Radium-223 Safety, Tolerability Confirmed in mCRPC Patients
In studies, subsequent use of chemotherapy and concomitant use of abiraterone or enzalutamide did not raise any new safety concerns.
Studies presented at the 2015 European Cancer Congress in Vienna have confirmed the safety and tolerability of radium-223 dichloride in patients with metastatic castration-resistant prostate cancer (mCRPC) and identified prognostic factors for achieving the optimal number of cycles of the drug in these patients for better outcomes.
Administered intravenously, radium-223 dichloride (radium-223) is approved by the FDA for treating men with mCRPC and symptomatic bone metastases and no visceral metastases. The drug mimics calcium in that it accumulates in areas of bone undergoing rapid turnover, such as sites of bone metastases. Radium-223 emits radiation in the form of alpha particles, which travel only a fraction of an inch, thus limiting damage to surrounding tissue. The drug's approval was based on the pivotal ALSYMPCA trial, which enrolled 921 mCRPC patients.
In a 3-year follow-up study, a team led by Oliver Sartor, MD, medical director of the Tulane Cancer Center at the Tulane University School of Medicine in New Orleans, analyzed data from 206 (22%) patients who constituted the chemotherapy post-study drug subgroup (142 who received radium-223 and 64 who received placebo). The researchers observed no new hematologic safety issues and demonstrated that patients could safely receive chemotherapy (most commonly docetaxel) following radium-223 treatment. Additionally, results showed that similar proportions of radium-223 and placebo recipients (29% and 33%, respectively) died during or within 30 days of completing chemotherapy.
“Taken together, there were no safety signals of note,” Dr. Sartor told Renal & Urology News. “The duration, hematologic parameters, and survival of patients treated with chemotherapy were similar whether or not radium-223 or placebo was used as protocol therapy. Though this study is retrospective, these findings support the notion that chemotherapy can be administered safely after radium.”
In a separate post-hoc subgroup analysis of 901 ALSYMPCA patients and 184 patients enrolled in a U.S. expanded access program (EAP), Dr. Sartor and collaborators found that patients with more advanced CRPC and symptomatic bone metastases are less likely to receive the recommended 6 injections of radium-223, the regimen associated with longer overall survival.
Among the 184 EAP patients, 85 (46%) received 1–4 injections and 99 (54%) received 5–6 injections; among the 901 ALSYMPCA patients, a higher percentage of radium-223 recipients— 436 (73%) of 599—compared with placebo patients—174 (58%) of 302 received 5–6 injections
The investigators looked for specific prognostic factors associated with receiving 1–4 injections versus 5–6 injections of radium-223. In the EAP subgroup, factors that predicted a reduced likelihood of receiving 5–6 injections included receipt of 3 or more prior anticancer therapies; baseline ECOG performance status (PS) of 2 or higher; and lower baseline hemoglobin level. In the ALSYMPCA subgroup, the predictive factors included higher log lactate dehydrogenase; lower albumin; baseline ECOG PS of 2 or higher; and higher log PSA.
For the EAP group, the researchers were unable to estimate overall survival because the median was not reached for the 5–6 injection group, but the median overall survival was 7.5 months for the 1–4 injection group, Dr. Sartor stated. Among the ALSYMPCA patients, the median overall survival for radium-223 recipients was 17.9 months for the 5–6 radium-223 injection subset versus 6.1 months for the patients who received 1–4 injections.
“Though we are unable to conclude that radium is causal in prolonging survival in these subset analyses,” Dr. Sartor said, “we feel that, in a contemporary setting, administering radium after 3 or more CRPC therapies, or to men with an ECOG PS or 2 or worse, or to men with significant anemia will have little impact on survival. Thus, radium is best used when one can anticipate delivery of 5–6 injections.”
In a third study presented at the congress, Joe M. O'Sullivan, MD, of Queen's University and the Northern Ireland Cancer Centre in Belfast, demonstrated that radium-223 administered concomitantly with either abiraterone or enzalutamide or both is well tolerated in mCRPC patients with bone metastases, with no new safety issues identified. Of 900 patients, 154, 50, and 189 received concomitant abiraterone, enzalutamide, and both drugs, respectively, and 507 received neither drug. The median duration of radium-223 therapy was 20.1 weeks. The median time on concomitant abiraterone or enzalutamide from the first radium-223 injection was 24.9 and 15.5 weeks, respectively.
The rate of adverse events was comparable across treatment groups, Dr. O'Sullivan's group reported. Overall survival was longer in patients who received radium-223 in combination with abiraterone and/or enzalutamide that in those who did not receive those medications concomitantly.
Commenting on all 3 studies, Dr. Sartor observed: “The safety of radium-223 has now been established in multiple settings. Concomitant treatment with radium-223 and enzalutamide or abiraterone appears to be safe. Whether or not there is better efficacy for concomitant abiraterone and radium-223, or for enzalutamide and radium-223, is now being addressed in prospective trials.”