Adding Chemotherapy to Hormone Therapy Extends Overall Survival in Metastatic Prostate Cancer
Results from a randomized phase III trial showed that men with metastatic hormone-sensitive prostate cancer who received docetaxel early during androgen deprivation therapy (ADT) live longer than men who received ADT alone.
New England Journal of Medicine, August 5, 2015. (See the article.)
Since the 1940s, the primary therapy for men with metastatic prostate cancer has been ADT to suppress production of the hormone testosterone, either with surgical castration or through the use of drugs that block the production or use of androgens. Androgens are a class of hormones that control the development and maintenance of male characteristics. Testosterone and dihydrotestosterone are the most abundant androgens in men. Almost all testosterone is produced in the testicles; a small amount is produced by the adrenal glands. Prostate cancer cells may also have the ability to produce testosterone.
ADT (also called hormone therapy) reduces the levels of male hormones in the body or blocks their effects on prostate cancer cells, which are usually sensitive to hormone therapy, at least initially. Chemotherapy is typically started only after the patient no longer responds to ADT, that is, when the disease becomes what is called "castration resistant.”
Although chemotherapy alone has been shown to extend survival in men with metastatic castration-resistant disease, chemotherapy with ADT has not been found to extend survival beyond that found with chemotherapy use alone in men with metastatic castration-sensitive disease. However, earlier studies were small and focused specifically on patients with lower tumor burden. In this study, researchers examined the benefit of adding docetaxel—a semi-synthetic, second-generation taxane with potent and broad cancer-fighting properties—to ADT at the beginning of a patient's treatment to determine whether survival would be extended compared with ADT alone.
In this study, a total of 790 patients were randomly assigned to ADT alone (393 men) or to combination therapy with ADT plus docetaxel (397 men) given every 3 weeks for six cycles. To determine whether any benefits of chemotherapy were limited to certain subsets of men, they were analyzed in groups according to several factors, including age, duration of prior adjuvant ADT (less than 12 months versus 12 months or more), and tumor volume, or the extent of metastases (high versus low).
Patients assigned to combination therapy were seen every 3 weeks during the period of docetaxel administration and then every 3 months. Patients assigned to ADT alone were seen every 3 months. The primary endpoint was overall survival. Secondary endpoints included prostate-specific antigen (PSA) response, for which a complete response was defined as a PSA level of less than 0.2 ng per milliliter on two consecutive measurements at least 4 weeks apart; the time to the development of castration-resistant prostate cancer; and the time to clinical disease progression. In addition, side effects, including allergic reactions, fatigue, and thromboembolic events were monitored for the full course of the trial.
Christopher J. Sweeney, M.B.B.S., of the Dana–Farber Cancer Institute in Boston, led the study, which was conducted by the Eastern Cooperative Oncology Group (ECOG) and the American College of Radiology Imaging Network (ACRIN), with funding from NCI. Sanofi US, the maker of docetaxel, provided the drug and a grant to ECOG-ACRIN.
At a median follow-up of approximately 29 months, there were 136 deaths in the ADT-alone group and 101 deaths in the combination group. Median overall survival in men treated with the combination therapy was 57.6 months and that in men treated with ADT alone was 44.0 months, a difference of 13.6 months. In men with high-volume disease, the difference in median overall survival was 17.0 months (49.2 months in the combination group versus 32.2 months in the ADT-alone group). At the time of the analysis, median survival had not yet been reached for men with low-volume disease in either treatment group. The combination therapy showed a survival benefit relative to ADT alone in all subgroups that were analyzed.
A complete PSA response at 12 months was seen in 27.7 percent of the men in the combination group and 16.8 percent of those in the ADT-alone group. Median time to the development of castration-resistant prostate cancer was 20.2 months in the combination group and 11.7 months in the ADT-alone group. Median time to clinical progression was 33.0 months with combination therapy and 19.8 months with ADT alone.
Among the patients in the combination group, approximately 2 percent had a treatment-related grade 3 or 4 allergic reaction, 4 percent had grade 3 fatigue, and 1 percent had a thromboembolic event. Six percent of the men in the combination group had febrile neutropenia and 2 percent had a grade 3 or 4 infection with neutropenia.
Ravi Madan, M.D., of NCI's Center for Cancer Research, noted that the patients in this trial had developed metastatic disease prior to the initiation of ADT, a situation that applies to a minority of metastatic prostate cancer patients. He said these findings do not apply to patients who develop metastatic disease while already being treated with ADT for a biochemical recurrence.
Dr. Madan also noted that a limitation of this study is the distinction between low-volume and high-volume disease, which is based on previous definitions but remains somewhat arbitrary. Patients were considered to have high-volume disease if they had four or more bone lesions (at least one of which was outside of the pelvis and spine) or cancer that had spread to other organs in the body. This definition may miss some patients who have extensive lymph node disease or patients with numerous bone lesions confined to the spine and pelvis. Nevertheless, since roughly one-third of the patients enrolled had low-volume disease and the overall study results showed a benefit for combining ADT with chemotherapy, Dr. Madan explained, there is strong rationale to treat all patients with metastatic castration-sensitive disease, whatever their tumor burden, with ADT and docetaxel.
"It is rare in the treatment of metastatic solid tumors that we have seen such a profound therapeutic benefit, demonstrating the ability to improve survival by greater than 1 year,” said Dr. Madan. "Although at the current point in follow-up, the median survival has not been reached in the patients with low-volume disease, the outcomes are roughly similar to the group with high-volume disease. In addition, the toxicity data suggest that the regimen was well tolerated, with 86 percent of patients completing all six docetaxel infusions. Thus, it is reasonable to treat all men who have metastatic castration-sensitive prostate cancer with ADT and docetaxel based on the data presented in this study.”
"The study demonstrated a substantial benefit from addition of chemotherapy to the standard ADT right at the start of the ADT treatment, when the disease is still castration sensitive,” noted Bhupinder Mann, M.B.B.S., of NCI's Division of Cancer Treatment and Diagnosis. "By contrast, in other studies there may not have been as many patients with high-volume disease, or the administration of docetaxel may have been more toxic for the patient population.” Dr. Mann also noted that there shouldn't be concerns about how to treat patients once they do develop resistance to ADT. "ADT resistance develops whether you give chemotherapy or not. When ADT resistance develops, you will use the agents that are approved for that population.”