Thursday, April 4, 2013

Zoledronic Acid Fails to Halt Metastasis in Prostate Cancer Kate Johnson Mar 26, 2013


MILAN, Italy — Zoledronic acid (Zometa, Novartis) is no better at preventing bone metastasis in high-risk prostate cancer patients than standard treatment, results from the Zometa European Study (ZEUS) show.
"There were no differences in the incidence of bone metastasis. The primary end point was not achieved so it's a negative trial," said principal investigator Manfred Wirth, MD, from the University Clinic of the Technical University of Dresden in Germany. There was also no survival benefit associated with zoledronic acid, he noted.
Dr. Wirth presented results from the bisphosphonate trial during a late-breaking session here at the European Association of Urology (EAU) 28th Annual Congress.
The randomized, open-label, multicenter study was conducted by the EAU, in cooperation with the Scandinavian Prostate Cancer Group, and the Arbeitsgemeinschaft Urologische Onkologie.
ZEUS involved 1433 men with high-risk prostate cancer, defined as a prostate-specific antigen (PSA) level of at least 20 ng/mL at the time of diagnosis, a Gleason score of 8 to 10, or lymph node positivity.
Subjects were randomized to receive zoledronic acid 4 mg infusions every 3 months for a total of 48 months (n = 716), or standard treatment only (n = 717). All participants received daily supplements of calcium 500 mg and vitamin D 400 to 500 IU.
The primary outcome of the study was the development of bone metastases during the 48 months of follow-up.
Secondary outcomes included time to first bone metastasis, overall survival, time to PSA doubling, safety, and, in a substudy in selected centers, bone mineral density and biochemical markers of bone turnover.
The extended median follow-up was 4.8 years in the zoledronic acid group and 4.7 years in the control group, and 41% of patients in the zoledronic acid group received all 16 doses.
The rates of bone metastasis were similar in the zoledronic acid and control groups (13.7% vs 13.0%;P = 0.721). "There was absolutely no difference between the groups," said Dr. Wirth.
There was also no difference in overall survival between the 2 groups (= 0.717). In addition, there was no significant difference between the death rate from prostate cancer and the rate from other causes, he noted.
Table. Rates of Bone Metastasis With and Without Previous Treatment
Previous Treatment
Zoledronic Acid, %
Control, %
With
11.2
9.9
Without
16.9
16.7
Equivocal bone scans "were something of a concern" in 29 patients in the control group and 56 in the zoledronic acid group; these patients were followed for an extra year. In that group, the rate of metastasis was higher in the control group than in the zoledronic acid group (17% vs 7%), Dr. Wirth reported.
"A very interesting" subanalysis showed that there were significantly lower rates of bone metastasis in those who had been locally treated than in those who had not (56% with radical prostatectomy and 44% with radiotherapy). This "seems to show that local curative treatment really is of benefit for patients...in this high-risk group," Dr. Wirth said.
The rate and severity of adverse effects was similar in the 2 groups, with the exception of osteonecrosis of the jaw (1 patient in the control group and 9 in the zoledronic acid group) and osteonecrosis of the left femoral head (1 patient in the zoledronic acid group), "which to my knowledge is not often reported" with zoledronic acid, he noted.
Another subgroup analysis showed significant regional differences in prostate cancer metastasis, he explained. With Germany as the reference (and the largest number of study subjects), the data showed a significantly increased risk for metastasis in Sweden (hazard ratio [HR], 2.3), the Netherlands (HR, 2.2), and Norway (HR, 1.9), and a reduced risk in Italy (HR, 0.8).
Negative Trial
"Sometimes a 'negative' study adds valuable support for our current standards of care," said Philip Saylor, MD, from the Massachusetts General Hospital Cancer Center in Boston, who was asked byMedscape Medical News to comment on the study.
"The ZEUS results affirm that we are well served to reserve the use of potent osteoclast inhibition — with either zoledronic acid or denosumab — for men with prostate cancer that is already metastatic to the bone and has progressed on first-line androgen-deprivation therapy," Dr. Saylor said.
Rather than preventing bone metastasis, zoledronic acid and denosumab have both been shown to significantly reduce the incidence of skeletal events, such as pathologic fractures and spinal cord compression, in prostate cancer patients with advanced disease, Dr. Saylor noted.
"Intensive osteoclast inhibition with monthly denosumab has been shown to modestly prolong metastasis-free survival by about 4 months in men who have progressed on first-line androgen-deprivation therapy" (Lancet. 2012;379:39-46), he explained. "Denosumab was notably not approved for this indication for a number of reasons, including the absence of an effect on overall survival."
He noted that "the clinically meaningful prevention of bone metastases will require agents that target the tumor and/or the bone microenvironment in some way that is distinct from osteoclast inhibition."
This study was funded by the European Association of Urology, in cooperation with the Scandinavian Prostate Cancer Group and the Arbeitsgemeinschaft Urologische Onkologie. Dr. Wirth and Dr. Saylor have disclosed no relevant financial relationships.
European Association of Urology (EAU) 28th Annual Congress. Presented March 19, 2013.

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