Prevention of Skeletal Complications in Metastatic CRPC
Prevention of Skeletal Complications in Metastatic CRPC
Overall, 951 patients randomized to zoledronic acid and 950 patients randomized to denosumab in the phase III study were evaluable for efficacy in the primary analysis. As reported previously, age, ECOG performance status, and the randomization stratification factors (baseline PSA ≥10 ng/ml, chemotherapy ≤6 weeks before randomization, and previous SRE) were balanced between treatment arms.
In a comparison of SSE and SRE as end points, there were 296 fewer first on-study SSEs than first on-study SREs (641 versus 937, respectively), and there were 340 fewer first and subsequent on-study SSEs than first and subsequent on-study SREs (738 versus 1078; Table 1). As anticipated, first on-study pathologic fractures were less numerous when defined as SSE than when defined as SRE (36 versus 328), as were first and subsequent on-study fractures (32 versus 391). In addition, the numbers of first on-study surgery to bone, first radiation to bone, and first spinal cord compression were similar when defined as SSE or SRE.
The numbers of patients with first on-study SSE were fewer in the denosumab arm (n = 241) versus the zoledronic acid arm (n = 289; Table 2); similar results were observed for patients with a first on-study SRE. Among the patients with a confirmed first on-study SSE, the numbers of patients in the denosumab and zoledronic acid arms with each event type (radiation to bone, symptomatic pathologic fracture, surgery to bone, and symptomatic spinal cord compression) were similar except for radiation to bone, which was less frequent in the denosumab arm than in the zoledronic acid arm (203 versus 233); similar results were observed for patients with a first on-study SRE.
First and subsequent on-study SSEs occurred in fewer patients in the denosumab arm (n = 329; 0.35 mean events per patient) versus the zoledronic acid arm (n = 409; 0.43 mean events per patient; Table 2); similar results were observed for patients with first and subsequent on-study SREs. Among the patients with first and subsequent on-study SSEs, the numbers of patients in the zoledronic acid and denosumab arms with each event type were similar except for radiation to bone, which was less frequent in the denosumab arm than in the zoledronic acid arm (272 versus 341); similar results were observed for patients with first and subsequent on-study SREs.
Compared with zoledronic acid, denosumab reduced the risk of first on-study SSE by 22% [HR, 0.78; 95% confidence interval (CI) 0.66–0.93; P = 0.005; Figure 1A]. Similarly, denosumab reduced the risk of first and subsequent on-study SSE by 22% versus zoledronic acid (rate ratio, 0.78; 95% CI 0.65–0.92; P = 0.004; Figure 1B). The median time to first on-study SSE was not reached in the denosumab arm and was 24.2 months in the zoledronic acid arm. As previously reported, denosumab reduced the risk of first on-study SRE, as well as the risk of first and subsequent SRE, by 18% versus zoledronic acid.
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Figure 1.
(A) Time to first on-study SSE and (B) first and subsequent on-study SSE. KM, Kaplan-Meier; NR, not yet reached.
Among patients with no/mild pain at baseline, the risk of developing moderate to severe pain on study was increased for patients with a first on-study occurrence of either an SSE (HR, 3.07; 95% CI 2.34–4.03; P < 0.0001) or an SRE (HR, 2.09; 95% CI 1.69–2.58; P < 0.0001; Figure 2).
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Figure 2.
Effect of first on-study SSE and SRE (versus no SSE or SRE, respectively) on the risk of time to >4-point worst pain score (moderate or severe pain) in patients with no/mild pain at baseline. N designates the number of patients with baseline worst pain score ≤4 points; n designates the number of patients with a first on-study SSE/SRE, beginning 28 days before the SSE/SRE occurrence.
Results
Patients
Overall, 951 patients randomized to zoledronic acid and 950 patients randomized to denosumab in the phase III study were evaluable for efficacy in the primary analysis. As reported previously, age, ECOG performance status, and the randomization stratification factors (baseline PSA ≥10 ng/ml, chemotherapy ≤6 weeks before randomization, and previous SRE) were balanced between treatment arms.
Incidence of Symptomatic Skeletal Events and Skeletal-related Events
In a comparison of SSE and SRE as end points, there were 296 fewer first on-study SSEs than first on-study SREs (641 versus 937, respectively), and there were 340 fewer first and subsequent on-study SSEs than first and subsequent on-study SREs (738 versus 1078; Table 1). As anticipated, first on-study pathologic fractures were less numerous when defined as SSE than when defined as SRE (36 versus 328), as were first and subsequent on-study fractures (32 versus 391). In addition, the numbers of first on-study surgery to bone, first radiation to bone, and first spinal cord compression were similar when defined as SSE or SRE.
Symptomatic Skeletal Events and Skeletal-related Events by Treatment Group
The numbers of patients with first on-study SSE were fewer in the denosumab arm (n = 241) versus the zoledronic acid arm (n = 289; Table 2); similar results were observed for patients with a first on-study SRE. Among the patients with a confirmed first on-study SSE, the numbers of patients in the denosumab and zoledronic acid arms with each event type (radiation to bone, symptomatic pathologic fracture, surgery to bone, and symptomatic spinal cord compression) were similar except for radiation to bone, which was less frequent in the denosumab arm than in the zoledronic acid arm (203 versus 233); similar results were observed for patients with a first on-study SRE.
First and subsequent on-study SSEs occurred in fewer patients in the denosumab arm (n = 329; 0.35 mean events per patient) versus the zoledronic acid arm (n = 409; 0.43 mean events per patient; Table 2); similar results were observed for patients with first and subsequent on-study SREs. Among the patients with first and subsequent on-study SSEs, the numbers of patients in the zoledronic acid and denosumab arms with each event type were similar except for radiation to bone, which was less frequent in the denosumab arm than in the zoledronic acid arm (272 versus 341); similar results were observed for patients with first and subsequent on-study SREs.
Risk of Symptomatic Skeletal Events and Skeletal-related Events
Compared with zoledronic acid, denosumab reduced the risk of first on-study SSE by 22% [HR, 0.78; 95% confidence interval (CI) 0.66–0.93; P = 0.005; Figure 1A]. Similarly, denosumab reduced the risk of first and subsequent on-study SSE by 22% versus zoledronic acid (rate ratio, 0.78; 95% CI 0.65–0.92; P = 0.004; Figure 1B). The median time to first on-study SSE was not reached in the denosumab arm and was 24.2 months in the zoledronic acid arm. As previously reported, denosumab reduced the risk of first on-study SRE, as well as the risk of first and subsequent SRE, by 18% versus zoledronic acid.
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Figure 1.
(A) Time to first on-study SSE and (B) first and subsequent on-study SSE. KM, Kaplan-Meier; NR, not yet reached.
Effect of First Skeletal-related Event and Symptomatic Skeletal Event on Time to Moderate or Severe Pain (>4-point Worst Pain Score)
Among patients with no/mild pain at baseline, the risk of developing moderate to severe pain on study was increased for patients with a first on-study occurrence of either an SSE (HR, 3.07; 95% CI 2.34–4.03; P < 0.0001) or an SRE (HR, 2.09; 95% CI 1.69–2.58; P < 0.0001; Figure 2).
(Enlarge Image)
Figure 2.
Effect of first on-study SSE and SRE (versus no SSE or SRE, respectively) on the risk of time to >4-point worst pain score (moderate or severe pain) in patients with no/mild pain at baseline. N designates the number of patients with baseline worst pain score ≤4 points; n designates the number of patients with a first on-study SSE/SRE, beginning 28 days before the SSE/SRE occurrence.
