CHICAGO, IL USA (UroToday.com) - Dr. Christopher Sweeney, a medical oncologist at the Dana-Farber Cancer Institute and Associate Professor of Medicine at Harvard Medical School presented an ASCO plenary session describing the results of ECOG study E3805, a cooperative group trial also known as CHAARTED.
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He began his talk by reviewing the history of androgen deprivation therapy (ADT) among men with prostate cancer, starting with initial evidence demonstrating clinical benefit in the 1940s. He proceeded to review evidence that men with greater metastatic burden tend to have shorter survival, and concluded with the landmark docetaxel studies demonstrating improvement in overall survival among men with metastatic castrate resistant prostate cancer (CRPC).
This background set the stage for a discussion of the rationale for the CHAARTED clinical trial. This study sought to determine the benefit of chemotherapy at the time of initiation of ADT among men with hormone-sensitive (or non-castrate resistant) metastatic prostate cancer. As with many other therapeutic trials, the investigators hypothesized that earlier incorporation of a treatment associated with an overall survival benefit in advanced metastatic CRPC would improve patient survival.
Investigators performed a phase III randomized controlled trial that randomized men with newly diagnosed metastatic prostate cancer to ADT alone or ADT plus 6 cycles of docetaxel, starting within 4 months of ADT initiation. Docetaxel was administered as it is in the metastatic CRPC setting (docetaxel 75 mg/m2 on day 1 of a 21-day cycle). Intermittent ADT was not permitted. Patients received standard dexamethasone pre-medication prior to docetaxel infusion, but were not required to take daily prednisone. Patients were stratified a priori by ECOG performance status (0-1 vs 2), age (≥ 70 vs < 70 years of age), burden of metastatic disease (high or visceral metastases and/or ≥ 4 bone metastases with at least 1 beyond the pelvis and vertebral column, vs low burden of disease), and whether men received combined androgen blockade vs standard ADT and zoledronic acid vs no zoledronic acid. Additionally men were stratified based on having > 12 months or ≤ 12 months of prior adjuvant ADT. If men received ADT prior to randomization, they were limited to having fewer than 120 days of therapy immediately prior to enrolling or adjuvant treatment < 24 months in duration with no progression within 12 months of completing treatment. Patients had generally good ECOG performance status (≤ 2), and had sufficient organ function to tolerate treatment with docetaxel.
The study focused on evaluating the following endpoints. The primary endpoint was overall survival. Secondary endpoints include the following:
- Rate of PSA < 0.2 ng/mL at 6 and 12 months,
- Time to biochemical, radiographic or symptomatic progressive disease,
- Adverse events,
- Quality of life by the FACT-P scale until 12 months after randomization, a quality of life measure validated in prostate cancer populations.
The study ultimately underwent 3 amendments, one of which permitted inclusion of men with low-volume disease.
CHAARTED accrued 790 total men between July 2006 and November 2012. A planned interim analysis performed after collection of 53% of the data met pre-specified criteria for significance in October 2013. The study was halted at that time, and the results were released. The results described in the presentation included all data through Jan 16, 2014, which was a median follow up of 29 months. At that time point there had been 136 deaths with ADT alone vs 101 deaths in the ADT plus docetaxel arm. Baseline characteristics of the two groups were well matched. Overall, 2/3 of patients included in the study had high volume disease.
In terms of the primary outcome, overall survival, patients treated with ADT plus up to 6 cycles of docetaxel experienced significantly longer overall survival as compared to men treated with ADT alone (median OS of ADT plus docetaxel was 57.6 months vs median OS of ADT alone was 44.0 months, p=0.003, or a median OS increase of 13.6 months). Men treated with docetaxel in addition to ADT were almost 40% less likely to die during the study (HR 0.61 for ADT plus docetaxel vs ADT alone). Investigators also reported overall survival results after stratifying by high- vs low-volume disease. Among men with high-volume disease, the improvement in overall survival was even more pronounced, with median OS of ADT plus docetaxel being 49.2 months, and median OS of ADT alone being 32.2 months (17 month improvement in median OS, p=0.0006). ADT plus docetaxel improved overall survival in all subgroups, though it provided greatest improvement among men with high burden of metastatic disease. Treatment with ADT plus docetaxel also improved all secondary endpoints.
View slides from Dr. Sweeney's presentation
The investigators also evaluated therapy after progression of disease on trial. Importantly, 40% of patients who received ADT alone received taxane-based chemotherapy, as compared with 23% of men receiving ADT plus docetaxel up front. Additionally, the investigators noted that 74% of the study population was able to receive 6 cycles of docetaxel without dose modifications or dose delays. Patients in the ADT plus docetaxel arm did not experience unexpected levels of adverse events.
Ultimately, the investigators concluded that treatment of hormone sensitive metastatic prostate cancer with ADT plus 6 cycles of docetaxel was tolerable, and was associated with significantly improved overall survival as compared to ADT alone. This effect was most pronounced among men with the highest burden of metastatic disease. They further noted a “clinical interpretation” that deemed 6 cycles of docetaxel a reasonable option for treatment of men with hormone sensitive metastatic prostate cancer initiating treatment with ADT. They further state that the benefit of the addition of docetaxel to standard ADT in these patients is apparent, but note that longer follow up will be required to fully evaluate men with low-volume metastatic disease.
This study has been called “practice changing” by multiple experts, and clearly the benefit of the addition of chemotherapy to ADT in these patients provides a greater improvement in overall survival than any treatment recently approved in the metastatic CRPC space. Though we can all see the benefit, only time will tell whether clinicians actually incorporate these findings into routine clinical care. Treatment of men with earlier stage disease with chemotherapy requires a close link between urologists who may be following patients with newly diagnosed metastatic disease, and timely referral. It is unclear whether this will happen, or whether early chemotherapy will go the way of other evidence-based recommendations that fail to be widely incorporated into clinical practice.
Click HERE to listen to an exclusive interview with Christopher Sweeney, MBBS, one of the authors of the study
Click HERE to read a press statement from ASCO
Presented by Christopher Sweeney, MBBS at the American Society of Clinical Oncology (ASCO) 50th Annual Meeting - May 30 - June 3, 2014 - Chicago, Illinois USA
Dana-Farber Cancer Institute, Boston, MA USA
Written by Alicia K. Morgans, MD, assistant professor of medicine and medical oncologist at Vanderbilt-Ingram Cancer Center, and medical writer for UroToday.com