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A new study showing a survival benefit of more than 1 year with a chemotherapy-hormonal therapy combination given prior to castration resistance is being hailed by a leading prostate cancer expert as possibly representing a “new standard” in care.
Chicago-A new study showing a survival benefit of more than 1 year with a chemotherapy-hormonal therapy combination given prior to castration resistance is being hailed by a leading prostate cancer expert as possibly representing a “new standard” in care.
The study’s authors, who presented their data at the American Society of Clinical Oncology annual meeting in Chicago, found that adding docetaxel (Taxotere) to standard hormone therapy dramatically improved survival in men with newly diagnosed hormone-sensitive prostate cancer compared with hormone therapy alone.
The improvement in survival was about 13 months in the docetaxel-treated cohort overall, with an even greater survival benefit for the subset of men with high-volume disease, said first author Christopher J. Sweeney, MBBS.
“This is one of the biggest improvements in survival we have seen in a trial involving patients with an adult metastatic solid tumor. The certainty of the data is strong for patients with a high volume of metastatic disease and clearly justifies the treatment burden,” said Dr. Sweeney, medical oncologist at the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute, Boston.
In the E3805 National Cancer Institute-funded study, 790 men with newly diagnosed metastatic prostate cancer were randomly assigned to upfront chemotherapy (a maximum of six cycles of docetaxel) plus androgen deprivation therapy (ADT) or to ADT alone for 18 weeks.
The study protocol allowed chemotherapy to be given at the investigator’s discretion upon evidence of disease progression. At enrollment, patients were stratified by extent of metastatic disease, either high volume or low volume. High-volume disease was defined as visceral metastasis and/or four or more bone metastases. About two-thirds in each treatment arm had evidence of high-volume disease. Approximately three-fourths in each arm had not received prior localized treatment.
A planned interim analysis met the criteria for significance and release of the study data. After a median follow-up of 29 months, 101 deaths were recorded in the docetaxel plus ADT arm compared with 136 in the ADT arm. The median overall survival (OS) was 57.6 months in the docetaxel plus ADT arm and 44.0 months in the ADT arm, corresponding to a hazard ratio (HR) of 0.61 (p=.0003).
“It means that a man is 39% more likely to be alive at each of the time points throughout this study compared to just being on testosterone suppression alone,” said Dr. Sweeney.
In men with high-volume disease, median OS was 49.2 months with docetaxel plus ADT compared with 32.2 months with ADT, corresponding to a 40% reduction in the risk of death with the addition of docetaxel (p=.0006). In men with low-volume disease, median OS had not been reached at the time of the analysis. The survival benefit with docetaxel was evident in all subgroups analyzed.
The median time to clinical disease progression was doubled in the docetaxel plus ADT arm at 32.7 months compared with the ADT alone arm at 19.8 months (HR=0.49; p<.0001). The median time to castration-resistant prostate cancer was also significantly improved with the addition of docetaxel compared with ADT alone (20.7 months vs. 14.7 months; p<.0001).
At disease progression, three-fourths of patients (129 of 174) in the ADT alone arm subsequently received docetaxel, Dr. Sweeney said.
Adverse effects in the men assigned to docetaxel included febrile neutropenia (6%) and significant effects on sensory nerves (1%) and on motor nerves (1%).
Dr. Sweeney emphasized that the results apply to “chemotherapy-fit” patients as determined by the treating clinician.
“Neuropathy can be a problem in a minority of patients, so if someone has diabetic injuries to the nerves and neuropathy, he may not be a candidate,” he said.
The study demonstrated that “by moving docetaxel from the castration-resistant stage, when men are not responding to testosterone-lowering agents, to the castration-sensitive state, when they are, the survival benefits are amplified, from 2 to 3 months to 13.6 months,” said Michael J. Morris, MD, medical oncologist at Memorial Sloan Kettering Cancer Center, New York, who was not involved in the study.
No other regimen tested in this setting comes close to the 17-month advantage in survival with docetaxel in patients with high-volume metastatic disease, Dr. Morris noted. The evidence is insufficient to recommend early docetaxel in patients with low-volume disease, he added.
J. Brantley Thrasher, MD, professor and chair of urology at the University of Kansas Medical Center in Kansas City, called the paper "very significant."
"To me this makes a lot of sense," said Dr. Thrasher, a Urology Times editorial consultant. "Many of the solid organ tumors that we treat respond well to hitting them early with chemotherapy instead of late when the tumors have changed dramatically after hormonal therapy. More follow-up is required to find out where those patients with smaller tumor burdens end up, but it certainly appears that all of these patients benefited from ADT plus docetaxel versus ADT alone.
"This could very well be a new standard but will likely require validation from further studies."
Dr. Sweeney discloses consultant or advisory roles with Astellas Pharma, BIND Biosciences, Bionomics, Exelixis, Genentech, Janssen Pharmaceuticals, Roche, and Sanofi. Several of his co-authors have consultant/advisory roles for and/or have received honoraria and/or research funding from Sanofi.UT
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