Zoledronic Acid Does Not Add to Upfront Docetaxel Survival Benefit in Advanced Prostate Cancer

Nicholas James, MD

An updated analysis of the STAMPEDE trial upholds the survival benefit observed with early use of docetaxel in advanced prostate cancer, but does not support the introduction of zoledronic acid.

Nicholas James, MD, of the University of Warwick and Queen Elizabeth Hospital Birmingham, in the United Kingdom, reported the results at the 2015 European Cancer Congress.

“We saw a statistically significant and highly clinically significant improvement in overall survival with the addition of docetaxel, for men starting hormone therapy for the first time. Docetaxel also significantly prolonged the time to first reported symptomatic skeletal-related event [SSE]. But we also saw no evidence supporting the upfront use of zoledronic acid,” James said.

STAMPEDE’s hypothesis was that early use of active therapies may give a larger absolute benefit in overall survival, and that the use of zoledronic acid would prolong the time to first SSE.

“We had in vitro evidence of synergy between docetaxel and zoledronic acid, and we anticipated that the combination would be well tolerated,” he said.

For the comparison, STAMPEDE accrued 2962 advanced hormone therapy-naïve prostate cancer patients. Subjects had newly diagnosed disease (metastatic, node-positive, or high-risk node-negative) or they had relapsed after prostatectomy or radiotherapy. Patient had a median age was 65 years; 61% had metastatic disease; and median PSA was 65 ng/mL. They were required to have a Gleason score of at least 8. STAMPEDE included multiple treatment arms, some of which were eliminated during the course of the trial and others added. The current analysis focused on the comparisons between standard treatment with androgen deprivation therapy with or without radiotherapy (n = 1184), versus standard treatment plus zoledronic acid (n = 593), docetaxel (n = 592) or the combination (n = 593).

Docetaxel was given at the standard target dose of 75 mg/m2 every 3 weeks for 6 cycles plus prednisolone at 10 mg daily. Zoledronic acid was dosed at 4 mg every 3 weeks for up to 18 weeks, then every 4 weeks up to 2 years.

The study’s primary outcome measure was overall survival. Secondary outcomes were failure-free survival, SSEs, toxicity, quality of life, and cost-effectiveness. James presented updated survival outcomes and the first SSE results for these comparisons, after a median follow-up of 43 months.

“In the updated survival analysis, we saw that the overall survival benefit with docetaxel remains, and there was a weak but non-significant trend to improved survival with zoledronic acid,” James reported.

With the standard of care, 415 deaths were observed, compared with the following survival outcomes in the experimental arms:

• 175 deaths among patients receiving standard treatment plus docetaxel (HR, 0.78; 95% CI, 0.66-0.93; P = .006)
• 201 deaths among patients receiving standard treatment plus zoledronic acid (HR, 0.94; 95% CI, 0.79-1.11; P = .450)
• 187 deaths among patients receiving docetaxel plus zoledronic acid (HR, 0.82; 95% CI 0.69-0.97; P = .022)

Examining the two experimental arms, James noted that slightly more deaths occurred with the combination arm (HR, 1.06; 95% CI, 0.86-1.30; P = .592). “There is a weak trend toward the monotherapy arm being better than the dual therapy arm,” he observed.

In preplanned analyses, the protective effect of docetaxel on survival was uniform across subgroups. Hazard ratios were similar for patients with newly diagnosed and previously treated disease.

For the docetaxel comparison to controls, benefit was greatest for patients who were metastatic at presentation (HR, 0.76; 95% CI, 0.62-0.92), compared with non-metastatic patients (HR = 0.95; 95% CI, 0.62-1.47). In the M0 subgroup receiving docetaxel, only 20 deaths related to prostate cancer were recorded, he noted.

“Their overall prognosis is much better than we might have anticipated when we set this trial up,” he commented.

For the comparison of standard treatment versus the addition of zoledronic acid in preventing SSEs, “given what might have been expected, we saw a remarkably weak effect,” said James. “We saw a trend, but it was definitely not significant, toward delaying SSEs with zoledronic acid.”

There were 328 SSEs in the standard-of-care arm and 153 in the zoledronic acid arm (HR, 0.89; 95% CI, 0.73-1.07; P = .221).

For patients with bone metastases at entry—a group for whom a protective effect was anticipated—there was a “very weak trend toward benefit with zoledronic acid that is nowhere near statistically significant,” he added.

In this group, 280 SSEs were recorded for the control arm and 130 for the zoledronic acid arm (HR, 0.94; 95% CI, 0.76-1.16; P = .564).

In contrast, with docetaxel, a large treatment effect was observed. While 328 SSEs occurred with standard treatment, 112 occurred in the docetaxel arm (HR, 0.60; 95% CI, 0.48-0.74; P = .00000127). A similar effect was observed for the newly diagnosed group with bone metastases.

There appeared to be no further benefit for adding zoledronic acid to docetaxel (HR, 0.55; 95% CI 0.44-0.69; P = .0000000277), “paralleling the survival results,” he noted.

An analysis of total SSEs (not just first-reported SSEs) will be performed in the future.

James ND, Sydes MR, Mason MD, et al. Docetaxel (Doc) +/- zoledronic acid (ZA) for hormone-naïve prostate cancer: First overall survival results from STAMPEDE & treatment effects within subgroups (NCT00268476). Presented at: 2015 European Cancer Congress; September 25-29; Vienna, Austria. Abstract LBA 19.