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CHICAGO -- Men with advanced prostate cancer lived significantly longer if they received upfront chemotherapy in addition to androgen deprivation, results of a randomized trial showed.

As compared with men who received only androgen deprivation therapy (ADT), those who also got docetaxel had a 10-month improvement in median overall survival (OS). The difference translated into a 24% reduction in the mortality hazard. Subgroup analysis showed that patients with metastatic disease at the start of treatment derived even greater benefit from docetaxel, a 22-month improvement in median overall survival.

The study is at least the third reported within the past year showing a significant survival benefit with upfront docetaxel, making a strong case for standard of care, as reported during a press briefing prior to the American Society of Clinical Oncology meeting, which begins here May 29.

"Our headline conclusion would be that docetaxel would be considered routine therapy for men with newly diagnosed metastatic disease," said , of the University of Warwick and Queen Elizabeth Hospital in Birmingham, England.

"For nonmetastatic disease, there remains uncertainty as to whether there is a survival benefit or not, but it certainly increased failure-free survival by a substantial amount, so we would argue that docetaxel should be considered for selected men with high-risk nonmetastatic disease in view of the substantial prolongation of failure-free survival."

The addition of zoledronic acid to ADT and docetaxel improved survival but not significantly so compared with docetaxel alone, he added. The addition of zoledronic acid alone did not improve OS or failure-free survival (FFS).

For years, ADT has represented front-line therapy for men with advanced prostate cancer. The of docetaxel (Taxotere) in castration-resistant prostate cancer led to speculation that upfront use of the taxane might offer benefits to men with advanced disease and no prior exposure to hormonal manipulation.

To examine the impact of upfront docetaxel in hormone-naive advanced prostate cancer, investigators throughout the U.K. randomized 3,000 patients 2:1:1:1 to four treatment groups: ADT alone, ADT plus docetaxel, ADT plus zoledronic acid, or ADT plus docetaxel and zoledronic acid.

Eligibility criteria allowed for enrollment of patients who had high-risk, locally advanced disease; lymph node-positive disease; metastatic disease; and patients with aggressive post-treatment relapse, defined as rapid rise in prostate-specific antigen (PSA) level or baseline PSA >20 ng/mL.

The patients had a median age of 65 and a median PSA of 65 ng/mL. James said 61% of the patients had metastatic disease, 14% had nodal involvement but no distant metastases, and 22% had neither nodal involvement nor metastasis.

The primary endpoint was OS. The data showed no beneficial effect of zoledronic acid on the primary endpoint, so James focused on the comparison of ADT alone versus ADT plus docetaxel.

After a median follow-up of 42 months, the docetaxel-ADT group had a median OS of 77 months versus 67 months for the patients who received only ADT (HR 0.76, 95% CI 0.63-0.91, P=0.003). Analysis of failure-free survival (a secondary endpoint) showed a 38% reduction in the hazard for progression or death (HR 0.62, 95% CI .54-0.70).

A subgroup analysis showed that patients who were free of distant metastasis at enrollment (M0) did not derive a significant survival benefit from the addition of docetaxel (HR 1.01, 95% CI 0.65-1.56). Men who had metastatic disease (M1) had a 27% improvement in survival (HR 0.73, 95% CI 0.59-0.89) and drove the survival benefit (43 versus 65 months).

James pointed out that 93 patients in the M0 subgroup had died during follow-up, too few deaths to reach definitive conclusions about the potential survival benefits of docetaxel in that subgroup of patients.

"About 40% of the patients are M0 ... . The M0 analysis is not fully powered up," he said. "There's a high degree of uncertainty as to where the real study of the hazard ratio of the M0 patients will turn out to lie."

The analysis of FFS showed a significant advantage for the docetaxel group overall and in patients who had no distant metastases (HR 0.57, 95% 0.42-0.76) or who had metastatic disease at enrollment (HR 0.62, 95% 0.54-0.73).

The growing data support for upfront chemotherapy reflects a major shift in the historical view of clinical management of advanced prostate cancer, as it primarily affects a population of older men, said press briefing moderator , of the Helen F. Graham Cancer Center in Wilmington, Del.

"The paradigm for years or even decades has been to treat this with hormone therapy because it is relatively less toxic ... ," he said. "The bias has been to hormone therapy until it's exhausted, until there's no response left, and then, at the last moment, use chemotherapy."

"Starting last year, we began to see that might be the wrong strategy, at least in some men. Giving chemotherapy early on, upfront, with hormone therapy, might be better than the sequence of hormone therapy and then chemotherapy only at the last stages."

Acknowledging that docetaxel currently does not have approval for upfront treatment of advanced prostate cancer, James said the mounting evidence could lead to regulatory approval and support in clinical guidelines.

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