Sequencing Chemo After Radium-223 Safe in mCRPC

Oliver Sartor, MD

Determining the optimal sequencing of novel agents with standard chemotherapy has become a key issue in the management of castration-resistant prostate cancer (CRPC). A posthoc analysis of the phase III ALSYMPCA trial has offered some clarity, showing that chemotherapy can be safely administered after radium-223 (Xofigo) in patients with metastatic CRPC.

In the ALSYMPCA trial, which was the basis of the FDA’s approval of radium-223, treatment with radium-223 demonstrated a median overall survival (OS) of 14.9 months compared with 11.3 months with placebo for patients with bone-metastatic CRPC (HR, 0.70; P <.001). Additionally, radium-223 was associated with a significant delay in both the median time to first symptomatic skeletal-related events and the time to an increase in the PSA level.

The ALSYMPCA subanalysis, which was presented at the 2015 European Cancer Congress, examined patients enrolled in the study who received chemotherapy following treatment with radium-223 or placebo. Follow-up was 3 years.

“This study has some limitations, including the fact that it represents a subset of patients based on postrandomization factors, including study drug treatment with radium-223 or placebo, and randomization of the original study does not ensure comparability of the treatment arms,” lead author Oliver Sartor, MD, medical director of the Tulane Cancer Center, said in an interview with OncLive.

“Given these limitations, this posthoc analysis indicates that chemotherapy following radium-223 appears to be safe, with no new hematologic concerns and no new detrimental effects on survival. Patients who were earlier in the course of disease and received all 6 injections of radium-223 were able to receive subsequent chemotherapy. This encouraging finding confirms the flexibility and versatility of radium-223, supporting the safety of administering chemotherapy after radium-223 regardless of prior docetaxel use,” Sartor said.

Twenty-two percent (n = 206) of the 921 patients enrolled in ALSYMPCA received chemotherapy post study, comprising 142 from the radium-223 arm and 64 from the placebo arm. Docetaxel was the most commonly used post-study chemotherapy: 70% of the post-radium-223 arm and 72% of the post-placebo arm were treated with docetaxel. Subgroup analysis was performed according to prior docetaxel use.

In the chemotherapy post-study drug subgroups, demographic and baseline characteristics were generally well balanced between the treatment arms, including age, baseline ECOG status, extent of disease, PSA levels, and other parameters.

As compared with the primary ALSYMPCA population, the chemotherapy post-study subgroup patients were younger, had better ECOG performance status, lower disease volume (number of metastases), lower total alkaline phosphatase levels, and lower PSA levels.

A greater percentage of patients in the post-study subgroup received all 6 planned injections of the drug, as compared with the number received in the overall ALSYMPCA population: for those assigned to radium-223, 63% of the overall ALSYMPCA population and 79% of the chemotherapy post-study subgroup received all 6 injections, and 47% and 58%, respectively, of the placebo group received all 6 injections.

Across both chemotherapy post-study group arms, median hematologic lab values remained constant from the last measurement before chemotherapy to 18 months after chemotherapy. These hematologic values were similar for patients who received prior docetaxel and no prior docetaxel. No treatment differences in hematologic values were observed within the no-prior and prior docetaxel subgroups.

In the two treatment arms, decreases from baseline measures in hemoglobin and neutrophil levels were similar. Decreases from baseline in platelets tended to be greater in the radium-223 arm compared with placebo, but this was likely due to radium-223 rather than subsequent chemotherapy, according to Sartor. Decreases in platelets were similar in patients who had prior docetaxel and no prior docetaxel. The rates of grade 3/4 hematologic adverse events were generally low, but were somewhat higher in the radium-223 arm compared with the placebo arm.

During or within 30 days of completing chemotherapy, no significant difference in survival was observed between radium-223 and placebo. Twenty-nine percent of patients in the radium-223 group and 33% in the placebo group died during and within 30 days of completing chemotherapy. The most common cause of death was prostate cancer (90% in the radium-223 arm and 95% in the placebo arm). Median OS from the start of chemotherapy was 18 months after radium-223 and 15.8 months after placebo, which was not statistically different.

Sartor O, Coleman RE, Nilsson S, et al. 3-year follow-up of chemotherapy following radium-223 dichloride (Ra-223) in castration-resistant prostate cancer (CRPC) patients (Pts) with symptomatic bone metastases (Mets) from ALSYMPCA. Presented at: 2015 European Cancer Congress; September 25-29; Vienna, Austria. Abstract 2510.