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Treatment With Radium-223 Plus Abiraterone Not Advisable in Metastatic Prostate Cancer


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The combination of radium-223 plus AAP (abiraterone acetate [Zytiga] and prednisone) was not superior to placebo plus AAP in the phase III ERA 223 trial, which enrolled men with asymptomatic bone-predominant metastatic castration-resistant prostate cancer.1 Patients treated with the combination had a shorter symptomatic skeletal event–free survival, as well as an increased rate of fractures and a numerically shorter median overall survival.


The first takeaway message from this study is that use of the combination of radium-223 and AAP is not recommended in this setting.
— Matthew R. Smith, MD, PhD

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These eagerly awaited results were presented at the European Society for Medical Oncology (ESMO) 2018 Congress. Although there are at least five relatively new treatments for castration-resistant prostate cancer, the best combinations and sequences are unknown. The results of ERA 223 were disappointing, but they provide important take-home points for oncologists who treat men with prostate cancer.

“The first takeaway message from this study is that use of the combination of radium-223 and AAP is not recommended in this setting,” stated lead author Matthew R. Smith, MD, PhD, Director of the Genitourinary Malignancies Program at the Massachusetts General Hospital Cancer Center, Boston.

Bone Health Considerations

Dr. Smith emphasized another important takeaway message: the bone health of patients with metastatic castration-resistant prostate cancer is an important consideration. In ERA 223, the fracture rate was substantially lower in patients who were receiving bone health agents at baseline.

“Other treatment for prostate cancer including abiraterone and prednisone, enzalutamide (Xtandi), and apalutamide (Erleada) appears to increase fracture risk, and most patients taking these drugs should be treated with a bone-health agent (bisphosphonate or denosumab) to prevent clinical fractures. Bone-health agents have not been adequately utilized for this group of patients,” Dr. Smith stated.

Eleni Efstathiou, MD, PhD

Eleni Efstathiou, MD, PhD

Eleni Efstathiou, MD, PhD, The University of Texas MD Anderson Cancer Center, Houston, and Co-Chair of the session where these results were presented, agreed about the importance of bone health agents. She noted that 60% of symptomatic skeletal events in the experimental arm occurred at nonmetastatic sites, and fractures were reduced by 60% in patients on bone health agents at baseline.

The combination of radium-223 plus AAP was chosen for the ERA 223 study based on the results of the -ALSYMPCA trial, which showed improved overall survival and time to first symptomatic skeletal-related event with radium-223 vs placebo, nonoverlapping toxicities of these two agents, and theoretically complementary mechanisms of action.2 In addition, evidence from a post hoc analysis of a phase III trial suggested there was a survival benefit when radium-223 was added to AAP or enzalutamide, Dr. Smith explained.

Study Details

ERA 223 included 806 patients with asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer and at least 2 bone metastases. Patients were randomly assigned 1:1 to AAP plus concurrent radium-223 vs AAP plus matching placebo. The primary endpoint was symptomatic skeletal event–free survival, defined as freedom from the use of external-beam radiation to relieve symptomatic skeletal events, new symptomatic pathologic bone fracture, spinal cord compression, tumor-related orthopedic surgical intervention, or death.

The study was unblinded prematurely because more fractures and deaths were reported in the experimental arm, but treatment was continued, and the protocol was amended to allow bone health agents in patients who were not taking them at baseline.

ERA 223 TRIAL

  • The combination of radium-223 plus abiraterone acetate/prednisone failed to show a benefit in men with bone-predominant metastatic castration-resistant prostate cancer. The treatment shortened symptomatic skeletal event–free survival and overall survival and increased fracture rates compared with abiraterone acetate/prednisone alone.
  • This combination cannot be recommended for men with bone-predominant metastatic castration-resistant prostate cancer.
  • Bone health agents are recommended for all men taking abiraterone acetate/prednisone, as well as for those on enzalutamide or apalutamide.

There was no significant difference between the two treatment arms for the primary endpoint of symptomatic skeletal event–free survival. The median symptomatic skeletal event–free survival was 22.3 months in the combination arm vs 26 months in the placebo arm. The fracture rate was increased in the combination arm: 26% vs 10% with placebo. Overall survival was not significantly different between the two arms but was numerically lower in those treated with AAP plus radium-223 compared with placebo: 30.7 months vs 33.3 months, respectively.

No difference was observed in treatment-related adverse events, serious adverse events, or events leading to treatment discontinuation—with the exception of bone fracture. Most adverse events were grade 1 to 3.

Fracture Data

“The imbalance in fractures prompted an independent review of patients with available imaging,” Dr. Smith said. “Patients with osteoporotic fractures showed the largest between-group -differences.”

A post hoc analysis of patients who were taking bone health agents still showed more fractures in the radium-223–containing arm. However, fracture rates were lower among those taking a bone health agent. Fractures were reported in 103 patients in the radium-223/AAP arm and 38 in the placebo/AAP arm. Independent review of patients with fractures showed that 76 patients in the combination arm had at least 1 fracture, compared with 23 patients in the placebo arm. Types and numbers of fractures were as follows: pathologic—19 vs 6, respectively; traumatic—27 vs 13; and osteoporotic—37 vs 4. 

DISCLOSURE: The study was supported by Bayer. Dr. Smith has received institutional research funding from Bayer, Janssen Oncology, and Gilead Sciences and is a consultant/advisor with Bayer, Janssen Oncology, Amgen, and Pfizer. Dr. -Efstathiou has received grant/research support from Medivation, Janssen, Sanofi, and Astellas; is a paid consultant with Bayer, Tolmar, and Takeda; has received honoraria from Sanofi and Janssen; and is a member of advisory committees and review panels for Sanofi.

REFERENCES

1. Smith M, et al: ERA 223. ESMO 2018 Congress. Abstract LBA30. Presented October 19, 2018.

2. Parker C, et al: Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 369:213-223, 2013.


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