Carlson, Robert H.
CHICAGO—Adding docetaxel chemotherapy to androgen-deprivation therapy (ADT) increased median overall survival by more than a year in men with newly diagnosed metastatic, hormone-sensitive prostate cancer in the Phase III ECOG E3805 study. As shown in a plenary study presented here at the American Society of Clinical Oncology Annual Meeting (Abstract LBA2), patients receiving the combination lived an average of 57.6 months versus 44.0 months for those treated with androgen-deprivation alone.
The survival improvement seen in the CHAARTED (ChemoHormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer) trial was even greater in men with high-extent disease, where median overall survival was 49.2 months with ADT plus docetaxel versus 32.2 months with ADT alone.
The report comes exactly 10 years after the results of the SWOG 9916 trial were presented at that year's ASCO Annual Meeting (2004), where docetaxel-based chemotherapy was shown to prolong survival in men with castration-resistant metastatic disease. Although this was revolutionary at the time, the survival benefit in SWOG 9916 was really quite modest: the median survival with docetaxel-estramustine was 18 months compared with 16 months for mitoxantrone-prednisone in patients with progressive hormone-refractory prostate cancer.
The report at this year's meeting, by Christopher Sweeney, MBBS, a medical oncologist at the Lank Center of Genitourinary Oncology at Dana-Farber Cancer Institute and Associate Professor of Harvard Medical School, explained that although hormone therapy has been a standard treatment for prostate cancer since the 1950s, this is the first study to identify a strategy that prolongs survival in patients with newly diagnosed metastatic disease.
Sweeney and the E3805 researchers concluded that hormone therapy plus docetaxel should be a new standard of treatment for men with high-extent disease who are fit for chemotherapy.
This should certainly be the case for men with high-volume metastatic disease, he said, because “the certainty of the data is strong for those patients and clearly justifies the treatment burden.” But longer follow-up is required for there to be more certainty about the benefit for patients with low-volume metastatic disease, Sweeney added.
‘GU Oncologists Will Pay Attention’
ASCO 2013–2014 President Clifford A. Hudis, said he was enthusiastic about the results of E3805: “How many times in advanced solid tumors do we see improvements in survival of a year or more—it just doesn't happen that much.”
CHRISTOPHER SWEENEY, MBBS
He predicted that the findings “will get a lot of attention from physicians in the GU community, who will be balancing the toxicities of docetaxel and looking for the subset of patients they can select based on volume.”
Hudis said the question comes up often in treatment of solid tumors, about whether to combine hormone therapy with chemotherapy for patients with metastatic disease, or save the more toxic chemotherapy for later sequential treatment. “This study shows a profound influence on survival, and not just progression, when chemotherapy is started early for men with high-volume disease.”
Hudis said the discussion will continue on whether all men with advanced prostate cancer should get chemotherapy with hormone therapy, or just men with high-volume disease—“I think the discussion will lean toward the latter,” he said.
“The study is also a powerful testimony to the importance of National Cancer Institute-led research, as these drugs are available in generic form today, and this research, funded by the federal funding apparatus for cooperative groups of the National Cancer Institute, might have otherwise not been pursued.”
In E3805, 790 men were enrolled in the study from July 2006 to November 2012: 393 received androgen-deprivation therapy, and 397 received the combination. Men were stratified by high-volume versus low-volume disease; by anti-androgen use beyond 30 days; by age 70 or younger versus over 70; by Eastern Cooperative Oncology Group performance status 0–1 versus 2; by having prior adjuvant visceral metastases and/or four or more bone metastases of more than 12 months versus 12 months or longer; and by whether patients had received an FDA-approved drug for delaying skeletal-related events.
The patients' median age was 63 (range of 36 to 91); 24 percent had prior radiotherapy and 24 percent had undergone prostatectomy; 64 percent in the ADT-alone arm had high-volume disease compared with 67 percent on ADT plus docetaxel.
Patients received ADT alone or the combination dosed at 75 mg/m2 every three weeks for six cycles within four months of starting ADT. With a median follow-up of 29 months, there were 137 deaths in the group receiving ADT alone versus 104 deaths in the ADT-plus-docetaxel group.
Sweeney said that initially, only high-volume patients were to be included but the protocol was amended to include low-volume patients because of slow accrual. Approximately two-thirds of patients had high-extent disease, defined by sites (major organs and/or bone) and the number of metastases. A strict definition was used, he explained, to avoid misclassifying patients if they had three or fewer bone metastases with one beyond the axial skeleton, or vertebral-degenerative changes misread as cancer.
At disease progression, 45 patients in the combination group received additional docetaxel. In the ADT-only group, 123 patients received docetaxel at disease progression. At a median follow-up of 29 months, there were 136 deaths in the ADT-alone group and 101 in the combination group.
Use of docetaxel also delayed disease progression, which was assessed by either a rise in prostate-specific antigen (PSA) level or the appearance of new metastases or symptom worsening. At one year, the proportion of patients with PSA levels less than 0.2 ng/mL was 11.7 percent in the ADT group versus 22.7 percent in the combination group. The median time to clinical progression was 19.8 months in the ADT group versus 32.7 months in the ADT-plus-docetaxel group.
“This new treatment paradigm will entail earlier, multidisciplinary care involving the collaboration of both urologists and oncologists, who both commonly treat men with prostate cancer,” Sweeney said.
He added that follow-up of patients will continue to assess survival benefits for patients with low-extent disease, and quality-of-life data from this study will be analyzed and reported at a later time. “Median overall survival for the subset with low-extent disease takes longer to reach as these patients respond better to ADT, and the median survival has not yet been reached,” he explained.
Discussant Remarks: Are the Results Believable?
Speaking at the plenary session, the study's Discussant, Michael J. Morris, MD, Associate Member of Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, said that Sweeney and colleagues have shown in E3805 that by moving docetaxel from the castration-resistant state, when men are not responding to testosterone-lowering agents, to the castration-sensitive state when they are, the survival benefits are amplified by 13.6 months and the reduction in risk of death is amplified by 40 percent. And there is a 17-month improvement in median overall survival in patients with high-volume metastatic disease.
“If you look at every drug that prolongs survival in castration-resistant disease, none even comes close in terms of survival prolongation, and our best therapies in metastatic castration-resistant disease are less than a third of that.
“But are these results believable?” Morris asked. His question was prompted by results from the French Phase III GETUG-AFU 15 trial published last year (Gravis et al: Lancet Oncology 2013;14:149-158), in which, similarly, patients with non-castrate metastatic prostate cancer were randomly assigned to either hormonal therapy alone or hormonal therapy and up to nine cycles of docetaxel. But those patients had no survival benefit relative to the control arm.
Indeed, interpretation of the data by the GETUG-AFU 15 authors was that docetaxel should not be used as part of first-line treatment for patients with non-castrate metastatic prostate cancer.
Morris answered his own question by noting that GETUG-AFU 15 was testing a series of very different concepts: First of all, GETUG-AFU 15 had fewer than half the number of patients that E3805 did, and about three-quarters of participants in the trial were low-risk patients—the opposite of the situation in E3805.
And twice as many GETUG-AFU 15 control patients went on to receive docetaxel when they became castration-resistant—twice as many as in E3805. “GETUG-AFU 15 was less of a study of ADT plus or minus docetaxel, and more of a study of early versus deferred docetaxel,” he said.
“For these and other reasons, GETUG-AFU 15 does not refute that high-volume patients benefit from chemotherapy—if anything it confirms that low-risk or low-volume patients should not get chemotherapy until there is better evidence to do so.”