Fred Saad, MD
In metastatic castration-resistant prostate cancer (mCRPC), pain and hemoglobin levels, PSA levels, and ECOG performance status may predict which patients will be able to receive the recommended 6-dose regimen of radium-223 dichloride (Xofigo), according to a recent posthoc analysis of 2 trials.
The 6-dose regimen has been associated with significantly longer overall survival (OS) when compared with 1- to 4-dose regimens of radium-223 in mCRPC.
The analysis, presented at the 2016 ASCO Annual Meeting, looked at patients from the phase IIIb International Expanded Access Program (iEAP) and the ALSYMPCA trials, both of which included patients with mCRPC who have bone metastases.
In the ALSYMPCA trial, 599 patients received radium-223 and 302 received placebo; in the single-arm iEAP, 696 patients received radium-223. Of those patients, 223 received 1 to 4 doses, while 473 received 5 to 6 doses of radium-223 in the iEAP. In the ALSYMPCA trial, 163 patients received 1 to 4 doses and 436 received 5 to 6 doses of radium-223.
In the iEAP, the median OS was 6.3 months in patients who received 1 to 4 injections of radium-223 and not yet been reached in patients who received 5 to 6 injections. In ALSYMPCA, the median OS was 6.2 months in patients with 1 to 4 injections and 17.9 months in patients with 5 to 6 injections.
The analysis of the iEAP showed that the ability to receive 5 to 6 injections was associated with less pain (none-mild vs moderate-severe; P
<.0001), lower ECOG score (0-1 vs ≥2; P
= .0081), lower PSA level (median <141 µg/L vs ≥141 µg/L; P
<.0001), and higher hemoglobin levels (≥10 g/dL vs <10 g/dL; P
= .0227) at baseline.
The analysis showed that 5 to 6 injections was associated with longer OS (P
<.0001). In the ALSYMPCA trial analysis, lower LDH, higher albumin, and lower log PSA levels were associated with a greater likelihood of receiving all 6 cycles of radium-223.
“We looked at what parameters predicted receiving 5 or 6 cycles and, as expected, patients who were healthier earlier in the disease continuum were more likely to get the full 6 cycles of radium-223,” lead investigator Fred Saad, MD, said in an interview with OncLive
“These are parameters that help us to figure out how to target patients more likely to get 5 or 6 cycles and, on the flip side, not wait too long to treat because then we are unlikely to give what we think is the most effective form and dose of radium-223,” added Saad, who is medical director, Interdisciplinary Urologic Oncology Group, chair, Prostate Cancer Research, University of Montreal Hospital Centers.
The international, prospective, double-blind, randomized ALSYMPCA trial was the basis of the FDA’s 2013 approval of radium-223 in CRPC. The study included patients with CRPC and more than 2 symptomatic skeletal events (SSE); however, patients with known visceral metastases or those who or were unfit for, or progressed on, docetaxel were not included.
Patients were randomized in a 2:1 ratio to receive 1 to 6 injections of radium-223 at 50 KBq/kg plus best standard of care or placebo combined with best standard of care. Radium-223 demonstrated a median OS of 14.9 months versus 11.3 months with placebo (HR, 0.70; 95% CI, 0.58-0.83; P
<.001). Time to first SSE was 15.6 months with radium-223 versus 9.8 months with placebo (HR, 0.66; 95% CI, 0.52-0.83; P
The phase IIIb iEAP included both symptomatic and asymptomatic patients. Patients who had been previously treated with novel agents were permitted in this study.
“This study included patients who received radium-223 in a contemporary setting where we now have access to other drugs on top of radium-223, such as abiraterone acetate (Zytiga) and enzalutamide (Xtandi), which were not available when the pivotal phase III study was done,” explained Saad.
The iEAP included patients with CRPC and more than 2 bone metastases; researchers followed them for 6 months following treatment. Of the enrolled patients, data from 486 (70%) were censored and the median OS in the 30% of patients treated with radium-223 was 16 months. The median time to first SSE was 18 months.
The key takeaway from the ALSYMPCA trial, the iEAP, and the posthoc analysis is the importance of identifying patients as early as possible who will be able to receive all 6 doses of radium-223, Saad said.
“Right now, the paradigm for most patients is the hormonal approach as the first-line approach for mCRPC,” said Saad. “However, when patients start to fail on these hormonal agents, the ideal setting would be to add radium while they are failing—in terms of PSA, asymptomatic or minimally symptomatic, and maybe with a radiographic progression—but not wait until they are totally falling apart. Six doses should really be the target. The practicing physician needs to recognize patients as early as possible who would be able to get the full 6 cycles and not wait too long for treatment.”
Saad F, Keizman D, O'Sullivan JR, et al. Analysis of overall survival by number of radium-223 injections received in an international Expanded Access Program (iEAP). J Clin Oncol. 2016;34 (suppl; abstr 5082).