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Satraplatin, an experimental agent, offered significant clinical benefit to men with hormone-refractory prostate cancer when added to prednisone in second-line chemotherapy, based on a phase III international trial.
An intent-to-treat analysis from the Satraplatin and Prednisone Against Refractory Prostate Cancer (SPARC) trial showed median progression-free survival improved 33% from 9.7 weeks with prednisone and placebo to 11.1 weeks with prednisone and satraplatin (hazard ratio 0.67, P = .0000003). This analysis was based on assessments by radiation and medical oncologists.
In a second intent-to-treat analysis based on investigator assessments, the improvement reached 42%. Satraplatin (Orplatna) increased median progression-free survival from 6 weeks with placebo to 16 weeks (hazard ratio 0.58, P = .000000000002).
The investigators, led by Dr. Cora N. Sternberg, also reported a significant reduction of pain in 24% of satraplatin patients vs. 14% of the placebo group (P = .005). The median duration of pain response was 39 weeks with satraplatin and 24 weeks with placebo.
"If [satraplatin is] approved, I firmly believe that we will have a new oral treatment for the second-line therapy of patients with metastatic hormone-refractory prostate cancer," said Dr. Sternberg, chief of the department of medical oncology, San Camillo & Forlanini Hospitals, Rome, Italy.
Satraplatin was under priority review at the U.S. Food and Drug Administration at the time of her presentation. On July 24, however, the FDA's Oncologic Drugs Advisory Committee unanimously recommended that approval not be granted before overall survival results become available.
Spectrum Pharmaceuticals Inc. subsequently announced that trial sponsor GPC Biotech Inc. had withdrawn the satraplatin application with plans to resubmit when those survival data are announced. Spectrum, which licensed worldwide development rights to GPC Biotech, said results are anticipated in 6 months, but the timing may change based on death rates in the trial.
The advent of first-line treatment with docetaxel in 2004 brought a significant improvement in survival and created a need for effective second-line chemotherapy, according to Dr. Sternberg. "Satraplatin is a novel oral platinum compound with activity against cell lines resistant to taxanes, anthracyclines, and other platinum compounds, and has shown activity in early prostate cancer trials."
The SPARC trial enrolled 950 men at 170 centers in 16 countries. All had metastatic hormone-refractory prostate cancer and had failed one line of prior chemotherapy. Half had received prior docetaxel, and about 30% prior bisphosphonates.
Median ages were 70 years in the satraplatin arm and 68 years in the placebo arm. Of the total cohort, 70% were over age 65, and one-fourth older than 75 years. Performance status was "generally good," she said.
Patients were randomized 2:1: 635 men received 80 mg/m² per day of oral satraplatin for 5 days every 5 weeks along with twice-daily prednisone, and 315 men got placebo plus prednisone. Patients also received an antiemetic on days 1-5. The median number of cycles in the satraplatin arm was four, compared with two in the placebo arm.
The therapy was well tolerated; 2.5% of patients given satraplatin and 0.6% of those on placebo discontinued because they experienced adverse events.
Progression-free survival was defined by a composite end point based on the first occurrence of tumor progression, a skeletal event, symptomatic progression, or death due to any cause. Pain assessment was based on daily diaries in which patients noted whether they had taken satraplatin and wrote down their pain levels based on a validated 6-point scale. Analgesic use also was recorded.
These diaries underwent blinded assessment by an independent review committee of radiologists and medical oncologists with no access to patient data. The committee concluded that, compared with placebo, satraplatin was associated with a 36% reduction in the risk of pain progression.
Putting the trial into clinical perspective is difficult because there is no FDA-approved second-line therapy against which to compare satraplatin, according to discussant Dr. Ian E. Tannock.
The basic tenet of a phase III trial is to compare the experimental therapy with the current standard of care. Absent that, the drug must, as in this case, be compared with a minimal treatment such as prednisone, said Dr. Tannock, a senior scientist at the Ontario Cancer Institute of Princess Margaret Hospital in Toronto.
He contended, however, that prednisone alone is by no means a standard treatment for men fit enough to receive second-line chemotherapy, and this trial does not show that satraplatin is superior to other chemotherapy regimens.
"Clearly [satraplatin] is better than prednisone; whether it's better than the other therapies that could be given, we simply don't know," he said.
Sternberg C.N. et al. Satraplatin (S) demonstrates significant clinical benefits for the treatment of patients with HRPC: Results of a randomized phase III trial. Abstract 5019.
Commentary |
A novel oral platinum chemotherapy compound, satraplatin, demonstrated significant clinical effects in a phase III trial that enrolled men with metastatic hormone-refractory prostate cancer. Data from the international Satraplatin and Prednisone Against Refractory Prostate Cancer (SPARC) trial show a 33% improvement in progression-free survival among the intent-to-treat population as a primary end point. For the entire intent-to-treat population, the hazard ratio was 0.67 in favor of satraplatin. In subsets of patients with significant pain or radiographic progression, the benefit was similar, with hazard ratios of 0.64 for both types of progression. Overall, satraplatin was well tolerated with 2.5% of patients discontinuing treatment due to adverse events, compared with 0.6% of placebo-treated patients. Grade 3/4 adverse events, including neutropenia, thrombocytopenia, anemia, vomiting, and diarrhea were all seen at significantly greater frequency in the satraplatin arm. This trial clearly demonstrates a greater clinical efficacy for satraplatin over prednisone in patients with metastatic hormone-refractory prostate cancer who had failed first-line chemotherapy. With no approved second-line chemotherapy for comparison, the results suggest satraplatin could fill an unmet need for advanced prostate cancer patients. One criticism, however, is that the study has not yet demonstrated a survival advantage for satraplatin over prednisone in this population. As it turns out, improved survival is necessary to fulfill the definition of a clinical benefit for FDA approval in this setting. — Daniel J. George, M.D., and Judd W. Moul, M.D.
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