The novel radiopharmaceutical for prostate cancer, radium Ra223 dichloride (Xofigo), is equally effective whether or not the patient has previously received chemotherapy with docetaxel, a new analysis concludes.
The product was approved last year for the treatment of metastatic castration-resistant prostate cancer (mCRPC) on the basis of results from the ALSYMCA study.
Now, the ALSYMCA investigators report a prespecified analysis that shows that radium-223 is effective in these patients, regardless of previous docetaxel use. The report was published online October 17 in the Lancet Oncology.
In an accompanying comment, Robert B. Den, MD, and W. Kevin Kelly, DO, from the Departments of Radiation and Medical Oncology, respectively, at Thomas Jefferson University in Philadelphia, say the new analysis shows that “men who have received previous docetaxel chemotherapy can be given radium-223 safely and its efficacy will be similar to patients who have not received previous docetaxel treatment.”
But they also advocate caution. “The oncology community needs to proceed cautiously, since the ALSYMPCA trial was not able to identify the optimum sequence of administration of docetaxel and radium-233. Additionally, the trial was designed before the approval of enzalutamide and abiraterone acetate, so the clinical benefit of concomitant or sequential use of radium-223 with these drugs is unknown. Perhaps most intriguing would be the opportunity to integrate immunotherapy.”
Dr Kelly indicated that the design of the ALSYMCA study was insightful because analyzing clinical outcomes on the basis of previous docetaxel use was not done in a post hoc manner, but was prespecified. “They were mindful of the significance of docetaxel for these patients,” he said.
Until recently, docetaxel was the only option available for patients with mCRPC. That is why the data suggesting clinical benefits with or without previous docetaxel is welcome news, he said.
However, there are now two other therapeutic options that can be used instead of chemotherapy in mCRPC — abiraterone (Zytiga), approved for first-line use in December 2012, and enzalutamide (Xtandi), approved for first-line use in September.
At present, it is unclear where radium-223 fits in with the use of these two therapies, although there are clinical trials underway to address this.
With or Without Previous Docetaxel
The subset analysis of the phase 3 ALSYMPCA study was reported by Peter Hoskin, MD, from the Mount Vernon Cancer Centre in Northwood, Middlesex, United Kingdom, and colleagues.
Median overall survival with radium-223 was 14.4 months for patients who received previous docetaxel and 16.1 months for patients who did not.
Correspondingly, median time to first symptomatic skeletal event was 13.5 months and 17.0 months, respectively, for the two groups.
Compared with placebo, hazard ratios for the two groups of patients were 0.70 and 0.69, respectively, and both were statistically significant.
Dr Hoskin and colleagues also report that patients who had previously received docetaxel had a higher incidence of hematologic toxicities of any grade, and 62% of patients previously treated with docetaxel had grade 3/4 adverse events, compared with 54% of patients without docetaxel. Patients who had previously been treated with docetaxel had a higher incidence of grade 3/4 thrombocytopenia with radium-223 than with placebo (9% vs 3%), whereas the incidence was similar between treatment groups among patients with no previous docetaxel use (3% vs 1%).
The incidences of grade 3/4 anemia and neutropenia were similar between the radium-223 and placebo groups within both docetaxel subgroups, and nonhematologic toxicities were similar in the two groups.
In their discussion, Dr Hoskin and colleagues state: “Extensive use of previous docetaxel treatment (e.g., more than 6 cycles) might contribute to adverse effects with radium-223; however, this possibility cannot be investigated, since cumulative docetaxel dosing data were not collected in this trial.”
This is an important point when sequencing two drugs, said Dr Kelly.
The optimum sequence for administering docetaxel and radium-223 was not answered by this study, according to Dr Kelly. In current clinical practice, knowing the optimum sequence would be important to optimize the clinical benefit and limit the toxicities from therapies, he said.
For instance, thrombocytopenia can be an adverse effect of radium-223, and how well patients tolerate docetaxel after radium-223 is still an open question. Previous experience with other radioisotopes, such as samarium-153 and strontium-89, has shown that additional chemotherapy after these treatments was difficult for many patients to tolerate.
Can Radium-223 Be Integrated With Immunotherapy?
In the comment, a question was raised as to how radium-223 can be integrated into immunotherapy. Radium-223 is an ideal agent to combine with immunotherapy, and might induce an immunologic response similar to the abscopal effect, Dr Kelly said. An abscopal effect is a phenomenon where local radiotherapy can induce systemic immunologic response and cause tumor regression at distal sites, he explained.
However, this speculation needs to be backed-up with data from clinical studies. Currently, novel immunotherapies such as ipilimumab (Yervoy) have not shown clinical benefit to date in men with mCRPC. A recent study with local radiotherapy with or without ipilimumab after docetaxel did not meet the primary end point of overall survival for men with mCRPC, Dr Kelly informed Medscape Medical News.
Radium-223 in Combination With Other Agents
With options expanding for men with mCRPC, Dr Kelly provided insights into the role of combination therapy for these patients.
Is combination therapy better than sequencing two agents? Dr Kelly indicated that the combination of docetaxel plus other agents has failed in multiple clinical studies. But clinicians are still hopeful other combinations will fare better.
Dr Hoskin and colleagues report that a phase 1/2 trial is ongoing to determine whether docetaxel and radium-223 is effective for men with mCRPC and bone metastases.
In addition, the ERA 223 trial is enrolling patients with mCRPC with bone metastases to determine if radium-223 and abiraterone will be more effective than abiraterone and placebo.
Radium-223 in Clinical Practice
One year after its approval, Medscape Medical News asked Dr Kelly about clinicians’ comfort level with radium-223.
Medical and radiation oncologists are very comfortable using radium-223 today, Dr Kelly said. When it was novel agent with unique properties, there were some logistical challenges, but most centers have worked these issues out, he added.
With multiple treatment options for mCRPC patients today, the choice of which agent is most appropriate for the patient at this time is multi-factorial. In Dr Kelly’s practice, he considers patient comorbidities, the extent of the cancer, previous treatments, and the patient’s long-term goals of care to determine which agent he recommends.