It is always thrilling when a treatment is working so well in a clinical trial that the study ends early and the FDA moves rapidly with approval. This was the case with a clinical study called ALSYMPCA (Alpharadin in Symptomatic Prostate Cancer Patients). The purpose of this Phase III trial was to compare the effectiveness of a promising radioisotope with that of a placebo in controlling prostate cancer that had spread to the bones, and to track survival.
Prostate cancer bone mets
When prostate cancer spreads to the bones, it is no longer able to be cured. Instead, therapies are aimed at controlling/reducing the bone lesions, preventing or slowing further cancer spread, strengthening bone, and managing pain. Treatments include chemotherapy, bone-strengthening drug protocols, fracture repair, and surgery or ablation (minimally invasive tumor destruction) as indicated.
Isotopes are elements that emit radiation. Certain isotopes have been used successfully with prostate cancer bone mets to control pain, improve quality of life, and to a lesser extent prolong survival. These include Strontium-89, Samarium-153, and Rhenium.
A more recent entry into the field is Radium-223 which has unique clinical properties.[i] Because it selectively seeks bone and bone formation, it binds with prostate cancer’s tumor-forming activity. Radium-223 emits high-energy alpha-particle radiation that has a toxic effect on the DNA of tumor cells. The path of the radioactive particles (alpha particles) emitted by Radium-223 is extremely short, so there is little-to-no effect on neighboring healthy tissues.
The ALSYMPCA study
The ALSYMPCA study began enrolling patients in 2008, the goal being to enroll 900 prostate cancer patients with bone mets but no other identified metastases. The study was carried out at 136 centers in 19 countries. On a 2-to-1 ratio, participants would be randomly assigned to receive either six intravenous injections of Radium-223 (one every 4 weeks) or to receive a placebo (whatever the current standard for managing prostate cancer bone mets at each center). Ultimately, 921 men were enrolled, and of that group, 614 received Radium-223 and 307 received placebo. Each patient was scheduled to be followed for three years, meaning that the those who entered the study in 2011 would be followed until 2014.
However, a remarkable thing occurred. An analysis of 809 cases conducted while the trial was still continuing (an interim analysis) found that that the Radium-223 therapy “was associated with significantly prolonged overall survival compared with placebo…”[ii] The investigators recommended closing the trial, and allowing the placebo patients to cross over and receive the Radium-223 protocol. On May 15, 2013 the U.S. Food and Drug Administration (FDA) expedited approval for Radium-223 for the treatment of prostate cancer bone mets that are causing symptoms.
A subsequent follow-up analysis confirmed that significant extension of survival for Radium-223 patients. Furthermore, there were fewer study related adverse events for Radium-223 than for the placebo treatments, and patients who received the isotope reported higher quality of life scores based on standardized questionnaires.
When the interim results were published, an accompanying editorial (Vapiwala & Gatstein, 2013) noted that the study “imparts some long-awaited momentum to research on the use of alpha emitters and shows an overall survival advantage with a compound that is safe and manageable for both patients and providers. Radium-223 will both complement and contend with existing therapies.”[iii]
Since the ALSYMPCA trial was closed, a surge of published studies and articles has occurred as Radium-223 is incorporated into treatments for prostate cancer bone mets. Since 2016 alone, 21 papers have already appeared. The ALSYMPCA study turned a dramatic page in the chapter on treating a difficult condition. Physicians and patients will undoubtedly continue to see improvements and advances based on this isotope, alone or in combination with other therapies.
[i] Raval A, Dan TD, Williams N, Pridjian A, Den R. Radioisotopes in management of metastatic prostate cancerIndian J Urol. 2016 Oct-Dec; 32(4): 277–281.
[iii] Vapiwala N, Glatstein E. Fighting prostate cancer with Radium-223—not your madame’s isotope. N Engl J Med. 2013 July 18;369:276-78.