Denosumab (Xgeva) significantly delayed time to first bone metastases among men with nonmetastatic castration-resistant prostate cancer enrolled in a phase III randomized, placebo-controlled trial. The time to first bone metastasis was 33.2 months among the 716 patients randomly assigned to receive subcutaneous denosumab vs 29.5 months for an equal number of patients randomly assigned to placebo (P = .032). Denosumab significantly increased bone metastasis–free survival (defined as the time to either the first metastasis or death) by a median of 4.2 months (P = .028), but not overall survival, which was 43.9 months among patients receiving denosumab vs 44.8 months for those receiving placebo (P = .91).
Unmet Clinical Need
“Prostate cancer patients who develop bone metastases usually have poor outcomes, so preventing the development of metastasis has been a major unmet clinical need,” stated Matthew Smith, MD, PhD, of Massachusetts General Hospital Cancer Center in Boston, the lead author of the study report published in The Lancet.1 “This first demonstration of a treatment that can meet that goal is a significant accomplishment that should lead to better treatment strategies,” he said.
“Our findings also provide the first direct clinical evidence for the important role of the bone microenvironment and RANKL signaling in the development of bone metastases in men with prostate cancer,” the investigators reported. RANKL is “an essential mediator of osteoclast formation, function, and survival,” the investigators noted, and denosumab, a fully human monoclonal antibody, specifically binds and inactivates RANKL.
“The trial was extremely well conducted,” Christopher J. Logothetis, MD, said in an interview with The ASCO Post. Dr. Logothetis is Chair of the Department of Genitourinary Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston, and wrote a comment2 accompanying the article by Dr. Smith and colleagues. “For the first time, they have demonstrated that there is a delay in the time to detectable bone metastases, but they provide no evidence that denosumab impacts overall survival,” Dr. Logothetis noted.
Denosumab Discontinuation
All study patients received a bilateral orchiectomy or continuous androgen-deprivation therapy with a gonadotropin-releasing hormone agonist or antagonist for at least 6 months before starting the study. Total serum testosterone had to be lower than 1.72 nmol/L (50 ng/dL), and the men had to be castration-resistant with three consecutive increasing prostate-specific antigen (PSA) tests, the last two 1.0 μg/L or higher.
All the men were considered at high risk for bone metastases, characterized by “PSA of 8.0 μg/L or higher within 3 months before randomization or PSA doubling time of 10 months or less, or both,” the authors wrote. Subcutaneous denosumab at 120 mg or subcutaneous placebo (sterile saline) was administered every 4 weeks. (The FDA has approved denosumab as two different products, one for treating osteoporosis [Prolia] and the other for the prevention of skeletal-related events in patients with solid tumors and bone metastases [Xgeva]. Both brand name formulations are marketed by Amgen, which funded the study.)
“Patients were discontinued from treatment when bone metastasis occurred so that they could receive standard treatment for bone metastasis per investigator discretion,” the authors reported. Discontinuation of denosumab was required by the study protocol, and this requirement, the investigators stated, “restricted our ability to evaluate overall survival with denosumab, since about 80% of the deaths occurred in patients who had discontinued investigational product. With a median time from bone metastasis to death of 19 months, a treatment effect of denosumab on overall survival would be difficult to identify, particularly in the context of all other prostate cancer therapies used during that period that could affect survival. This same requirement also limited our ability to establish when asymptomatic bone metastases became symptomatic, since patients were removed from the study once a bone metastasis was detected and symptoms might not yet have occurred,” they added.
“If they were looking for greater impact,” Dr. Logothetis said, the investigators should have continued giving denosumab to patients even after evidence of metastases. “If there is one criticism of the study,” he added, it is that both arms of the study should have been continued to see if the benefit from denosumab extended out further.
Dilemma Related to Timing
The dilemma, according to Dr. Logothetis, concerns whether there is sufficient evidence to recommend denosumab for patients who have high-risk features as defined in the study. “[T]he delay in time to metastases documented by Smith and colleagues is similar to the delay in time to skeletal-related events reported in a comparison of denosumab against zoledronic acid in men with metastatic castration-resistant prostate cancer,” he wrote in The Lancet, citing a study by Fizazi et al.3 “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,” Dr. Logothetis commented.
“Despite differences in the study design, the magnitude of benefit attributed to denosumab is approximately equal in the premetastatic and (previously reported) metastatic settings. This similarity challenges the notion that benefit will be lost if denosumab therapy is delayed,” he told The ASCO Post.
“The next question is, how do we address this dilemma?” Dr. Logothetis said. Rather than using “the blunt instrument of a bisphosphonate,” distinct agents that target specific molecular pathways are being developed, and theoretically, it should be possible to select the patients likely to benefit. “We have to work toward better identifying subsets most likely to benefit, with an impact on survival.”
Markers for identifying these subsets of patients do not currently exist, “but we are all in a hurry working on them,” Dr. Logothetis said. “Candidate markers are being considered,” he noted, but “they are not ready for prime time.”
Smith and colleagues “provided the first proof of principle that you can target a molecular pathway to prolong survival [in this setting],” Dr. Logothetis added. “So if we understood better how to select patients based on that molecular pathway, theoretically, we would get a greater advantage.” ■
Disclosure: Drs. Smith and Logothetis reported no potential conflicts of interest.
References
1. Smith MR, Saad F, Coleman R, et al: Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: Results of a phase 3, randomised, placebo-controlled trial. Lancet 379:39-46, 2012.
2. Logothetis CJ: Treatment of prostate cancer metastases: More than semantics. Lancet 379:4-6, 2012.
3. Fizazi K, Carducci M, Smith M, et al: Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: A randomised, double-blind study. Lancet 377:813-822, 2011.
