Enzalutamide plus radium-223 improves rPFS in mCRPC

First-line treatment with enzalutamide plus radium-223 (Ra223) results in significant improvements in radiological progression-free survival (rPFS) in patients with metastatic castration-resistant prostate cancer (mCRPC), results of the EORTC 1222/PEACE-3 trial have shown.

“An interim analysis at 80 percent of events suggests an overall survival (OS) advantage for combining enzalutamide and Ra223, which need to be further confirmed,” the researchers said.

From November 2015 to March 2023, PEACE-3 randomized a total of 446 patients, including 11 who received abiraterone, to receive enzalutamide (without placebo) or enzalutamide with six cycles of Ra223. The co-administration of zoledronic acid or denosumab was mandatory as of March 2018.

Significant improvements were observed in rPFS (hazard ratio [HR], 0.69, 95 percent confidence interval [CI], 0.54‒0.87; p=0.0009). Specifically, the median rPFS was 16.4 months (95 percent CI, 13.8‒19.2) with enzalutamide alone and 19.4 months (95 percent CI, 17.1‒25.3) with the combination therapy. [Ann Oncol 2025;36:1058-1067]

The preplanned interim analysis, conducted at 80 percent of the OS events, revealed an HR of 0.69 (95 percent CI, 0.52‒0.90; p=0.0031). The median OS was 35.0 months (95 percent CI, 28.8‒38.9) in the enzalutamide arm and 42.3 months (95 percent CI, 36.8‒49.1) in the combination arm. The results will be tested further at the final OS analysis, according to the researchers.

In terms of safety, treatment-emergent adverse events (TEAEs) grade ≥3 occurred in 55.8 percent of patients in the enzalutamide arm and in 65.6 percent of those in the combination arm. Hypertension (34 percent) was the most frequent grade ≥3 TEAE recorded, followed by fatigue (6 percent), fracture (5 percent), anaemia (5 percent), and neutropenia (5 percent).

Moreover, fractures occurred in 30 (13.4 percent) patients in the enzalutamide arm and 53 (24.3 percent) patients in the combination arm.

“As expected, toxicity had been moderate,” the researchers said. “Hence, combining enzalutamide and Ra223 is a new treatment option for patients with mCRPC.”

Mechanism of action

The unusual ratio between rPFS and OS appears suggestive of the mechanism of action of Ra223, which remains unclear. In particular, whether Ra223 has a direct cytotoxic effect on cancer cells or if it creates a less favourable environment in the bone for the metastases to grow remains to be understood. [Int J Mol Sci 2019;20:3899]

In preclinical studies, Ra223 is incorporated into the bone matrix, preventing the proliferation of cancer cells and the differentiation of osteoblasts and osteoclasts.

“The binding of Ra223 to bone tissue occurs due to active incorporation by osteoblasts and passive binding as a calcium mimetic to hydroxyapatite,” the researchers said. “Consequently, calcium disrupts the vicious cycle of bone metastasis.”

Moreover, mice xenograft models showed deposits of Ra223 within prostate cells, indicating a direct effect on tumour metastasis. However, more studies are needed to know the extent and nature of co-localization with tumour cells, according to the researchers.

“Preclinical data indicate that Ra223 may need to be combined with other agents to target larger areas of bone metastases, especially in bone metastases with weaker osteoblastic reactions,” they added. [J Natl Cancer Inst 2019;111:1042-1050]