Lancet publishes data on denosumab in men with mCRPC

Full data from the randomized, double-blind, multi-center, Phase III clinical trial comparing denosumab to zoledronic acid in the prevention of skeletal-related events in men with castration-resistant prostate cancer (CRPC) has now been published in The Lancet.

These data were first presented at the annual meeting of the American Society for Clinical Oncology in Chicago last June. In their newly published paper, Fizazi et al. have formally confirmed the data previously reported.

The study enrolled 1,904 men with CRPC at over 300 study sites in 39 countries. All patients had to be bisphosphonate-naive. In other words, they had never previously received any drug like zoledronic acid (Zometa) as an agent for the prevention of fractures or other bone-related complications of advanced prostate cancer. Patients were randomized to one or other of two groups:
  • Patients in Group A  received a subcutaneous injection of denosumab (120 mg) and an intravenous infusion of a placebo every 4 weeks.
  • Patients in Group B were given a subcutaneous injection of a placebo and an  intravenous infusion of zoledronic acid (4 mg) every 4 weeks.
The patients were also stratified by previous skeletal-related event, by their PSA level, and by whether they had received chemotherapy for prostate cancer within 6 weeks before randomization. This was done to make sure that comparable numbers of each of these categories of patient were enrolled in each arm of the trial. The use of supplemental calcium and vitamin D was strongly recommended for all trial participants.
The results of the study can be summarized as follows:
  • 1,901/1,904 patients initially randomized were eligible for the efficacy analysis.
    • 950 were assigned to Group A.
    • 951 were assigned to Group B.
  • Average (median) time on study at the cut-off date for primary analysis was 12.2 months for patients in Group A and 11.2 months for patients in group B.
  • Average (median) time to first on-study skeletal-related event was 20.7 months for patients in Group A and 17·1 months for patients in Group B (hazard ratio [HR] = 0·82)
  • Adverse events were recorded in 916/950 patients (97 percent) in Group A and in 918/951 patients (97 percent) in Group B.
  • Serious adverse events were recorded in 594/950 patients (63 percent) in Group A and 568/951 patients (60 percent) in Group B.
  • Hypocalcaemia occurred with significantly greater frequency in Group A (121 cases; 13 percent) than in Group B (55 cases; 6 percent).
  • Osteonecrosis of the jaw (ONJ) occurred infrequently (22 cases, 2 percent in Group A; 12 cases, 1 percent in Group B).

In summary, treatment with denosumab in this set of patients appeared to delay the time to a first skeletal-related event by about 3.6 months compared to zoledronic acid. However, this benefit came with a small increase in risk for hypocalcemia and ONJ.

It is relevant to note that, at least in the USA today, guidelines suggest that patients who are receiving hormone therapy for progressive prostate cancer should receive supplementary treatment to prevent skeletal-related events such as bone thinning and fractures long before they become castration resistant. Denosumab (Xgeva®) was approved for prescription to patients with solid tumors — including prostate cancer in late 2010. The precise indication approved by the US Food & Drug administration is for the “Prevention of skeletal-related events in patients with bone metastases from solid tumor.” In other words, it has not yet been formally approved for use in the treatment of men with prostate cancer who are receiving hormone therapy but have no visible sign of metastasis. However, additional data, released last December by Amgen, have suggested that denosumab also delays time to onset of bone metastasis in men with CRPC. These data are still to be formally presented at a major meeting.

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