionizing radiation with high energy and extremely short penetration (<100 µm; 2–10 cell diameters), causing highly localized tumor cell killing with minimal side effects to normal cells.
The FDA and EMA recently approved radium-223 for the treatment of patients with CRPC and symptomatic bone metastases on the basis of the results of the ALSYMPCA trial. This Phase III placebo-controlled trial assessed the efficacy and safety of radium-223 in patients with CRPC and symptomatic bone metastases pretreated with or unfit for docetaxel. The primary end point was OS; secondary end points included time to first SSE, time to an increase in alkaline phosphatase or PSA levels and safety. A total of 921 patients were randomized with an allocation ratio of 2:1 to receive radium-223 at a dose of 50 kBq/Kg administered as six injections at 4-weekly intervals or placebo. Radium-223 was well tolerated and significantly improved OS by 30% (14.9 versus 11.3 months; HR: 0.70; 95% CI: 0.58–0.83; p < 0.001) and delayed time to first SSE; details from this pivotal trial are reported in Table 3.
Bone-targeting & Bone Metastasis-targeting Agents
Metastatic cancer cells in the bone microenvironment release a number of cytokines and growth factors that induce an alteration of bone resorption/formation processes, resulting in lytic bone lesions, blastic bone lesions or both. Although metastatic bone lesions from prostate cancer are typically osteoblastic, osteolysis is also a common feature. Increased osteoclastic activity is not confined to metastatic sites only; rather, it may also be found in the whole bone tissue. This is commonly caused by secondary hyperparathyroidism due to the so-called 'hungry bone syndrome' and by androgen deprivation-induced osteoporosis. Due to increased osteolysis, bone metastatic prostate cancer patients commonly experience SREs. If the disease is androgen sensitive, SREs are rare. However, they become frequent when the tumor is castration resistant. SREs are associated with reduced survival and quality of life and also impose a significant healthcare burden.
Zoledronic Acid
Zoledronic acid, a powerful third-generation nitrogen-containing bisphosphonate, was the first agent to be approved for the management of bone metastases in patients with CRPC. In 2002, a Phase III placebo-controlled trial of zoledronic acid versus placebo was conducted in 643 patients with mCRPC. Zoledronic acid 4 mg was administered every 21 days and significantly reduced the incidence of SREs; 44% of patients in the placebo group experienced a SRE compared with 33% in the experimental group (p = 0.021; Table 3). Zoledronic acid also significantly increased the time to first SRE (488 vs 321 days; p = 0.009). Pain scores and the use of analgesic drugs favored zoledronic acid, but there were no differences in either disease progression or OS.
Denosumab
The RANK/RANKL pathway plays a central role in bone resorption regulation. RANKL is part of the TNF family and is produced by osteoblasts. RANKL is able to bind RANK on the surface of both osteoclast precursors and osteoclasts, inducing osteoclast maturation, survival and activity.
Denosumab is a fully human monoclonal antibody against RANKL and prevents RANKL from activating its receptor, RANK, thus inhibiting osteoclast formation, function and survival, decreasing bone resorption and increasing bone mass and strength in both cortical and trabecular bone. When compared with zoledronic acid in a Phase III trial that enrolled 1904 patients with mCRPC to the bone, denosumab at 120 mg every 28 days improved the median time to first SRE by 3.6 months (HR: 0.82; p = 0.008); results from this pivotal study are reported in Table 3. The two groups had similar OS and time to disease progression. Adverse event rates were also similar, with the exception of an increased incidence of hypocalcemia (13% in the denosumab group vs 6% in the zoledronic acid group; p < 0.0001). Based on these data, the FDA and EMA have approved denosumab for the treatment of mCRPC patients with bone metastases.
Radium-223 Dichloride
Radium-223 is a targeted α-emitter that acts as a calcium mimetic and selectively binds areas of new bone growth in and around bone metastases. Unlike β-emitting agents that are myelotoxic, radium-233 emits ionizing radiation with high energy and extremely short penetration (<100 µm; 2–10 cell diameters), causing highly localized tumor cell killing with minimal side effects to normal cells.
The FDA and EMA recently approved radium-223 for the treatment of patients with CRPC and symptomatic bone metastases on the basis of the results of the ALSYMPCA trial. This Phase III placebo-controlled trial assessed the efficacy and safety of radium-223 in patients with CRPC and symptomatic bone metastases pretreated with or unfit for docetaxel. The primary end point was OS; secondary end points included time to first SSE, time to an increase in alkaline phosphatase or PSA levels and safety. A total of 921 patients were randomized with an allocation ratio of 2:1 to receive radium-223 at a dose of 50 kBq/Kg administered as six injections at 4-weekly intervals or placebo. Radium-223 was well tolerated and significantly improved OS by 30% (14.9 versus 11.3 months; HR: 0.70; 95% CI: 0.58–0.83; p < 0.001) and delayed time to first SSE; details from this pivotal trial are reported in Table 3.
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