Further analyses of data subsets from the ALSYMPCA study of the alpha particle-emitting isotope Ra-223 (Xofigo) were presented at ASCO, providing additional evidence of efficacy and safety of the recently FDA approved therapeutic agent.
CHICAGO-Further analyses of data subsets from the ALSYMPCA study of the alpha particle-emitting isotope Ra-223 (Xofigo) were presented at the 2013 annual meeting of the American Society of Clinical Oncology (ASCO). Findings provide additional evidence of efficacy and safety of the new therapeutic agent, recently approved by the United States Food and Drug Administration for treatment of patients with castration-resistant prostate cancer (CRPC), symptomatic bone metastases, and no known visceral metastatic disease.
ALSYMPCA was an international, randomized, double-blind, placebo-controlled phase III study of Ra-223 plus best standard of care compared with a placebo plus best standard of care in men with symptomatic metastatic CRPC. The trial enrolled 922 patients at more than 100 centers in 19 countries.
Post-hoc analyses of pain parameters were presented by Sten Nilsson, MD, of Karolinska University Hospital, Stockholm, Sweden (abstract 5038), and colleagues, who said the results “provide consistent evidence that, in addition to prolonging survival, Ra-223 reduces pain and opioid use in CRPC patients with bone metastases.” The investigators analyzed time to initial opioid use and time to electron beam radiation therapy. Patients with no opioid use at baseline were included in the pain analyses. All patients were included in the analysis for the prespecified endpoint time to electron beam radiation therapy.
Concomitant opioid use was recorded from first study drug injection to 12 weeks after the last injection. Pain-related quality of life was analyzed based on the sum of four questions within the FACT-P prostate cancer subscale. Baseline pain characteristics were similar between the treatment groups (approximately 55% of patients had moderate to severe pain and opioid use).
Time to electron beam radiation therapy was significantly longer with Ra-223 vs placebo (hazard ratio [HR] = 0.670; 95% CI, 0.525–0.854). “Despite a longer observation time, fewer Ra-223 patients (50%) than placebo patients (62%) reported bone pain as an adverse event,” investigators reported. Median time to initial opioid use was significantly longer in the Ra-223 group, with a risk reduction of 38%, compared to placebo (HR = 0.621; 95% CI, 0.456–0.846). And fewer Ra-223 patients (36%) than placebo patients (50%) required opioids for pain relief.
The quality of life pain score indicated reduced pain for Ra-223 patients relative to placebo patients at week 16 (P = .001). Patients in the Ra-223 group had significant pain reduction relative to baseline both at week 16 (P < .001) and week 24 (P = .001).
The hematologic safety profile and results from a post-hoc analysis assessing prognostic factors for changes in hematologic parameters in ALSYMPCA patients were presented by Chris Parker, MD, of the Royal Marsden NHS Foundation Trust, Sutton, United Kingdom.
Patients were randomized 2:1 to six injections of Ra-223 or matching placebo and stratified by prior docetaxel use, total alkaline phosphatase (tALP), and current bisphosphonate use. Multivariate regression analysis was performed to explore the relationship of six baseline factors with maximum percent change of hematologic parameters from baseline up to 24 weeks on treatment. The analysis included 901 patients (Ra-223, n = 600; placebo, n = 301).
Overall grade 3/4 adverse events were similar between the two groups. Treatment with Ra-223, prior docetaxel use, extent of disease greater than six bone metastases, and tALP equal to or greater than 220 U/L, but not current bisphosphonate use, were associated with decreases from baseline in hemoglobin (Hb), neutrophils, and platelets. Prior electron beam radiation therapy to bone for pain was associated with increases. “Overall, there was a low risk for hematologic adverse events with Ra-223 treatment in CRPC patients with bone metastases,” the investigators concluded. “The strongest prognostic factors for decreases in neutrophils and platelets were Ra-223 treatment and prior docetaxel use. Baseline tALP ≥ 220 U/L was a strong predictor of decrease in Hb.”
A predefined subgroup analysis of efficacy and safety of Ra-223 in patients who did or did not receive prior docetaxel was presented by Nicholas J. Vogelzang, MD, of Comprehensive Cancer Centers of Nevada, Las Vegas. Patients eligible for assessment had progressive, symptomatic CRPC with two or more bone metastases; had no known visceral metastases; were receiving best standard of care; and had either received prior docetaxel or were unfit for or declined prior docetaxel.
Of 921 randomized patients, 395 (43%) had no prior treatment with docetaxel (Ra-223, n = 262; placebo, n = 133) and 526 (57%) received prior docetaxel (Ra-223, n = 352; placebo, n = 174). Median ages were 74 years in the group with no prior docetaxel treatment and 69 years in the group with prior docetaxel.
Median overall survival in patients with no prior docetaxel was 16.1 months in the Ra-223 group vs 11.5 months in the placebo group (HR = 0.745; 95% CI, 0.562–0.987; P = .039). In patients with prior docetaxel, median overall survival was 14.4 months in the Ra-223 group vs 11.3 months in the placebo group (HR = 0.710; 95% CI, 0.565–0.891; P = .003). “Overall, there was a low incidence of myelosuppression,” reported the investigators. More incidences of neutropenia and thrombocytopenia occurred in patients with prior docetaxel.
The investigators concluded that Ra-223 “significantly prolonged overall survival and had a highly favorable safety profile in CRPC patients with bone metastases, regardless of whether they had prior docetaxel or no prior docetaxel. Prior docetaxel patients had a slightly increased rate of grade 3 and grade 4 bone marrow suppression with Ra-223.”
Commenting on the various updated ALSYMPCA trial findings, Vogelzang said, “Quality of life has definitely improved with the drug. Along with that there is reduction in the need for radiation, which goes along with quality of life, and reduction in the need for morphine or opioid drugs. There was a slight lowering of the blood counts in the trial but it turns out that most of that can be attributed to the use of chemotherapy, although there is a small amount of white blood cell, red blood cell, and platelet reduction. But it is very small. This drug improves pain, it improves quality of life, and it is very easy on the patient.”