CHICAGO (FRONTLINE MEDICAL NEWS)Using chemotherapy earlier in the course of advanced prostate cancer improves outcomes, according to first survival results of the STAMPEDE trial (Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy).

Results showed that adding docetaxel to the standard of hormone therapy at the time of diagnosis reduced the risk of treatment failure or death by 38% and the risk of death by 24%, researchers reported in a press briefing held in advance of the annual meeting of the American Society of Clinical Oncology. The benefit was clear among men with metastatic disease but less so among those with nonmetastatic disease.

“Docetaxel improves survival in men with hormone-naive prostate cancer starting hormone therapy for the first time,” concluded lead researcher Dr. Nicholas David James, director of the cancer research unit at the University of Warwick and consultant in clinical oncology at Queen Elizabeth Hospital Birmingham (England).

“Docetaxel should be considered as routine practice in men with newly diagnosed metastatic disease,” he asserted. “For nonmetastatic disease, there remains uncertainty as to whether there is a survival benefit or not, but it certainly improves failure-free survival by a substantial amount, so we would argue that it should be considered for selected men with high-risk nonmetastatic disease.”

Clinicians should use an individualized approach to adding docetaxel in the subgroup with nonmetastatic disease. “What I am doing in my own clinic, for example, is having a discussion with the patients about the pros and cons. … I think it will be something we discuss on a case-by-case basis,” he said, adding that a planned meta-analysis should better clarify the survival benefit in this subgroup.

Dr. Peter Paul Yu, ASCO president and a medical oncologist and hematologist, who is director of cancer research at the Palo Alto Medical Foundation, Sunnyvale, Calif., said that the STAMPEDE data contribute to an ongoing paradigm shift in treating advanced prostate cancer.

“The paradigm for years or even decades has been to treat this with hormone therapy because [it] is relatively less toxic. … The advice has been to use hormone therapy until it’s exhausted, until there is no response left, and then at the last moment use chemotherapy, which often is a potentially self-defeating strategy because you are using chemotherapy when the disease has evolved to a point where it’s much more aggressive,” he said.

Accumulating data, however, suggest that a strategy of combining chemotherapy with hormonal therapy upfront yields better outcomes than their sequential use. “This paradigm shift is continuing and should be highlighted,” he maintained.

“The really interesting thing is the hint … and I would say a very strong hint as an editorial comment, that this strategy of bringing chemotherapy early on can have a benefit even in men who do not have evidence of metastases at the time they are starting hormone therapy … what we would traditionally call the adjuvant use of chemotherapy,” Dr. Yu added.

Men were eligible for STAMPEDE if they were starting long-term hormone therapy for the first time and had high-risk locally advanced disease, lymph node–positive disease, metastatic disease, or disease that had relapsed aggressively after surgery or radiation therapy. STAMPEDE has an innovative, adaptive design whereby novel agents can be incrementally added to those found to be efficacious in earlier arms, generating a new standard of care. The trial receives funding and support in part from Sanofi-Aventis, Novartis, Pfizer, Janssen, and Astellas.

Dr. James presented findings for four of the trial’s nine arms, in which 2,962 patients were randomized to standard of care (androgen deprivation therapy with or without radiation therapy) alone, or with the addition of six cycles of docetaxel (Taxotere), 2 years of the bisphosphonate zoledronic acid (Zometa), or both.

Docetaxel is approved by the U.S. Food and Drug Administration for treatment of metastatic hormone-refractory prostate cancer, and zoledronic acid is approved for the treatment of hypercalcemia due to cancer.

With a median follow-up of 42 months, compared with standard care alone, adding docetaxel significantly reduced the risks of failure-free survival events (hazard ratio, 0.62) and death (HR, 0.76). Median overall survival was 77 months with the drug and 67 months without it, and the difference was largely driven by prostate cancer deaths, according to Dr. James.

About 60% of the men had metastases. In stratified analyses, adding docetaxel improved failure-free survival whether men had metastatic disease or not, but it improved overall survival only in those with metastatic disease (43 vs. 65 months). However, the standard-care arm in the nonmetastatic subgroup performed better than expected, and there have been too few deaths in that subgroup overall to fully power the analysis, Dr. James said.

Toxicity with the addition of docetaxel was manageable. Zoledronic acid did not improve either outcome relative to hormone therapy alone, and adding both zoledronic acid and docetaxel netted similar results to those seen with docetaxel alone.

Several other therapies, including next-generation hormone therapies and chemotherapy agents, also are showing promise in prostate cancer, and the optimal timing and sequencing of agents is unknown. STAMPEDE is the first to look at docetaxel and these hormone therapies at the time of diagnosis of advanced disease, he noted.

At present, the data support giving docetaxel before either abiraterone or enzalutamide in this treatment setting, as the drug’s survival advantage persisted even though patients often went on to receive those hormone therapies; however, that strategy might change with future results from this and other trials. “To be honest, it would be a nice position to be in if we had two treatments that improved overall survival upfront. That just gives us a choice. It would be good news obviously,” he concluded.

Dr. James disclosed that he has a consulting, advisory, or speakers’ bureau role with or receives honoraria or research funding (institutional) from Sanofi, Bayer, Merck, Astellas, Janssen, Pierre Fabre, Ferring, OncoGenex, and Pfizer.


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