Prostate cancer experts have often stated it is important to add a bone-protecting agent for patients on treatment for metastatic castration-resistant prostate cancer. Recent evidence in support of this recommendation comes from a study presented during the 2021 ASCO Annual Meeting, confirming a substantial reduction in fracture risk when bone-protecting agents are given during treatment with enzalutamide with or without radium-223.¹ These data represent an updated safety analysis of the randomized phase III EORTC 1333/PEACE III trial.

“This updated safety analysis confirms the importance of giving a bone-protecting agent when treating patients with castration-resistant prostate cancer and bone metastases,” stated lead author Silke Gillessen, MD, of the Oncology Institute of Southern Switzerland. “Skeletal complications are common in patients with advanced prostate cancer, and they have an impact on the quality of life of our patients,” she added.

“Based on our study, we will continue to motivate all investigators to include bone-protecting agents in the treatment of patients with metastatic castration-resistant prostate cancer.”

— Silke Gillessen, MD

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“We know bone-protecting agents can be used to prevent bone loss in men taking androgen-deprivation therapy. Bone-protecting agents can also delay the time to first skeletal-related events in men with metastatic castration-resistant prostate cancer and bone metastasis. There are two different indications with different doses used for men receiving androgen-deprivation therapy and men with metastatic castration-resistant prostate cancer and bone loss,” explained Dr. Gillessen.

Background

Osteoporotic fractures are reported in up to 11% of patients treated with androgen-deprivation therapy and an androgen receptor (AR) pathway inhibitor. Skeletal-related events due to osseous metastases are reported in up to 40% of men treated with androgen-deprivation therapy and an AR pathway inhibitor. These skeletal-related events include pathologic bone fracture, spinal cord compression, orthopedic surgery, and palliative radiation.

“Osteoporotic fractures in men on androgen-deprivation therapy are probably underestimated and more frequent than reported,” Dr. Gillessen stated.

Guidelines from the National Comprehensive Cancer Network (NCCN) and the European Society for Medical Oncology (ESMO) recommend the use of bone-protecting agents such as zoledronic acid and denosumab in patients with castration-resistant prostate cancer and bone metastases. However, anecdotal evidence suggests that this recommendation is not always followed.

Study Design

The EORTC 1333/PEACE III trial randomly assigned 264 patients 1:1 to receive enzalutamide at 160 mg/d with or without radium-223 at 55 kBq/kg every 4 weeks for six cycles. Patients had metastatic castration-resistant prostate cancer with at least two bone metastases and were either asymptomatic or mildly symptomatic. No prior treatment was allowed with CYP17 inhibitors, enzalutamide, other radionuclides, or hemibody radiotherapy. The primary endpoint was radiographic progression-free survival.

The conduct of the ongoing EORTC 1333/PEACE III trial was affected by the results of the ERA 223 trial, which compared radium-223 plus abiraterone acetate vs abiraterone acetate alone in men with chemotherapy-naive castration-resistant prostate cancer and bone metastases.² The primary endpoint of the ERA 223 trial was symptomatic skeletal-related events–free survival.

Early unblinding of the ERA 223 trial revealed an unacceptably high fracture rate and death in the combination-therapy arm. About 60% of patients enrolled in the trial did not receive a bone-protecting agent. A post hoc analysis showed that fracture rates were significantly reduced in both arms of the trial in men who received a bone-protecting agent.

“Of note, [in the ERA 223 trial], about 75% of fractures that occurred were not at the site of bone metastases,” Dr. Gillessen noted.

Based on the post hoc analysis of the ERA 223 trial, the independent data monitoring committee of the EORTC 1333/PEACE III trial mandated the use of bone-protecting agents in all study participants at least 6 weeks prior to the initiation of radium-223. At the time of the mandate, 45% of enrollees in the EORTC 1333/PEACE III trial had not received a bone-protecting agent; once the mandate was announced, 74 patients in each arm received a bone-protecting agent. After the mandate, 2.9% of all patients had not received a bone-protecting agent.

Effect of Bone-Protecting Agents

“The cumulative incidence of fracture was greater in the combination arm without the use of a bone-protecting agent,” Dr. Gillessen continued. “And it was much lower in both arms when a bone-protecting agent was given.”

Without a bone-protecting agent, the cumulative incidence of fracture at 1 year was 37.1% in the combination arm and 15.6% with enzalutamide alone. When a bone-protecting agent was used, the 1-year cumulative incidence of fracture was 2.7% and 2.6%, respectively, in both arms.

At 18 months, the cumulative incidence of fracture without a bone-protecting agent was 45.9% with the combination therapy and 21.9% with enzalutamide alone. When a bone-protecting agent was used, the 18-month cumulative incidence of fracture was 4.3% and 2.6%, respectively.

At 21 months, patients in the combination arm who had not received a bone-protecting agent had a cumulative incidence of fracture of 52% vs 21.9% in the enzalutamide-alone arm. Among patients who received a bone-protecting agent, corresponding cumulative fracture rates were 4.3% and 2.6%, respectively.

“Our updated safety analysis confirms that the risk of fracture is well controlled in both arms when patients receive a bone-protecting agent,” Dr. Gillessen said. “Based on our study, we will continue to motivate all investigators to include bone-protecting agents in the treatment of patients with metastatic castration-resistant prostate cancer. This study also confirms the importance of complying with international recommendations and giving a bone-protecting agent when treating patients with bone metastasis to prevent skeletal complications. Accrual to our study continues, and we will report efficacy results in the future. The independent data monitoring committee will continue to monitor the study closely.” 

DISCLOSURE: The study was funded by Bayer and Astellas. Dr. Gillessen has served as a consultant or advisor to Amgen, Astellas Pharma, Bayer, Janssen, MSD Oncology, Orion Pharma GmbH, Pfizer, Roche, and Tolero Pharmaceuticals; has served on the speakers bureau of Janssen-Cilag; has been reimbursed for travel, accommodations, and expenses from ProteoMediX; and holds other relationships with Aranda Pharma and ProteoMediX.

REFERENCES

1. Gillessen S, Choudhury A, Rodriguez-Vita A, et al: Decreased fracture rate by mandating bone-protecting agents in the EORTC 1333/PEACE III trial combining Ra223 with enzalutamide versus enzalutamide alone: An updated safety analysis. 2021 ASCO Annual Meeting. Abstract 5002. Presented June 8, 2021.

2. Smith M, Parker C, Saad F, et al: Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 20:408-419, 2019.