Presenter: C. N. Sternberg Presenter's Affiliation: San Camillo Forlanini Hospital, Rome, Italy Type of Session: Scientific
Previously there had only been a limited role for chemotherapy in the treatment of prostate cancer.
In 2004 docetaxol was approved as first line treatment for hormone refractory prostate cancer (HRPC). The continued development of newer agents to treated HRPC is essential.
Previous studies have suggested that satraplatin (S) has efficacy in prostate cancer cell lines which are refractory to anthracyclines, taxanes, and other platinum agents.
EORTC 30972 was a phase III trial which demonstrated that combined treatment with S and prednisone resulted in a doubling of progression free survival (PFS) compared with prednisone alone. EORTC 30972 was a smaller study with 50 patients. However, these promising results were the basis for the present phase III study of S with prednisone compared with prednisone plus placebo in the treatment of HRPC.
Materials and Methods
The present study is a phase III, randomized, double blinded, placebo controlled study comparing combined treatment with S and prednisone with prednisone and placebo in HRPC. Patients were randomized 2:1 to the S arm compared with the prednisone arm. All analyses were conducted on an intent-to-treat basis.
Patients had to have documented metastatic disease.
Patients had to have HRPC.
S was given at a dose of 80 mg/m2 daily, five days a week. Each course of therapy lasted five weeks. Nausea was controlled with oral antiemetics. Prednisone was given orally at a dose of 5 mg twice a day. Patients randomized to the control arm received a placebo for S and antiemetics.
The primary endpoint of this study was progression free survival (PFS) and overall survival (OS). The secondary endpoints were time to pain progression, pain response, tumor response and PSA response to treatment.
PFS was a composite endpoint, defined as the time until radiologic progression of disease, symptomatic progression disease, skeletal events, or death from any cause. Prostate specific antigen (PSA) levels were not used as a criterion for progression.
All patients kept a pain journal during treatment. Pain was rated on a six point scale which had been previously validated. Patients recorded pain and analgesic regularly. The pain journals were reviewed by an independent committee that was blinded to the treatment arms.
Between September of 2004 and January of 2006, 950 patients were accrued to the study and 635 were randomized to the S arm and 315 to the placebo arm.
Patient characteristics between the two groups were well balanced.
51% of patients had been previously treated with docetaxol.
68% of patients were older than 65 years of age and 27% were older than 75.
Patients in the S arm received a median of four courses of therapy (range 1-28) and patients in the placebo arm received a median of two courses of therapy (range 1-16).
The independent review committee determined that 802 patients had progression of disease and the majority (80%) were related to radiologic progression, pain progression or death.
Treatment with S reduced the risk of progression by 31% (HR=0.69, 95% confidence interval (CI): 0.60-0.80; p<0.00001). Treatment with S reduced the risk of pain progression by 33% (HR=0.67, 95% CI 0.54-0.83; p=0.00028). PSA response was higher in the S arm compared with the placebo arm (25% versus 12%; p=0.00007), as was objective tumor response (7% versus 1%; p<0.002), pain response (24% versus 14%; p<0.005), and the duration of pain response (HR= 0.59; 95% CI: 0.35-1.00; p=0.049). The benefits of treatment with S were seen across all groups, including patients who had been previously treated with docetaxol.
Toxicity with S was limited. The most common hematologic toxicity related to treatment with S was myelosupression. Grade 4 neutropenia was uncommon, occurring in 4% of patients. One patient had grade 4 thrombocytopenia. The most common non-hematologic toxicities were infection (4%), vomiting (2%), and diarrhea (2%). No ototoxicity was seen. Ultimately, 2.5% of patients in the S group had to discontinue therapy due to toxic events, compared with 0.6% on the placebo arm.
The authors conclude that S is an effective second line treatment for HRPC. They found that there was a benefit with treatment with S across all groups and that S was effective in patients who had previously been treated with docetaxol.
They concluded that S also added little toxicity to prednisone and was generally well tolerated.
The present phase III study demonstrated a significant benefit with S treatment across multiple endpoints in patients with HRPC. These results suggest that S, if approved, would be an effective second line treatment for HRPC, even in patients previously treated with docetaxol. Approximately 30% of patients had received bisphosphonates previously emphasizing that many of these patients had osseus metastasis which is a significant cause of pain in HRPC patients. S not only improved progression free survival but also appeared to effectively palliate pain and prolongs relief from pain which could be of great benefit to patients with numerous hormone refractory osseus metastasis.
The control group in the present study, prednisone, would not be commonly used as a mono-agent in second line treatment of HRPC. A more appropriate control may have been a treatment which is used more frequently as second line therapy. For example, patients who had not previously received docetaxol for failure (approximately 50% of patients in the present study) could have been randomized to docetaxol versus S. This could be a potential area of study for the future and will help determine is S is a better first line agent than docetaxol in the treatment of patients with HRPC.
As the survival with prostate cancer improves and the number of patients with HRPC increases, newer systemic agents will be needed to delay progression of disease and palliate pain. S appears to be well tolerated and has shown great potential as a second line treatment. Further studies are needed to evaluate its use as a first line treatment.
Feb 10, 2011 - The results of two phase 3, randomized controlled trials suggest that two therapies, sunitinib and everolimus, hold promise in the treatment of patients with advanced pancreatic neuroendocrine tumors; the findings of these trials have been published in the Feb. 10 issue of the New England Journal of Medicine.