Year : 2014 | Volume
: 30 | Issue : 1 | Page : 122--123
A new agent in therapeutic armamentarium of survival enhancing drugs in castrate resistant prostate cancer
|How to cite this article:|
Abrol N. A new agent in therapeutic armamentarium of survival enhancing drugs in castrate resistant prostate cancer.Indian J Urol 2014;30:122-123
|How to cite this URL:|
Abrol N. A new agent in therapeutic armamentarium of survival enhancing drugs in castrate resistant prostate cancer. Indian J Urol [serial online] 2014 [cited 2021 Apr 12 ];30:122-123
Available from: https://www.indianjurol.com/text.asp?2014/30/1/122/124223
Parker et al. report results of a phase 3, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of radium-223 in men with castrate resistant prostate cancer (CRPC) and bone metastasis.  The study included a total of 921 patients with CRPC (serum testosterone < 50 ng/dl) and two or more symptomatic bone metastasis in the absence of visceral metastasis. All patients had either previously received, were not fit to receive or had refused docetaxel for inclusion in this study. They were randomly assigned in a 2:1 ratio to receive injection of radium-223 versus placebo every 4 weeks. Primary end point of the study was overall survival. Time to first skeletal event and biochemical responses (prostate specific antigen and alkaline phosphatase) were secondary end points. Safety was studied by reporting all adverse events that occurred within 12 weeks after the last injection of study drug. Pre-specified interim and updated analysis were performed at points when 314 deaths and 528 deaths occurred respectively.
At interim analysis (809 patients; radium: Placebo = 541:268), median survival in radium group was significantly higher (14.0 months vs. 11.2 months; hazard ratio 0.70; 95% confidence interval [CI] 0.55-0.88). There was 30% reduction in risk of death in the radium group. In the updated analysis (921 patients; radium: placebo = 614:307), median overall survival in radium group was 14.9 months when compared with 11.3 months in the placebo group (hazard ratio 0.70; 95% CI 0.58-0.83). This overall reduction in risk of death was seen across all subgroups. On assessment of secondary end points, there was a significant difference in both groups suggesting benefit of radium as compared to placebo. No significant difference in grade 3 or 4 adverse events was noted in both groups while significantly more patients in radium group had improvement in quality-of-life.
Skeletal related events are a major cause of morbidity and mortality in prostate cancer. Bisphosphonates, receptor activator of NF-kB ligand (RANKL) inhibitor denosumab, and bone seeking radiopharmaceuticals are the main bone targeted approaches. Zoledronate, denosumab and previously described beta emitting radiopharmaceuticals (strontium-89 and samarium-153) provide only symptomatic relief without conferring survival advantage.  Radium-223 is the first alpha emitter to undergo phase 3 trial. Alpha particles have high linear energy transfer and short penetration when compared with beta particles. This study reported significant improvement in symptoms, delay in skeletal events and 30% reduction in risk of death in radium group.  The study included only symptomatic bone metastasis, whereas previous trials also included asymptomatic fractures. Patients with visceral metastasis were excluded. Patients in both the arms were permitted to receive standard therapies that were variably chosen by treating physicians. Hence, results of this study may be generally applied to CRPC patients with symptomatic bone metastasis.
There are other non-bone-targeted survival enhancing approaches for CRPC with bone metastasis. Docetaxel was the first drug to demonstrate survival advantage in CRPC. Subsequently, cabazitaxel had a similar effect on survival.  Abiraterone, a selective inhibitor of androgen biosynthesis, and enzalutamide, an androgen receptor antagonist and signaling inhibitor, have also been shown to prolong survival. , Trials of cabazitaxel, abiraterone and enzalutamide were specifically conducted in post-docetaxel progressing CRPC. , Many patients with CRPC cannot receive docetaxel due to poor performance status, contraindications to docetaxel, or intolerable side effects. In the present trial, this important group of docetaxel naïve patients was also addressed.
In conclusion by demonstrating significant improvement in symptoms, overall survival advantage and safety, this study provides an impetus for research on the use of alpha particles in medicine. With the documented efficacy of radium-223 in docetaxel naοve patients, thecurrent first line role of chemotherapy in CRPC may be reexamined. While further research is needed to define where exactly radium-223 fits in the armamentarium, it remains a viable and safe option in CRPC patients with symptomatic osseous metastasis in the absence of visceral metastasis.
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