Christopher Sweeney, MBBS
In what was described as “an almost unprecedented improvement in median survival,” the addition of the chemotherapy drug docetaxel to standard hormone therapy prolonged life for men with newly diagnosed metastatic, hormone-sensitive prostate cancer by nearly 14 months. The survival benefit was the greatest for men with extensive disease spread.
The findings from a federally funded, randomized phase III study, CHAARTED (E3805), were reported during a June 1 press briefing at the 2014 American Society of Clinical Oncology (ASCO) Annual Meeting.
“Hormone therapy has been a standard treatment for prostate cancer since the 1940s,” said lead study author Christopher Sweeney, MBBS, medical oncologist at the Lank Center of Genitourinary Oncology at the Dana-Farber Cancer Institute in Boston. “This is the first study to identify a strategy that prolongs survival in newly diagnosed metastatic prostate cancer. The benefit is substantial and warrants this being a new standard treatment for men who have high-extent disease and are fit for chemotherapy.”
“In prostate cancer, I am not aware of a historical study that ever offered up this magnitude of improvement in survival,” added ASCO President Clifford A. Hudis, MD, chief of the Breast Cancer Medical Service at Memorial Sloan Kettering Cancer Center and professor of Medicine at Weill Cornell Medical College, both in New York. “Across all solid tumors, this is an almost unprecedented improvement in median survival, and I think it can be transformative for people.”
Androgen deprivation therapy (ADT) alone is the standard first-line treatment for hormone-sensitive prostate cancer, Sweeney said. The disease eventually becomes resistant to the therapy in most patients, and chemotherapy is typically initiated only when that occurs, ASCO added in a press release.
About 30,000 patients die of hormone-resistant prostate cancer in the United States every year, according to ASCO.
Docetaxel was approved in 2004 as the first agent to improve overall survival (OS) for patients with metastatic, castration-resistant prostate cancer, and investigators embarked on the E3805 study to determine whether the drug would work in earlier-stage disease, Sweeney said.
Initial data from the study were released in September 2013, after an interim analysis in which 53.1% of data was available. Sweeney’s report at ASCO was an update reflecting data collected as of January 16, 2014.
In the 8-year, National Cancer Institute-led study, 790 men with newly diagnosed metastatic prostate cancer were randomly assigned 1:1 to receive either ADT alone or ADT with docetaxel, which was dosed at 75mg/m2
every 3 weeks for 6 cycles within 4 months of starting ADT. After the combination cohort completed 6 courses of docetaxel, all patients continued on ADT alone. The patients were stratified so that the study arms would be balanced, Sweeney said.
Approximately two-thirds of patients had high-extent disease.
OS was the primary endpoint, and the study was powered to assess for a 33.3% improvement in median OS (80% power and 1-sided alpha = 2.5%), the authors wrote in their abstract.
At a median follow-up of 29 months, median OS was 44 months in the ADT group and 57.6 months in the ADT-plus-docetaxel group, or a 39% higher likelihood of survival in the combination arm at any study time point (hazard ratio 0.61, P
= .0003), Sweeney reported. The relative improvement in median OS was largest (32.2 months ADT-only versus 49.2 months combination) among the 520 patients with high-extent disease, who had either 4 or more bone metastases or liver or lung metastases, he said. Patients with low-extent disease respond better to ADT, and thus the median OS for this subset has not yet been reached.
Docetaxel also delayed disease progression. At 1 year, the proportion of patients with prostate-specific antigen (PSA) levels less than 0.2 ng/mL (considered a sign of a better remission) was 11.7% in the ADT group versus 22.7% in the ADT-plus-docetaxel group, Sweeney said. The median time to clinical progression (new symptoms or metastases detected on a scan) was 19.8 months in the ADT group versus 32.7 months in the ADT-plus-docetaxel group, he said, and the measuring time to the development of CRPC—whether determined due to a rise in PSA, new symptoms, or scan—was 14.7 months in the ADT group and 20.7 months in the ADT-plus-docetaxel group.
While on treatment, the disease worsened in 145 patients in the combination group, 49 of whom received additional docetaxel. In the ADT-only group, 174 patients experienced worsening of disease, and 129 of them received docetaxel at progression, Sweeney said.
At the median 29-month follow-up, he said, there had been 136 deaths in the ADT-alone group versus 101 in the ADT-plus-docetaxel group.