November 16, 2011 — A pivotal trial showing that denosumab (Xvega, Amgen) delays the onset of bone metastases in patients with castration-resistant prostate cancer (CRPC) was published online today in the Lancet.
"Our study is the first controlled trial to demonstrate prevention of bone metastases in men with prostate cancer," said lead author Matthew Smith, MD, PhD, professor of medicine at Harvard Medical School and director of genitourinary oncology at Massachusetts General Hospital in Boston.
The study was conducted in 1432 men with nonmetastatic CRPC who were at high risk of developing bone metastases, the team reports. Denosumab significantly increased the time to development of bone metastases, compared with placebo, by a median of 4.2 months (29.5 vs 25.2 months; hazard ratio, 0.85; P = .028). However, there was no difference in overall survival.
When this study was recently highlighted at the 2011 European Multidisciplinary Cancer Congress, experts greeted the finding with enthusiasm, as reported at the time by Medscape Medical News. This is the first agent that has been shown to delay the onset of bone metastasis in CRPC; hence, it "represents a paradigm shift in our beliefs about the limited efficacy of presently available antimetastatic strategies," said Joaquim Bellmunt, MD, from the Valle d'Hebron University Hospital, Barcelona, Spain, at the time.
An editorial accompanying the study is more circumspect. Christopher Logothetis, MD, chair of genitourinary medical oncology at the University of Texas M.D. Anderson Cancer Center in Houston, questions some of the findings.
However, Dr. Smith, lead author of the study, told Medscape Medical News that "the editorial suffers from flawed logic."
Editorial Comments
Dr. Logothetis asserts that the results of this study do not support broad use of denosumab as a preventive agent for bone metastases in prostate cancer.
He adds that the data so far support the use of denosumab as an alternative to zoledronic acid (Zometa, Novartis) to delay the time to skeletal-related events in men with metastatic CRPC.
This is currently an approved use of the drug; denosumab is licensed for use in cancer patients who already have bone metastases. The trial pushed the envelope, suggesting use in patients who don't yet have but who are likely to develop bone metastases. The results show that denosumab prolongs the time to development of bone metastasis; these data have been filed by the manufacturer for approval of this use.
Dr. Logothetis appears not to be convinced by the study results. He points out that the delay in time to metastases (median, 4.2 months) reported by Dr. Smith and colleagues in men with nonmetastatic CRPC is similar to the delay in time to skeletal-related events in the comparison of denosumab and zoledronic acid in men with metastatic CRPC by Fizazi and colleagues (Lancet. 2011:377:813-822).
"Because the duration of benefit is similar in both the premetastatic and metastatic settings, with no prolongation of survival in either group, deferral of treatment until metastases are evident is the preferred approach," he writes.
"I strongly disagree," Dr. Smith told Medscape Medical News.
"The comparison of the 2 randomized controlled trials is logically flawed because the patient populations, comparators, and primary end points differed between the studies," Dr. Smith said.
"Our study was a placebo-controlled trial of men with nonmetastatic castration-resistant prostate cancer and had the primary end point of bone metastasis-free survival," he explained. "The other denosumab study was a randomized comparison of zoledronic acid in men with established bone metastases and had a primary end point of skeletal-related events (radiation therapy or surgery to bone, pathological fractures, or spinal cord compression)."
Selecting Patients Likely to Benefit
The editorialist suggests that one possible explanation for the findings is that the patients might already have started to develop bone metastases, even though they were clinically undetectable. Therefore, the trial was not really looking at the "so-called metastatic prevention properties of denosumab, but rather explored the drugs effects on the biological continuum of metastases," Dr. Logothetis explains.
"Improved selection of patients likely to benefit from treatment will be needed to make meaningful advances in patient survival," he adds.
Dr. Smith disagrees with these suggestions. He pointed out that "major features of the study included careful screening of subjects at baseline (by imaging) to exclude men with detectable bone metastases, confirmation of bone metastases by bone scan and a second imaging modality, and central review of all imaging tests. "
"The speculation by the editorialist about the biological continuum of bone metastases has no bearing on the strength of our observations from this global placebo-controlled prospective clinical study," Dr. Smith asserted.
As for selecting patients who were likely to benefit from this therapy, Dr. Smith pointed out that the study did just that. "A key of our study was inclusion of men at high risk of developing bone metastases, based on elevated PSA [prostate-specific antigen] and/or more rapid PSA doubling time."
Patients enrolled into this study had a PSA of 8 µg/L or higher in the 3 months before randomization and/or a PSA doubling time of 10 months or less. They also had to be castration-resistant with 3 consecutive increasing PSA tests separated by at least 2 weeks, to have been previously been treated with continuous androgen-deprivation therapy for at least 6 months, or to have undergone a bilateral orchiectomy.
Delayed Time to Metastases
The results of this study show that treatment with denosumab (120 mg subcutaneously every 4 weeks) significantly prolonged the time to first bone metastasis and was associated with fewer symptomatic bone metastases than placebo, the researchers report.
These findings provide the "first direct clinical evidence for the important role of the bone environment and RANKL signaling in the development of bone metastases in men with prostate cancer," they add.
Denosumab is an inhibitor of receptor activator of nuclear factor kappa-B (RANK) ligand, which mediates the interaction between osteoblasts and osteoclasts in the so-called vicious cycle that characterizes bone metastases in prostate cancer, the editorialist explains.
This study was funded by Amgen, the manufacturer of denosumab. Dr. Smith and several of his coauthors report consulting for Amgen and Novartis. Several of the coauthors are employees of Amgen and have received stock or stock options. Dr. Logothetis has disclosed no relevant financial relationships.
Lancet. Published online November 16, 2011. Abstract, Editorial
"Our study is the first controlled trial to demonstrate prevention of bone metastases in men with prostate cancer," said lead author Matthew Smith, MD, PhD, professor of medicine at Harvard Medical School and director of genitourinary oncology at Massachusetts General Hospital in Boston.
The study was conducted in 1432 men with nonmetastatic CRPC who were at high risk of developing bone metastases, the team reports. Denosumab significantly increased the time to development of bone metastases, compared with placebo, by a median of 4.2 months (29.5 vs 25.2 months; hazard ratio, 0.85; P = .028). However, there was no difference in overall survival.
When this study was recently highlighted at the 2011 European Multidisciplinary Cancer Congress, experts greeted the finding with enthusiasm, as reported at the time by Medscape Medical News. This is the first agent that has been shown to delay the onset of bone metastasis in CRPC; hence, it "represents a paradigm shift in our beliefs about the limited efficacy of presently available antimetastatic strategies," said Joaquim Bellmunt, MD, from the Valle d'Hebron University Hospital, Barcelona, Spain, at the time.
An editorial accompanying the study is more circumspect. Christopher Logothetis, MD, chair of genitourinary medical oncology at the University of Texas M.D. Anderson Cancer Center in Houston, questions some of the findings.
However, Dr. Smith, lead author of the study, told Medscape Medical News that "the editorial suffers from flawed logic."
Editorial Comments
Dr. Logothetis asserts that the results of this study do not support broad use of denosumab as a preventive agent for bone metastases in prostate cancer.
He adds that the data so far support the use of denosumab as an alternative to zoledronic acid (Zometa, Novartis) to delay the time to skeletal-related events in men with metastatic CRPC.
This is currently an approved use of the drug; denosumab is licensed for use in cancer patients who already have bone metastases. The trial pushed the envelope, suggesting use in patients who don't yet have but who are likely to develop bone metastases. The results show that denosumab prolongs the time to development of bone metastasis; these data have been filed by the manufacturer for approval of this use.
Dr. Logothetis appears not to be convinced by the study results. He points out that the delay in time to metastases (median, 4.2 months) reported by Dr. Smith and colleagues in men with nonmetastatic CRPC is similar to the delay in time to skeletal-related events in the comparison of denosumab and zoledronic acid in men with metastatic CRPC by Fizazi and colleagues (Lancet. 2011:377:813-822).
"Because the duration of benefit is similar in both the premetastatic and metastatic settings, with no prolongation of survival in either group, deferral of treatment until metastases are evident is the preferred approach," he writes.
"I strongly disagree," Dr. Smith told Medscape Medical News.
"The comparison of the 2 randomized controlled trials is logically flawed because the patient populations, comparators, and primary end points differed between the studies," Dr. Smith said.
"Our study was a placebo-controlled trial of men with nonmetastatic castration-resistant prostate cancer and had the primary end point of bone metastasis-free survival," he explained. "The other denosumab study was a randomized comparison of zoledronic acid in men with established bone metastases and had a primary end point of skeletal-related events (radiation therapy or surgery to bone, pathological fractures, or spinal cord compression)."
Selecting Patients Likely to Benefit
The editorialist suggests that one possible explanation for the findings is that the patients might already have started to develop bone metastases, even though they were clinically undetectable. Therefore, the trial was not really looking at the "so-called metastatic prevention properties of denosumab, but rather explored the drugs effects on the biological continuum of metastases," Dr. Logothetis explains.
"Improved selection of patients likely to benefit from treatment will be needed to make meaningful advances in patient survival," he adds.
Dr. Smith disagrees with these suggestions. He pointed out that "major features of the study included careful screening of subjects at baseline (by imaging) to exclude men with detectable bone metastases, confirmation of bone metastases by bone scan and a second imaging modality, and central review of all imaging tests. "
"The speculation by the editorialist about the biological continuum of bone metastases has no bearing on the strength of our observations from this global placebo-controlled prospective clinical study," Dr. Smith asserted.
As for selecting patients who were likely to benefit from this therapy, Dr. Smith pointed out that the study did just that. "A key of our study was inclusion of men at high risk of developing bone metastases, based on elevated PSA [prostate-specific antigen] and/or more rapid PSA doubling time."
Patients enrolled into this study had a PSA of 8 µg/L or higher in the 3 months before randomization and/or a PSA doubling time of 10 months or less. They also had to be castration-resistant with 3 consecutive increasing PSA tests separated by at least 2 weeks, to have been previously been treated with continuous androgen-deprivation therapy for at least 6 months, or to have undergone a bilateral orchiectomy.
Delayed Time to Metastases
The results of this study show that treatment with denosumab (120 mg subcutaneously every 4 weeks) significantly prolonged the time to first bone metastasis and was associated with fewer symptomatic bone metastases than placebo, the researchers report.
These findings provide the "first direct clinical evidence for the important role of the bone environment and RANKL signaling in the development of bone metastases in men with prostate cancer," they add.
Denosumab is an inhibitor of receptor activator of nuclear factor kappa-B (RANK) ligand, which mediates the interaction between osteoblasts and osteoclasts in the so-called vicious cycle that characterizes bone metastases in prostate cancer, the editorialist explains.
This study was funded by Amgen, the manufacturer of denosumab. Dr. Smith and several of his coauthors report consulting for Amgen and Novartis. Several of the coauthors are employees of Amgen and have received stock or stock options. Dr. Logothetis has disclosed no relevant financial relationships.
Lancet. Published online November 16, 2011. Abstract, Editorial
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